DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION

Advisory Committee on 

Immunization Practices (ACIP)

Summary Report

June 24-26, 2009 

 Atlanta, Georgia 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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Table of Contents Page

Acronyms 5-6 

Agenda 7-10 

Wednesday, June 24

Welcome and Introductions 11-15 

General Recommendations

Introduction 

Combination Vaccinations 

Special Situations 

Vaccination Records

16-28 

Rabies Vaccine 

Introduction 

 Reduced Rabies Vaccine Schedule: Post-Exposure Prophylaxis 

29-37 

Poliovirus Vaccine 

Introduction 

 Updated Recommendations for Routine Poliovirus Immunization 

 Update: VFC Vote

37-43 

Measles, Mumps, and Rubella Vaccine 

 Introduction 

 Proposed Changes to Current Evidence of Immunity Requirements for MMR Vaccination for Healthcare Personnel 

43-53 

Human Papillomavirus (HPV) Vaccines 

 Introduction 

 Bivalent HPV Vaccine 

 Quadrivalent HPV Vaccine 

 Cost-Effectiveness of Male Vaccination 

 Overview of Cost-Effectiveness Models of Male Vaccination 

 Issues and Potential Recommendation Options: Vaccination of Males 

53-76 

Meningococcal Vaccine 

 Overview of Work Group Activities 

 Update: New Meningococcal Conjugate Vaccine (MenACYW-CRM) 

 Estimate of Effectiveness of Meningococcal Conjugate Vaccine (MCV4) 

 Recommendations for MCV4 Vaccination for Persons at Prolonged Increased Risk for Meningococcal Disease 

 Update: VFC Vote 

76-95 

Japanese Encephalitis (JE) Vaccine

 Introduction 

 Revised JE Vaccine Recommendations 

95-103 

Hepatitis Vaccines

 Introduction 

 Hepatitis B in Long-Term Care Residents and the Role of Vaccination 

 

104-111 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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Yellow Fever (YF) Vaccine

 Introduction: Yellow Fever Vaccine Work Group 

 Proposed Updates to the ACIP YF Vaccine Recommendations 

111-116

Public Comment 116 

Thursday, June 24

Unfinished Business 116-119

Agency Updates

 CDC / CCID / NCIRD 

 Center for Medicare and Medicaid Services (CMS) 

 Department of Defense (DoD) 

 Department of Veteran’s Affairs (DVA)

 Food and Drug Administration (FDA) 

 Heath Resources and Services Administration (HRSA) 

 Indian Health Services (I HS)

 Immunization Safety Office (ISO) 

 National Institutes for Health (NIH) 

 National Vaccine Advisory Committee (NVAC) 

 National Vaccine Program Office (NVPO) 

119-123

Haemophilus Influenzae B (Hib) Vaccine

 Introduction: Overview of Session 

 GSK Monovalent Hib Vaccine 

 Hib Surveillance 

 Vaccine Supply 

 Hib Vaccine Implementation Plan 

123-131

Vaccine Supply 132-136

Measles-Mumps-Rubella-Varicella (MMRV) Vaccine Safety 

 Introduction 

 Parental Perceptions of MMRV Vaccine 

 Evaluation of MMRV and Febrile Seizures: VSD Expanded Chart Review Study 

 Synthesis of Safety Evidence for MMRV Vaccine and Febrile Seizure risk 

 Synthesis of Analytic Framework for MMRV Vaccine Policy Options; Options for Recommendations 

 Update: VFC Resolution 

137-165

Role of Pharmacists in Vaccine Administration 166-169

Influenza

 Session Introduction 

 Session Overview 

 2008-09 Influenza Epidemiology: Seasonal and Novel Influenza A(H1N1) 

 Influenza Antiviral Medications 

 Novel Influenza A(H1N1) Vaccine Development and Progress 

 Review of Existing Vaccine Prioritization Guidance 

170-207

Public Comment 207-208

Friday, June 26

Novel Influenza A(H1N1)

 Virology and Immunology

 Vaccine Program Implementation Plans

 Review of Planned Vaccine Effectiveness Studies

 Review of Influenza Vaccine Safety Monitoring Plans

208-232
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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 Summary of Issues

Pneumococcal Vaccines

 Overview of Session

 Planning for Use of PPSV23 to Prevent Novel Influenza A(H1N1)-Associated Pneumococcal Disease

 Invasive Pneumococcal Disease Burden Caused by PCV13 Serotypes

 Options for PVC13 Catch-Up Immunization Strategies

 Update on Investigational 13-Valent Pneumococcal Vaccine (PCV13)

 Public Health and Economic Impact of PCV13 

232-253

Public Comment 252

Certification 252

Participant Roster 253-260
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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Acronyms

AAFP American Academy of Family Physicians

AAP American Academy of Pediatrics

ACIP Advisory Committee on Immunization Practices

AGS American Geriatrics Society

ATP According to Protocol

BLA Biologics License Application

BOI Burden of Illness

CAIS Childhood / Adolescent Immunization Schedule

CAIV-T Cold-Adapted Influenza Vaccine

CCID Coordinating Center for Infectious Diseases

CDC Centers for Disease Control and Prevention

CID Committee on Infectious Diseases (CID) of the American Academy of Pediatrics 

(AAP)

CIN Cervical Intraepithelial Neoplasia

CMS Centers for Medicare and Medicaid Services

DBD Division of Bacterial Diseases (of NCIRD)

DHQP Division of Healthcare Quality Promotion

DoD Department of Defense

DSMBs Data Safety Monitoring Boards

DSTDP Division of Sexually Transmitted Diseases Prevention [of NCHHSTP]

DVA Department of Veterans Affairs

DVBID Division of Vector-Borne Infectious Diseases

DVD Division of Viral Diseases (of NCIRD)

DVH Division of Viral Hepatitis (of NCIRD)

DVRD Division of Viral and Rickettsial Diseases

EIS Epidemic Intelligence Service 

EMR Electronic Medical Records 

FDA Food and Drug Administration

GBS Guillain Barré Syndrome

GID Global Immunization Division

GMCs Geometric Mean Concentrations 

GMTs Geometric Mean Titers

GSK GlaxoSmithKline

HICPAC Healthcare Infection Control Practices Advisory Committee 

HepA Hepatitis A

HepB Hepatitis B

HHS Department of Health and Human Services 

Hib Haemophilus influenzae B 

HMO Health Maintenance Organization

HPV Human Papillomavirus

HRIG Human Rabies Immune Globulin

HRSA Health Resources and Services Administration 

ID Influenza Division (of NCIRD)

IDSA Infectious Disease Society of America

IgG Immunoglobulin G

IgM Immunoglobulin M

IHS Indian Health Services

ILI Influenza-Like Illness

IND Investigational New Drug
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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IOM Institute of Medicine

ISD Immunization Services Division (of NCIRD)

ISO Immunization Safety Office (of CDC/OD/Office of the Chief Science Officer)

ITT Intent to Treat

MCO Managed Care Organization 

MenACYWCRMMeningococcal Conjugate Vaccine

MCV4 Meningococcal Conjugate Vaccine

MMRV Measles, Mumps, Rubella, Varicella

MMWR Morbidity and Mortality Weekly Report

mOPV1 Monovalent Polio Vaccine Type 1

NACCHO National Association of County and City Health Officials 

NACI Canadian National Advisory Committee on Immunizations 

NCHHSTP National Center for HIV, Hepatitis, STD, and TB Prevention (of CDC/CCID)

NCHS National Center for Health Statistics 

NCIRD National Center for Immunization and Respiratory Diseases (of CDC/CCID)

NCPDCID National Center for Preparedness, Detection, and Control of Infectious 

Diseases

NCZVED National Center for Zoonotic, Vector-Borne, and Enteric Diseases (of 

CDC/CCID)

NIH National Institutes of Health

NIS National Immunization Survey

NVAC National Vaccine Advisory Committee 

NVPO National Vaccine Program Office

OCSO Office of the Chief Science Officer

OD Office of the Director (of CDC)

P&I Pneumonia and Influenza

PCV Pneumococcal Conjugate Vaccine

PEP Post-Exposure Prophylaxis

PhRMA Pharmaceutical Research Manufacturers of America

RCA Rapid Cycle Analysis

SAGE Strategic Advisory Group of Experts 

sBLA Supplemental Biologics License Application

SHEA Society for Healthcare Epidemiology of America

SIVAC Supporting Immunization and Vaccine Advisory Committee 

SMEs Subject Matter Experts

VAERS Vaccine Adverse Event Reporting System

VFC Vaccines for Children

VSD Vaccine Safety Datalink

VZV Varicella-Zoster Virus

WG Work Group

WHO World Health Organization
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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MEETING OF THE ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES (ACIP)

Centers for Disease Control and Prevention

1600 Clifton Road, NE, Tom Harkin Global Communications Center (Building 19), Atlanta, Georgia

June 24-26, 2009

AGENDA ITEM PURPOSE PRESIDER/PRESENTER(s)

Wednesday, June 24, 2009

8:00

 

Welcome & Introductions

 Opening remarks

 Introductions and administrative announcements

 

Dr. Thomas R. Frieden (Director, 

CDC and Administrator, ATSDR)

Dr. Dale Morse (Chair, ACIP)

Dr. Larry Pickering (Executive 

Secretary, ACIP; CDC)

8:30 General Recommendations

 Introduction

 Combination vaccines

 Special situations information & discussion

 Vaccination records

Information

Vote

Vote

Vote

Dr. Ciro Sumaya (ACIP, WG Chair)

Dr. Andrew Kroger 

(CDC/CCID/NCIRD/ISD)

9:40 Rabies Vaccine

 Introduction

 Reduced rabies vaccine schedule (post-exposure 

prophylaxis)

Information

Discussion

Vote

Dr. Paul Cieslak (ACIP, WG Chair)

Dr. Charles Rupprecht 

(CDC/CCID/NCZVED/DVRD)

10:55 Break

11:25 Poliovirus Vaccine

 Introduction

 Updated recommendations for routine poliovirus

 immunization

 Update VFC vote

Information

Discussion

Vote

VFC Vote

Dr. Lance Chilton (ACIP, WG Chair)

Dr. Gregory Wallace 

(CDC/CCID/NCIRD/DVD) 

Dr. Jeanne Santoli 

(CDC/CCID/NCIRD/ISD)

11:55 Measles, Mumps and Rubella Vaccine

 Introduction

 Proposed changes to current evidence of immunity

 requirements for MMR vaccination for healthcare

 personnel

Information

Discussion

Vote

Ms. Kris Ehresmann 

 (ACIP, WG Chair) 

Dr. Kathleen Gallagher 

 (CDC/CCID/NCIRD/DVD)

12:30 Lunch
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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1:30 Human Papillomavirus (HPV) Vaccines

 Introduction

 Bivalent HPV vaccine

 Quadrivalent HPV vaccine

 Cost-effectiveness of male vaccination

 Overview of cost-effectiveness models of male 

vaccination

 Issues and potential recommendation options: 

vaccination of males

Information

and 

Discussion

Dr. Janet Englund (ACIP, WG Chair)

Dr. Gary Dubin (GSK)

Dr. Rick Haupt (Merck)

Dr. Jane Kim (Harvard University)

Dr. Harrell Chesson 

(CDC/CCID/NCHHSTP/DSTDP)

Dr. Lauri Markowitz 

(CDC/CCID/NCHHSTP/DSTDP)

3:00 Meningococcal Conjugate Vaccine (MCV4)

 Overview of Work Group activities

 Update: new meningococcal conjugate vaccine 

(MenACYW-CRM)

 Estimate of Effectiveness of Meningococcal Conjugate

Vaccine (MCV4) 

 Recommendations for MCV4 revaccination for

 persons at prolonged increased risk for meningococcal 

 Disease

 Update: VFC vote

Information

Information

Information

Discussion

Information

Discussion

Vote

VFC Vote

Dr. Carol Baker (ACIP, WG Chair)

Dr. Peter Dull (Novartis Vaccines)

Ms. Jessica MacNeil 

 (CDC/CCID/NCIRD/DBD)

Dr. Amanda Cohn 

(CDC/CCID/NCIRD/DBD)

Dr. Jeanne Santoli 

(CDC/CCID/NCIRD/ISD)

Wednesday June 24, 2009 – continued

4:00 break

4:15 Japanese Encephalitis (JE) Vaccine

 Introduction

 Revised JE vaccine recommendations Information

Discussion

Vote

Dr. Paul Cieslak (ACIP, WG Chair)

Dr. Marc Fischer 

(CDC/CCID/NCZVED/DVBID)

5:00 Hepatitis Vaccines

 Introduction

 Hepatitis B in long-term care residents and the role of 

vaccination

Information

Discussion

Dr. Mark Sawyer (ACIP, WG Chair)

Dr. Nicola Thompson

(CDC/CCID/NCHHSTP/DVH)

5:30 Yellow Fever (YF) Vaccine

 Introduction: Yellow Fever Vaccine Work Group

 Proposed updates to the ACIP YF vaccine 

recommendations

Information

Discussion

Dr. Carol Baker (ACIP, WG Chair)

Dr. Erin Staples 

 (CDC/CCID/NCZVED/DVBID)

5:45 Public Comment

6:00 Adjourn

Thursday, June 25, 2009

8:00 Unfinished Business Dr. Dale Morse (Chair, ACIP)

8:30 Agency Updates (CDC, CMS, DOD, DVA, FDA, HRSA, IHS, 

NIH, NVAC, NVPO)

Information ACIP Ex Officio Members
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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8:45 Haemophilus influenzae b (Hib) Vaccine

 Introduction: overview of session

 GSK monovalent Hib vaccine

 Hib surveillance

 Vaccine supply

 Hib vaccine implementation plan

Information

Information

Information

Information

Information

Discussion

Dr. Abigail Shefer 

(CDC/CCID/NCIRD/ISD)

Dr. Remon Abu-Elazeed (GSK)

Dr. Michael Jackson 

(CDC/CCID/NCIRD/DBD)

Dr. Jeanne Santoli 

(CDC/CCID/NCIRD/ISD)

Dr. Abigail Shefer 

(CDC/CCID/NCIRD/ISD)

9:45 Vaccine Supply Information 

Discussion

Dr. Jeanne Santoli 

(CDC/CCID/NCIRD/ISD)

10:00 Break

10:30 Measles-Mumps-Rubella-Varicella Vaccine Safety

 Introduction

 Parental perceptions of MMRV vaccine

 Evaluation of MMRV and Febrile seizures: VSD 

 expanded chart review study

 Synthesis of safety evidence for MMRV vaccine and 

febrile seizure risk

 Synthesis of analytic framework for MMRV vaccine 

policy options; options for recommendations

 Update VFC resolution

Information

Discussion

Information

Discussion

Information

Discussion

Information

Discussion

Information

Discussion

Vote

VFC Vote

Dr. Jonathan Temte 

 (ACIP, WG Chair)

Mr. Alan Janssen 

(CDC/CCID/NCIRD/ISD)

Dr. Nicola Klein, Northern California

 Kaiser Permanente

Dr. Karen Broder 

(CDC/CCID/NCPDCID/DHQP/ISO)

Dr. Mona Marin 

(CDC/CCID/NCIRD/DVD)

Dr. Jeanne Santoli 

(CDC/CCID/NCIRD/ISD)

12:30 Lunch

Thursday June 25, 2009 - continued

1:45 Role of Pharmacists in Vaccine Administration Information

Discussion

Dr. Stephan Foster (ACIP Liaison 

American Pharmacists Association)

2 :00 Influenza

 Session introduction

 Session overview

 2008-09 influenza epidemiology: seasonal and novel 

influenza A (H1N1)

Information

Information

Information

Discussion

Dr. Kathy Neuzil (ACIP, WG Chair)

Dr. Anthony Fiore 

(CDC/CCID/NCIRD/ID) 

Dr. Lyn Finelli 

(CDC/CCID/NCIRD/ID)

3:15 break

3:30 Influenza

 Influenza antiviral medications

 Novel influenza A (H1N1) vaccine development and 

progress

 Review of existing vaccine prioritization guidance

Information

Discussion 

Vote

Information

Discussion

Information

Dr. Anthony Fiore 

(CDC/CCID/NCIRD/ID)

Dr. Robin Robinson (BARDA)

Dr. Norman Baylor (FDA)

Dr. Linda Lambert (NIH)

Dr. Bruce Gellin (NVPO)

Dr. Tom Shimabukuro 

(CDC/CCID/NCIRD/ISD)
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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5:30 Public Comment

5:45 Adjourn

Friday, June 26, 2009

8:00 Novel Influenza A (H1N1)

 Virology and immunology

 Vaccine program implementation plans

 Review of planned vaccine effectiveness studies

 Review of influenza vaccine safety monitoring plans

 Summary of issues

Information

and 

Discussion

Dr. Nancy Cox 

(CDC/CCID/NCIRD/ID)

Dr. Pascale Wortley 

(CDC/CCID/NCIRD/ISD)

Dr. David Shay 

(CDC/CCID/NCIRD/ID)

Dr. Jose Sanchez (DOD)

Dr. Cindy Weinbaum (CDC/CCID/ 

NCPDCID/DHQP/ISO)

Dr. Anthony Fiore 

(CDC/CCID/NCIRD/ID)

Dr. Kathy Neuzil (ACIP, WG Chair)

10:00 Break

10:30 Pneumococcal Vaccines

 Overview of session

 Planning for use of PPSV23 to prevent novel

 influenza A (H1N1) - associated pneumococcal disease

 Invasive pneumococcal disease burden caused by

 PCV13 serotypes 

 Options for PCV13 catch-up immunization strategies

 Update on investigational 13- valent pneumococcal 

vaccine (PCV13)

 Public health and economic impact of PCV13

Information 

Discussion

Information

and

Discussion

Information

Information 

Dr. Michael Marcy (ACIP, WG Chair)

Dr. Matthew Moore 

 (CDC/CCID/NCIRD/DBD)

Dr. Pekka Nuorti 

(CDC/CCID/NCIRD/DBD)

“ 

Dr. Peter Paradiso (Wyeth)

Dr. David Strutton (Wyeth)

12:30 Public Comment

12:45 Adjourn
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

11 

June 24, 2009

Dr. Tom Frieden

Director, Centers for Disease Control and Prevention

Administrator, Agency for Toxic Substances and Disease Registry

Dr. Larry Pickering 

Executive Secretary, ACIP / CDC

Dr. Dale Morse

Chair, ACIP

Dr. Pickering called the meeting to order, introducing with great pleasure Dr. Tom Frieden, the 

newly appointed Director of the United States (US) Centers for Disease Control and Prevention 

(CDC) and Administrator of the Agency for Toxic Substances and Disease Registry (ATSDR). 

Prior to having assumed his post at CDC just 16 days before this meeting, Dr. Frieden served 

as Commissioner of the New York City Department of Health and Mental Hygiene, a position he 

held for 8 1⁄2 years. During his tenure, important advances in New York City were made in 

reduction in cigarette smoking; chronic disease control, including diabetes mellitus and obesity; 

and enhancement of the largest community health records project in the country. Dr. Frieden is 

a physician with training in internal medicine, infectious diseases, public health, and 

epidemiology, and is specifically known for his expertise in tuberculosis control. Dr. Frieden 

began his career at CDC as an Epidemic Intelligence Service (EIS) Officer stationed at the New 

York City Health Department. Dr. Frieden went on to serve as director of the Bureau of 

Tuberculosis Control and Assistant Commissioner for the New York City Health Department. In 

that role, he led a program that rapidly reduced tuberculosis, including a reduction in cases of 

multi-drug resistant tuberculosis by about 80%. Dr. Frieden then worked for 5 years on 

assignment to the World Health Organization (WHO) in India where he assisted with national 

tuberculosis control efforts. The program in India has now treated more than 10 million patients 

and saved more than 1 million lives. Dr. Pickering stressed that the ACIP members, the 26 

liaison organizations, the 8 ex officio members, and members of the audience (including 

international delegates from Japan and the Agency of Preventive Medicine in Paris, France) 

were thrilled to welcome Dr. Frieden to the June 2009 meeting of the ACIP.

Dr. Frieden expressed his gratitude, pointing out that it had thus far been a great 2 1⁄2 weeks and 

that he wished he could stay for the ACIP meeting all day. The first thing he learned about 

being the CDC Director was that it would have been very helpful if he could have cloned himself 

first, because he was supposed to be in three places at once most of the time. He said he was 

delighted to join the meeting for at least a short time to recognize the terrific and incredibly 

important work that ACIP does. Sometimes, when close to a process, it is possible to lose sight 

of the big picture in terms of the importance of ACIP’s work, particularly as the country moves 

forward with health reform under the current administration. The evidence base and 

effectiveness of vaccination is prominent in the understanding and rigor of groups such as 

ACIP. In fact, ACIP is a model for evidence-based decision making—a model that is well worth 

understanding and emulating elsewhere in the health system. In addition, Dr. Frieden 

recognized ACIP for 45 years of outstanding leadership in immunization policy. In many ways, 

Welcome & Introductions
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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vaccines are not only one of the great success stories of public health, but also hold the 

potential to have the ultimate in sustainability, which is what eradication represents (e.g., 

smallpox, and hopefully soon polio). ACIP is the prototype for immunization committees in other 

countries, and it is hoped that evidence-based vaccine immunization policy will become the 

norm in the US and globally.

There is much in the news in terms of vaccination and influenza. Novel H1N1 presents major 

challenges in spite of enormous thinking and preparation for pandemic influenza. During this 

meeting, ACIP was to hear information presented on H1N1, and very important immunization 

decisions would need to be made in near real-time over the coming days, weeks, and months 

as they began to learn more about the pattern of infection, disease, and severity of illness; 

transmission / rapidity of transmission; and availability of vaccines. In addition, it would be 

essential to continue with the shared responsibility and understanding that the government, 

health providers, individual patients, and others play key roles in the H1N1 effort. 

Not only do vaccines effectively prevent disease and save money, but also they are very 

effective at reducing racial and ethnic disparities. Vaccines are available to all, they prevent 

illness in all, and they have a great ability to make a considerable difference in health status. 

At the same time, a number of issues remain to be understood and studied Also known is that 

the Vaccines for Children Program (VFC) relies heavily upon ACIP, is part of the ACIP 

meetings, is a critically important component of the US healthcare landscape, and offers 

important lessons learned as efforts are made to improve vaccinations for children, adolescents, 

and adults.

Dr. Frieden concluded that he primarily wished to thank ACIP for what they do; the attention 

they give to challenging issues, many of which involve complex reviews of data; their valuable 

questions and input, and their suggestions / recommendations. It is imperative to focus on two 

issues: 1) building the data: rigorously assessing what the data show and where that leads 

them in terms of recommendations, taking into consideration the costs and benefits; and 

2) transparency: all deliberations and other information about vaccine policy must be 

completely open and completely transparent. CDC and ACIP have a bond of trust with the 

American public, and it is their shared responsibility to respect the intelligence, integrity, and 

caring of parents, healthcare workers, and others to develop health-based recommendations. 

People must clearly understand how decisions are reached. That is the most prudent way to 

make the best possible decisions. In closing, Dr. Frieden thanked the ACIP membership and 

saluted them for their excellent work in achieving evidence-based public health policy. 

Dr. Morse thanked Dr. Frieden for addressing ACIP, stressing that it meant a great deal to have 

the support of the CDC Director and for him to take time to deliver the keynote address. As a 

fellow New Yorker who was glad to see Dr. Frieden in attendance, Dr. Morse said it was New 

York’s loss and CDC’s and the nation’s gain.

Dr. Pickering recognized several people throughout the room who were to be in attendance 

throughout the duration of the ACIP meeting to assist with various meeting functions: Antonette 

Hill, Committee Management Specialist for ACIP, Natalie Greene, Tamara Miller, Tanya 

Lennon, Suzette Law, and Cindy Fowler. He also indicated that boxed lunches were to be 

provided for each of the three days of the meeting in the hallway outside of the auditorium for a 

cost of $10. Coffee and tea were also to be available for the duration of the meeting.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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Handouts of all presentations were distributed to the ACIP members and were made available 

for members of the public each day on the tables outside of the auditorium. Slides presented 

for this meeting will be posted on the ACIP website, generally within a week of the end of the 

meeting, while the minutes of the meeting will be posted within 90 days of the termination of the 

meeting. 

Members of the press interested in conducting interviews with ACIP members were instructed to 

contact Tom Skinner for his assistance in arranging interviews, and the press table located in 

the auditorium was pointed.

Recognizing the extent of the interest in this particular meeting, two additional rooms were 

reserved (247 / 248) as overflow space for additional seating. These rooms are located across 

the hall from the auditorium where the meeting could be viewed in real-time via audio visual all 

three days. 

Dr. Pickering recognized and welcomed the following international visitors: Dr. Kamel Senouci, 

Director of the Supporting Immunization and Vaccine Advisory Committee (SIVAC) Initiative of 

the Agence de Médicine Préventive, Institut Pasteur, Paris France. This program aims at 

contributing to the development of national immunization technical advisory groups in six 

resource-poor countries in Africa and six in Asia. These committees will help national health 

authorities to establish vaccination advisory groups adapted to their needs and to introduce new 

vaccines in these areas. This project was funded by a $10 million grant from the Bill & Melinda 

Gates Foundation, and will be conducted in partnership with the International Vaccine Institute 

in Seoul, Korea and in cooperation with the World Health Organization (WHO) and its regional 

and national offices. Dr. Pickering also extended gratitude to three visitors from Japan led by 

Dr. Nobuhiko Okabe, the Director of the Infectious Disease Surveillance Center at the National 

Institute of Infectious Diseases in Tokyo, Japan. They came to participate in the meeting of 

ACIP to observe the US process of immunization policy development, which reflects 

international reach. 

Also in attendance was new liaison representative Dr. Alexis Elward from Washington University 

School of Medicine in St. Louis, who was selected to represent the Healthcare Infection Control 

Practices Advisory Committee (HICPAC) as its liaison representative to ACIP. 

All ACIP members were present with the exception of Dr. Susan Lett who had a previous 

commitment on Wednesday and Thursday, but attended Friday and was connected by 

telephone for certain sessions. Ms. Amy Groom attended on behalf of Dr. James Cheek from 

the Indian Health Services (IHS) who was unable to attend. Dr. Sandy Fryhofer attended on 

behalf of Dr. Greg Poland from the American College of Physicians (ACP) who was unable to 

attend. Dr. Mark Notalski attended on behalf of Dr. Tamara Lewis from American’s Health 

Insurance Plan (AHIP) who was unable to attend. Dr. David Salisbury from the Department of 

Health United Kingdom was unable to attend.

To avoid interruptions during the meeting, those present were instructed to conduct all business 

not directly related to discussions of ACIP in the hallways to avoid disruptions to people in the 

audience. Attendees were also instructed to turn off all cell phones or place them in the vibrate 

mode to avoid disruption.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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The ACIP home page was shown on the screen. The url is: www.cdc.gov/vaccines/recs/acip/ 

This website is updated at frequent intervals with current versions of the meeting agenda, 

minutes, presentations, and other information. Other useful and interesting and useful were 

also shown, which included the following:

Vaccine Safety: www.cdc.gov/vaccinesafety/

Vaccine Abbreviations: http://www.cdc.gov/vaccines/recs/acip/vac-abbrev.htm

Vaccine Scheduler: http://www.cdc.gov/vaccines/recs/scheduler/catchup.htm

Given that the meeting could not begin unless a quorum of members was present, all appointed 

members were asked to return from breaks and lunch in a timely manner to participate in the 

meeting. Dr. Pickering stressed the importance of this due to the record number of votes 

scheduled during this meeting (n=8).

The ACIP charter gives the Executive Secretary, or his or her designee, the authority to 

temporarily designate ex-officio members as voting members. This occurs only when there are 

fewer than 8 appointed members available or qualified to vote due to potential conflicts of 

interest (COIs). Ex-officio members are requested formally to vote when necessary and to

disclose any potential conflicts of interest if, indeed, they were going to vote. 

Topics presented at the ACIP meeting include open discussion with time reserved for public 

comment. In certain circumstances, a formal comment period may be scheduled during the 

deliberations of a specific agenda item rather than at the end of the day. Comments from the 

public may be received during open discussions depending upon time constraints. Those who 

planned to make public comments were instructed to visit the registration table at the rear of the 

auditorium to have Antonette Hill record their name and provide information on the process. 

Those who registered to make public comments prior to the meeting were instructed to with Ms. 

Hill to verify that their names were listed and to receive any additional information.

Microphones were placed at each end of the committee tables for the members of the audience 

to use when they addressed the committee. Those planning to make comments were instructed 

to identify themselves and their organization before making their comments. 

As had occurred in previous ACIP meetings, the committee discussed topics related to vaccine 

safety and engaged in a discussion about of the supply and availability of recently licensed and 

approved vaccines.

With regard to disclosure, the goal in appointing members to the ACIP is to achieve the greatest 

level of expertise while minimizing the potential for actual or perceived conflicts of interest. To 

summarize conflict of interest provisions applicable to the ACIP, as noted in the ACIP policies 

and procedures manual, members of the ACIP agree to forego participation in certain activities 

related to vaccines during their tenure on the committee. For certain other interests that 

potentially enhance the members’ expertise while serving on the committee, CDC has issued 

limited conflict of interest waivers. Members who conduct vaccine clinical trials or who serve on 

data safety monitoring boards may serve as consultants to present to the committee on matters 

related to those specific vaccines; however, they are prohibited from participating in 

deliberations or committee votes on issues related to those specific vaccines. Regarding other 

vaccines of the affected company, a member may participate in a discussion with a proviso that 

he or she abstains on all votes related to that vaccine company. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

15

The ACIP Secretariat solicits applications throughout the year for candidates to serve on ACIP. 

Detailed instructions for submissions of name of potential candidates may be found on the ACIP 

website. Applications may be submitted at any time of the year. Materials in support of the next 

cycle of applications for ACIP membership (beginning July 2010) are due no later than 

November 15, 2009. ACIP meeting registration dates are established for security reasons. The 

CDC complex is a secured environment and pre-registration for meetings is posted on the ACIP 

website. This pre-registration is time-sensitive for international visitors since the Office of 

Security and Emergency Preparedness is required to pre-approve access for all non-US citizens 

visiting CDC facilities. The next ACIP meeting is October 21-22, 2009.

Dr. Morse expressed CDC and ACIP’s appreciation to Dr. Robert Beck who was cycling off the 

ACIP committee following four years of dedicated service as a consumer representative. Mr. 

Beck’s previous top leadership positions with autism groups, and in the creation of a new 

national early childhood development screening intervention program that was adopted by the 

CDC and the Department of Education has proven to be of tremendous benefit to ACIP for four 

years. While serving on the ACIP panel, Mr. Beck chaired the Evidence-Based 

Recommendation Work Group and participated in the Anthrax, HPV, Japanese Encephalitis

(JE) and other vaccine work groups. More important have been his major contributions to 

ACIP’s deliberations where he has provided a unique perspective, asked probing questions, 

provided keen insights, and kept everyone well-rooted in the real world. With gratitude from 

CDC and ACIP, Mr. Beck was presented with a certificate and an award made of glass to 

represent what he had added to the transparency and clarity of ACIP’s work. 

Mr. Beck said he was absolutely overwhelmed by the ACIP experience over the past four years, 

and by having the opportunity and privilege to work with some of the most wonderful people he 

had ever met. He stressed how talented each member of the committee is, and acknowledged 

the incredible amount of time and effort each of them contributes. Even after 20 plus years of 

being in and out of government, until joining ACIP, he had no idea how much work they do and 

how important the individuals are who make up the committee. Their work benefits the public 

health of the entire nation. He concluded that it had truly been his privilege to be a member, 

and that he had been deeply touched by each member in the nicest way. He wished them all 

the very best of continued success.

The following conflicts of interest were declared: 

Dr. Janet Englund: sanofi pasteur; MedImmune; Novartis Pharmaceuticals, ADMA Biologics, 

Inc.

Dr. Cody Meissner: Payments are made to Tufts Medical Center from Wyeth and MedImmune

The remainder of the members declared no conflicts. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

16 

Overview

Ciro Sumaya, MD, MPH

ACIP Chair

Dr. Sumaya pointed out that the general recommendations are published in the Morbidity and 

Mortality Weekly Report (MMWR) at approximately three- to five-year intervals. General 

recommendations addresses immunization issues relevant to all vaccines, and topics ad hoc 

that cannot be attributed to a single vaccine. General recommendations are directed to 

providers who are administering many different vaccines every day, and who come from 

variable backgrounds (e.g., physicians, nurse-practitioners, nurses, pharmacists, medical 

assistants). Thus, the recommendations are made as user-friendly as possible.

During this session, information was presented on combination vaccines, special situations, and 

vaccination records. There are complex issues that must be addressed with respect to 

combination vaccinations. Working from the last iteration of the general recommendations, the 

General Recommendations Work Group refined, reviewed, and made some changes. Special 

situations were reviewed from an updating / editing standpoint, with few changes. The vaccine 

records section, a very important and fast moving field, was edited and updated. 

For the next session of ACIP in October 2009, the final recommendations on altered immunecompetence will be reviewed. There remain some outstanding issues in this area, particularly 

with respect to transplant patients. In addition, the vaccination programs will be reviewed for 

infants and children, adolescents, and adults. A final vote on the entire document is anticipated 

during the October 2009 meeting. The document will then proceed to the CDC clearance, with 

an expected publication date of April 2010. 

Andrew Kroger, MD, MPH

CDC / NCIRD / ISD / EIPB 

Turning first to combination vaccines, Dr. Kroger indicated that the general recommendations 

language is derived from a 1999 specific Morbidity and Mortality Weekly Report (MMWR) on 

combination vaccines for childhood immunization that describes what combination vaccines are, 

states a preference for the use of combination vaccines, and offers supplementary guidance on 

issues like the interchangeability of products and extra vaccination doses. It has been 10 years 

since that specific statement was published, since which the environment has changed. There 

are many new vaccines, and many new combination vaccines. It will be important to define 

what a combination vaccine is definitively. New reactogenicity data with one combination 

vaccine (e.g., MMRV) suggest a higher risk of febrile seizures with the combination product 

compared to single component administration. 

Originally a work group dedicated solely to combination vaccines was constituted to address the 

fact that the 10-year old recommendations must be updated. This workgroup initially focused 

on specific products such as Pentacel® and KINRIXTM. It was clear from the outset that a more 

general perspective was necessary, not only because of the issues with the MMRV vaccine 

General Recommendations
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

17

specifically, but also because any discussion of combination vaccines brings in general 

immunization topics like simultaneous vaccination, vaccine administration, and other types of 

programmatic issues. It was deemed necessary to deal with these issues, which is when the 

task fell to the General Recommendations Work Group. A manuscript was drafted and 

reviewed by four members of the original Combination Vaccines Work Group prior to being 

discussed by the General Recommendations Work Group, a draft of which was provided to the 

ACIP members in their briefing documents. On page 2, line 6, a combination vaccination is 

defined as “a product whose components can be equally divided into independently available 

routine vaccines.”

The draft also contains Table 5 which is located at the end of the Combination Vaccine section. 

This table lists the combination vaccines, which include: COMVAXTM, TriHIBit ®, Twinrix®, 

PEDIARIXTM, ProQuad ®, KINRIXTM and Pentacel®. The definition would exclude a laundry 

list of other vaccines (e.g., HepB, RV, TT, DT, DTaP, Hib, IPV, PCV7, MMR, Var, HepA, TIV, 

LAIV, MCV4, Tdap, Td, HPV, PSV4, PPSV23, ZOS, Ty21A, YF, JE, Typhim VI, Rabies, BCG, 

Anthrax, and Smallpox. Vaccines such as inactivated polio virus vaccine, IPV, pneumococcal 

conjugate vaccine, PCV7, MMR, Td, and TDaP are excluded from the definition even though 

they do consist of multiple antigens for different strains of the various microbes or the antigens. 

For these, separate components are not routinely available. The Tdap vaccine is not 

considered to be a combination vaccine by the strict definition because it really cannot be 

equally divided into separate vaccines; that is, Td is an available vaccine, but a single antigen 

acellular pertussis component does not exist. 

In addition, Dr. Kroger pointed out that the general preference statement needed to be revisited. 

As listed in the 2006 general recommendations, the current stated preference for combination 

vaccines is, “Use of licensed combination vaccines is preferred to separate injection of their 

equivalent component vaccines to reduce the number of injections and missed opportunities to 

protect through vaccination.”

Based on the history, the work group met by teleconference to discuss the advantages and 

disadvantages of combination vaccines. Before offering options for revisions to this statement, 

Dr. Kroger reviewed these advantages and disadvantages with the larger membership. 

Vaccines have site-specific requirements. As many as nine vaccines could be recommended at 

a single visit. If the wrong site is used, vaccine could be less effective (HepB, Rabies) or more 

reactogenic (most adjuvant-containing vaccines injected subcutaneously). A challenge of 

vaccine administration and particular guidance needed for specific vaccines include: the need to 

re-administer vaccine doses if the wrong site is used for Hepatitis B or Rabies vaccine; and 

issues of reactogenicity when vaccines that contain aluminum adjuvants are injected 

subcutaneously. Another topic that has been discussed is the issue of patient preference for a 

reduced number of injections. The existing literature on this topic does not narrowly address a 

combination vaccine. A paper published in 2001 by Maureen Kolasa [Kolasa MS, et. Al. Impact 

of Multiple Injections on Immunization Rates Among Vulnerable Children. Am J Prev Med. 

2001; 21(4), p. 261-266] suggests that providers and patients seemed comfortable with 

increasing the number of injections per visit from 3 to 4, but this was in a historical context of the 

switch from the oral polio vaccine to the inactivated polio vaccine. There have been other 

discussions and focus groups about this topic, but there is limited published literature.

There is evidence in the literature that combination vaccines improve vaccination coverage. In 

a retrospective analysis of over 18,000 Georgia infants, Marshall and colleagues demonstrated 

that the use of COMVAXTM and PEDIARIXTM improved the coverage of the DTaP, IPV, 4:3:1, 

4:3:1:3, and 3:3:3 (by 3 to 6 percentage points) [Marshall GS, Happe LE, Lunacsek OE et. Al. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

18

Pediatr Infect Dis J 2007. 26:496-500, 2007]. These are good data and this is an important 

question. More data are need with respect to exactly why the coverage has improved in terms 

of whether it is due to reduced injections, reduced requirements for visits, or both. While this is 

really unknown, it is probably a combination of both. 

There is also improvement of vaccination timeliness. There are several studies on this. In 2700

children in Germany, it was documented that vaccine doses were given earlier if combination 

products were used. The difference was not huge (less than a month) [Kalies H, Grote V, 

Verstraeten T, et al. The use of combination vaccines has improved timeliness of vaccination in 

children. Pediatr Infect Dis J. 2006;25:507–512]. A study of 5,000 children in Georgia 

documented a timeliness rate of 66% versus 61% for the DTaP, IPV, Hib, and HepB 

components if the DTaP-HepB-IPV vaccine was used [Happe LE, Lunacsek OE, Kruzikas DT, 

et al. Impact of a pentavalent combination vaccine on immunization timeliness in a state 

Medicaid population. Pediatr Infect Dis J. 2009; 28:98-101].

Reduced shipping and storage costs are also advantageous. With regard to the outright cost of 

vaccines, the cost of shipping can be presumed to be less if shipping fewer products. Older 

combination vaccines are, on average, cheaper than the sum of the components. However, for 

newer vaccines, the combinations are more expensive. The issue of storage is complicated and 

relates to how providers respond to any type of preference recommendation in the first place. If 

preference is given, they may purchase both combination and single component vaccines. It is 

likely that they will not purchase as much of the single component product, which probably 

would have an effect of reducing the amount of storage space required. Vaccines are stored in 

refrigerator and freezers. If more storage space is required, there will be a cost for an additional 

unit. Providers who purchase single components MMR and Var vaccines, and combination

MMRV vaccine, store them all in the freezer, although MMR does not need to be stored there. 

There were discussions in the work group pertaining to how complicated it is for providers to 

use a single component MMR vaccine with the single component varicella vaccine, given that 

one must be frozen and one can either be frozen or refrigerated. Providers probably 

preferentially place the MMR in the freezer, which may have a storage effect due to the need for 

freezer space in the first place or the lack of enough freezer space. With MMRV vaccine alone, 

one could argue that a simple freezer message could be endorsed. 

Another advantage is the reduced cost of extra health care visits. It is not crystal clear why 

combination vaccines improve rates, but perhaps it is related to reduced healthcare visits. Data 

from the 1999 National Immunization Survey indicate that 71% of children receive no more than

four immunizations per visit. What is not definitive in that data is whether more than four doses 

were acceptable and if not, how that would affect extra vaccination coverage. Data on missed 

opportunities to vaccinate discuss the fact that not all of the doses may have been given at a 

visit that were recommended for that visit, but it is not entirely clear how the combination versus 

single component factors into this or how much weight can be given to this difference. CDC 

recommends vaccination not only at well visits, but also at any kind of visit as long as the child 

is not ill. Thus, there are many reasons for missed opportunities that are beyond the scope of 

combination vaccines. Combination vaccines also facilitate the addition of new vaccines into 

immunization programs, and present opportunities to educate and re-educate providers about 

the diseases prevented by various components. This is another opportunity to bring training 

messages forward. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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There are disadvantages of combination vaccine as well. The first regards increased risk of 

adverse reactions. There is known to be approximately a two-fold higher risk of febrile seizures 

in children 12 to 23 months old vaccinated with MMRV instead of MMR + V. Additionally, an 

observational study of 3938 6- to 10-week old infants showed an infant receiving Pediarix® to 

be 6.8 times more likely to receive a fever work-up than infants who received the single 

component vaccines [MMWR March 14,2008 57; Thompson LA, Irigoyen M Matiz LA, et al. The 

impact of DTaP-IPV-HB vaccine on use of health services for young infants. Pediatr Infect Dis J. 

2006;25:826-831]. This was already expected from the pre-licensure trials and this particular 

issue is currently undergoing follow-up studies to clarify exactly what this increased risk is 

about.

Confusion and uncertainty also represent a disadvantage. CDC recommendations are very 

complicated, so confusion and uncertainty make constant education necessary. In the case of a 

combination vaccine preference, we have witnessed extra doses of an antigen being 

administered. Patients are seen by different providers, they have different contracts for different 

types of vaccines, and data from the National Center for Health Statistics (NCHS) suggests that 

95% of children do have a usual place of health-care. Thus, 5.5% of children see more than 

one provider. With the complexity of health care delivery as it is, multiple venues for vaccine 

administration are expected. A single provider may be limited with a particular choice of a 

formulation for a set of antigens. He/she may only provide one particular combination product 

and since every single possible combination is not available for every provider, a patient who

sees multiple providers may be in the environment where they have to be administered an extra 

antigen or perhaps even skip an essential antigen if a provider decides not to administer the 

combination product. 

There is evidence that vaccine components are not as effective when given in combination 

(e.g., reduced immunogenicity). This reduced immunogenicity typically occurs when a particular 

combination vaccine is given off-label or against ACIP recommendations. An example is 

TriHIBit ® which is licensed for the fourth or last dose of the Hib series. If it is given as one of 

the first 3 doses, pre-licensure trials suggest reduced immunogenicity of the Hib components in 

this instance. ACIP recommends repeating the Hib component. This would not be a problem if 

vaccines were administered correctly all of the time; however, this does not happen and 

mistakes do occur.

Extra doses of antigen in the fixed product represent another disadvantage. This can be an 

issue even when a patient stays with the same provider. Sometimes an extra dose of antigen is 

necessary when using combination vaccines. Because CDC universally recommends a birth 

dose of Hepatitis B vaccine, if the provider chooses to use 3 doses of PEDIARIXTM as per the 

product insert recommendations, they will administer 4 doses of the Hepatitis B component 

overall because PEDIARIXTM cannot be used for the birth dose of Hepatitis B vaccine. 

Similarly, if Pentacel® is administered per product insert, 5 doses of IPV total would be 

administered in 41% of states per an informal survey of state health departments in 2008. 

Another disadvantage pertains to differences in shelf life. Combination products can have a 

shorter shelf life. PEDIARIXTM is an example of this. The shelf life of PEDIARIXTM is 24 months 

and the shelf life of the single component INFANRIX ® is 36 months. The actual number may 

vary from what is listed in the product insert because obviously things can change depending 

upon supply issues. However, many providers are going to use the information that is 

presented to them in the product insert.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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Based on the aforementioned advantages and disadvantages, the work group crafted three 

potential options for revision to the general preference statement for combination vaccines and 

discussed the pros and cons of each. 

Option 1 is to make no changes to the 2006 statement, leaving it as, “the use of licensed 

combination vaccines is preferred over separate injections of their equivalent component 

vaccines if licensed and indicated for the patient’s age.” This option was not favored by any 

members of the work group. The pros are that this option requires no revised communications 

messages, it is the status quo, and it is simple to implement. The cons are that providers are 

currently faced with a lack of flexibility regarding choice of antigens due to restrictions that may 

exist for their formularies, increased costs of vaccinations, increased activities like screening 

and counseling that may need to occur with the use of a combination product, et cetera. Just 

because there are fewer injections does not necessarily mean that there is any less labor 

involved, and that comes with a cost and should be appropriately reimbursed. Another con to 

leaving the recommendation as is regards the history of ACIP having removed a preference for 

the particular specific combination vaccine, MMRV, over MMR + V so it seems like some 

change in this language should naturally follow. 

Option 2 involves adding language to the existing preference for combination vaccines to state, 

“The use of a combination vaccine generally is preferred over separate injections of its 

equivalent component vaccines if licensed and indicated for the patient’s age, but depends on 

the vaccination status of the patient, provider preference, patient preference, the potential for 

adverse events, and vaccine availability.” The pros for this statement are that it is still a general 

recommendation for combination vaccine with caveats. There will be a potential for less missed 

opportunities, it recognizes programmatic issues and vaccine availability as important 

considerations, and it is permissive and allows a choice for the provider and patient. The major 

con is that the language is somewhat wordy and complex and it may take some time for people 

to remember the criteria.

Option 3 is to state that there “is no preference for the use of combination vaccines over 

separate injections of the equivalent component vaccines.” The pros for this option are that it is 

concise statement, emphasizes choice for provider and patient, provides a clean slate for 

evaluating safety and efficacy of vaccines in the pipeline, and the vaccine contracting 

environment already restricts the choice of formulation. The cons for Option 3 include the 

potential limitation of administration site space, storage space may be limited (single component 

products take up more space), and reduced availability of combination vaccines leads to more 

injections. 

Following the work group discussion of the advantages, disadvantages, and options, no 

members chose Option 1, a few chose Option 3, and many providers chose Option 2. Some 

members of the work group who chose Option 2 were comfortable with Option 3, but a plurality 

of the work group members who actually expressed a preference favored the general 

preference for combination vaccines with criteria and caveats. There was considerable 

discussion and the work group believed that they needed to ask ACIP to weigh in on Option 2 

versus Option 3.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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Discussion

Dr. Marcy pointed out that there is another advantage to combination vaccines. There are two 

studies showing that it takes about a minute plus or minus to draw up the vaccine. A 

practitioner who has many patients and many vaccines can save a half an hour in the course of 

a day, which is no small amount. If he gives DTaP, Hep B, and IPV, it is worth $25 in 

administration fees. If he gives DTaP, Hep B, and IPV separately it is worth $75 in 

administration fees. Thus, the separate vaccines do have an economic advantage for the 

practitioner who wishes to use them separately.

Dr. Ehresmann indicated that her personal preference was Option 3 for a number of reasons. 

From the perspective of a state health department and making vaccines available, there are 

clear advantages to using combination vaccines for the provider and the patient. The statement 

in the general recommendations will not likely stop manufacturers from producing combination 

vaccines, but may stop providers from using them. It “levels the playing field” in terms of choice. 

Dr. Sawyer indicated that he was a work group member and an Option 2 advocate. Given that 

private insurers and others may mandate that providers use separate vaccines, he expressed 

concern that Option 3 may lead to the unintended consequence that separate vaccines are 

given even when not intended.

From a practitioner standpoint, Dr. Temte noted that one of the disadvantages regarded the 

decrease in availability of single component vaccines. Among the members of the American 

Academy of Family Physicians (AAFP) from whom he had heard, there was a major issue 

regarding HIB vaccines. Anytime recommendations are changed or interim guidance is offered 

because of vaccines not being available, it creates significant problems for the vaccine provider 

community. One of the disadvantages is the seeming decrease of availability of single 

component vaccines. He wondered whether the work group addressed this.

Dr. Kroger responded that the issue was at least considered when the group discussed the 

limitations. They did not address issues of shortages per se. There is language that discusses 

shortages later in the section following the preference statement. That is an important limitation 

in terms of which particular antigens can be used or not used at a particular time. 

Dr. Meissner expressed concern about how combination vaccines might be perceived by the 

public. The definition is interesting in terms of which vaccines can be conveniently separated. 

However, people may perceive MMRV as a combination that could be administered as a 

monovalent vaccine if there is not some statement. For example, in Option 3 the recognition is 

completely removed of the advantages of the combination vaccines. This could become a 

slippery slope and there will be more interest among certain segments of the population about 

using monovalent vaccines.

Dr. Judson suggested that the solution was to remove any economic advantage to giving 

separate antigens, or conversely to potentially reward giving combinations because of the 

complexity and additional counseling that has to take place.

Given that there are probably arguments both ways, Dr. Morse pointed out that a cost-benefit 

analysis may be needed to make determinations either way.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

22

Dr. Englund indicated that she favored Option 2, pointing out that there had been a major effort 

by pediatricians over the past 20 years to move toward combination vaccines because of the 

updates showing that this is patient and family preference. To move away from the direction 

practice had been moving for 20 years seemed to be a major step backwards.

Dr. Baker also favored Option 2; however, she did not believe anyone would understand it as 

written. It could be solved generally by revising it to “preferred over individual components.” It 

could remain with the rest of the language in the text, by leaving “generally preferred” at the end 

of the sentence, or including a quick “but” with a quick phrase.

Dr. Cieslak also expressed a preference for Option 2, but because of the number of conditions,

he thought it amounted to not being a recommendation. He suggested truncating it after “age.”

Dr. Meissner suggested reviewing the combination vaccine section in the 2009 Red Book, which 

was recently distributed, as a potential template for phrasing this recommendation.

Dr. Sumaya noted that the work group did not achieve consensus; however, a larger portion of 

the group preferred Option 2. While he agreed with truncating it after “age,” it would really then 

become Option 1. Perhaps they could truncate it and pick one or two priority items to be 

explicit. 

Dr. Sawyer suggested keeping the patient and provider preference statements, which would 

encompass the rest of them. The provider should take adverse events into account, while the 

patient will take number of injections into account. He thought it should be truncated at 

“depends on provider and patient preference.”

Dr. Morse inquired as to why the work group felt it was necessary to include “if licensed and 

indicated for the patient’s age” because it seemed like that was general.

Dr. Kroger responded that it was a holdover of the status quo statement. He thought it was 

important to emphasize this point because of the position, timing, and spacing section. They 

want to ensure that vaccines are being administered at the ages for which they are 

recommended and if licensed for a particular dose and a particular age.

Dr. Ehresmann made a motion to support Option 2 with modification to the wording. She 

suggested rather than saying “provider and patient preference” to state that it is the patient’s 

preference, but the provider’s preference based on their deliberation over a scientific evaluation.

Dr. Baker seconded the motion for Option 2.

Dr. Chilton was opposed to saying just “patient preference.” While respect for patient 

preference is good, the language would require the physician to stock all of the available 

vaccines, which is neither possible nor reasonable.

Dr. Duchin (NACCHO) favored Option 2 in that combinations are generally preferred; however, 

he thought it was very important for ACIP to annotate the recommendation with the specific 

considerations that health care providers might take into account when they decide whether or 

not they want to use a given combination vaccine. There are many different combination 

vaccines, each with its own plusses and minuses. Vaccines will also appear in the future after 

this recommendation is issued that may have unforeseen cost and benefits. He wondered if, 

when ACIP statements are issued on individual vaccines, there will also be a preference 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

23

expressed in those statements for combinations and how that would relate to this 

recommendation and the general recommendations as a whole.

Dr. Leonard Freidland (GSK) clarified that the shelf life for both INFANRIX® and PEDIARIXTM is 

36 months. Providers will not find shelf life dates in product inserts. Instead they are directed to 

look at the expiration data on the vaccine being used, and not to use the vaccine has expired. 

He also indicated that the follow-up on the adverse event profile for PEDIARIXTM has been 

completed. He directed the committee to an article in Pediatrics in December 2008. A postmarketing study was conducted in which over 60,000 infants received PEDIARIXTM and close to 

60,000 control subjects received separate vaccines. 120,000 doses of each vaccine were 

followed. Short reviews were conducted for 22,500 infants who received PEDIARIXTM and 

similar numbers of the separate vaccines. There was no increased evidence of medically 

attended fever within 4 days after vaccination after any dose in the infants who received 

PEDIARIXTM versus the separate vaccines.

Dr. Phil Hosbach (sanofi pasteur) said that sanofi pasteur was pleased to see that Option 2 was 

being consider, given all of the investment. The policy drove manufacturers to spend hundreds 

of millions of dollars to develop combination vaccines for the benefits that were outlined. He 

begged the chair’s indulgence to make a recommendation for the wording that might help 

simplify this, “Use of licensed combination vaccines are generally preferred to reduce number of 

injections and missed opportunities. Vaccine-specific considerations that might modify this 

general preference are discussed in the recommendations for specific recommendations for 

individual vaccines.”

Dr. Mark Feinberg (Merck; NVAC) stressed that the discussion ACIP was having carried with it 

long-term implications. Manufacturers do respond to the guidance offered by providers and 

importantly by ACIP in terms of what vaccines to develop in the future. One of the components 

under discussion by the National Vaccine Program Office (NVPO), NVAC, and a number of 

other partners is the National Vaccine Plan. One of the components of the National Vaccine 

Plan is focused on stimulating the development of optimized and appropriate vaccines for the 

future. A clear determinant to what manufacturers do and how quickly they do it has to do with 

the clarity of guidance provided by important groups like ACIP. Therefore, he encouraged ACIP 

members to take their discussions very seriously. If they could not achieve clarity and 

consensus during this meeting about the guidance they wanted to provide, he suggested that 

they take this back to the work group and present it at a later time when a clear 

recommendation that would provide the best guidance for public health in the future was 

developed.

Deborah Wexler (Immunization Action Coalition) raised an issue that troubles nurses with 

regard to combination vaccines in that some vaccines are not licensed for use in certain age 

groups. PEDIARIXTM is recommended for doses 2, 4, and 6 months of age or the first 3 doses. 

Some nurses need to give those three doses, DTaP #4, IPV #3, and Hepatitis B #3 at 18 

months of age. PEDIARIXTM is not licensed for that use. Many children need KINRIXTM, DTaP, 

and IPV at age 3 who are behind on immunizations. Most nurses would prefer giving a 

combination vaccine to those children. With that in mind she wondered whether ACIP would 

make a recommendation outside of FDA licensure, which ACIP has a history of doing, to make 

it easier to facilitate giving those three doses of vaccine somewhat outside of the FDA 

recommendations for the use of PEDIARIXTM or the use of DTaP / IPV vaccine. 

Dr. Ehresmann said her concern about the wording was that “provider preference” did not give 

enough credit to the provider for their assessment and evaluation of the patient.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

24

Dr. Baker thought they agreed to insert “licensed” in the statement for licensed combination 

vaccines, given some combination vaccines are not licensed for certain ages.

Dr. Sandy Fryhofer (American College of Physicians) indicated that she is a practitioner who 

treats the mothers of children. Given that vaccines are in the spotlight, she expressed her hope 

that some language would be included about adverse events. Her fear was that if only a 

combination vaccine was available, many mothers may opt out entirely not have their children 

vaccinated. This is also an ethnic and racial disparities issue because some of these individuals 

might not have the option of going to a private facility to acquire their vaccines if they cannot 

obtain it through public means.

Dr. Morse clarified that from the discussion, it appeared that there was significant consensus for 

Option 2, but that the actual wording had not been solidified. He thought they should define 

exactly what they were voting for, or at least the general principle of the vote, and then return 

the next day with specific language. 

Dr. Lett pointed out that one variable which must be kept in mind was vaccine availability. 

Dr. Kroger clarified the proposed revisions: add “licensed” before the first combination, change 

“provider preference” to “provider evaluation,” keep “patient preference,” leave “vaccine 

availability,” and perhaps remove “vaccination status of the patient.”

Dr. Baker suggested the following language, “The use of a licensed combination vaccine 

generally is preferred over separate vaccine components or component vaccines, but depends 

on patient preference and evaluation or assessment.” She preferred “provider assessment” 

rather than “evaluation,” although she was willing to accept “evaluation." 

Dr. Judson thought the goal was to shorten this as much as possible, but it now seemed that 

they had 5 or 6 options on the table. He thought that critical for the first sentence was the 

statement that the “combination vaccine is preferred and if licensed for the patient’s age,” which

would be helpful to a skilled practitioner. However, if indicated did not seem useful because it 

did not seem that anyone would use a vaccine if it was not indicated. He thought the second 

part really was about provider preference because patients would likely not make that decision 

separate from or even in opposition to the provider.

Dr. Baker stressed that patient preference was an increasingly important issue.

It struck Dr. Beck that the issue really regarded how they modified the word “provider.” 

Everything else seemed to be fitting into place. He agreed that patient preference was 

important, but that there must be a way of describing the involvement of the provider in this joint 

decision. 

Dr. Sawyer agreed that one or two words were needed to describe provider involvement. He 

reminded everyone that in the text would be all of the advantages and disadvantages that were 

outlined, which the provider is supposed read and evaluate for each patient. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

25 

Motion: General Recommendations for Combination Vaccines

Dr. Ehresmann made a motion to approve Option 2 with modifications to be made to the 

wording by the work group as discussed. Dr. Baker seconded the motion. The motion carried 

with 15 affirmative votes, 0 abstentions, and 0 negative votes. 

The following Option 2 clarification was presented to the ACIP members during the second day of the June 2009 meeting: 

The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines. 

Considerations should include provider assessment*, patient preference, and the potential for adverse events. 

*Provider assessment should include storage costs, number of injections, vaccine availability, vaccination status, likelihood of 

improved coverage, and likelihood of patient return visits. 

 

Dr. Kroger then directed the members’ attention to the recommendation regarding Special 

Situations, which is a laundry list of topics faced by providers on a regular basis, including:

 Concurrently Administering Antimicrobial Agents and Vaccines

 Tuberculosis Screening and Skin Test Reactivity

 Severe Allergy to Vaccine Components

 Latex Allergy

 Vaccination of Preterm Infants

 Breast Feeding and Vaccination 

 Vaccination During Pregnancy

 Persons Vaccinated Outside the United States

 Vaccinating Persons with Bleeding Disorder and Persons Receiving Anticoagulant Therapy

Two of these sections, Tuberculosis Screening and Skin Test Reactivity and Vaccination of 

Preterm Infants, required minor updates to address new vaccine-specific recommendations that 

have been published. For tuberculosis screening and skin test reactivity, the general 

recommendations have not recommended an interval between the live viral vaccine and a 

tuberculosis test. It is known that diseases such as measles can suppress the response to a 

tuberculosis test and generate false negatives. There is a need to adjust the general 

recommendations to take into account new tuberculosis-specific recommendations that have 

been published for two-step testing, which involves basically two doses of the purified protein 

derivative. A recommendation is also needed to clarify whether the risk of test suppression from 

a live vaccine also exists for a new TB test. Since the last recommendations were published, 

there is a newly available test known as the interferon-gamma release assay. Based on 

consultation with the TB subject matter experts (SMEs), the recommendation should be for the 

same spacing intervals with live vaccines and the new tuberculosis tests. This is basically a 

minor update. 

Vaccination of preterm infants requires an update as well. ACIP has generally recommended 

vaccinating preterm infants following the same chronologic age recommendation as term 

infants, but there have always been a few exceptions to this. Additional language will be added

to emphasize testing of HBsAg-unknown mothers for HBsAg even after HepB is administered. 

This is an important part of determination to use HBIG within 7 days of birth. Another minor 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

26

clarification is the recommendation to defer rotavirus vaccination of infants 6 weeks old and still 

in neonatal nursery (or neonatal intensive care unit).

Two special situations, Vaccination During Pregnancy and Persons Vaccinated Outside the 

United States, require fairly major revisions. A reference has been added to Vaccination During 

Pregnancy for ACIP’s Guiding Principles for Development of ACIP Recommendations for 

Vaccination during Pregnancy and Breastfeeding, which was published in May 2008. New 

concepts have also been added from the Tdap pregnancy-specific document, also published in 

May of 2008 that recommend: Deferral of Tdap (ACIP Vaccine-specific recommendations), use 

of Td, limited situations when Td can be deferred (new reference MMWR May 30, 2008), and 

use of Tdap postpartum regardless of interval from last Td. Based primarily on expert opinion, 

the risk of infant pertussis disease from withholding a dose of Tdap from a post-partum woman 

outweighs the risk of a local reaction to the Tdap vaccine from a post-partum woman who may 

have received Td in pregnancy. The work group acknowledged that there may be future ongoing discussion of this topic. It was not clear how specifically to word this in the general 

recommendations statement. Further consideration should be given to this issue, given that 

there is a considerable amount of language in the 2006 document specifically regarding the use 

of tetanus toxoid-containing vaccines in pregnancy.

The work group wanted to clarify ACIP’s counseling recommendations for pregnant women that 

may have inadvertently been administered MMR vaccine. The 2006 document mentions a 

theoretical risk, but does not describe in detail why the risk exists. The new language is as 

follows:

Data from studies of children born to mothers vaccinated with rubella vaccine during 

pregnancy demonstrate rubella antibody levels that probably represent passive transfer 

of mother’s antibodies during pregnancy. No cases of congenital rubella or varicella 

syndrome or abnormalities attributable to fetal infection have been observed among 

infants born to susceptible women who received rubella or varicella vaccines during 

pregnancy, although a theoretical concern exists . . . If vaccination of an unknowingly 

pregnant woman occurs or if she becomes pregnant within 4 weeks after MMR or 

varicella vaccination, she should be counseled about the theoretical basis of concern for 

the fetus; however, MMR or varicella vaccination during pregnancy should not be 

regarded as a reason to terminate pregnancy (6, 8, 189).

This language originated in the leads from the MMWR series published in JAMA in June 1989, 

so this much specificity has not been carried forward through all of the documents since then, 

but it is cited in all of those documents, so it was presented here as part of the general 

recommendations.

Another topic in special situation that requires some changes is Persons Vaccinated Outside of 

the United States (US). The 2002 document was originally written to focus exclusively on 

internationally adopted children, but it has been broadened to include all persons vaccinated 

outside of the US, which means that ACIP needs to take into account the new vaccines since 

2006: rotovirus vaccine, human papilloma virus vaccine, and zoster vaccine. 

The Vaccination Records section revisions consist primarily of clarifications and updates. 

Strong emphasis is placed on the role of a vaccination record in avoiding extra doses. The 

language that has been added reads:
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

27

Appropriate and timely vaccination documentation not only helps ensure that persons in 

need of one or more recommended vaccine doses receive them, but also that 

adequately vaccinated patients are not administered excess doses. Curtailing the 

number of excess doses administered to patients aids in controlling costs incurred by 

patients, providers, insurers, vaccination programs, and other stakeholders. 

Additionally, there are isolated examples of excess doses increasing the risk of an 

adverse reaction (e.g. excess reduced doses of tetanus toxoid and frequent dosing of 

pneumococcal polysaccharide vaccine causing local reactions). 

The effect of this language is primarily to emphasize the importance of provider records and 

provider responsibility. Language is included to stress that providers should document serology 

results, vaccination doses, et cetera. Additional language is included to encouraging postpartum mothers to receive a record on discharge from the hospital because Hepatitis B vaccine 

should be given in that venue. Language is also included to describe potential capabilities of 

immunization information systems (IIS) with respect to vaccine management and documentation 

of adverse events, and there is an update on statistics pertaining to IIS enrollment.

Discussion

Dr. Chilton pointed out two minor differences between the general recommendations and the 

rotavirus statement. There is a statement in the rotavirus policy statement saying that some 

experts would prefer the vaccine that does not contain latex or that does not have a latex 

stopper for those patients who are at high risk of later having a latex allergy (e.g., spina bifida

patients). The rotavirus policy statement also includes a proviso that if there are epidemiologic 

considerations that dictate use of rotavirus vaccine in a newborn intensive care unit, it could be 

done using local some expert opinions. He wondered whether this language could be included 

in the general recommendations as well.

Dr. Kroger agreed that it would be a good idea to add language along those lines.

Dr. Morse wondered whether everything had to be included in the general recommendations or 

if the general guidelines could refer to the other guidelines.

Dr. Englund was concerned that if they changed the general recommendations they would have 

to change the rotavirus recommendations as well. Perhaps referring to the specific guidelines 

was a better idea for the deferral of rotavirus vaccination of preterm infants 6 weeks old.

Dr. Temte noted that while for vaccination records some language was included about 

immunization information systems, there appeared to be nothing about electronic medical 

records (EMRs). He uses EMRs regularly with virtually every adult patient. Their EMRs have a 

tab to the Wisconsin immunization registry. Given the effort on the part of the current

administration toward the use of EMRs in general, it should be in the forefront of ACIP’s 

recommendations to fully integrate EMRs with immunization information systems.

Dr. Kroger suggested making a reference under provider responsibilities to the fact that these 

products exist.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

28 

With respect to recommending the interferon-gamma release assays, Dr. Marcy thought there 

was limited data for children under 4 or 5 years of age. In terms of measles vaccine, he 

suggested including a caveat regarding the age limitation for data. A second data-driven part is 

on page 21, “regardless of recent history of Td vaccination, pregnant women should receive a 

dose of TDaP as soon as possible after delivery.” If Td has been given to a woman at the 

beginning of the second trimester and following delivery, this is about six months. He knew of 

no data showing the safety of TDaP less than 18 months after Td. Scott Halpern’s data goes 

down to 18 months.

Dr. Pickering responded that a recent article was published showing the period of 1 month with 

no adverse events. However, the numbers were small

The discussion reminded Dr. Morse of the annual discussions of the children, adolescent, and 

adult guidelines when additional ideas were proposed. He thought they must look at this as a 

continuous quality improvement and that all of the excellent ideas proposed should go back to 

the work group so that they could continue to upgrade and improve this document each time. 

He stressed that it was not necessary to complete the final product at each meeting because 

they would never complete it. He had thus far heard no arguments against the 

recommendations which include minimum additional language and / or minor clarifications. 

Therefore, he suggested moving forward with a caveat that they would continue to improve the 

revisions with the next iteration.

Dr. Baker agreed with Dr. Marcy that there was no convincing data on safety; however, it is a 

risk-benefit issue because of the incredible risk to the baby of acquiring pertussis, which is likely 

to be fatal if the mother and everyone around the baby are not immunized. 

Motion: Special Situations and Vaccination Records

Dr. Baker made a motion to approve the recommendation of the work group regarding Special 

Situations and Vaccination Records. Dr. Sawyer seconded the motion. The motion carried with

15 affirmative votes, 0 abstentions, and 0 negative votes. 

Dr. Judson noted that while they voted to approve, he wondered whether there were statements 

as there were for Tb Screening and Skin Test Reactivity that may conflict with or connect to 

other recommendations. For instance, booster skin testing or double skin testing is generally for 

people over 40 in whom immunity may have waned. If this is stated to pediatricians trying to 

give doses to infants or children, this will be confusing as it does not apply to them. There are 

no data for infants and children for QuantiFERON ®, let alone where practitioners might order it.

Dr. Morse requested that Dr. Judson put this in writing and refer it back to the work group so 

that it could be included in the deliberations.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

29 

Background

Dr. Paul Cieslak 

ACIP, WG Chair

Dr. Cieslak briefly reviewed the background information pertaining to rabies vaccine. Given that 

the human rabies vaccine supply has been tenuous since 2007, ACIP formed a work group to 

draft interim recommendations regarding how the supply should be managed in the event of a 

shortage. Draft interim recommendations in the event of a shortage of rabies biologics were 

previously distributed to ACIP in which alternative schedules during a shortage were proposed. 

The work group proposed alternative schedules, including a 4-dose schedule, and it was the 

opinion of the work group that the 4-dose schedule would not result in reduced efficacy in the 

post-exposure setting. Therefore, the work group was asked to evaluate alternative schedules, 

specifically for more routine use.

There are two rabies vaccines available in the US. The Novartis vaccine is the purified chick 

embryo cell vaccine, which is available for post-exposure and pre-exposure immunization 

without any current limitations. The sanofi pasteur vaccine, the human diploid cell vaccine, is 

available only for post-exposure prophylaxis at this time. Due to supply issues, there must be a 

local public health risk assessment and a password restricts its use [www.sanofipasteur.com].

The terms of reference for the ACIP Rabies Work Group were to review the evidence for a 

reduced schedule of rabies vaccine in the post-exposure setting; provide the available evidence 

to ACIP for discussion of dropping the 5th dose; and revise the existing statement accordingly. 

Human Rabies Biologics: Consideration of a 

Reduced Vaccine Schedule in Post-Exposure Prophylaxis

Dr. Charles Rupprecht 

CDC / CCID / NCZVED / DVRD

Dr. Rupprecht reported that the sources of evidence the work group has reviewed included 

basic studies of rabies virus pathogensis, overall immunization principles and kinetics

specifically regarding rabies vaccines, available data from human clinical trials, national and 

international epidemiological surveillance data. Members of industry and international subject 

matter experts, particularly with regard to the WHO collaborating centers, have been consulted 

as well.

The supply limitations developed during late 2007 when the 2008 ACIP rabies statement was 

already well into its editorial deliberations with the MMWR. The work group felt strongly that 

there should be discussions with ACIP and preparation of recommendations well before the 

onset of a true shortage. Besides increases in vaccine availability, a reduced schedule would 

possibly result in minimization of adverse biomedical events, will limit additional health 

expenditure, and provide a rational legacy for development of future biologics. With the onset of 

Rabies Vaccine
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

30

the application of comparative health effectiveness data, the work group felt strongly that the 

current institution of the ACIP evidenced-based approach would be a sound one for the 

objective rationale application toward rabies immunizations.

The work group also recognizes that this would be a departure from the claim of the product 

insert. However, using the following figure from a prior publication by Pickering and Orenstein, 

Dr. Rupprecht reminded ACIP members that this body does not simply “rubber stamp” label 

claims:

Obviously, immunization practices differ from what the claims are specifically. It is also 

important to recognize that, on the basis of the available data, there were no comparative 

clinical trials that specifically assessed the administration of human rabies immune globulin in 1, 

2, 3, or 4 doses. The product inserts were developed on the basis of the existing 5-dose 

schedule.

Historically, rabies immunizations have undergone changes in schedules, routes, and the 

formatted material that was used going back to the 1885 premier work by Pasteur when 14-21 

doses of sequentially desiccated spinal cord of rabid rabbit was homogenized and used as a 

vaccine. Originally, in 1980s the human diploid cell vaccine was suggested for an optional 6th

90-day dose which was then later dropped without any experimental comparative studies as 

well as in the US and a 5-dose series was used and similarly incorporated with the purified chick 

embryo vaccine, the PCEC vaccine. Similarly, there has been a 4-dose series in long use from 

a global standpoint, the 2-1-1 series in which 2 doses of vaccine are administered on day 0 

(requires availability of both vaccine doses on day 0, limits IM sites for HRIG, et cetera). The 

work group did not consider this particular schedule for several reasons, not the least of which 

was that they felt strongly that there was no utility of 2 doses being administered on day 0 

compared to the single dose. In addition, there was concern that because of the possibility for 

complications or mistakes, administration of 2 doses on day 0, with having to have an infiltration 

site for immune globulin, further negated the utility of having a 2-1-1 schedule as opposed to 

simply dropping of the 5th dose for a 4 dose total regimen. In regard to rabies virus 

pathobiology, the work group believes that what occurs in the first few days is critical by a 

current modern understanding of this acute, progressive encephalitis. The rationale for all postexposure prophylaxis is to prevent viral invasion from the locality to the nervous system. All of 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

31

the ACIP recommendations from inception to date have emphasized early wound care, passive 

immunity (e.g., infiltration of rabies immune globulin at the bite site), and rabies vaccine to 

stimulate the development of active immunity via a prime-boost strategy.

The following model of rabies virus pathogenesis was first proposed in the 1960s, and from 

experimental studies to date strongly suggests that the reason post-exposure prophylaxis works 

in the hours to days after exposure is because the virus is retained in the periphery:

TIME

AMOUNT

General Scheme Of Rabies Virus Pathogenesis 

?

US median incubation 

period is ~35 days

0

Neuronal retrograde viral transport is estimated at 50 - 100 mm/day (Tsiang al 1991)

When comparing incubation periods of human rabies cases that occurred in the US in past 

decades, a median is approximately one month. Clearly the administration of a 5th dose on day 

28 after exposure has little if anything to do with the amelioration of basic rabies virus 

pathogenesis and similarly has probably no saving utility for severe exposures on the face, 

head, or direct inoculation into the brain itself.

Based on a variety of clinical studies, rapid induction of rabies virus neutralizing antibodies is 

accepted as a critical surrogate of successful intervention. In clinical trials of rabies vaccination, 

all healthy individuals developed detectable rabies virus neutralizing antibodies by day 14. No 

significant differences were documented between a 4- versus a 5-dose rabies vaccine schedule 

in the relative amount of neutralizing antibodies produced. In comparison of studies using 4 

doses of vaccine, when given in a regimen that included rabies immune globulin, equivalent 

outcomes were observed. It is clear from these clinical studies that there is a relatively rapid 

induction of rabies virus neutralizing antibodies, which has been accepted as a critical surrogate 

of successful intervention since there is no defined seroprotective level per se. A combination 

of these studies over time, regardless of the type of the two vaccines licensed in the US, is 

compared in the following graph: 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

32

0.01

0.1

1

10

100

Study 1 Study 2 Study 3 Study 4 Study 5 Study 6 Study 7 Study 8

0 3 7 14 28 56-90 180

Day after initial vaccination

Geometric Mean Titers IU/mL

HRIG (Study 9)

Rabies virus neutralizing antibody response in humans after rabies vaccine and HR

As reflected in the graph, rapidly from day 0 to day 14, everyone develops rabies virus 

neutralizing antibody. Relatively shortly thereafter, the antibodies begin slowly to decline 

regardless of the administration of the 5th dose on day 28. Based upon epidemiological 

surveillance, in the US no failure of human post-exposure prophylaxis has been identified during 

the past 30 years (since use of modern cell culture vaccines and RIG). Outside of the US, 

rabies has occurred in human patients who had no prophylaxis, substantial delays in initiation of 

prophylaxis, or significant deviations from recommended prophylaxis. The work group could 

find no failures attributable to an absence of the fifth and last vaccine dose on day 28.

In terms of public compliance, cross-sectional studies at the state or county level indicate that 

public adherence to the existing human PEP schedule is not 100%. One study of human PEP 

in New York (1998-2000) found that approximately 13% of persons did not complete the full 

schedule, and approximately 2% only completed 4 vaccine doses, 2 of which involved 

documented exposures to laboratory-confirmed rabid animals, without incident.

Grossly extrapolated, approximately 1,000 persons likely receive only 3 to 4 doses of vaccine in 

the US each year, of which approximately 30 to 40 would involve exposures to rabid animals.

In addition, unpublished epidemiological data collected by CDC during a 2008 investigation of 

frequencies of animal exposures and a correlation with prophylaxis in Puerto Rico demonstrated 

that a 4-dose vaccine regimen provided an immunological response comparable to the standard 

5-dose regimen. In this limited survey 30 (16%) of 191 patients exposed to suspected rabid 

animals received fewer than 5 doses of vaccine. Consent and sera were obtained from 18 

patients, from whom three had received only 1 vaccine dose, 6 had received 2 doses, 5 had 

received 3 doses, and 4 had received 4 doses. Eleven (61%) of the 18 sera (two of the 2-dose 

patients, all 5 of the 3-dose patients, and all 4 of the 4-dose patients) exhibited complete virus 

neutralization at the 1:5 dilution using the RFFIT assay. Adequate titers were detected in the 

sera of all 9 patients who received only 3 or 4 doses of vaccine, 118, 144, 146 and 153 days 

after the 3rd (and last) doses and 126, 143, 168 and 215 days after the 4th doses of vaccine 

were administered. To date, none of these patients have developed rabies. [K. Robertson et al., 

2009 (unpublished)].

From the time of Pasteur, animals have been used as important surrogates in preclinical testing 

of rabies vaccines. Such research on basic immune response and vaccine efficacy in a variety 

of species have provided significant inferences to human clinical trials. Models from laboratory 

rodents to non-human primates demonstrate that the absolute number of doses of a potent 

vaccine is not critical if timely intervention occurs after experimental infection, including the 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

33

combined use of immune globulins. For example, in a recent mouse model in which all 10 

animals in the control group succumbed, and in which post exposure prophylaxis was instituted 

24 hours after exposure, in the 4 comparative groups of animals that either received 1 dose, 2 

dose, 3 dose, or 4 doses of vaccine, the number of animals surviving in each of those groups 

respectively was 8 of 10, 9 of 10, 9 of 10, and 7 of 10. The survivorship rate was irrelevant to 

the number of doses administered. The animals in each group were bled 3 months after the 

exposure and initiation of PEP. Similar to the human data obtained from Puerto Rico, as the 

number of doses increased from 2, to 3, to 4, there were no significant differences of 

survivorship. 

In another animal model using Syrian hamsters, it was also demonstrated that regardless of the 

absolute number of vaccine doses in PEP initiated 24 hours after animals were infected with 

rabies virus compared to controls, there was no significant difference in survivorship of those 

animals. From the standpoint of randomness in this experiment, there was 100% protection in a 

group where animals that received 4 doses as opposed to 89% survivorship in a group where 5 

doses of vaccine were administered [R. Franka et al., 2009, Vaccine, submitted]. 

With respect to health economics in the US, there may potentially be some minimal cost 

decreases to health care payers and the health care system if the regimen was reduced from 5 

to 4 doses. The work group recognized that there were not going to be any new clinical trials, 

nor any insipient changes in the label insert regardless of the ACIP recommendation. The 

number of visits by patients would decrease as a consequence of eliminating that last visit 

which is quite important, particularly in rural areas where individuals have to travel a number of 

miles. Insured patients are unlikely to see an increased cost per dose (cost per complete series 

of vaccine should remain unchanged). Preliminary assessments support the positive national 

health benefits associated with a reduced schedule of rabies vaccination. Overall, there is no 

anticipation that changing the current recommended schedule of 5 vaccine doses to 4 vaccine 

doses during rabies post-exposure prophylaxis would substantially alter the health economics of 

rabies prophylaxis.

In summary, no direct post-exposure efficacy trials have compared 5 doses to 4. The work 

group review included published and unpublished studies of rabies virus pathogenesis, 

experimental animal studies, human clinical trials, and epidemiologic surveillance data. The 

work group concluded that taken in toto, the evidence suggests that no rabies case would result 

from reducing the post-exposure vaccination schedule from 5 doses to 4. Based upon

feedback, a draft document was prepared by the rabies working group for ACIP review and 

vote.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

34

Discussion

Dr. Baker thought the new document was highly improved and she supported the work group’s 

recommendation.

Dr. Meissner pointed out that human nature being what it is, if there is a small percentage of 

exposed individuals who do not obtain all 5 doses and receive only 4, presumably if 4 doses are 

recommended, there will be a small percentage who will receive only 3 doses. Based upon the 

data, it appears as though that this is still likely to provide adequate protection. He also noted 

that the 2009 Red Book still recommends 5 doses and references the 2008 ACIP guidelines, 

which is likely to engender a great deal of confusion for pediatricians.

 

Dr. Rupprecht confirmed that Dr. Meissner was correct in his assumption on the basis of the 

comparative data. Most of the critical functions occur between day 0 and 14.

While Dr. Chilton appreciated the very good wording in the new document, he wondered what 

the ramifications may be of handing the manufacturer a de facto 20% windfall increase in profits 

by stating in the document that the cost of 4 vaccine doses is likely to be as great as that of 5.

Dr. Meltzer, a senior health economist and a member of the work group, took responsibility for 

that comment. It was based on a comment made to ACIP in the public forum last session 

during which one of the manufacturers said that they currently sell this as an entire treatment 

rather than a per dose treatment and they are unlikely to change the price per treatment. In the 

notes and in the write up, this is referenced. He did not believe anything ACIP said gave license 

in and of itself to any manufacturer to raise or reduce the prices, given that they work based on 

market forces.

Dr. Rupprecht added that it was their attempt to be transparent on the basis of the remarks that 

were made during the last meeting.

Dr. Morse noted that in the report it was noted that a substantial review of the Zagreb 2-1-1 

regimen was not included. However, he wondered what evidence was included as supportive. 

The regimen approved by WHO in 1992 has continued to be in practice. 

Dr. Rupprecht responded that those original studies were actually suggested in the 1980s and 

reviewed by WHO subsequently. From some of the work that was done, as well as some other 

comparative data, it has been shown there is an maximum amount of effective antigen that can 

be presented to the immune system at any one time, after which no further increases occur in 

antibodies, GMTs, protection, et cetera. That can be demonstrated experimentally and 

clinically, which is one of the reasons the work group felt strongly that there really was no utility 

of 2 doses of vaccine administered on day 0. Similarly, there were some suggestions clinically 

that when the Zagreb schedule was used, there was some strong suggestion of interference of 

immune globulin with those 2 doses of vaccine that were administered on day 0. Hence, on the 

basis of the clinical suggestions of potential interference and the lack of any utility of providing 

what is already a very potent product on day 0, and because of the implications during a 

shortage of not necessarily having 2 doses present on day 0, the work group believed that 

inclusion of the Zagreb schedule would only lead to additional confusion.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

35

Dr. Judson noted that 20 to 30 years ago, there was a statement some place that there was no 

evidence that rabies post-exposure prophylaxis started after 72 hours, or 3 days, or 4 days was 

effective. Now they were saying that there have been no cases of rabies if post-exposure 

prophylaxis was used. He wondered whether the prior impression had been modified.

Dr. Rupprecht replied that the review of the cases in which human rabies developed in spite of 

post-exposure prophylaxis suggested that immune globulin was not used, immune globulin was 

inappropriately used, or there was a significant delay in use. The excellent review by Wilde and 

others showed that there were some other complicating factors. The majority of failures were in 

cases in which heterologous products were suggested. The work group made note of and 

brought to the committee’s attention some of their concerns about the unavailability of intact 

immune globulins (IG). For example, if one used F(ab)2 prime products in which the Fc fraction 

is removed from the IG, that will significantly alter the kinetics, biological half life of circulating 

fragments and outcome of intervention. There have been no failures with timely use of one of 

the human rabies immune globulin products licensed in the US. The last major epidemiological 

study of post-exposure prophylaxis was the one by Helmick et al that suggested that there was 

a median delay of approximately 5 days between when a person was exposed and when they 

presented for post-exposure prophylaxis. That does not mean people should delay that long or 

misconstrue the numbers and present at their leisure. Obviously, this is an urgent emergency. 

Delay could result in death. They do not want the 5-day or 72-hour numbers to suggest that 

people should be turned away. In fact, there was a notable case in the US of a person exposed 

abroad. When she presented to her clinician, due to the amount of time that had passed from 

exposure, she was told that she should have already had prophylaxis and that it is too late to 

give it now. Probably the best would be to say that it is an urgent emergency and that timely 

application is highly recommended. 

Dr. Duchin (NACCHO) agreed with this recommendation, but had a lingering concern about the 

fact that health care providers may be troubled by the discrepancy in the package labeling with 

the FDA recommendation versus the ACIP guidance. He wondered if ACIP could provide 

standardized language that health jurisdictions across the country could use when responding 

to these concerns so that they would all be speaking with one voice. He also wondered whether 

there was any precedent of a discrepancy of this type.

Dr. Rupprecht indicated that in the preamble of the recommendation, there should be some 

discussion along those lines as to the evidence-based approach and whether it supports the 

utility of 4 versus 5 doses, what the basis of that evidence is, and that clearly it would be in 

conflict with what the product claim would be. There had already been a considerable amount 

of outreach to health departments in 2009 due to the on-going supply issues. Depending upon 

the recommendations of ACIP, new outreach efforts would likely begin immediately. 

In terms of other discrepancies between labeling and ACIP recommendations, Dr. Morse noted 

that in 2008 Hepatitis A vaccine could be used in lieu of immunoglobulin for basic post-exposure 

prophylaxis.

Dr. Rupprecht added that historically, from the standpoint of the rabies vaccine, the last time 

there was the discrepancy was when ACIP first recommended intradermal vaccination for preexposure purposes before the product was licensed. Discussion of times when there have been 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

36

discrepancies would be useful in the preamble for better health communications and clarity with 

practitioners. 

Dr. Baker noted that another example was the label on influenza vaccinations, which do not 

include pregnant women as a target population.

Ms. Stinchfield pointed out that another cost consideration is the amount of nursing time that 

goes into reminder recall and follow-up. A reduction of 20% in that effort would be substantial.

Clement Lewin (Novartis Vaccines) indicated that the supply constraints that existed in 2008 no 

longer represented a problem. Novartis has invested approximately $100 million in increasing 

the capacity of and upgrading the facility in Marburg. He also re-emphasized a point that he 

made at the last meeting, which was that the ACIP recommendation would essentially be an offlabel recommendation. Novartis does not recommend the use of its vaccines off label; 

therefore, if any provider or health care personnel contact the company, the answer would be 

that 5 doses are recommended in accordance with the label. This is likely to lead to 

considerable confusion. Many people have highlighted that ACIP recommendations have not 

always been aligned with the package insert. While that was true, in the 10 to 15 years he had 

been working in vaccines, he could not recall ACIP actually making a broad recommendation. 

This would be like saying they decided HPV vaccine should be 2 doses based on the evidence, 

but the FDA has not approved that indication. This very broad decision was highly likely to 

cause a significant amount of confusion amongst the medical community.

Dr. Ehresmann noted that during the last ACIP meeting there was also a comment that the 

manufacturer did not intend to request a change for the package insert. She wondered whether 

there was a way that someone other than the manufacturer could do so.

Dr. Baylor (FDA) A change must be requested by the US license holder, which would be the 

manufacturer. Although there are examples of safety issues in which the FDA could request 

that manufacturers submit safety data, the FDA did not perceive dropping a dose as a safety 

issue per se. 

Dr. Temte did not foresee a problem. If there is clear ACIP guidance, it will be translated to 

state partners, practitioners, and other experts. From a clinician’s point of view, he said he 

rarely consults a product insert on a vaccine.

Dr. Morse was struck by the fact that the Zagreb 4-dose regimen has been approved since 1992 

by WHO. He wondered whether there was a second package insert used by manufacturers in 

other countries or if that was simply not addressed. 

Dr. Hosbach (sanofi pasteur) responded that he was unfamiliar with package inserts outside the 

US. He pointed out that historically, manufacturers were permitted to include ACIP 

recommendations in the package insert. That was somewhat helpful when there was a conflict. 

However, that is no long permissible by FDA. As a manufacturer, they do receive many calls 

from physicians and providers about how to utilize vaccines, including rabies vaccine. They 

also will recommend what is on the package insert in these cases.

Chris Hahn (CSTE) commented that at the city health department, they receive numerous calls 

from providers as well. Their response would be that ACIP has recommended 4 doses, but that 

they should be aware that the FDA package insert still says 5 doses. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

37 

Dr. Morse wondered how the Red Book would handle this. 

Dr. Pickering responded that it would be updated in the on-line version immediately.

Dr. Bocchini (AAP) responded that the Committee on Infectious Diseases (COID) would review 

the recommendations and make a decision, which would be published in the AAP newsletter 

and included in the Red Book on-line immediately to make practitioners aware as soon as 

possible.

Dr. Baker requested elaboration on what city, local, and / or state health departments say about 

ACIP’s influenza and Hepatitis A recommendations with respect to pregnant women. 

Dr. Hahn (CSTE) responded that if they were aware of discrepancies, they try to give the 

provider all of the information. They do not receive a lot of calls from providers about influenza 

vaccination for pregnant women. She thought the ACIP recommendation was fairly well 

accepted in the provider community and was simply followed. 

Dr. Ehresmann said that Minnesota would follow the ACIP recommendations in general as a 

standard and would explain any discrepancies. 

Dr. Morse said that New York would tend to go with the ACIP recommendations. They would 

also raise the issue with the State Advisory Committee to seek their support.

Motion: Reducing Rabies Post-Exposure Prophylaxis from 5 to 4 Doses

Dr. Baker made a motion to approve the recommendation of the work group regarding a 

reduced schedule from 5 to 4 doses for rabies post-exposure prophylaxis. Dr. Meissner 

seconded the motion. The motion carried with 14 affirmative votes, 1 abstention, and 0 

negative votes. 

Overview

Dr. Lance Chilton

Poliovirus Vaccine Work Group Chair

Dr. Chilton stressed that polio still exists. Poliovirus has spread from Nigeria, India, 

Afghanistan, and Pakistan where it is still endemic. Therefore, it continues to be a threat to the 

US and the reminder of the world at this point despite the desire to have solved the problem by 

the year 2000. By 2010, the problem still will not be solved. There is still a threat of long 

distance importation to poliovirus into the US and for that reason, the decisions on poliovirus 

vaccine dosing and intervals remains important. The problem that needed to be solved by the 

work group and ACIP regarded when a third dose of inactivated polio vaccine should be given, 

and when or whether a fourth dose is needed. The work group plan was limited. They engaged 

in conference calls between February and April. At the end of those calls, there was remarkable 

unanimity of opinion. 

Poliovirus Vaccine
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

38

Polio Eradication Program: India 2009 Observations

Robert L. Beck, JD

ACIP Member

Mr. Beck said he was privileged to be part of a group of 45 volunteer Rotarians from around the 

world who travelled to India in February 2009 to vaccinate children against polio. They worked 

in the streets and slums in several cities in northern India where they vaccinated more than 

1,000 children. He spent about a month in India working with the polio program and then 

travelling on my his own through northern and central India, based upon which he made several 

observations. The polio program is successful. One of the three endemic strains of polio in 

India has been successfully eradicated, and the two remaining strains show great promise that 

they will be eradicated as well. That is a major step forward.

This program is not a once a year event, but is offered several times a year due to limits within 

the current oral vaccine and because of migrating populations. It is a very people-intensive 

project, with thousands of government and volunteers involved to vaccinate millions of children.

The program has been in operation for decades and with the successes, personnel are showing 

signs of wearing out. Mr. Beck believes that Indian state and local personnel need visible, 

public encouragement and recognition to keep up program momentum. Continued funding 

remains important, but personnel support is also needed. Thus, one of the comments he 

brought back to India and the US was that he thought something needed to be done to buoy up 

the people working at the state and local levels to help them stay the course of their important 

involvement in the program. 

The program is also unique from another standpoint. The Gates family and foundation have 

contributed hundreds of millions of dollars for support of the program. The Rotary Foundation 

has also donated hundreds of millions of dollars and is one of the best known US charities. 

CDC is the primary face of the US government in this project and is also doing a good job.

The combination of these three organizations makes this project a uniquely positive American /

USA story, and that story should be told.

The program is really also a world class international relations opportunity. To Mr. Beck it is 

akin to the Marshall Plan following WW II. Its success has the potential for a strategic, macro, 

impact in this region of the world. It is a non-military program. Implementation is through local 

people, for benefit of local people. Billions of people in the relevant geographic area will see the 

benefits from such a program, including 1.5 billion Indians, 3.0 Chinese just over the rather 

porous border, and billions more residing in Russia and India’s Muslim neighboring countries. 

This program is an immense international opportunity in addition to its wonderful public health 

benefits.

Mr. Beck extended his personal gratitude to Dr. Jean Smith who is a tremendously dedicated 

person. Dr. Smith lived and worked in India for many years. Her work included the polio 

program. She arranged special briefings for him before his India trip to make it more

meaningful.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

39

In summation, Mr. Beck concluded that the Polio Eradication Program is a major public health 

success in India. It has the potential for becoming a major international relations success in the 

region, and this program is worth continued support.

Updated Recommendations for Routine Poliovirus Immunization

Gregory S. Wallace, MD, MS, MPH, Medical Officer

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Wallace presented a follow-up to the Poliovirus Work Group’s February 2009 presentation 

regarding the deliberations of the work group on the recommendations for the routine 

inactivated polio vaccine (IPV) schedule, including a schedule when combination vaccines are 

used, minimum intervals for IPV, and when accelerated schedules should / should not be used.

The work group proposed no changes to the current routine schedule for poliovirus vaccines. If 

4 doses of IPV-containing vaccine are administered prior to age 4 years, an additional dose 

should be administered at age 4 to 6 years. For instance, with Pentacel, if the first 4 doses for 

DTaP, Hib, and IPV are given as per the schedule, an additional dose is proposed at 4 to 6 

years of age. This is equivalent to Canada’s routine IPV schedule. The reason for this proposal 

from the work group has to do with the continued threat of importation, given that polio has not 

yet been eradicated, and because incomplete data are available on the duration of immunity 

into adulthood with last dose at age 15 to 18 months. A footnote is proposed to the 

recommended schedule to emphasize the 4- to 6-year old dose, which reads, “The final dose in 

the series should be administered on or after the 4th birthday.” 

With regard to minimum intervals for IPV, age and dose intervals do affect the seroconversion

response. Seroconversion rates are generally better when administered at 2, 4, and 6 months 

of age with the primary schedule, as opposed to the 2, 3, 4 month, or 6, 10, 14 week schedule. 

In addition, maternal antibody levels at the first dose are inversely related to seroconversion

levels, particularly in the first 6 months of life. Longer intervals are optimal for booster response, 

and there should be at least 6 month intervals prior to the booster dose as this is optimal for 

memory cell maturation.

For the proposed catch-up schedule, the only change is the interval between the third and fourth 

dose being extended to 6 months. It was 4 weeks previously. There is also proposed footnote 

language about early doses that reads, “In the first 6 months of life, minimum age and minimum 

intervals are only indicated if the person is at risk for imminent exposure to circulating poliovirus 

(e.g., traveling to a polio endemic region or during an outbreak). A fourth dose is not necessary 

if the third dose was administered at age 4 years or older and at least 6 months have elapsed 

since the second dose.” That is equivalent to the routine recommendation for adults who have 

not been previously vaccinated.

With respect to next steps, pending an ACIP vote and deliberations and Notice to Readers, the 

draft is ready to be sent through clearance to clarify and summarize the recommendations. This 

will be available for reference and text for 2010 immunization schedule and the updated general 

recommendations publication. The nearly 10-year old ACIP recommendations and reports will 

be updated in the near future, but no fundamental changes are proposed. This will potentially 

be ready for a vote in October 2009.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

40

Discussion

Dr. Sawyer expressed concern about the minimum interval language. He asked whether the 

intent was for the same language to be a footnote on the regular schedule in addition to the 

catch up schedule (e.g., in the first 6 months of life, the minimum age and minimum intervals are 

only indicated if the person is at risk for imminent exposure). That will not apply to anyone 

unless they travel outside of the US. He wondered if, for example, a patient presented to their 

provider only 5 weeks after the previous dose the recommendation was that they not receive the 

next dose. This did not seem like a very practical recommendation, and he suggested softening 

of that statement so that it is not interpreted that the provider should not give this vaccine under 

any circumstances. A soft minimum interval that applies in some circumstances but not in 

another is really not tenable. It comes into play with some software programs because an 

immunization registry will program forecasting based on minimum intervals, but there are 

examples where Comprehensive Clinic Assessment Software Application (CoCASA), a CDC 

program used to assess immunization coverage, does not respect the same minimum intervals 

with regard to missing immunizations or invalid doses. That has created confusion in San Diego 

because clinics are following the immunization registry forecast, and then are being evaluated 

by the county health department with CoCASA such that they receive two different answers 

about whether a dose was or was not appropriate.

Dr. Wallace responded that for the general routine schedule, the footnotes do not usually 

include minimum intervals, and he thought everyone was aware of the space issues for the 

schedule itself. Certainly, the text can be included in the MMWR that announces a schedule 

that addresses accelerated schedules and minimum intervals. The concern has been minimum 

intervals being used inappropriately as routine accelerated schedules, which was why the work 

group felt the need for that and to provide the information on the first 6 months of life; however, 

the minimum intervals are as they are, so if a 4-week interval is used between dose 1 and 2 and 

2 and 3, it would be considered a valid dose by CDC.

With regard to the 4-year old age group dose in light of the Hib shortage, it seemed to Dr. 

Schuchat that there would be many children over the next year or so who would be receiving 

their booster dose of Hib-containing vaccine late at perhaps age 3. She wondered if the 

committee considered whether someone received their 4th dose of IPV-containing vaccine at 

age 3, they would require another polio dose at 4 to 5 years of age. 

Dr. Wallace responded that this issue did arise. While the work group recognized that this is an 

issue, they did not feel that there was sufficient information to inform that adequately. They had 

developed footnotes and information with many more caveats, but the work group ultimately 

decided that this would add to the confusion rather than clear it up.

To provide some level of comfort, David Greenberg (sanofi pasteur) reported that in the clinical 

trials, the Pentacel doses were given on schedule at 2, 4, and 6 months of age with the 4th dose 

at 15 to 18 months of age. There was good persistence of antibody with 95% of children 

maintaining seroprotective levels at 4 to 5 years of age. Not that this would change the 

language, but just to offer some additional reassurance that there are antibody levels that 

persist for years.

Dr. Wallace responded that this information was considered by the work group, but the 

deliberation of the work group pertained more to what is unknown into adulthood. In the pre-
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

41 

eradication era, they wanted to err on the side of making sure that coverage and protection was 

as complete as possible. This may become less of an issue as more data become available 

about protection in adults.

Dr. Sawyer remained somewhat uncomfortable with the modification of a catch-up schedule. 

The intent of a catch up schedule is to catch children up. It seemed as though they were 

recommending that children could be caught up for everything else except polio. Translating 

that into practice is very challenging for a provider. Providers will give children their DTaP but 

not give their polio and will hope to get them back in for that. Given the potential for confusion, 

he suggested changing the language from “only indicated” to “only recommended” or “usually 

recommended.” The implication of the word “indicated” is that it is contra-indicated in other 

circumstances.

Dr. Wallace agreed that the language could be changed from “indicated” to “recommended” or 

“routinely recommended”. To be clear, he stressed that the point of the footnote was not to tell 

people not to catch children up. It was to offer information so that people did not accelerate a 

routine schedule only in the first 6 months of life. This would involve potentially one or two 

doses at the most. However, it is important not to have a routine 6-, 10-, 14-week schedule.

Motion: Poliovirus Vaccine

Dr. Temte made a motion to approve the recommendation of the work group regarding 

poliovirus vaccine with the slight modification suggested by Dr. Sawyer. Dr. Ehresmann 

seconded the motion. The motion carried with 13 affirmative votes, 1 abstention, and 1 

negative votes. 

Dr. Sawyer clarified that he voted “no” because he remained concerned about the concept of a 

minimum interval, which they did not really mean in certain circumstances. To him, if they were 

not comfortable with the minimum of 4 weeks, it needed to be changed to whatever they were 

comfortable with. Practitioners will have to deal with this question a lot in deciding what truly 

constitutes a valid dose.

Dr. Seward thought there was additional wording in the MMWR. There are scientific data 

showing that there is quite inferior immune response if three doses are given of IPV on the 

accelerated schedule, so the routine recommendation is 2, 4, and 6 months. What they were 

thinking about with combination vaccines is the tendency for the catch-up vaccination schedule 

to become routine. Therefore, they wanted fairly strong wording to indicate that it should not be 

used on a routine basis. Acceleration should only be used under very rare situations. Catch-up 

is a separate issue. If a child is one year old and they have not had any vaccine, the risk of no 

protection is being weighed in terms of achieving some immune response as quickly as 

possible.

Given the global epidemiology of polio as it has been known for some years, Dr. Judson 

wondered why the US still started so young. Many of these questions would not arise if not 

starting at such a young age. That obviously excludes people who would be travelling or in very 

special situations.

Dr. Morse thought it was linked to other immunizations, which is a longer discussion. 

Regarding the issue of catch-up versus regular schedule, Dr. Sawyer pointed out that the 

current language was in conflict with the general principles of immunization, which says to give 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

42 

every vaccine that can be given at a visit as long as they are within the recommended age 

limits. Contradiction in this language compared to other language raises the potential for 

problems.

VFC Resolution Update: Polio-Containing Vaccines

Dr. Jeanne M. Santoli

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Dr. Santoli reviewed proposed changes to the VFC resolution that would address the minimum 

interval issue that was just discussed, as well as continuing to streamline the resolutions 

through references to published links.

Going through the components of the VFC resolution, the eligible group is defined as infants 

and children at least six weeks of age for the recommended schedule for 2, 4, and 6 to 18 

months, and 4 to 6 years. The resolution refers to the current polio statement found at:

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4905a1.htm

For the dosage intervals, specific information is included based on the day’s discussion. The 

minimum interval from doses 3 to 4 is extended from 4 weeks to 6 months. The minimum 

interval from dose 1 to 2 and dose 2 to 3 remains at 4 weeks, and the minimum age for dose 1 

remains 6 weeks of age. In addition, because each product has particular characteristics, the 

following links to the ACIP recommendations and notices that are related to each product are 

included: 

 http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4905a1.htm

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5210a8.htm

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5739a5.htm

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5739a4.htm

For the recommended dosage and the contraindications, the resolution refers to the FDA 

webpage through which package inserts can be found:

http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833

When a new recommendation and / or notice related to the changes that were voted upon is 

published, the language and links in this document that can be replaced by that new link. This 

is similar to the pneumococcal resolution discussed in February 2008. 

Motion: VFC Resolution Update for Polio-Containing Vaccines

Dr. Chilton made a motion to approve the VFC resolution as stated. Dr. Baker seconded the 

motion. The motion carried with 14 affirmative votes, 1 abstention, and 0 negative votes. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

43 

Discussion

Dr. Katz said that given the remarks by Dr. Chilton, Mr. Beck, and Dr. Judson, he thought there

was an element of reality which had not quite been portrayed. The polio eradication effort was 

supposed to have ended in 2000, making the effort 9 years behind. Each year, the reported 

numbers of cases are almost the same. For 2008 it was 1,562 cases. He stressed that those 

were paralytic cases. For every paralytic case, there can be anywhere from 100 to 1,000 

individuals excreting virus silently and causing transmission. Nigeria has had the same 

numbers of polio cases almost every year for the last 7 years because of failure to deliver 

vaccine. In contrast, children in India (Uttar Pradesh and Bihar) receive 7 to 10 doses of oral 

vaccine and they still have not eliminated polio. Thus, there may be a problem with the overall 

approach. As Mr. Beck pointed out, there is volunteer and donor fatigue. He reminded 

everyone that both CDC and WHO have committees on polio research and it is quite apparent 

that the programs followed since 1988 are simply not bringing polio to an end. There must be 

changes in the initiative, imagination, and funding of CDC and WHO to determine better ways to 

eradicate polio. Otherwise, they would have to accept it as a disease that will never be 

eliminated. 

Overview

Ms. Kristen Ehresmann

ACIP Member 

Ms. Ehresmann pointed out that the ACIP measles, mumps, rubella (MMR) vaccine policy 

statement had not changed since 1998, with the exception of some changes related to the 

mumps outbreak in 2006. During the 10 years since the last policy statement was published, 

there was a shift into an era of post-elimination for measles and rubella. It is important to 

remember this in making decisions and discussing this topic. Decisions should be made that 

include aggressive follow-up to maintain this post-elimination status. There was vigorous 

discussion among the MMR Vaccine Work Group members. Within the work group, she was 

the lone vote with a public health perspective. Therefore, the proposed changes that the CDC 

staff provided the group did not go over very well and she I was solemnly voted down. The 

concern of her colleagues was feasibility and cost-benefit for institutions if a fairly strong 

approach was taken to recommending two doses of vaccination all of the time for persons born 

before 1957. Thus, they worked with CDC staff to develop excellent compromise language that 

addressed the concerns of the clinical and public health sectors. The new language was 

unanimously accepted. It was also presented to the Healthcare Infection Control Practices 

Advisory Committee (HICPAC) and was approved during their recent meeting. 

Measles, Mumps, Rubella Vaccine
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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Proposed Changes of MMR Vaccine Evidence of 

Immunity Requirements for Healthcare Personnel

Dr. Kathleen Gallagher

Division of Viral Diseases, NCIRD

Dr. Gallagher presented an update on the proposed changes to the MMR vaccine evidence of 

immunity requirements for healthcare personnel. With regard to background, today’s healthcare 

workers are at increased exposure to a variety of infectious diseases, including vaccine 

preventable diseases. There are specific recommendations to address vaccination or the 

corresponding proof of immunity requirements for healthcare workers. The two documents that 

address those issues were published in the MMWR in 1997 (Immunization of Healthcare 

Workers) and 1998 (Measles, Mumps, and Rubella—Vaccine Use and Strategies for Elimination 

of Measles, Mumps, Rubella, and Congenital Rubella Syndrome and Control of Mumps). 

During the national mumps outbreak in 2006, vaccine policy recommendations for children and 

high risk groups, including health care workers, were revised including the addition of 1 to 2 

doses of the mumps or MMR vaccine.

Although these diseases are rare, measles and mumps in health care facilities continue to 

occur. Virtually all measles cases will visit at least one health care facility during their infectious 

period. Quite frequently, because measles is not the initial diagnosis suspected, they have 

multiple health care exposures. A study conducted in Washington State in the late 1990s 

showed that health care workers had a much greater increased risk of acquiring measles when 

compared with adults of their own age with the relative risk of 19 (95% CI 7.4, 45.4, p< 0.01)

[Steingart KR, Tomas AR Dykewicz CA, Redd SC. Transmission of measles virus in healthcare 

settings during a communitywide outbreak. Infect Control Hosp Epidemiol. 1999; 20: 115-19]. It 

is known from measles epidemiology that in the late 1980s and early 1990s, many health care 

workers were reported with measles (n=643), 27% of whom were born before 1957 [CDC. 

MMWR. 1998; 47{RR-8}:1-57]. During the 2006 mumps outbreak in the US, there were 

numerous health care related exposures.

It is also known that nosocomial transmission of measles and mumps occurs in health care 

facilities and has been documented. In the post-elimination era for measles, from 2001-2008 

there were 27 reported measles cases that were transmitted in health care facilities, which is 

about 5% of all US measles cases. In 2008, this was 11% of cases. There is considerable 

economic expense and a large public health effort involved with trying to contain these 

exposures and outbreaks. In 2008, Arizona had the largest US nosocomial outbreak of measles 

in over 20 years (n=14). There were many health care related exposures, not just in the original 

hospital. In three hospitals in this Arizona community, almost 8000 health care workers were 

exposed, of whom 25% had no documentation of immunity to measles in their occupational 

health records. These workers were serologically screened and 5% of the employees born 

before 1957 and 11% of those born after were susceptible to measles based on serologic 

testing. Nosocomial transmission of mumps can occur as well. The last well-documented 

occurrence of this was in Tennessee in 1986 and 1987 when there was nosocomial 

transmission of mumps in two hospital emergency departments that infected six health care 

workers and in two long-term care facilities where nine patients were infected.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

45

The current ACIP recommendations state that health care personnel without other evidence of 

immunity should routinely receive two doses of MMR vaccine for measles and mumps and one

dose of MMR vaccine for rubella. These recommendations also stress the importance of 

vaccination to protect healthcare personnel and their responsibility to avoid transmitting these 

diseases and thereby causing harm to patients. These recommendations also include a 

permissive recommendation for one or two doses of MMR vaccine for unvaccinated health care 

workers born before 1957.

The current ACIP MMR vaccine presumptive evidence of immunity requirements for health care 

workers indicate that health care workers are considered to be presumptively immune if they 

have met one of four conditions: documentation of administration of appropriate vaccination 

against measles, mumps, and rubella; laboratory evidence of immunity; documentation of 

physician diagnosed disease for measles and mumps (this is not allowed for rubella); or birth

before 1957. The latter three evidence of immunity criteria are what health care personnel are 

required to provide as far as documentation to be exempt from being vaccinated. There are 

also numerous footnotes in this language:

*May vary depending on current state or local requirements.

+ Health-care facilities should consider recommending a dose of MMR vaccine for 

unvaccinated workers born before 1957 who are at risk for occupational exposure to 

measles and who do not have a history of measles disease or laboratory evidence of 

measles immunity.

The footnotes allow variability with regard to state and local requirements and again provide 

some permissive vaccination consideration for health care personnel born before 1957.

The language for measles and mumps outbreaks states, “During outbreaks, health-care 

facilities also should strongly consider recommending a dose of MMR vaccine to unvaccinated 

health-care workers born before 1957 who do not have serologic evidence of measles or rubella 

immunity or a history of measles disease.” [CDC. MMWR 1998;47{RR-8}:1-57]. The language 

for a mumps outbreak states, “During an outbreak, health-care facilities should strongly consider

recommending 2 doses of a live mumps virus vaccine to unvaccinated workers born before 

1957 who do not have evidence of mumps immunity.” [CDC. MMWR Notice to Readers. 

2006;55(22):629-630].

The changes proposed during the February 2009 ACIP and HICPAC meetings included the 

addition of laboratory confirmation of disease, elimination of documentation of physician 

diagnosed disease for measles and mumps, and elimination of birth year before 1957 to state, 

“Currently, healthcare personnel are considered immune if they have one or more of the 

following: 1) Appropriate vaccination against measles, mumps, and rubella (i.e., administration 

on or after the first birthday of two doses of live measles and mumps vaccine separated by 

greater than or equal to 28 days and at least one dose of live rubella vaccine); 2) Laboratory 

evidence of immunity or laboratory-confirmation of disease.”

During those two meetings feedback was received from both groups that suggested mixed 

support for the removal of birth year before 1957 as proof of immunity. Members of HICPAC 

and ACIP felt that requiring unvaccinated health care workers born before 1957 to be either 

serologically screened or vaccinated was not cost-effective, especially given the current low 

burden of disease. Thus, the issue was further discussed with the ACIP Adult Vaccine Work 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

46

Group along with some external invitees, including some members of HICPAC. Based upon 

these deliberations, proposed language was developed. The proposed language was 

presented during the June 2009 HICPAC meeting and was voted on and approved by that body.

The first proposed change is the addition of laboratory confirmation of disease as adequate 

proof of immunity for measles, mumps, and rubella. The rationale for this is that this change is 

being made for completeness and consistency. Although they are rare, cases of measles, 

mumps, and rubella still occur. Naturally acquired immunity is robust and long-lasting; 

therefore, it is reasonable to conclude that if a health care worker can provide laboratory 

evidence of disease, they should be considered immune. For surveillance purposes, this type 

of data is routinely relied upon to define whether or not a person is a case of measles, mumps, 

and rubella. This proposed change will also be consistent with the varicella recommendations 

which already include laboratory confirmation of disease [CDC. Prevention of Varicella. 

Recommendations of ACIP. MMWR. 2007;56{RR-4}:1-37]. 

The second proposed change is to delete the documentation of physician diagnosed disease as

adequate evidence of immunity for measles, mumps, and rubella. The impetus behind this 

change comes from many state and local public health colleagues who anecdotally report 

situations in which this criterion is not being adhered to as intended. For example, there have 

been anecdotal reports of scenarios in which physicians on staff at a facility where they are 

exposed report that they remember having measles as a child, which serves as their 

documentation of physician-diagnosed measles. In practice, it has become increasingly difficult 

for any health care worker who may have had clinical measles or mumps to be able to contact 

their childhood provider as they are either no longer in practice or are deceased. In addition, 

the accuracy of a clinical diagnosis of disease without laboratory confirmation has declined 

substantially, especially with vaccine modified disease (mumps). 

Numerous studies have documented the decline in the predictive value positive of clinical 

diagnosis (in the absence of lab confirmation) with declines in disease incidence. In the case of 

mumps, it is known that there are numerous etiologies for non-epidemic parotitis. A study 

conducted in the early 1970s demonstrated that only 40% of vaccinated patients with parotitis 

could be lab confirmed as having mumps [Brunell, 1972]. Another study conducted over 30 

years later showed that only 2% of 800 clinical mumps cases were lab confirmed and alternative 

etiologies could be found for 14% of these cases [Davidkins, 2005]. Studies conducted to assist 

with the documentation of measles elimination in the US showed the PVP declining from 74% to 

1% [Hutchins, 2004]. Additionally, 87% of cases of rash illness that met the measles clinical 

case definition during 1997 / 1998 were ruled out with appropriate lab test [Harpaz, 2004]. 

Changes are also proposed to the footnotes to the tables, which refer to both routine 

circumstances and outbreak situations. For routine circumstances, the wording recommended 

is, “For unvaccinated personnel born before 1957 who lack laboratory evidence of measles, 

mumps and/or rubella immunity or laboratory confirmation of disease, healthcare facilities 

should strongly consider recommending two doses of MMR vaccine (for measles and mumps) 

and one dose of MMR vaccine (for rubella), respectively.” The change here from the current 

wording would basically be to change the wording from “consider” to “strongly consider” and 

from one to two doses of MMR for measles and mumps. The recommendations for rubella 

would remain unchanged. For outbreaks, the wording would read, “For unvaccinated personnel 

born before 1957, who lack laboratory evidence of measles, mumps and/or rubella immunity or 

laboratory confirmation of disease, health care facilities should recommend two doses of MMR 

vaccine during an outbreak of measles or mumps and one dose during an outbreak of rubella.” 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

47

The change here is a wording change that from “should strongly consider recommending” to just 

“recommending” and from one doses of MMR to two doses of MMR.

The rationale for changing the language in these footnotes is that it allows health care workers 

born before 1957 to still be considered immune, but also allows facilities that have been 

screening and / or vaccinating these individuals to have ACIP and HICPAC support to continue 

this practice. Health care facilities can weigh for themselves the risk of an exposure to measles, 

mumps, or rubella in their facility and the cost associated to them if such an exposure were to 

occur. It also allows for aggressive vaccination of health care providers, including those born 

before 1957, when an outbreak occurs.

It is known from anecdotal reports and from surveys conducted in convenience samples that 

some health care facilities are already screening and / or vaccinating health care workers for 

measles, mumps, and rubella regardless of age. Of 38 respondents to a survey sent out on an 

occupational health listserv for health care facilities earlier this year, 26% reported that they 

conducted serologic screening and / or vaccination of all their employees, regardless of age. An 

additional 21% reported that they screened and vaccinated all new employees, regardless of 

age. The footnote wording proposed for routine circumstances will provide the support of ACIP 

and HICPAC for these facilities to continue these practices.

The anticipated burden to health care facilities in implementing these policies is likely to be low. 

A few health care workers will likely have lab confirmation of disease and there should be little

or no cost associated with this change. It would basically be the health care worker having to 

acquire documentation from their medical provider. The proportion of health care workers with 

a history of disease as their only documentation of evidence of immunity is likely small, and 

many of these employees are likely to have been born before 1957. These policies could be 

implemented with other annual routine disease prevention measures, such as influenza 

vaccination and tuberculosis (TB) testing. Implementation could be started soon and phased in 

within a few years.

In conclusion, current policy was established more than a decade ago and needs to be updated. 

In the era of both measles and rubella elimination, the goal is 100% immunity in high risk 

populations. The tolerance for any cases or exposures has decreased. Health care personnel 

are at high risk for exposure, so it is important to protect them preemptively. Given the current 

epidemiology of measles worldwide, it is likely that there will be continued importations in the 

US, and measles exposures and outbreaks are likely to continue in health care facilities. Future 

mumps exposures in health care facilities are also likely. Some facilities already have policies 

in place that are consistent with the proposed changes. 

Discussion

Dr. Baker requested further information about the intent of “strongly recommended” from 

“recommended” for routine.

Dr. Gallagher responded that the original proposal was to remove the 1957 requirement entirely. 

This was a compromise to provide stronger language in support of facilities that were already 

doing this even though it was not the current recommendation.

It was not clear to Dr. Baker why, if some facilities were already doing this, they needed ACIP’s 

support. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

48

Ms. Ehresmann replied that the rationale was that ideally they would like a statement reading, “It 

is recommended, even in a routine setting.” However, the work group recognized from the 

feedback received from clinicians and the membership that this would not be practical or 

financially feasible for many institutions. 

Dr. Chilton sympathized with the Tucson hospitals where this occurred, given that this was the 

largest outbreak in the last 20 years. However, the fact that it involved 8000 health care 

workers, some of whom were born before 1957, was not persuasive to him that the entire 

country should be immunizing everybody his age or thereabout. The costs associated with that 

seemed to be much greater than the benefit associated with adopting a changed policy for that 

throughout the country.

Dr. Gallagher agreed, indicating that this comment was also made during the February 2009 

ACIP and HICPAC meetings. The proposed revision would actually allow birth before 1957 to 

remain as proof of immunity. The caveat was that if facilities were so inclined, the 

recommendation would support that. The work group heard people’s concern about the cost 

and benefit of vaccinating everybody before 1957, especially considering that few health care 

workers have been affected by this. It is also known anecdotally and from the surveys that 

some facilities are already doing this preemptively because they have made a choice for riskbenefit or other reason in their facilities to vaccinate everybody born before 1957. The work 

group felt that the proposed language would help support that.

Dr. Judson agreed with Dr. Baker that there should probably be only one level of 

recommendations: recommended or not recommended. He also noted that he was involved in 

some of the discussions through the Adult Vaccine Work Group on hospital workers, and was 

head of a hospital infection control committee for about 20 years at Denver General Hospital. 

There have only been a handful of cases in the US. No cases have been endogenously 

transmitted for a very long time. All of the outbreaks have stemmed from importations. When 

he reviewed the state health department records in Colorado, he found that there have been no 

cases of measles in health care workers and only one or two exposures. Thus, the 

recommendation is speaking to a problem that does not exist in most places. In another 10 

years, this will be completely irrelevant because nobody working then will likely have been born 

before 1957.

Dr. Seward said she perceived these as minor changes to the existing recommendations. She 

pointed out that it is currently standard of care to vaccinate during an outbreak. Over the last 10 

years, she had never come across a health department that did not screen and vaccinate every 

healthcare worker born before 1957 during outbreaks. That is the current standard of care.

Dr. Judson agreed and thought that this was why there was no problem. He did not plan to vote 

against this. He found these to be very minor issues and that measles control in the US has 

been highly successful. 

With regard to Dr. Judson’s comment about one level of language, Dr. Temte reported that two 

days earlier the Evidence-Based Work Group strongly advised against doing anything other 

than “recommend” or “do not recommend.” He thought it was also confusing to see “should 

consider” and “recommend” in quick success. This seemed to be saying, “We should do this, 

but we are going to back away from this because we are only considering it.” He cautioned that 

using three partial words together really watered down the recommendation.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

49

Dr. Sawyer said that the term “health care facility” suggested to him larger entities that have 

policy making bodies, which most single private offices probably do not have. It was not clear to 

him whether this recommendation extended to all places where health care is delivered.

Dr. Gallagher responded that when she used the term “health care facilities” in her presentation, 

frequently it was because the groups surveyed represented larger health care facilities. 

However, the recommendations would apply to all health care workers.

Dr. Sumaya said he had no preference for saying “strongly considered” versus “considered” or 

“strongly recommended.” He wondered what the difference was in true contraindications. 

Dr. Marcy wondered why documentation of physician diagnosed rubella was not one of the 

criteria.

Dr. Gallagher replied that rubella cannot be well-diagnosed clinically.

Dr. Marcy pointed out that the same was true for measles and mumps, so “physician diagnosed” 

should be eliminated for them as well. The last three cases he saw of mumps were of 

neumoparatitis and lymphadenitis. “Physician diagnosed” is simply meaningless. This is still 

included for international travelers and students at post-high school. He supported use of 

“should consider” versus “may wish to consider.”

Dr. Gallagher responded that the recommendations they were discussing focused only on 

health care workers. When the full 1998 recommendations are updated, consideration could be 

given to eliminating “physician diagnosed for international travelers and post-high school 

students.

Dr. Morse pointed out that some agreed upon, standardized criteria should be developed to 

avoid problems within individual discussions and negotiations.

Dr. Meissner inquired as to whether they should say “laboratory evidence of immunity” or if they 

should be more specific. With the 2006 mumps outbreak, they learned that cellular immunity 

did not correspond to protection against disease.

Dr. Gallagher requested clarification about whether Dr. Meissner was suggesting that something 

specific be included about types of laboratory confirmation that are acceptable.

Dr. Meissner responded that people do not look at cellular immunity as a measure. It is a 

complicated assay, and cellular immunity is not necessarily a marker of immunity. The question 

regarded whether to be specific about what constitutes immunity. He was thinking specifically in 

terms of those born before 1957.

Dr. Seward suggested defaulting to the guidance in the surveillance manual for the case 

definitions and what constitutes confirmation of disease, which is immunoglobulin M (IgM), 

polymerase chain reaction (PCR) culture, and rise in immunoglobulin G (IgG).

Ms. Ehresmann summarized that it appeared that there was agreement for some of the 

proposed changes. Eliminating physician diagnosis of measles, adding laboratory confirmation, 

and outbreak seemed to have consensus. They appeared to be stuck on routine circumstances 

and the language issue (strongly consider, et cetera). She wondered whether it would be 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

50

possible to make a recommendation to vote on less than everything or address the issues upon 

which they seemed to be stuck.

Dr. Gallagher put up the proposed wording, upon which ACIP members were to vote:

Proposed Wording: Table 1

Acceptable presumptive evidence of immunity to measles, rubella and mumps for persons who 

work in health care facilities* (Table 1)

1) Documented administration of ...( 2 doses of live measles virus vaccine, one dose of live 

rubella vaccine, two doses of live mumps)┼, or

2) Laboratory evidence of immunity or laboratory-confirmation of disease, or

3) Born before 1957 & £ @

For rubella, the following statement is included “(except women of childbearing age who could 

become pregnant ++)” 

Proposed Language: Footnotes

(For persons born before 1957)

Footnote for ROUTINE circumstances:

£ “For unvaccinated personnel born before 1957 who lack laboratory evidence of 

measles, mumps and/or rubella immunity or laboratory confirmation of disease, 

healthcare facilities should strongly consider recommending two doses of MMR vaccine 

(for measles and mumps) and one dose of MMR vaccine (for rubella), respectively.” 

Footnote for OUTBREAKS: 

@ “For unvaccinated personnel born before 1957 who lack laboratory evidence of 

measles, mumps and/or rubella immunity or laboratory confirmation of disease, 

healthcare facilities should recommend two doses of MMR vaccine during an outbreak of 

measles or mumps and one dose during an outbreak of rubella.”

Discussion

Dr. Seward reminded everyone that the wording in existence from the 1998 iteration is “should 

consider” for the routine recommendation, and a lot of people are already doing this.

Dr. Neuzil wondered whether they wanted facilities to “consider recommending” or “to 

vaccinate.”

Dr. Seward replied that this was pretty standard language that implies vaccinating.

Dr. Neuzil thought this should be very clear, “Should strongly consider administering or 

vaccinating with 2 doses.”

Dr. Judson noted that the positive predictive value of a clinical diagnosis of mumps and rubella 

was never very good, except in an epidemic or a very common situation, so it was probably 

worthless. Most physicians could diagnose measles very well when the disease was occurring 

frequently; however, now they cannot. Positive predictive value becomes virtually meaningless 

for measles which barely exists except for the occasional importation. Citing studies from the 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

51 

1990s or 2000s really has no meaning to current deliberations. He thought “clinical diagnosis” 

should be removed in all cases as evidence of immunity.

Ms. Ehresmann pointed out that they appeared to have reached consensus on everything but 

the routine circumstance. The 1998 language says “should consider recommending,” for which 

a suggestion was made to more clearly specify vaccinating versus recommending. With that in 

mind, she wondered if they could move forward with a vote. She was unclear on the use of the 

term “strongly” because there was a lot of discussion that it was not appropriate to use

modifiers. 

Dr. Pickering thought that the evidence-based medicine guidelines were not quite finished, but 

there is a move toward evidence bases for everything. Most evidence-based guidelines do not 

include adverbs as descriptors. 

Dr. Katz wondered whether “two doses of MMR vaccine,” could be stated as “two properly 

spaced doses.”

Dr. Gallagher replied that this wording is in the table, but they could add it to the footnote or 

refer back to the table to define what “appropriately administered” means. 

Motion 1: MMR Vaccine Evidence of Immunity for Healthcare Personnel

Ms. Ehresmann made a motion to approve the recommendation of the work group for evidence

of immunity for healthcare personnel with the suggested changes. Dr. Baker seconded the 

motion. No vote was take, given that the discussion continued.

Following up from the HICPAC perspective, Dr. Elward pointed out that in the discussion during 

the February 2009 ACIP meeting, concern was expressed about making across the board 

recommendations of vaccination in routine circumstances due to the cost implications and the 

unfunded mandate it might impose on health care facilities in the absence of evidence that there 

are problems with measles control outside of outbreak situations. She indicated that HICPAC 

approved the language shown with these footnotes.

Dr. Morse noted that consideration should be given to whether ACIP was comfortable with 

having a different recommendation from HICPAC. 

Dr. Seward said it would be preferable for the ACIP recommendation to be the same as 

HICPAC.

Dr. Schuchat reminded everyone that HICPAC and ACIP are advisory committees to CDC. 

CDC will utilize the committees’ recommendations to develop and issue final recommendations. 

Therefore, it is unlikely that there would be two different recommendations. CDC is trying to 

harmonize with itself.

Dr. Cieslak proposed that they remove the footnote for routine circumstances from the motion.

Dr. Gallagher wondered whether, based on the wording changes suggested for the first 

footnote, a change needed to be made to the wording on the second footnote to make the 

language consistent (e.g., change the word “recommend” to “vaccinate”).
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

52 

Dr. Neuzil stressed that they were not making the recommendation for facilities to consider 

recommending. She believed they were making a recommendation to vaccinate, which was her 

interpretation of what she was voting on.

Dr. Chilton pointed out that based on the data presented, it appeared that only 5% of those born 

before 1957 would be susceptible. Therefore, the cost to prevent cases to those born before 

1957 who are exposed to measles, mumps, or rubella is about $2,800 per person. That 

seemed unacceptable.

Dr. Judson added that an arbitrary cut off had been established for immunity for which there is 

no real basis. He thought 5% may be a very high figure. That is, probably well less than 5% 

would actually be susceptible.

Motion 2: MMR Vaccine Evidence of Immunity for Healthcare Personnel

In light of the comments made by Drs. Schuchat and Seward, Ms. Ehresmann revised her 

motion to approve the recommendation of the work group for evidence of immunity for 

healthcare personnel as it was written to be consistent with HICPAC. Dr. Baker withdrew her 

second and Dr. Sawyer seconded the revised motion. The motion did not carry with 4 

affirmative votes, 0 abstentions, and 11 negative votes. 

Motion 3: MMR Vaccine Evidence of Immunity for Healthcare Personnel

Dr. Baker made a motion to accept the footnote for outbreaks as listed and modify routine 

circumstances to read “for unvaccinated personnel born before 1957 who lack laboratory 

evidence of measles, mumps and / or rubella immunity or laboratory confirmation of disease,

health care facilities should consider vaccinating personnel with two doses of MMR vaccine at 

the appropriate interval.” Dr. Neuzil seconded the motion. The motion carried with 11 

affirmative votes, 0 abstentions, and 4 negative votes. 

Dr. Cieslak requested clarification regarding whether this actually represented a change. The 

old language did not discuss the number of doses for routine vaccination. 

Dr. Seward replied that the old language was one dose for measles and one dose for rubella 

and until 2006, it was one dose for mumps. In 2006 it was changed to two doses for mumps, 

which is the current routine recommendation. The measles is the most severe of the three 

illnesses, so they thought it was logical to make the routine recommendation consistent for 

outbreaks and give two doses for measles as well. For routine, it was a change from one dose 

to two for measles. It is currently two doses for mumps. That was changed in 2006. It has 

always been one for rubella because rubella is basically a one-dose policy. This is just making 

it consistent for measles and mumps.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

53 

Dr. Judson said there was a scientific dissidence. For the outbreaks having two doses, he did 

not believe there was any evidence or immune-competent adults to suggest that a second dose 

would do anything to respond to an outbreak. By the time this second dose is administered, the 

outbreak is over and the population is generally immune, especially for measles.

It was noted that the outbreak in Arizona lasted for about 5 months.

Overview

Janet Englund, MD

Chair, ACIP HPV Vaccine Workgroup 

Dr. Englund indicated that during this session, members would be hearing about two issues that 

would soon be coming up for an ACIP vote: 1) bivalent HPV vaccine in females, last discussed 

with ACIP in October 2008; and 2) quadrivalent HPV vaccine in males, not previously 

considered by ACIP. 

The bivalent HPV vaccine is a two-component HPV vaccine. The biologic license for application 

was first submitted with interim data from the phase III vaccine trial in 2007. Following feedback 

from the FDA, GlaxoSmithKline (GSK) decided to wait for end-of-study data, which was 

submitted to the FDA in March 2009. The HPV Vaccine Work Group is preparing for an ACIP 

vote, which may take place in October 2009. Therefore, data are being presented to the full 

ACIP membership during this session so that they would be prepared for the potential upcoming 

vote. Also, a supplementary BLA was submitted for the quadrivalent HPV vaccine in males in 

December 2008. The HPV Vaccine Work Group is likewise preparing for a potential ACIP vote 

in October 2009.

Workgroup activities throughout the past several months have included a great deal of 

discussion about the bivalent HPV vaccine and the quadrivalent HPV vaccine. Bivalent HPV 

vaccine discussions have included ASO4 adjuvant mechanism of action / meta-analysis of 

adverse events, final Phase III efficacy results and cross protection data, comparative bivalent / 

quadrivalent immunogenicity, co-administration with other adolescent vaccines, and potential 

recommendations. Quadrivalent HPV vaccine in males discussions have included safety and 

efficacy in males, acceptability of male vaccination, cost-effectiveness, and recommendation 

options. 

Update on GSK Cervical Cancer Candidate 

Vaccine (Cervarix®) Including Final Efficacy Results 

Gary Dubin, MD

GlaxoSmithKline 

Dr. Dubin provided the committee with an update on new clinical data available for the GSK 

cervical cancer candidate vaccine Cervarix®, including an update on the current regulatory 

status of the vaccine.

Human Papillomavirus (HPV) Vaccines
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

54

The GSK vaccine is formulated with HPV 16 and HPV 18 virus-like particles and the AS04 

adjuvant system which includes aluminum hydroxide salts and monophosphoryl lipid A. AS04 is 

included in the vaccine because in early clinical development, it was shown to enhance immune 

responses to the virus-like particles. GSK has conducted an extensive clinical development 

program, including approximately 30,000 women ages 10 years and up. Cervarix® is now 

licensed in over 95 countries, including the 27 countries of the European Union (EU). In some 

of these countries, there are on-going post-licensure activities to generate additional information 

in the real-world use setting. There are new clinical data that were submitted to the FDA in 

March 2009. The Center for Biologics Evaluation and Research (CBER) review clock is now restarted. The primary new clinical data include final efficacy data from the pivotal trial of HPV008, which was presented previously as interim data.

There were a number of previous ACIP presentations between 2005 and 2009, which included 

the following:

 Phase 2 data: vaccine efficacy, safety and immunogenicity (including long-term 

follow-up) [Harper DM et al. Lancet 2004; 364:1757-65; and Harper DM et al. 

Lancet 2006; 367:1247-55]

 Interim results of pivotal Phase 3 efficacy trial in 15-25 year olds [Paavonen J et 

al. Lancet 2007;369:2161-70]

 Age bridging data in 10-14 and 26-55 year olds [Pedersen C et al, J Adol. Health 

2007, 40(6):564-71; and Schwarz T et al. Vaccine 2009; 27(4):581-7]

 Integrated safety analysis from 11 trials involving ~30,000 women (~16,000 

receiving active vaccine) [Descamps D et al. Vaccine 2009, 5(5) [Epub]]

 Meta-analysis of autoimmune diseases with ~68,000 subjects in clinical trials 

(~37,000 receiving AS04-containing vaccines) [Verstraeten T et al. Vaccine 

2008, 26(51):6630-8]

 Adjuvant system mechanism of action 

The new data upon which Dr. Dubin focused during this session included the following:

 Final efficacy analysis of pivotal Phase 3 trial (HPV-008)

 Comparative study of immunogencity and safety of GSK vaccine and Gardasil®

(HPV-010) [Gardasil® is a registered trademark of Merck & Co Inc.].

The HPV-008 study enrolled over 18,000 women in 14 countries. It was a double blind

randomized trial in which subjects received either the HPV vaccine or Hepatitis A vaccine as a 

control. It was an event-triggered study in that the interim analysis was event-triggered and the 

final analysis was triggered by the requisite number of cervical intraepithelial neoplasia (CIN)2+ 

events that were pre-specified in the study protocol. Subjects were followed for 48 months in 

this study. When the interim analysis was conducted, the mean follow-up time completed at 

that point had been 15 months for follow-up on average following the first dose of vaccine. With 

the final analysis, the mean follow-up time was about 39 months following the first dose of 

vaccine. Thus, there was a considerable amount of additional follow-up time and many more 

end points accrued that made this analysis much more statistically powerful than the interim 

analysis. An end-of-study analysis will be conducted when all subjects complete the 48 months 

of plan study follow-up.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

55

The primary objective of the study was to assess efficacy against CIN2+ associated with HPV16 

or 18. This was assessed in the according to protocol (ATP) cohort and importantly, the 

endpoint was evaluated in women who were DNA negative and CR negative at month 0 and 

DNA negative at month 6 for the HPV type considered in the analysis, so very much an ATP 

analysis. There are important secondary and exploratory objectives assessed in this study,

which included the assessment of efficacy against CIN2+ and CIN3+ lesions, irrespective of the 

HPV type detected in the lesion; efficacy against persistent infections and CIN2+ lesions 

associated with non-vaccine oncogenic types; evaluations on the vaccine impact in reducing the 

need for colposcopy and on cervical excision procedures (including LEEP, laser knife, or cone 

biopsy); and vaccine safety.

The interim analysis was triggered when 23 cases of the primary endpoint were observed in the 

total vaccinated cohort, which was met in November 2006. The results from that interim 

analysis were published in 2007 [Paavonen et al, Lancet, 2007;369:2161-70]. The final analysis

was to be triggered when at least 36 cases of the primary endpoint, CIN2+ associated with 

HPV-16 or 18 were observed in the ATP cohort. This trigger was met in October 2008. The 

CIN2+ endpoint assessments used HPV DNA detection methodology that was published 

previously. This detection system allows detection of 14 oncogenic HPV types, including 

HPV16 & 18. Two types of analyses have been performed. One analysis was the pre-specified 

analysis, which evaluated the association of virus and the CIN2+ lesions just by simple DNA 

detection. An additional analysis using an HPV Type Assignment Algorithm (TAA) to assign 

likely causality in cases where multiply infected lesions were detected was also performed.

Understanding the cohorts that were evaluated in the HPV-008 trial is important because there 

are a number of different evaluations. The total vaccinated cohort (TVC) included all women 

who received at least one dose of vaccine regardless of their baseline cytologic, serologic, or 

HPV DNA status. This cohort included over 18,000 women and case counting started on day 1. 

Another cohort evaluated was the according-to-protocol cohort. This cohort included all women 

who complied with the protocol, received all 3 doses of study vaccines and had normal or lowgrade cytology at month 0. An additional cohort evaluated is referred to as the TVC naïve. This 

is a subset of the TVC, which included all women who received at least one dose of vaccine and 

who, at baseline, had normal cytology, were HPV DNA negative for all 14 oncogenic types 

detected in GSK’s assays, and were seronegative for HPV 16 and HPV18 at study entry. These 

two cohorts are believed to be important because they approximate groups that have public 

health relevance. The TVC cohort approximates the general population, which includes 

sexually active young women with prevalent infections and lesions. The TVC naïve cohort 

approximates the primary target population for universal vaccination programs, mostly young 

women before onset of sexual activity or before sexual debut.

With respect to the results of the primary objective, vaccine efficacy against CIN2+ lesions 

associated with HPV16 and 18 was high and statistically significant using either the composite 

endpoint of the two HPV types considered in the analysis, HPV16 or 18, or considering the two 

types individually. The analysis using the Type Assignment Algorithm (TAA), was to assign 

causality in lesions with multiple infections, also showed very high level of efficacy—about 98% 

protection for the composite endpoint. As mentioned earlier, the primary endpoint only 

considered lesions in women who were seronegative as baseline for the respective type 

considered in the analysis. GSK, therefore, evaluated the primary objective in women

irrespective of their baseline serostatus. This is a larger group of women, including women who 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

56

were seropositive or seronegative at entry. The high level of efficacy is maintained in this 

broader cohort with point estimates that are actually quite similar than the estimates seen in the 

more restricted primary endpoint analysis. Vaccine efficacy was also evaluated against HPV 16 

and 18 CIN2+ lesions in the TVC naïve and the TVC cohorts. Vaccine efficacy was very high in 

the TVC naïve cohort at over 98%. In the TVC cohort, vaccine efficacy was 53%. It should be 

noted, however, that the CIN2+ lesions in this analysis included lesions associated with preexisting infections—an important point to consider.

Another important analysis in the assessment of vaccine efficacy was evaluating efficacy, not 

only against CIN2+ lesions associated with HPV16 or 18, but evaluating efficacy against lesions 

irrespective of the HPV type in the lesions. These analyses are important because they provide 

perspectives on the overall public health impact that the vaccine is expected to provide against 

clinically relevant lesions irrespective of whether it is a vaccine type. In the TVC naïve cohort, 

the vaccine prevented about 70% of CIN2+ lesions and about 87% of CIN3+ lesions overall. An 

epidemiologic estimate of the proportion of CIN2+ and CIN3+ lesions associated with HPV 16 

and 18 suggests that the vaccine efficacy extends beyond what would be expected of a vaccine 

that would provide protection only against vaccine types. Regarding the results in the TVC 

cohort, efficacy against CIN2+ and CIN3+ lesions was 30% and 33% respectively. Again, 

however, it should be noted that the majority of these endpoints were the result of pre-existing 

infections. That point is emphasized in terms of the cumulative incidence of lesions over time in 

the TVC. Lesions development occurs at the same rates in both the vaccine and the control 

groups until about month 18 when there begins to be separation of the curves. This is because 

most of the lesions that develop early in the trial, during the first 18 months, were derived from 

pre-existing infections. It is only after there is a wash out of these lesions that the prophylactic 

affected the vaccine becomes apparent, during the latter part of the follow-up. The efficacy of 

the vaccine was also evaluated in the prevention of colposcopy referral and cervical excision 

procedures, which included LEEP, laser knife, or cone biopsy. These endpoints have public 

health relevance. Additionally, cervical excision procedures may be linked to subsequent issues 

like cervical incompetence. In both the TVC naïve and the TVC cohort, substantial reductions 

are observed in these important endpoints.

In regard to efficacy data against CIN2+ lesions associated with non-vaccine oncogenic HPV 

types, efficacy was evaluated using composite endpoints for a number of oncogenic HPV types.

Efficacy was also evaluated individually for a few of the most important vaccine types. Vaccine 

efficacy against HPV 31 and 45, considered as a composite endpoint in the TVC naïve cohort, 

was 100% and in the TVC cohort was 52%. Again, many of the lesions in the TVC were the 

result of pre-existing infections. There were substantial and significant reductions in CIN2+ 

lesions associated with composites of HPV types that constitute the A9 species. The A9 

species is the family of viruses that are phylogenetically related to HPV 16. Significant 

reductions were also seen in CIN2+ lesions associated with viruses in the A7 species, which are 

viruses phylogenetically related to HPV 18. With regard to the 10 most frequent HPV types 

associated with cervical cancer, there was a significant reduction in CIN2+ lesions associated 

with these types, evaluated as a composite endpoint. Pertaining to HPV 31 and HPV 45,, there 

was a high level of protection against 6 month persistent infection and CIN2+ lesions for HPV 

31. For HPV 45, there was a high level of protection against 6 month persistent infection in the 

TVC naïve. While there were a limited number of CIN2+ cases associated with HPV-45, there 

were no cases in the vaccine group. In the TVC cohort, there was statistically significant 

evidence of efficacy against lesions associated with both HPV 31 and HPV 45 CIN2+ lesions 

and also persistent infection.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

57

Most of the safety data from the trial were published at the time the interim analysis was 

conducted. However, long-term outcomes, such as the occurrence of serious adverse events, 

medically significant conditions prompting physician visits, new onset autoimmune diseases,

and pregnancy outcomes were assessed through the long-term follow up phase of this study. 

For each of these safety endpoints, the occurrence rates were quite similar between the vaccine

(N = 9,319) and the control (N = 9,325) groups. Serious adverse events (SAE) were 7.5% in 

each the vaccine and control group. Medically significant conditions (e.g., prompted a physician 

visit) were 31.8% in the vaccine group and 32.4% in the controls. New onset autoimmune 

disease was 0.8% in each group. In terms of selected pregnancy outcomes, congenital 

anomalies were 0.7% in the vaccine group and 0.5% in the controls, and spontaneous abortions

were 9.1% in the vaccine group and 8.7% in the controls.

To conclude on HPV-008, the trial confirms vaccine efficacy against CIN2+ associated with HPV

16 and 18 as a composite endpoint or with the two vaccine types considered separately. The 

study also showed significant impact on CIN2+ and CIN3+ lesions overall, irrespective of the 

HPV type found in the lesion, and irrespective of the baseline DNA status of subjects. Efficacy

was observed against CIN2+caused by specific non-vaccine types. A significant impact was 

seen on colposcopy referrals and cervical excision procedures. Consistent with what was 

observed in the interim analysis of this study, the final analysis confirms a favorable safety 

profile.

Regarding the HPV-010, this is the first head-to-head study comparing the GSK vaccine and 

Gardasil® with respect to immunogenicity and safety. High efficacy has been observed for both 

vaccines in the pre-licensure setting. Any differences in the long-term protection between the 

two vaccines, if they exist, are unlikely to become apparent for many years. Additionally, 

apparent differences in the cross protection profiles of the vaccines could potentially be related 

to immunologic responses against vaccine antigens. It is important to note that published 

immunogenicity data on the two vaccines cannot be compared directly because of differences in 

study methodologies and differences in serologic assays. This study is the first head-to-head 

comparative study evaluating the two licensed vaccines. GSK’s vaccine is not licensed in the 

US, but is licensed in other countries using the same methodology to assess immunogenicity 

and safety.

The composition of the two vaccines is an important consideration in thinking about the results. 

The GSK vaccine contains 20 micrograms each of HPV 16 and HPV 18 virus-like particles. The 

antigens are expressed in a baculovirus expression vector system and the vaccine contains the 

AS04 adjuvant system. Gardasil® contains 40 micrograms of HPV16, 20 micrograms of HPV

18, and additionally the vaccine contains HPV 6 and 11 virus-like particles. The virus-like 

particles are expressed using a yeast system and the vaccine contains an aluminum 

hydroxyphosphate sulphate adjuvant.

The primary objective of the study was to compare the geometric mean antibody titers (GMTs)

for HPV 16 and 18 using seroneutralizing antibodies as the measure at month 7. That is one 

month after completion of the three-dose series for both vaccines in women aged 18-26 years. 

This testing was performed at the GSK biologicals labs using a pseudovirion-based 

neutralization assay (PBNA) developed by the National Cancer Institute (NCI) [Pastrana et al. 

Virology 2004;321:205-16]. There were some important secondary endpoints assessed in the 

study, which included serum neutralizing geometric mean antibody titers in month 7 in women in 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

58

2 other age strata: 27 to 35 years and 36 to 45 years. Neutralizing antibody levels were 

assessed in cervico-vaginal secretions (CVS) using PBNA. The frequency of antigen-specific 

memory T-cells and B-cells were assess, as were reactogenicity and safety.

The HPV-010 study was conducted in 40 US study centers using observer blind methodology, 

which is the highest level of blinding possible given the use of commercial supplies of Gardasil®. 

Over 1100 women between the ages of 18 and 45 years were randomized to receive vaccine 

according to the schedules either 0, 1, 6 months for the GSK vaccine or 0, 2, 6 months for 

Gardasil®. A single dose of aluminum hydroxide placebo was administered either at month 2 in 

the GSK vaccine group or month 1 in the Gardasil® group to maintain the study blind. 

Enrollment was stratified into 3 age strata between 18 and 45 years of age. Importantly, 

statistical criteria to assess immunologic differences between the vaccines, including tests of 

statistical superiority for the immunogenicity endpoints, were all pre-specified.

Regarding the primary and secondary age stratified analyses, in each of the three age strata, 

the GMT for the GSK vaccine group compared to the Gardasil® group were statistically 

significantly higher in the GSK group versus the group of women receiving Gardasil®. The HPV 

16 neutralizing antibody geometric mean antibody titers, assessed at month 7, were between 2-

and 5-fold higher in the GSK vaccine group depending on the age strata. The HPV 18 

neutralizing antibody geometric mean antibody titers, assessed at month 7, were between 7 and 

9 fold higher. Remember, the antigen content of the two vaccines differs for HPV 16 in that 

Gardasil® has 40 micrograms of HPV 16 virus like particles and the GSK vaccine has 20. For 

HPV 18, the two vaccines have the same relative antigen content. Positivity rates at Month 7 

for HPV-16 and -18 antibodies measured in cervico-vaginal secretions (CVS) by PBNA (women 

18-45 years) was higher with GSK Vaccine than with Gardasil®. The frequency of circulating 

antigen-specific memory B-cells at Month 7 was 2.7-fold higher with GSK vaccine than with 

Gardasil® for HPV-16 and HPV-18 . The frequency of CD4+ T-cell responses at Month 7 was 

significantly higher with GSK vaccine than with Gardasil® for HPV-16 and HPV-18.

Turning to the safety evaluations, a higher percentage of women in this study who received the 

GSK vaccine reported solicited local symptoms within the 7 days after any vaccine dose. 

Symptoms in both groups tended to be transient, and all of the solicited symptoms resolved 

within the 7 day observation period. Solicited general symptoms were generally comparable, 

except for fatigue and myalgia which occurred at a somewhat higher rate in the GSK vaccine 

group. Again, these symptoms were transient, and resolved. Unsolicited symptoms, including 

serious adverse events, occurred at similar rates in the two groups. Importantly, when 

compliance with completion of the three dose course in the two groups was assessed, the 

compliance levels were high and comparable. Both groups had about 84% of subjects 

completing the three-dose schedule.

In conclusion, in the HPV-010 study in month 7 after vaccination, immune responses were 

significantly higher with the GSK vaccine compared to Gardasil®. This included parameters 

such as serum neutralizing antibody responses and antibody positivity rates in CVS, memory Bcell frequencies, and T-cell frequencies. The vaccine safety profiles were consistent with 

previous studies of both vaccines. The differences observed in reactogenicity did not impact 

compliance with completion of the 3-dose course. GSK believes that long-term follow-up 

evaluations in the post licensure setting will be helpful to assess the duration of protection with 

the two vaccines, and will also help to determine the clinical relevance of the observed 

differences in immune responses from this study.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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Overall conclusions and observations are that HPV-008 efficacy data confirm the efficacy of the 

vaccine against CIN2+ associated with vaccine types, and extends the efficacy profile of the 

vaccine including demonstration of an impact on the CIN2+ overall and associated with nonvaccine types, including HPV 31 (HPV-16 related) and HPV 45 (HPV-18 related). The HPV010 data confirmed that the GSK vaccine and Gardasil® induced different immunologic 

responses. The differences in responses were observed for both HPV 16 and 18 components, 

although the largest differences observed were for HPV 18 where the two vaccines have the 

same virus like particle (VLP) dosage. Although the importance of these differences is 

unknown, they may represent determinants of duration of protection against HPV16 or 18 and / 

or protection against non-vaccine types. GSK thinks it is important to recognize that disease 

modeling will help to determine how the observed differences in vaccine profiles might ultimately 

translate into differences in the public health impact of the vaccines. These data, taken together 

with long-term data from Phase II efficacy studies, indicate that the GSK HPV vaccine is likely to 

provide long-lasting protection against cervical cancer. 

Discussion

Dr. Judson asked whether there was any reason to think that the superior neutralizing antibody 

response in the GSK vaccine was related to a difference in adjuvants.

Dr. Dubin replied that although it was difficult to know for sure. most of the evidence suggested 

that it was the adjuvant that resulted in the difference. This comes from previous studies that 

have compared different formulations of GSK vaccines using AS04 or aluminum hydroxide as 

an adjuvant, in which the results were very similar to those observed in the 010 study. 

Significantly higher neutralizing antibody titers were observed with the AS04 adjuvant compared 

to aluminum hydroxide, and a slightly higher rate of reactogenicity is observed. It is hard to 

know whether they are mechanistically related, although they certainly could be.

In the analysis of the reduction in CIN2+ due to the non-vaccine serotypes, Dr. Marcy wondered 

how many of the infections ascribed with non-vaccine serotypes were dual infections with 16 

and 18, such that some of that response could be due to the 16/18 response.

Dr. Dubin responded that it was now very clear when data from these large studies are 

evaluated that it is not uncommon to have lesions where multiple HPV types are detected. The 

analyses shown were pre-specified in which they assessed only the types that were considered 

in the analysis. That being said, GSK has conducted additional analyses in which lesions that 

contain HPV-16 or 18 co-infections have been removed and there is still evidence of statistically 

significant protection against CIN2+ lesions. Some of this data will be available in the public 

domain soon. It was not presented here because there was limited time to go through the 

complexity of multiple infections. It is hard to know when there are multiple infections which 

type is actually is driving the lesions, so an analysis that excludes co-infected lesions is 

considered to be a very conservative analysis. An analysis that does not exclude them is 

considered to be the other end of the spectrum. Therefore, the results from these two kinds of 

analyses represent a range that probably reflects the spectrum of cross-protection.

Dr. Meissner noted that the concentration of antibodies necessary to neutralize 31 and 45 

presumably was higher than the concentration necessary to neutralize 16 and 18 because those 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

60

were in the vaccine itself. As time goes by, with waning titers, he wondered whether the ability 

of those antibodies to neutralize the non-vaccine serotypes may be reduced or even disappear.

Dr. Dubin stressed that it was important to point out that, with respect to the mechanism of cross 

protection, it is not clear whether it is an antibody-mediated phenomenon or whether it is related 

to induction of T-cell responses. That is one of the reasons that some of the GSK studies not 

only assessed antibody responses, but also, as in the 010 study, they assessed T-cell reactivity. 

In the HPV-008 study, there are now data out through 3 1⁄2 years, so what he showed was a 

cumulative estimate of efficacy over that time period. There are also data, not shown here, from 

another study in which efficacy has been assessed out through 7.4 years (not using CIN2+ as 

the endpoint, but in one of the Phase II studies) in which incident infection was an endpoint. 

There is evidence of sustained protection against both HPV31 and 45 through that entire followup period, which GSK believes will predict protection against associated lesions as they 

continue to engage in follow-up in this program.

Dr. Neuzil thought that the best information regarding the public health impact of this vaccine on 

cervical cancer was the overall vaccine efficacy against CIN2+ and CIN3+ irrespective of HPV 

type in the lesion [Slide 12].

Dr. Dubin agreed. Two cohorts are analyzed. The broadest is the TVC cohort that includes all 

women enrolled in this study regardless of their baseline serostatus and regardless of what type 

was ultimately detected in a lesion. The point estimate of efficacy, again CIN2+ of 30%, is what 

would be expected if the vaccine were introduced into a population of women that includes 

women who have pre-existing infections and pre-existing lesions. The TVC naïve cohort is a 

subset of that cohort and includes only women who had no evidence of oncogenic infection at 

entry into the study. Other than that, there are no restrictions. 

Regarding the data on local adverse effects, Dr. Duchin (NACCHO) inquired as to whether Dr. 

Dubin could show them the data on general adverse effects, which he mentioned was higher in 

the GSK vaccine for fatigue and myalgia. 

Dr. Dubin responded that the solicited general symptoms were generally comparable for both 

vaccines except for fatigue and myalgia

Dr. Baker asked about syncope for each group.

Dr. Dubin replied that in the larger study there were 18,000 subjects. In that study, there were 

reports of syncope, but they occurred at the same rates in the two groups. In fact, he thought 

the numbers were exactly balanced with a total of 11 subjects in the HPV group and in the 

Hepatitis A control group that had syncope develop after vaccination and one subject in each 

group who developed pre-syncope. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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GARDASIL® Update: Safety & Efficacy in Boys and Men

Richard M. Haupt, MD, MPH

Clinical Research

Infectious Diseases & Vaccines

Merck Research Laboratories

Dr. Haupt reminded everyone that he had presented a lot of these data during the February 

2009 ACIP meeting. In addition to presenting data on boys and men from the safety and 

efficacy study, Protocol 20, designed specifically to assess disease and infection endpoints, Dr. 

Haupt presented immunogenicity data in 9 to 15 year old males. These data were collected 

over 5 years ago from an immunobridging study, which was submitted to the FDA with the 

original biological license application. During this session, Dr. Haupt focused on the 

immunogenicity data in male subjects 9 to 15 years of age, and the efficacy and safety data in 

16-26 year-old men.

In the clinical program for men and boys there are two adolescent studies, Protocols 16 and 18. 

Protocol 16 was an immunobridging and safety study in which immune responses were 

examined using the Merck competitive Luminex immunoassay. This was assessed in 10 to 15 

year old adolescent girls and adolescent boys and compared to a control group of 16 to 23 year 

old women as a means to bridge the efficacy being observed in women 16 to 23 years of age to 

that of the adolescent population. Protocol 18 was an immunogenicity and safety study of 

GARDASIL in 9-15 year-old boys and girls. This protocol also included a saline placebo arm to 

evaluate reactogenicity. It was a safety study that examined immunogenicity and safety, and 

included both the aluminum adjuvant as a control arm and a saline placebo only. That study 

was extended to a 36-month follow-up, and has subsequently been extended to a long-term 

effectiveness study. Merck is following both girls and boys in that study for 10 years to assess 

long-term effectiveness and safety. Disease endpoints are being collected over time from that 

population.

Protocol 20 is the male study. It is a randomized, double-blind, placebo-control trial. It was 

designed to be a 36-month study. Earlier on 2009, based on the very high efficacy 

demonstrated and the safety profile, Merck’s data and safety monitoring review board 

recommended that this study be ended early and that vaccination of the placebo recipients be 

started. Based on that recommendation, the 36-month study plan will be shortened. The study 

enrolled heterosexual as well as men having sex with men (MSM), for a total of about 4000 

subjects of whom about 600 are in the MSM population. For men enrolled in this trial, Day 1 

polymerase chain reaction (PCR) and serology result were obtained for the 4 types in Gardasil®

(6/11/16/18). Men were excluded who had more than 6 lifetime sex partners, so a lower risk 

population is represented. However, they could still have had as many as 5 lifetime sex 

partners. The point is that when men were examined across the board in this study, about 83% 

were naïve at baseline to all four types. That offers a sense of the susceptibility of a sexually 

active male population to the vaccine types that are in Gardasil®. There is a great opportunity 

to prevent infection / disease caused by these four types—even in men who are sexually active.

Regarding disease endpoint efficacy, the primary endpoint was a 6/11/16/18 related external 

genital lesion (EGL). EGL was a composite endpoint that included genital warts and PIN of any 

grade. PIN is defined as penile, perineal, or perianal intraepithelial neoplasia. Primary endpoint 

efficacy was very high at 90%, which is highly statistically significant. This is driven 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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predominately by genital warts. There were three cases in the Gardasil® group, 28 for genital 

warts in the placebo, for vaccine efficacy of 89.4%. There was 100% efficacy against PIN, 

although there were very few numbers. PIN is a fairly rare condition and this study was never 

powered to demonstrate efficacy against PIN. It was designed as an extension to examine 

infection and disease endpoints and to demonstrate efficacy in males for specific disease 

endpoints.

There were two secondary objectives that were infection endpoints. One was efficacy against 

the persistence of infection. Much like in the women’s studies, that is defined as persistent 

infection with two or more consecutive positive samples with the same HPV type 6 months 

apart. There was also an anytime DNA detection, which is a large category that includes any 

one-time positivity whatsoever (swab, biopsy, et cetera). Persistent infections are very 

important as a predictor for disease development. There was approximately 86% efficacy. The 

efficacy against individual types in that analysis was high for all four types, and there was 

modest efficacy in the endpoint of anytime DNA detection.

Immune response was examined measured with Merck’s competitive Luminex immunoassay, 

which is an assay that measures one specific neutralizing antibody against a known neutralizing 

epitope. The bottom line is that much like what has been observed in women, the virus-like 

particles (VLPs) in Gardasil® are highly immunogenic. There was virtually 100% 

seroconversion as measured in the peak response at month 7. There were very high geometric 

mean titers (GMTs). As with GMTs in women, over time as measured by Merck’s assay, some 

individuals reach a point at which their antibody level cannot be measured. However, continued 

efficacy is observed even in the face of that.

In terms of general safety, and much like was seen in women, the most common adverse 

events observed in men were local injection site reactions. It was the most common vaccinerelated adverse event as well. In the boys and men, very rare serious adverse events were 

seen and none were observed that were vaccine related. Very few men who discontinued, and 

they certainly had very few discontinued to what was considered to be vaccine related.

In addition, Merck examined immune response in 9 to 15 year old adolescent boys. There are 

times when efficacy studies in certain sub-populations cannot be conducted. This is one of 

those experiences where it would be unfeasible to conduct an efficacy study because of issues 

of sexuality and genital sampling. In discussions with the FDA, it was agreed that 

immunobridging to this population was an appropriate way to infer efficacy in the 9-15 year old 

population to demonstrate that immune responses to GARDASIL® in 9- to 15-year-olds are noninferior to those in 16- to 26-year-olds and to demonstrate that GARDASIL® is well-tolerated in 

9- to 15-year-olds. The data from 9 to 15 year old adolescents across all four vaccine types 

demonstrated a non-inferior immune response. In fact, an immune response in the adolescent 

boys was 2- to 3-fold on average higher than what was observed for adult males. In terms of 

immune response to HPV 6, there is a higher level in the younger adolescent and then it 

declines as the boys go through puberty and reaches a similar level across the older age groups 

studied. This profile is virtually identical for the other three types (11, 16, 18). The same profile 

has been observed in women as well. There is nothing different about the adverse event profile 

in the younger adolescent boy populations. The most common adverse event was local 

injection site reactions to the vaccine. There were very few serious adverse events and very 

rare discontinuations due to vaccination.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

63 

In summary with respect to safety and efficacy in boys and men, genital HPV infections lead to 

a significant burden of disease in men. HPV 16 and 18 are important cancer-causing HPV 

types in men and are responsible for the majority of HPV-related penile, anal, and 

oropharyngeal cancers and their associated pre-cancers. HPV types 6/11 cause over 90% of 

genital warts and RRP. GARDASIL® is highly efficacious against HPV 6/11/16/18-related 

persistent infections and genital warts in men. This efficacy may also translate to reduced 

transmission of vaccine type HPV strains between sexual partners. Immune response in 9 to 15 

year-old boys is non-inferior to the immune response in16 to 26 year-old men. GARDASIL® 

was generally well-tolerated in 9 to 26 year-old boys and men. Vaccination of boys and men will 

contribute to an additional public health benefit of GARDASIL®. 

Dr. Haupt concluded with the following list of completed and on-going studies: 



























018-20 (Adolescent Long-Term Safety & Effectiveness) 

Duration of efficacy of GARDASIL®

Impact of GARDASIL® on rates of disease caused by non-vaccine HPV types

Long-term safety & immunogenicity of GARDASIL®

021(HIV-Infected Children)

To evaluate the safety & immunogenicity of GARDASIL® in HIV-Infected children

To determine the impact of nadir CD4 counts (prior to institution of ART) on peak 

immune responses to GARDASIL® 

024 (Concomitant REPEVAXTM [Tdap-IPV]) 

025 (Concomitant ADACELTM & MENACTRATM)

036 (HIV-Infected Men [AMC]) 

Safety & immunogenicity of GARDASIL® in HIV-infected men

046 – Sub-Saharan Africa 

Safety & immunogenicity study

Discussion

Dr. Meissner inquired as to whether Dr. Haupt cared to respond to the data that was presented 

by GSK showing antibody titers 2- to 9-fold higher against 16 and 18 at 7 months follow-up, and 

what clinical significance he thought this had, particularly in terms of long-term immunity and 

need for booster doses.

Dr. Haupt concluded what it is certainly interesting data, but it is not clear that those differences 

really correlate with any difference in efficacy or duration of protection. At this point, it is known 

that both vaccines are highly immunogenic and a lot of antibody is produced by both vaccines 

depending upon which assay is used and how it is measured. Whether those differences are 

clinically meaningful is completely unclear at this time.

Dr. Marcy inquired as to whether genital warts were divided into circumcised and uncircumcised 

men.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

64

Dr. Haupt responded that they captured circumcision data on male subjects who participated 

and examined efficacy for all endpoints based on different baseline covariates. Efficacy was 

assessed based on baseline circumcision, and no difference was observed. It did not appear 

that circumcision impacted efficacy. There are some other natural history data pertaining to the 

impact of circumcision and use of condoms. However, from a pure efficacy perspective, the 

vaccine is highly efficacious no matter what baseline determinant somebody has.

Dr. Judson asked whether there had been any demonstrated differences of any type between 

the Merck and GSK VLPs. 

Dr. Haupt responded that the vaccines are manufactured very differently. It is very likely that 

even though they are 16 / 18 VLP’s, there will be some minor amino acid differences. The VLPs 

of GSK are truncated at the C-terminal end.

Dr. Dubin added that the genetic sequences used to express the VLPs are different. 

Presumably that might translate into some differences in the conformation of the VLPs. There 

has not been any direct comparison that he was aware of regarding the conformation or epitope 

mapping looking at the two VLPs. Given the differences in the genetic sequences used to 

produce the VLPs, he expected that there may be some differences in conformation.

Dr. Haupt noted that this was part of the problem. Even if there is known amino acid sequence 

difference, it is not clear how that translates into the conformation of differences. Conformation 

is important for immune response.

Cost-Effectiveness of HPV Vaccination of Boys in the US

Jane J. Kim, PhD

Center for Health Decision Science

Department of Health Policy and Management

Harvard School of Public Health

Dr. Kim reiterated that human papillomaviruses (HPV) impose a significant burden on 

population health. Infections with high risk oncogenic HPV are associated with 100% of cervical 

cancers, the majority of anal cancers, and a smaller proportion of other anogenital, 

oropharyngeal, and oral cancers. The majority of these HPV related cases are caused by types 

16 and 18. Infections with low risk, non-oncogenic HPV are associated with cervical lesions as 

well as the vast majority of genital warts, and juvenile onset recurrent respiratory papillomatosis 

(JORRP), a rare but severe respiratory condition in children. The majority of these cases are 

attributable to HPV types 6 and 11.

The objective of this analysis was to evaluate the cost-effectiveness of including pre-adolescent 

boys in a routine HPV vaccination program of pre-adolescent girls in the US. The analytic 

approach was similar to the analysis of catch-up vaccination that was presented to ACIP in June 

2008. A series of mathematical models were employed that simulate the natural history of 

disease. Epidemiological, clinical, and economic data were synthesized from various sources 

such as cohort studies, clinical trials, and national surveys. Because not all model parameters 

can be informed directly by the available data, the models were calibrated to achieve good fit to 

empirical data. Model validation exercises were then undertaken to ensure that the predicted

outcomes were consistent with observations from independent data that were not used in model 

development. The models were used to simulate different interventions and estimate their 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

65

consequences, such as quality-adjusted life expectancy and costs. The final step was to 

explore the influence of alternative scenarios, assumptions, and parameter values.

Because of the inherent tradeoffs associated with different model types, multiple models were 

used for this analysis. The first was a dynamic transmission model of HPV type 16 and 18 

infection among males and females, which captures the direct and indirect benefits of 

vaccination. This model was used to calculate the percent reductions in HPV 16 and 18 

incidences associated with different vaccination strategies. These estimates of HPV incidence 

reduction were applied directly to a microsimulation model of cervical carcinogenesis, which 

captures cervical outcomes associated with all HPV types and detailed screening strategies. 

This model was used to assess the cost-effectiveness of HPV vaccination and cervical cancer 

screening in the US. Separate Markov cohort models were developed to simulate the incidence 

of other HPV 16 / 18 related cancers and HPV 6 / 11 related genital warts and JORRP to 

capture the potential benefits of the vaccine on other health conditions.

Briefly, the dynamic model for females reflects sexual transmission of HPV 16 and 18 only. 

Those who are uninfected can acquire an HPV 16 or 18 infection, develop pre-cancerous 

lesions classified as CIN1 and CIN2,3 and over time may develop invasive cancer. Women 

who clear their infection or lesion develop natural immunity to that same type, and then they can 

subsequently reacquire the same type of infection at a reduced rate or acquire a new infection 

with the other type. The history of prior infection is tracked throughout the analysis. Once 

vaccination is introduced, women enter a corresponding vaccinated state. The model has a 

similar structure for males reflecting HPV infection only. The dynamic model is age-structured 

and stratifies the population into four sexual activity levels. Females and males form sexual 

partnerships over time, depending on age and sexual activity level. HPV incidence is a function 

of number of sexual partners, HPV prevalence in the population at a given time, and the 

transmission probabilities of HPV type 16 and 18.

The microsimulation model is an individual-based model that has detailed screening and 

vaccination modules and tracks the history of each individual woman. All HPV types are 

included in this model, stratified as HPV 16, 18, other high risk types, and low risk types. We 

leverage the strengths of both models by using the dynamic model to estimate reductions in 

age-specific HPV 16 and 18 incidence with vaccination, and then applying those reductions to 

the corresponding inputs in the microsimulation model. This linkage between the two models 

allows investigators to reflect herd immunity as well as all HPV types, detailed screening 

scenarios, and individual level heterogeneity. Natural history parameters in both models were 

from epidemiological studies, cancer registries, and demographic statistics primarily from the 

US. After initial parameterization, the models were calibrated to ensure a good fit to empirical 

data using a likelihood-based approach. Selected data on females and males were as follows:

 

Selected Data on Non-Cervical Conditions

(Females)

Annual Incidence

(per 100,000)

5-year 

survival (%) Utilities Cost per case($)

Vulva cancer 0.2-19.6 77.8 0.68 20,430

Vaginal cancer 0.1-6.0 55.7 0.68 23,440

Anal cancer 0.1-5.6 66.2 0.68 31,300

Mouth cancer 0.2-13.9 62.6 0.68 37,370

Oro-pharynx cancer 0.1-1.1 62.6 0.68 37,370

Genital warts 7.0-620.0 100.0 0.91 430

JORRP (age 0-14) 4.3 100.0 0.69 62,010

 

Selected Data on Non-Cervical Conditions

(Males)

Annual Incidence

(per 100,000)

5-year 

survival (%) Utilities Cost per case($)

Penile cancer 0.1-7.6 75.0 0.68 17,110

Anal cancer 0.1-4.3 64.1 0.68 31,300

Mouth cancer 0.1-17.7 57.6 0.68 37,370

Oro-pharynx cancer 0.1-2.9 57.6 0.68 37,370

Genital warts 13.0-501.0 100.0 0.91 430
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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The primary analysis included outcomes related to cervical disease as well as other HPV 16-

and 18-associated cancers for both females and males relevant to both the bivalent and 

quadrivalent vaccines. Secondary analyses included HPV 6 and 11 genital warts as well as 6 

and 11 associated JORRP, relevant to the quadrivalent vaccine only. Analysis was conducted 

from the societal perspective, including direct medical and non-medical costs regardless of 

payer. As recommended for cost-effectiveness analysis in the US, health and economic 

outcomes were discounted at a rate of 3% per year. 

Health outcomes were expressed in terms quality-adjusted life years (QALYs), which is life 

expectancy that is adjusted to reflect diminished quality of life due to disease. Health state 

utilities, which generally range from 0 reflecting the worst health state to 1 reflecting perfect 

health for invasive cancer, genital warts, and JORRP were obtained from the published 

literature. Economic outcomes included lifetime costs of interventions, including direct medical 

costs such as vaccination, screening, diagnosis, and treatment as well as direct non-medical 

costs such as patient time participating in the intervention and transportation. Patient time costs 

due to lost productivity were not included in this analysis. In the base case, it was assumed that 

the cost per vaccinated individual was roughly $500 inclusive of three doses, supplies, 

administration, and patient time and transport.

Results were expressed as incremental cost-effectiveness ratios measured by the net increase 

in healthcare costs divided by the net gain in health effect when comparing one intervention to 

another. These ratios are a measure of value for resources and are used to compare this value 

across different interventions and diseases. The strategies in this analysis included routine 

vaccination of 12 year old girls and routine vaccination of 12 year old girls and boys. All 

strategies included screening with cytology based on current screening rates. The lifetime 

health and economic outcomes were captured for all birth cohorts over a 10-year period of the 

vaccination program.

With respect to vaccination, it was assumed in the base case analysis that coverage for both 

girls and boys with the full three dose series was 75%, that efficacy for girls and boys was 100% 

over the lifetime among those without prior infection with vaccine targeted HPV types, and that 

the cost per vaccinated individual was $500. Alternative assumptions were evaluated and 

sensitivity analysis included lower vaccination coverage, lower efficacy, duration of protection 

and vaccine cost. With respect to cervical screening, the base case analysis assumed cytology 

screening starting three years after sexual debut, consistent with current guidelines. Screening 

frequency was based on coverage rates reported by the National Health Interview Survey 

(NHIS). PAP test sensitivity ranged from 70% to 80% for detecting CIN with a specificity of 

95%. The cost of $85 included the test costs, the office visit, and patient time and transport. In 

secondary analysis, alternative screening strategies were explored including HPV DNA testing 

for primary screening starting at later ages every 1 to 3 years.

In the primary analysis, the cost-effectiveness of including boys in an HPV 16 /18 vaccination 

program was assumed. These results reflect female outcomes only and the first set of results 

includes benefits related to cervical disease only. Under assumptions of 75% coverage and 

complete lifelong vaccine protection, routine HPV vaccination of 12 year old girls who were 

screened at current rates in adulthood had an incremental cost-effectiveness ratio of $40,310 

per quality adjusted life expectancy (QALY) gained compared to screening alone. Adding 12 

year old boys to the vaccination program provided benefits for higher costs and had a costeffectiveness ratio of roughly $180,000 per QALY compared to vaccinating girls only. These 

ratios decreased or became more attractive when the vaccine’s benefits on other HPV 16 and 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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18 related female cancers were included. For example, under an assumption of 50% efficacy 

against non-cervical cancers, vaccinating girls alone decreased to $33,000 per QALY and 

vaccinated both girls and boys costs $157,000 per QALY. 

Under a more optimistic scenario of the 100% efficacy against the other female cancers, the 

ratios decreased to less than $30,000 per QALY for vaccinating girls alone and $140,000 per 

QALY for vaccinating girls and boys; when including cancer benefits for both females and 

males, these cost-effectiveness ratios fell to $30,000 per QALY and $131,000 per QALY, 

respectively, when assuming 50% efficacy against non-cervical cancers, and to $24,000 and 

$103,000 per QALY when assuming 100% efficacy. To evaluate the quadrivalent vaccine, 

cervical disease and genital warts only were included. When including genital wart benefits for 

females only, the ratio for vaccinating girls decreased to $32,000 per QALY and vaccinating 

both girls and boys decreased to $158,000 per QALY. When including warts benefits for 

females and males, the ratios decreased even further as expected to roughly $28,000 and 

$124,000 per QALY for the two vaccination strategies.

Scanning the results across the scenarios of other health outcomes, the cost-effectiveness ratio 

for vaccinating girls alone remains comfortably below $50,000 per QALY even when outcomes 

include cervical disease only. The ratio for the strategy of including boys, on the other hand, 

depends on the health conditions included and falls near or below $100,000 per QALY when all 

cancers or all outcomes are included. When vaccine efficacy was reduced to 75% in boys only, 

the ratio associated with the strategy of vaccinating boys increased by 80% to 117% depending 

on outcomes included. For example, when reflecting only benefits associated with cervical 

disease, the cost-effectiveness ratio of vaccinating both girls and boys increased from $180,000 

to $325,000 per QALY when efficacy decreased from 100% to 75% in boys. When reflecting all 

health outcomes, this ratio increased from $78,000 to $170,000 per QALY.

Additional sensitivity analysis included reduced vaccination coverage with scenarios of cervical 

outcomes alone, all outcomes assuming 50% efficacy, and all outcomes assuming 100% 

efficacy. When strategies were evaluated in the context of 50% vaccination coverage, the 

corresponding ratios for both strategies improved due to slightly higher levels of herd immunity 

benefits. The strategy of including boys in the vaccination program was roughly $100,000 per 

QALY under an assumption of 50% efficacy and remained below $100,000 per QALY with 

100% efficacy.

The impact of the vaccine cost, which in the base case was $500 per vaccinated individual, was 

also examined. Using a vaccine cost of $360, when all outcomes are considered, vaccinating 

girls and boys decreased to $89,000 per QALY under an assumption of 50% efficacy and 

$53,000 per QALY with 100% efficacy. In contrast, when the vaccine costs increased to $600, 

the ratios became less attractive than the base case. In this scenario, the strategy of 

vaccinating girls and boys remained well above $100,000 per QALY when efficacy was 50% 

and approached $100,000 per QALY when efficacy was 100%. Results were also sensitive to 

assumptions of waning vaccine protection; when vaccine protection was assumed to be 10 

years, both vaccination strategies had ratios that exceeded $100,000 per QALY. In contrast, 

changes in screening practice involving less frequent screening with HPV DNA testing and 

primary screening made vaccination strategies more attractive. Results were insensitive to 

changes in health state utilities associated with genital warts or duration of warts, and also when 

a higher proportion of oral and oropharyngeal cancers attributable to HPV type 16 and 18 were 

assumed.
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As with all model-based analyses, this analysis had several unavoidable limitations, including 

uncertainties with respect to natural history, especially the non-cervical diseases. There are 

also uncertainties with respect to the vaccine properties for females and especially for males. 

With respect to the analytic assumptions, decrements in quality of life associated with detection 

and treatment of pre-cancerous lesions that result from screening were not included. Inclusion 

of these utilities would favor vaccination strategies since HPV vaccination is expected to reduce 

the prevalence of vaccine type lesions. Conversely, diminished quality of life was also not 

included due to potential adverse events associated with vaccination, which would favor the 

screening strategies. Also, this analysis did not evaluate catch-up programs. It is expected, 

however, that in the context of catch-up vaccination among young females, extending 

vaccination to boys would be even less attractive than suggested by the current analysis.

In summary, provided vaccine efficacy was high and long-lasting, routine HPV vaccination of 

12-year-old girls was stably less than $50,000 per QALY across a wide range of assumptions 

compared to screening alone. This result is consistent with most previous cost-effectiveness 

studies. Including pre-adolescent boys resulted in higher costs and benefits, and generally had 

cost-effectiveness ratios that exceeded $100,000 per QALY. This was especially true when 

vaccine efficacy was differentially lower in males than females. Only when all potential health 

benefits from the vaccine were included under optimistic assumptions of 100% efficacy, for both 

females and males over the lifetime, or 50% lifelong efficacy with lower vaccine cost, did 

vaccinating both girls and boys fall below $100,000 per QALY.

Overview of Cost-Effectiveness Models of 

Male HPV Vaccination in the United States

Harrell Chesson, PhD

NCHHSTP / CDC

Dr. Chesson began with a review of what is known about the cost-effectiveness of HPV 

vaccination in general. Vaccination of 12 year old girls has been shown to be cost-effective, 

with cost-effectiveness estimates ranging from $0 to $50,000 per QALY gained. This result has 

been consistent across a wide range of models. However, there is more uncertainty and less 

precision in the cost-effectiveness estimates for vaccination of females over the age of 12 and 

for vaccination of males. He then presented a summary of the published cost-effectiveness 

studies of male HPV vaccination, and compared and reviewed two unpublished models.

In a study by Taira and colleagues (2004), the cost per QALY of male vaccination was about 

$440,000 in the base case scenario with 70% coverage. However, when vaccine coverage of 

females was reduced to 30%, the cost per QALY was reduced as well to about $40,000. This 

finding that the benefits of the male vaccination increase and the cost-effectiveness becomes 

more favorable with lower vaccine coverage has been found in several models of costeffectiveness and the impact of male vaccination. It was also shown in the model by Elbasha 

and colleagues, who in the base case found a cost per QALY of $40,000 at 70% coverage. 

However, with higher coverage, the cost per QALY increased but with lower coverage of 

females, the cost per QALY decreased. The Jit study was based in the UK. These 

investigators found a cost per QALY gained for male vaccination of about $1,000,000 with 80% 

coverage and lifelong duration of vaccine protection. The key themes from the published 

studies are that male vaccination has less impact and is less cost-effective as vaccine coverage 

of females increases. However, vaccine coverage is not the only factor that affects costeffectiveness. There is considerable uncertainty in the natural history, disease cost and quality 

of life assumptions, and vaccine characteristics. Because of these uncertainties, there is a wide 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

69

range of cost-effectiveness ratio across models and within models. The published models have 

focused on the prevention of cervical intraepithelial neoplasia (CIN) cervical cancer and genital 

warts; however, the recent trends in the cost-effectiveness models for HPV have been to 

include additional HPV related outcomes that might be prevented through vaccination such as 

non-cervical cancers and recurrent respiratory papillomatosis (RRP). 

Two preliminary models have been expanded to include all of these health outcomes. These 

include the Kim / Goldie model that Dr. Kim just summarized, as well as the Merck model which 

looks at adding vaccination of males 9 to 26 years old to a vaccination program for females 9 to 

26. Both models examine the cost-effectiveness of adding male vaccination to a female only 

vaccination program in the context of current cervical cancer screening in the US. To review the 

Merck model briefly, they assumed effective vaccine coverage by age 18 of about 35% in 

females and 23% in males. First dose coverage assumptions were higher, but they assumed 

that only about 50% of those vaccinated with the first dose would complete the series. Vaccine 

efficacy against infection and disease was based on the clinical trials. They assumed lifelong 

duration of vaccine protection and assumed that there would be no benefit for those who do not 

receive all three doses. They assumed the vaccine cost would be $133 per dose, inclusive of 

administrative costs. They used the US health care system perspective in which vaccine costs 

as well as disease treatment costs were assessed without regard to who paid these costs. Cost 

and benefits of vaccination were evaluated over a 100-year time horizon with future cost and 

benefits discounted at 3% annually. 

The incremental benefit, in terms of reducing cervical cancer, for male vaccination is quite small 

and it takes about 40 years to even see this difference. Although the additional benefit of male 

vaccination is more noticeable for the male anal cancer outcome than for cervical cancer, it still 

remains that the majority of the benefits that can be obtained from vaccinating both sexes can 

be obtained from vaccinating females only. In the Merck model, the cost per QALY of female 

only vaccination was about $2,000. The incremental cost per QALY of adding male vaccination 

was about $25,000. In terms of the gain and changes in cost and QALYs,per person in the 

population, adding males costs about $22 as opposed to the incremental cost of female 

vaccination, which is about $9. The change in benefits was much lower for male vaccination, 

and was roughly 1/6 the marginal benefit in terms of QALYs gained as compared to female only 

vaccination. 

The estimated cost per QALY depends on which health outcomes are included in the model. 

When including cervical outcomes only, the cost per QALY of male vaccination is over 

$200,000. However, as more outcomes are included, the cost per QALY decreases to 

$25,000. When the impact of genital warts on quality of life is reduced by 50% and the duration 

of genital warts is reduced to three months, these changes in the genital warts assumptions 

make a fairly big impact on the cost per QALY estimates when including only a few of the health 

outcomes. However, when all health outcomes are included, the changes in genital warts 

assumptions do not have as much of an impact. It is important to point out that just focusing on 

the diseases for which there is evidence of vaccine impact, the cost per QALY of male 

vaccination is $70,000 per QALY or above and is very sensitive to changes in the model 

assumptions, such as those related to genital warts.
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In terms of the results of the two models, when including only cervical outcomes, both models 

suggest a cost per QALY of male vaccination in the neighborhood of $200,000; however, when 

including all health outcomes, the cost per QALY of male vaccination is about $25,000 in the 

Merck model, which is lower than the estimates from the Kim / Goldie model that Dr. Kim just 

presented in which the cost per QALY of male vaccination can range from $78,000 to $170,000 

depending on the vaccine efficacy assumptions. However, this is not really an apples to apples 

comparison because there are several differences in the questions being addressed by the 

models. For example, the vaccine coverage is much higher in the Kim / Goldie model and the 

Kim / Goldie model focuses only on vaccination of 12 year olds. With respect to similarities and 

differences in the models, both models included a wide range of health outcomes. The only 

difference is that the Merck model included vaginal pre-cancers. Both models were able to 

include the indirect effects of vaccination or herd immunity. Both models did incorporate current 

cervical cancer screening, although the methods they used to do so differed. They also 

examined a long time horizon, although again, the methods they used to do so differed. Both 

models assumed at least some degree of natural immunity following HPV infection and 

clearance. As noted, the effective coverage in the Merck model was much lower than in the 

Kim / Goldie model.

The Kim / Goldie model used a higher cost of vaccination and this is partly because they 

included patient time and travel costs—not only in their cost of vaccination, but in the cost of the 

disease treatment. The Merck model included the quality of life impact of CIN, and the Kim / 

Goldie model did not. The models could be made more comparable by aligning three key 

assumptions: Cost of vaccination, including administration costs (Merck $400 per series base 

case, Kim / Goldie $360); vaccine coverage and adherence (Merck 75% coverage / 100% 

adherence; Kim / Goldie 75% coverage / 100% adherence base case); and ages vaccinated 

(Merck 9 to 12; Kim / Goldie 12 base case). In the sensitivity analyses, assumptions were 

changed from the base case. The scenario in which the Kim / Goldie cost was changed to $360 

per series was selected for this comparison as it was more comparable to the Merck 

assumptions. The scenario of the Merck model in which 100% vaccine adherence was 

assumed was selected for this comparison as it was more in line with the Kim / Goldie model. 

Under this scenario, the cost per QALY of HPV vaccination, adding males to the female only 

vaccination program, was about $90,000 in the Kim / Goldie model and about $40,000 in the 

Merck model. When the models were aligned on these three assumptions, the disparity in the 

outcomes was greatly reduced, although the estimates are still somewhat different.

To summarize, male vaccination costs more than $100,000 per QALY in most scenarios in the 

Kim / Goldie model. Cost per QALY was < $100,000 only when all health benefits were 

included with 100% lifetime efficacy, or with 50% lifetime efficacy at lower vaccine cost. Male 

vaccination cost less than $50,000 per QALY in the most scenarios in the Merck model. Cost 

per QALY was >$100,000 when including only cervical, vaginal, and vulvar cancers and genital 

warts in the scenario of 75% effective coverage in females. The differences across these 

models were reduced, but not eliminated, when selected assumptions were aligned.

To conclude, estimates of the cost-effectiveness of male vaccination can vary across models 

and even within models when key assumptions are changed. This is due to the uncertainty in 

the influential factors that impact the cost-effectiveness of male vaccination including the HPV 

diseases included in the model, vaccine coverage and efficacy, and other assumptions. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

71

Discussion

Dr. Temte thought first time HPV coverage in adolescent females was approximately 25%. 

From a programmatic standpoint, he wondered whether it was better to push forward to 

immunize all girls or have a recommendation in which they try to immunize both boys and girls 

with the idea that perhaps by trying to reach both they would achieve better results than with 

just the female recommendation.

Dr. Kim responded that while she did not have a definitive answer, she could offer a qualitative 

one. All of the models are consistent in finding that the cost-effectiveness of vaccinating girls is 

certainly higher than vaccinating boys. Dollar for dollar, the goal would be to achieve coverage 

in girls based on the data there is currently on vaccine efficacy. To answer the question, it really 

depends on what the cost is of achieving the increase in coverage in females in terms of 

whether there is an added cost to that and how that relate to the improvements that might be 

achieved in health related to boys. Her group has personally not assessed any cost threshold 

analyses to say that going from 50% to 75% coverage would add X cost for reaching another 

25% of girls compared to what it means to go from 0% to 25% coverage in boys. A head-tohead analysis has not been done.

Dr. Dasbach (Merck) indicated that Merck has conducted some of those analyses. What they 

have tried to do with the model that Dr. Chesson just presented was to reflect current coverage 

levels to at least what is being observed in the US currently, and what would happen if male 

vaccinations were added on top of that. If coverage levels are low, it makes a lot of sense to 

increase coverage either by vaccinating more females or more males.

Dr. Temte asked whether that was dollar for dollar as female coverage was increased. It looked 

like the models were pretty consistent in that as female coverage increases, the costeffectiveness ratio, the cost per QALY for males, skyrockets. This raised a question about what 

the best value would be. 

Dr. Kim responded that this is precisely what they were trying to help inform. It is true that the 

models are consistent in that as coverage is increased in girls, the value of adding boys 

decreases. However, there might be other reasons that are not included in these models, such 

as whether including boys actually helps reach more girls or whether opening up vaccination to 

boys helps gain more coverage in girls. That type of scenario has not been included her their 

analyses to date.

In terms of how things play out in public health protective “bank for the buck” Dr. Judson pointed 

out that one variation not used was that very often the interventions are gotten into the people 

who may least need them and are most able to pay for them. Thus, one way of looking at this

would be that if 50% coverage is reached in girls at 12, they only account for 10% of all eventual 

cervical cancer. That is a major public health concern. He also requested clarity on what it cost 

to prevent a penile wart for one year in a man in terms of quality of life assumptions were used.

Dr. Kim responded that they were using consistent results (e.g., the same QALY assumptions 

as the Merck model). She said she could not personally vouch for the quality of life decrement 

associated with penile warts. Returning to Dr. Judson’s first question, although they did not look 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

72

at the impact of disparities in vaccination coverage among females or males in this particular 

analysis, they did include that analysis in the catch-up analysis and found that their results were 

very sensitive to correlations between vaccination coverage and screening coverage. If 

restricting vaccination coverage to women who will eventually get screened, the costeffectiveness of vaccination at any age becomes highly unattractive and that worsens as the 

correlation becomes stronger. For genital warts, a decrement in quality of life of .09 was 

assumed. The scale of health utilities is usually from 0 to 1, 0 reflecting death or the worst 

health state, and 1 reflecting perfect health. A .09 in theory would be indifferent to a 9% risk of 

death to get rid of the genital warts at that time period.

Dr. Dasbach indicated that the cost of genital warts was about $500 to $600 per episode of 

care. Just within the US alone, the economic burden is about over $200,000,000 per year in 

terms of treatment. In terms of the QALYs, a similar estimate is used in terms of the disutility or 

the quality of life weight associated with warts, and that was also about .09 on a scale of 0 to1. 

What that means with respect to cervical cancer is that decrement is assumed to be closer to.25 

to .5 depending on whether it was local or distal cancer. Also important in terms of looking at 

this QALY is the duration of the event, so within the Merck model it was assumed that the 

median length of a genital wart was about 6 months.

Dr. Cieslak pointed out that these models were somewhat of a black box because everything 

that was going into them was not known to the ACIP members. Given that he always thought of 

the burden of HPV as being a question of the incidence and severity of cervical cancer, he was 

surprised to see the large decrements in cost per QALY gained as lesser incidence of diseases 

in males were added. This was counterintuitive to him. He wondered if Dr. Chesson could offer 

further insight. 

Dr. Chesson responded that the female vaccination has a major impact on cervical cancer, so 

that does not leave as much room for the male vaccination to do as much good in terms of 

reducing the cervical outcomes. Change in cervical cancer was very small by adding male 

vaccination. 

Dr. Cieslak said he understood, but as other things were added, there were profound drops in 

cost per QALY.

Dr. Chesson responded that a major reason for the genital warts drop was that even though the 

cost per case was about $500 when multiplied that by all cases, is was a substantial burden 

than could be offset. So not only is it a change in the QALYs that is driving this, but also it is a 

change in the cost associated with the disease outcomes, particularly in genital warts.

Dr. Dasbach added that in terms of what they did with respect to male disease as well as female 

disease, all of the data were calibrated to current levels that are being observed in the US with 

respect to incidence. They then assessed the reductions that vaccination would provide in 

terms of the benefits of preventing those diseases. The reason decreases are seem in males is 

that, as Dr. Chesson was mentioning, there are now direct benefits to males in the female 

diseases and those are all indirect benefits that male vaccination provides. So in vaccinating 

males, there are indirect and direct benefits.

Dr. Sumaya wondered whether the time and effort of the vaccine process was or could be 

included. There may be cost differentials on the acceptability of the vaccine with at risk 

populations. In other words, he thought there would be greater acceptability / interest in the 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

73

vaccine as opposed to men and he wondered whether there was any cost differentiation with

that phenomenon.

Dr. Kim responded that this would depend on the level of the coverage actually achieved in both 

genders. The cost-effectiveness and the value of vaccinating either girls or boys is very 

sensitive to assumptions of coverage, so they would have to evaluate specific scenarios. 

Additional cost would be tacked on to implementing or trying to get that coverage for the 

vaccination strategies. That would differentially disadvantage the vaccination strategies 

compared to, for instance, screening alone.

Dr. Morse pointed out that it appeared that age at immunization would have a major influence 

on the model, especially as immunization levels increase. Thus, the cost of immunizing an 

older group of the cohorts 20 to 26 years of age might be much more expensive.

HPV Vaccines: Issues for ACIP Consideration

Lauri Markowitz, MD

ACIP HPV Vaccine Workgroup

NCHHSTP / CDC

Dr. Markowitz provided a brief overview of issues that ACIP will likely need to consider during 

the October 2009 meeting. These include the two issues heard during this meeting (e.g., 

quadrivalent vaccine in males and bivalent vaccine in females). 

A variety of issues need to be considered for HPV vaccine in males. These include the burden 

of disease in males, vaccine efficacy, immunogenicity, safety, vaccine acceptability, and impact 

and cost-effectiveness. It is known that HPV prevalence and incidence are high in sexually 

active men. HPV incidence in men is similar to that in females. There are still unknowns 

regarding the transmission and natural history of HPV, particularly in males. In terms of HPVassociated disease in males, HPV types 16 / 18 cause the majority of HPV-associated anal, 

penile, and oropharyngeal cancers (~7000 invasive cancers / year). HPV types 6 / 11 cause

RRP and over 90% of genital warts (.25 -.5 million / year). There are some high risk groups, 

such as MSM, which has not been discussed with ACIP. This group has high rates of HPV 

infection and HPV related outcomes. The quadrivalent vaccine is generally well-tolerated in 

males. There is high efficacy for protection against vaccine-type persistent infection (VE = 86%) 

and genital warts (VE = 89%). Of note, there are no data yet on efficacy for prevention of precancers in males, although studies on these endpoints are on-going. 

In terms of the modeling and economic analyses, male vaccination provides little additional 

benefit for prevention of cervical cancer if there is high vaccine coverage in females. Costeffectiveness estimates are more favorable as more health outcomes are included. In the Kim /

Goldie model, male vaccination cost > $100,000 per QALY in most scenarios. The incremental 

cost effectiveness was < $100,000 per QALY only when all health benefits were included with 

100% lifetime efficacy, or with 50% efficacy and lower vaccine cost. In the Merck model, the 

cost per QALY was < $50,000 in almost every scenario in which all health outcomes were 

included. The cost per QALY was in the $75,000 range when including only cervical, vulvar, 

and vaginal cancers and genital warts.

With regard to a recommendation for quadrivalent HPV vaccine for males, several questions 

must be considered: Should there be data on efficacy for prevention of pre-cancer lesions in 

males before making recommendations? How much should health economic models impact 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

74

decisions? What endpoints should be included? What about vaccine coverage in females? 

Considerations for supporting a recommendation for vaccination of males include the fact that 

HPV does cause disease in males as well as females. The vaccine has high efficacy for 

prevention of genital warts and a strong likelihood for prevention of cancers in males. There is 

also high efficacy for prevention of persistent infection in males. In some models, which 

included the most favorable assumptions and high efficacy, the cost per QALY was less than 

$50,000. There are also issues of equity; that is, should the vaccine be made available to 

males as it is for females? There are also programmatic considerations. Would a genderneutral vaccination program facilitate vaccine delivery? The work group realizes at the present 

time there are really no data to support that hypothesis.

Considerations for not supporting HPV vaccine recommendations for males include the fact that 

there are no data on the efficacy for prevention of pre-cancer lesions, and in the Kim / Goldie 

model, the cost per QALY for male vaccination exceeded $100,000 under most scenarios 

examined. In the Merck model, the cost per QALY was about $70,000 or $75,000 when 

focusing only on health outcomes for which we evidence of impact.

The options for HPV vaccine recommendations in males that have been discussed in the work 

group include a routine vaccination at age 11-12 with a permissive recommendation or a catchup to some older age. The reason a permissive recommendation only was supported by many 

work group members was the need to wait for more efficacy data against other endpoints and / 

or the fact that the model showed that the vaccination of males is not cost-effective. There was 

also discussion of specific recommendations for high risk groups, particularly men who have sex 

with men. It was recognized that this would be difficult to implement and that many MSM would 

already have been infected at the time they self-identified.

Regarding the work group’s discussions related to the bivalent vaccine in females, 

considerations were previously presented to ACIP in October 2007. In addition to making 

specific recommendations for use of this vaccine, there is a need to consider issues related to 

having two licensed HPV vaccines in the US—the focus of this session. The following table 

reflects the characteristics of the two vaccines, both of which are L1 virus-like particle or VLP 

vaccines: 

Quadrivalent (Merck) Bivalent (GSK)

VLP types and 

Composition

20 μg HPV 6

40 μg HPV 11 

40 μg HPV 16 

20 μg HPV 18

20 μg HPV 16

20 μg HPV 18

Producer cells Saccharomyces cerevisiae (bread yeast) -

expressing L1

Trichoplusia ni insect cell line infected 

with L1 recombinant baculovirus 

Adjuvant Alum:

225 μg Aluminum Hydroxyphosphate 

Sulfate

AS04:

500 μg Aluminum Hydroxide 50 μg 3-

deacylated Monophosphoryl Lipid A 

Schedule 0,2,6 months 0,1,6 months

Some issues to consider related to having two licensed HPV vaccines for use in females

include: Should a preference be stated for one vaccine? Are there differences related to 

protection against HPV 16 / 18, other oncogenic types, and / or HPV 6 / 11? Are there 

differences in cost-effectiveness? Can the vaccines be used interchangeably in the vaccination 

series for protection against HPV 16 / 18? The current understanding of both vaccines is 

reflected in the following table:
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

75

Attribute Quadrivalent Bivalent

Protection against HPV 16/18 

related CIN2/3 and AIS*

>98% >93%

Protection against HPV 6/11 related 

genital lesions

100% -

Cross-protection against CIN2/3 due 

to high risk types other than HPV 

16,18

Some 16 related 

types?

Some 16 and 18 

related types?

Seroconversion to vaccine types ~100% ~100% 

Geometric mean antibody titers bivalent > quadrivalent 

Duration of protection Unclear if any 

differences

Unclear if any 

differences

Local Reactogenicity bivalent > quadrivalent 

Cost of vaccine dose** $130 private 

$105 contract

?

Both vaccines may offer some protection against non-vaccine types and there may be 

differences. Seroconversion to the vaccine types occurred in almost all vaccines, and after a 

three dose series for both vaccines. The data from the comparative trial illustrates that the 

bivalent vaccine does produce higher titers than the quadrivalent vaccine, but both vaccines 

produce titers that are substantially higher than those after natural infection. The implications of 

this, in terms of differences in duration of protection, are unclear. There is higher local 

reactogenicity after the bivalent vaccine; however, both vaccines have good tolerability profiles. 

At present, the cost in the US is only known for the quadrivalent vaccine. 

In terms of cross protection, based on data from a meta-analysis of HPV types associated with 

cervical cancers worldwide, HPV 16 and 18 account for 70% of cervical cancers. Some nonvaccine oncogenic types account for a smaller percentage of cervical cancers. Two of the more 

common types of these non vaccine types are 45 and 31 [Smith J. et al, Int J Cancer 2007].

In terms of protection against type 31 and 45 related CIN2/3 and persistent infection among 

women who were in the naïve group, they were naïve to 14 types at baseline. There was 100% 

protection against CIN2/3 or AIS due to 31 or 45 and this was significant for 31. There was also 

significant protection against 6 month persistent infection with both of these types. For the 

quadrivalent vaccine, previously published data earlier this year show protection against type 31 

related CIN2/3 and persistent infection, but not for type 45. This analysis for the quadrivalent 

vaccine was among women who were naïve to 12 oncogenic types at baseline. Efficacy has 

also been examined for CIN2/3 due to groups of non-vaccine oncogenic types. In these 

analyses, there were some protection from lesions due to types due in the A9 species (these 

are types related to HPV 16) for the bivalent vaccine and for the quadrivalent vaccine as well. 

For types related to HPV 18, there is significant protection for the bivalent vaccine but not the 

quadrivalent vaccine. For a combined endpoint of CIN2/3 due to any of 10 non vaccine types, 

efficacy was 68% for the bivalent vaccine and 33% for the quadrivalent vaccine [Paavonen et al, 

presented at IPC, Malmo Sweden (May 2009); Brown et al, JID 2009;199]. A note of caution 

about these analyses of cross protection is that the analyses shown earlier did not exclude 

lesions in which there was also infection with a vaccine type, so it is possible that some of the 

observed protection could have been due to the vaccine types. Also, it is quite difficult to 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

76 

directly compare results from the trials for a variety of reasons in terms of the way the 

populations were selected and the way the analyses were conducted.

Taking into account the available data, the work group has discussed options regarding making 

recommendations for two licensed vaccines and whether a statement of preference should be 

made for one vaccine or the other. While there was not complete consensus, the majority of 

members on the work group felt that a statement should include the following elements: There 

should be a statement of the differences in protection provided by the vaccines, specifically 

differences with regard to protection against HPV 6 and 11. The quadrivalent vaccine provides 

protection against genital warts. There could potentially be a statement about differences in 

cross protection. There should be an encouragement to providers to understand differences 

between the two vaccines. For protection against 6, 11, 16, or 18 related outcomes, the 

quadrivalent vaccine is recommended. For protection against HPV 16 and 18 related 

outcomes, either the quadrivalent or the bivalent vaccine is recommended. Concerning the 

issue of interchangeability of the vaccines, it was acknowledged that there would be no data at 

the time recommendations would need to be made regarding this issue. A possible statement 

could be, “Whenever feasible, the same brand of HPV vaccine should be used for all doses of 

the vaccination series. If vaccination providers do not know or have available the type of HPV 

vaccine previously administered to a female, any vaccine should be used to continue or 

complete the series to provide protection against types 16/18.” There are many other issues 

that would need to be addressed for the bivalent vaccine recommendations, which will be 

addressed during the October 2009 meeting.

The future plans for the HPV vaccine work group are to continue to review data, refine the 

understanding of the cost-effectiveness analyses, discuss options for recommendations for 

these two issues, and prepare draft recommendations and options for the October 2009 ACIP 

meeting if there is FDA approval.

Overview of Work Group Activities 

Carol J. Baker, MD

Advisory Committee on Immunization Practices

Dr. Baker indicated that during this session, the following topics would be presented upon:

 Update on immunogenicity and safety of a second meningococcal conjugate vaccine 

(MenACWY-CRM) for 11 to 55 year olds

 No VFC vote required; no proposed changes to recommendations for vaccination

 Early estimate of vaccine effectiveness of meningococcal conjugate vaccine (MCV4)

 3 years after vaccine implementation: unable as yet to evaluate duration of protection

 Proposed revaccination recommendations for persons at high-risk for invasive 

meningococcal disease

Meningococcal Conjugate Vaccine (MCV4)
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

77

With regard to why revaccination needed to be considered, the 2005 ACIP recommendation for 

revaccination after MCV4 states the following:

“ACIP expects that MCV4 will provide longer protection than MPSV4; however, studies 

are needed to confirm this assumption. More data will likely become available within the 

next 5 years to guide recommendations on revaccination for persons who were 

previously vaccinated with MCV4.”

Although they are only at the 4-year mark, some considerations need to be made. First, it is 

likely that the early meningococcal conjugate vaccine (MCV4) vaccinees likely will have been 

persons in high risk groups for invasive meningococcal disease. They probably received 

vaccines the earliest, and probably represent a very small part of the total vaccine target. There 

has also been a shift in thinking about the duration of protection regarding conjugate vaccines, 

because immunologic memory or boost ability may not actually correlate with protection. 

To prepare the committee for the future, Dr. Baker reported that the work group would be 

considering a recommendation for revaccination of adolescents vaccinated 5 years ago who 

would be entering college. This is a very large cohort of approximately 600,000 students 

annually. According to the data, a very small proportion of entering college students will have 

been vaccinated 5 years ago (e.g., coverage <4% in 2005; 11% in Fall 2006). Costeffectiveness of revaccination of college freshmen living in dormitories needs to be assessed. 

An additional year may allow for more definitive effectiveness evaluations to be completed. 

In addition, a recommendation for routine vaccination of infants and / or toddlers with 

meningococcal conjugate vaccines must be considered. There is a potential for three vaccines 

to be licensed in 2010-2011: MCV4-D 2-dose series (9,12 months), HibMenCY 4-dose series 

(2,4,6,12 months), and MenACWY-CRM 4-dose series (2,4,6,12 months). The work group will 

also continue to evaluate data on the burden of disease and cost-effectiveness of vaccines in 

infants. 

The work group anticipates a revision of the 2005 ACIP meningococcal conjugate vaccine 

statement in the Fall of 2009. The revision is expected to reaffirm the current 2- to 10-year old 

and adolescent recommendations, which are for high risk 2- to 10-year olds and all adolescents; 

include additional safety data, especially regarding Guillain-Barré Syndrome (GBS) monitoring; 

add the MenACYW-CRM vaccine information; include data concerning duration of protection; 

and include recommendations for revaccination of high risk groups. In 2010-2011, the work 

group will begin to present data that will lead to a recommendation for infant vaccination.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

78

MenACWY-CRM (Menveo®) Clinical Trial and Product Overview

Peter Dull, MD

Head Development Meningococcal Vaccines

Novartis Vaccines

Dr. Dull offered a brief, broad overview regarding the Novartis Vaccines Meningococcal Vaccine 

Program with respect to vaccine characteristics, the overall clinical program, and the specific 

data on adolescents currently under review.

Novartis Vaccines, as a company, has a longstanding interest and scientific expertise in 

meningococcal disease prevention. The program is intended, rather ambitiously, to control 

disease in all disease-causing serogroups and all age ranges beginning from two months of 

age. The history of the Novartis Vaccine Program begins with a monovalent MenC vaccine, 

which was a CRM conjugate vaccine, which was originally licensed in the United Kingdom (UK) 

in response to a serogroup C outbreak in late 1999. MenACWY-CRM was built upon the 

successful MenC-CRM vaccine platform and is a CRM-based conjugate quadrivalent vaccine 

with initial indication for adolescents through 55 years of age. The goal is to move into younger 

age groups, with applications forthcoming submissions planned for 2 to 10 year olds and 

infants. Ultimately, Novartis expects to provide broadly protective MenB infant vaccine. This 

vaccine is currently undergoing Phase III studies in Europe in >4000 infants. This vaccine 

would provide the penultimate cornerstone to complete the meningococcal disease prevention 

goal.

With regard to MenACWY-CRM, Menveo® is the trade name that will be used. A unique 

conjugation process is used utilizing the protein carrier, CRM197. CRM197 is a non-toxic 

mutant of diphtheria toxin that requires no formaldehyde detoxification, which avoids crosslinking to accessory antigens. It has been used successfully in pneumococcal and Hib 

conjugate vaccines. Other specific unique features of this vaccine include the conjugation 

chemistry [Bardotti A et al. Vaccine. 2008;26:2284–2296]. Purified polysaccharides are 

optimally sized then linked to the CRM197 to produce the conjugates. Standardized 

polysaccharide sizing allows for consistency in the end product, as well as retention of structural 

identity.

The vaccine has 10 micrograms of MenA with 5 microgram of the C, W, and Y component. It 

contains no adjuvant and no preservative. The presentation will be “vial-vial”, with the liquid 

component containing the MenCWY, which is reconstituted into the lyophilized MenA 

component.

The clinical development dates back to about 2002. The clinical trial database is quite 

extensive, with 24 clinical trials either completed or on-going. Over 16,000 subjects have now 

received one or more doses of the final formulation. The objectives of the program are to 

demonstrate immunogenicity across broad range of age groups, persistence of bactericidal 

antibodies, safety and tolerability, and concomitant use with routine vaccines. Serology using 

exogenous human complement has been agreed to with the FDA as being the licensure criteria 

for this vaccine. The data presented during this session is derived using human complement as 

a reagent.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

79

Several Menveo® studies have either completed or are on-going. The following table 

summarizes the findings of key MenACWY-CRM (Menveo®) Clinical Trials:

Age 

group Doses Phase Comparator Key Results

19–55 

y

1 III Menactra®

 Well tolerated

 Noninferior immunogenicity with statistically higher 

immunogenicity response for serogroups CWY

11–18 

y

1

II Menomune®

 Well tolerated

 Statistically higher immunogenicity 

 Persistent immune response

III Menactra

 Well tolerated

 Noninferior immunogenicity for ACWY with 

statistically higher immunogenicity response for 

serogroups AWY

III Concomitant

 Supports co-administration or sequential 

administration with HPV and adolescent Tdap 

2–10 

y

1

II Menomune

 Well tolerated

 Statistically higher immunogenicity

III Menactra  Study ongoing 

0–2 y

1-2 

(toddlers)

4 

(infants)

II MenC

 Well tolerated

 Comparable immunogenicity to 

MenC-CRM

III No 

comparator

 Study ongoing

The MenACWY-CRM (Menveo®) versus Menactra® in Adolescents Phase III Study is a large 

study performed in 40 study sites throughout the US, with a primary endpoint of non-inferiority 

with pre-specified superiority analysis if non-inferiority is first satisfied and approximately 2000 

subjects. Adolescents were enrolled with a lot consistency study embedded, and were 

randomized to receive either one dose of Menactra® or one of three lots of Menveo®. Blood 

was drawn at baseline and 30 days, and there was a 6-month safety follow-up period. Two-year 

data of persistence with a subset of approximately 400 subjects from the same cohort has 

recently become available, which Dr. Dull reported on during this session. 

Seroresponse was the pre-specified primary immunogenicity endpoint agreed upon with FDA. 

For a subject with hSBA titer <1:4 at baseline, seroresponse is defined as a post-vaccination 

hSBA titer ≥1:8. For a subject with hSBA titer ≥1:4 at baseline, seroresponse is defined as a 

post-vaccination hSBA titer of at least 4 times their baseline titer. With respect to seroresponse 

one month post-vaccination, across all four serogroups, the non-inferiority criteria were 

achieved and statistically significant differences were also observed for the A, W, and Y 

serogroups. That is the regulatory endpoint, but speaking to the public health endpoint, for 

those who are protected after vaccination regardless of pre-titer a similar theme emerged. 

Again, non-inferiority was achieved across all four serogroups A, C, W, and Y, and for the A, W, 

and Y, there were statistically significant differences between the two vaccines. In another posthoc analysis among those who are seronegative at baseline, across all measures the same 

theme emerges: non-inferiority for serogroups A, C, W, and Y, with statistically significant 

differences for A, W, and Y. Regarding the Y response, unique in the US and among much of 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

80

the developed world, there has been an emergence of serogroup Y as a serogroup of interest, 

constituting upwards of 1/3 of disease in recent surveillance data. Regarding hSBA titers ≥ 1:8 

at 22 months post-vaccination in the same subset of approximately 400 adolescents, the same 

theme emerged. For A, W, and Y a statistically significant difference was maintained between 

the two vaccines. In terms of local reactogenicity within 7 days of vaccination, both vaccines 

were well tolerated, with comparable reactogenicity and incidences of local injection-site 

reactions were similar between groups. With respect to systemic reactogenicity within 7 days of 

vaccination, rates of systemic symptoms were similar between groups. No serious adverse 

events were assessed as vaccine-related, and there were no study withdrawals due to adverse 

events.

Concomitant administration was examined in a large Phase III study conducted in Latin 

American to examine Menveo® administered alone versus Menveo® co-administered with Tdap 

and HPV vaccines. There was also an analysis of sequential administration with diphtheriacontaining vaccines such as MenACWY-CRM given one month before Tdap. There was no 

incremental increase in reactogenicity of two diphtheria-containing vaccines. This has been 

observed in other studies and is not completely surprising. That is, the safety profile was 

comparable whether given alone, sequentially, or concomitantly with the other study vaccines. 

Non-inferior immunogenicity was measured by percentage with hSBA ≥ 1:8 for all 

meningococcal serogroups; percentage with diphtheria and tetanus antibody concentrations 

≥ 1.0 IU/mL; and percentage with HPV seroconversion and GMTs. There were robust 

responses to all pertussis antigens, and the non-inferiority criteria were met for PT. From an 

immunogenicity standpoint, non-inferiority was achieved for the meningococcal serogroups for 

the diphtheria, tetanus, and HPV. With regard to pertussis antigen responses, non-inferiority 

was achieved for pertussis toxin. Robust responses were achieved across all three antigens, 

but there was a decrement in the response to filamentous hemagglutinin (FHA) and pertactin 

(PRN).

In summary, the Menveo® program seeks to provide protection beginning from 2 months of 

age, and there are data from Phase II that support infant vaccination with a 2-4-6 schedule. 

There is favorable immunogenicity compared with the currently licensed quadrivalent 

meningococcal conjugate vaccine, MenACWY-D (Menactra®), in adolescents. The percentage 

of seroresponders and hSBA ≥ 1:8 is statistically significantly higher for serogroups A, W-135, 

and Y. GMTs are statistically significantly higher for serogroups A, C, W-135, and Y. There is a 

statistically significantly higher percentage of those who maintain hSBA ≥ 1:8 at 22 months postvaccination. Menveo® is well-tolerated in all age groups. Data support concomitant use with 

routine adolescent vaccines. Phase III studies are in progress to support licensure in infants 

beginning from 2 months of age.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

81

Estimate of Effectiveness of Meningococcal Conjugate Vaccine (MCV4)

Ms. Jessica MacNeil, MPH

Division of Bacterial Diseases

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Ms. MacNeil presented an analysis that provided an early estimate of the effectiveness of 

meningococcal conjugate vaccine (MCV4), as well as a description of cases of meningococcal 

disease in persons vaccinated with MCV4.

Regarding the timeline for MCV4 recommendations, MCV4 was licensed in January 2005 for 

use in 11 to 55 year olds. In May 2005, ACIP recommended vaccination of adolescents at three 

time points, at 11 to 12 years of age, or at high school or college entry if not previously 

vaccinated. Expected shortages limited the use of MCV4 in 2005 and 2006. During that time, 

vaccination focused primarily on persons entering high school and college, while 11 to 12 year 

olds were asked to defer vaccination until a later time. As supply improved, ACIP revised their 

recommendations to call for a routine vaccination of all 11 to 18 year olds at the earliest 

opportunity in June 2007. 

MCV4 was licensed on the basis of safety and immunogenicity, and was demonstrated to be 

non-inferior to meningococcal polysaccharide vaccine (MPSV4), the vaccine then licensed for 

use in the US. Previous studies have shown that polysaccharide vaccine is 85% effective 

against serogroup C meningococcal disease [1Rosenstein N, Levine O, Taylor J, et al. “Efficacy 

of meningococcal vaccine and barriers to vaccination.” JAMA 1998;279:435-9]. In prelicensure clinical trials with MCV4, 92% of subjects demonstrated seroresponse to serogroup C, 

while 82% seroresponded to serogroup Y. The incidence of meningococcal disease was at a 

historic low prior to the implementation of MCV4, and this has delayed efforts to conduct a 

vaccine effectiveness analysis using case-control methodology. 

However, through efforts to conduct a case-control study, CDC became aware of a number of 

cases of meningococcal disease in MCV4 recipients. The cases Ms. MacNeil presented during 

this session all occurred between January 2005 and December 2008, and were identified by 

Active Bacterial Core Surveillance Sites (ABCs) and MeningNet sites, which are participating in 

an on-going MCV4 effectiveness case-control study. Surveillance for meningococcal disease in 

these sites is a mixture of both active and enhanced passive surveillance. Data were collected 

for each of these cases through case report forms and medical record reviews. The following 

map reflects the ABCs and the MeningNet sites included in this analysis. Together, the ABCs 

and MeningNet sites cover 54% of the US population:
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

82

5

ABCs and MeningNet Sites

ABCs

MeningNet

• ABCs and MeningNet cover 54% of US population

Cases were included in this analysis if they had isolation of a vaccine preventable serogroup of 

Neisseria meningitidis (serogroup A, C, Y, or W-135), or detection of DNA from a vaccine 

preventable serogroup in a clinical specimen taken from a normally sterile site, more than 10 

days after vaccination with MCV4. From 2005 to 2008, 14 cases of meningococcal disease 

were identified in MCV4 recipients. Of these, 13 (93%) were culture confirmed, 1 case was 

polymerase chain reaction positive (PCR+) with clinically compatible illness, 8 (57%) cases 

were caused by serogroup C, and 6 (43%) cases were caused by serogroup Y. All 14 cases 

had received MCV4, and no common lot of vaccine was identified among the cases. The 

median time from vaccination to disease onset was 395 days (range 43 to 1,021) and cases in 

vaccinated persons were identified in 6 of the 20 participating case-control study sites. Of 

these, 7 (50%) cases were male, 7 (50%) cases were attending college, and 2 (14%) cases 

were military recruits. The median age at vaccination was 18.4 years (range 12.6 to 20.5), the 

median age at time of disease was 19.9 years (range 15.2 to 21.6 years). Nearly half of the 

cases occurred within the first year following vaccination, with other cases occurring 1 to 2 years 

or more 2 years post-vaccination. In interpreting these data, it is important to note that MCV4 

coverage was low in 2005 and 2006. Only cases who were vaccinated early had time to be 

observed 2 to 3 years post-vaccination. With time, this distribution is expected to change.

With regard to the clinical description of the cases, 13 (93%) cases were hospitalized. The 

median hospitalization time was 3 days (range 0 to 46 days). There were 3 fatal cases (21% 

case fatality). Meningitis was reported in 6 (43%) cases and bacteremia in 8 (57%) cases. 

Regarding underlying conditions, Case 1 had a pulmonary embolism and deep vein thrombosis; 

Case 2 had Type 1 diabetes and mitro valve prolapse; Case 3 had irritable bowel syndrome and 

eczema; Case 4 was a current smoker; Case 5 had a history of pyelonephritis; Cases 6, 8, 10, 

11, and 12 had no reported underlying conditions, Case 7 had seasonal allergies; Case 9 had a 

prior history of bacterial meningitis and recurrent infections; Case 13 was taking a medication 

that inhibits complement; and underlying medical conditions were unknown for Case 14.

It is expected that cases of meningococcal disease would occur in vaccinated persons; 

however, as CDC began to receive reports of cases in vaccinated persons, they wondered 

whether the 14 observed cases were within the range of what would typically be expected. To 

estimate the expected number of cases in vaccinated persons, a simulation approach was used. 

The simulation approach is useful for modeling phenomena with significant uncertainty in inputs 

such as MCV4 coverage in the analysis. The simulations rely on repeated random sampling. 

The estimates of vaccine effectiveness were varied in the simulations to determine how likely 

the observed outcome of 14 cases in vaccinated persons was. Because the population under 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

83

surveillance included only ABCs and MeningNet sites, the calculation of expected number of 

cases was limited to this population as well. In the analysis, an incidence rate of .38 per 

100,000 was used, which was the incidence of serogroup C and Y disease among 13 to18 year 

olds. It was calculated using 2002-2006 ABCs data, and was estimated to the US population. 

This incidence rate is similar to the observed rates in the unvaccinated that were calculated 

using data from the 20 participating case-control study sites. National immunization survey 

(NIS) teen estimates for MCV4 coverage were used when they were available. NIS teen 

provides coverage estimates for 13 to 17 year olds and at this time is complete for 2006 and 

2007. In the analysis, CDC was interested in estimating cases for 2005-2008. For 2005 and 

2008, coverage had to be estimated based on the limited distribution and claims data available. 

In 2005, estimated coverage for 13 to 17 year olds was 4%. In 2008, coverage was estimated 

to have increased to approximately 50% in this age group.

Because NIS Teen only provides coverage estimates for 13 to 17 year olds, coverage also had 

to be estimated for 18 year olds. For the primary analysis, CDC used the best estimates of 

what coverage actually was in 18 year olds and increased coverage over time from 2005 to 

2008. Because there was greater uncertainty in the estimates for 18 year olds, a sensitivity 

analysis was also done for varying coverage estimates among those 18 years of age or older. 

Determining the coverage in 18 year olds was the most challenging aspect of this analysis 

because it was complicated by the fact that coverage among all 18 year olds is very different 

than coverage among college freshmen. Coverage also likely varies between colleges. The 

following table summarizes the coverage estimates used in the primary analysis:

17

Vaccine Coverage Matrix: Primary 

Analysis

13-17 years 18 years 19 years 20 years 21 years

2005 4% 25%

2006 ~11%1 37.5% 25%

2007 ~32%2 50% 37.5% 25%

2008 50% 62.5% 50% 37.5% 25%

1National Vaccination Coverage Among Adolescents Aged 13-17 Years – United 

States, 2006. MMWR: Aug 31,2007

2Vaccination Coverage Among Adolescents Aged 13-17 Years – United States, 

2007. MMWR: Oct 10, 2008

These coverage estimates represent the best estimate as to what coverage actually was in 

each year and each group. The way these coverage estimates are applied also accounts for 

the fact that those over 18 will not continue to be vaccinated with MCV4 and, therefore, 

maintains the coverage level reached at 18 years of age for that birth cohort. These 18 year 

olds are also maintained in the populations, so the total population in the analysis increases 

over time.

Regarding the methodology used in the simulations, a record was created for each person in 

the birth cohort. A vaccination status was then assigned to each person, which was determined 

by a uniform random number in the coverage assumptions for that birth cohort. The disease 

status was then assigned to each person, which was also determined by uniform random 

number along with vaccine effectiveness and incidence rate assumptions. Each simulation was 

run 1,000 times. When it was complete, it produced a range of expected values given the 

assumptions used. The results of the simulations were used to determine the probability of 

seeing 14 or more observed cases by determining the area under the curve on the right tail of 

the histogram. Based on best estimate of coverage in 18 year olds, if MCV4 was 90% effective, 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

84

a median of 7 cases would be expected, and the probability of observing 14 or more cases of 

meningococcal disease in vaccinated persons would be 2.9%; therefore, based on the best 

estimates of MCV4 coverage, vaccine effectiveness appears to be greater than 80%. It is 

unlikely to be 90% effective.

Regarding the sensitivity analysis of the probability of seeing 14 or more cases based each 

coverage assumption and level of vaccine effectiveness tested, 18 year old coverage was held 

constant for each birth cohort. If there was 50% coverage (coverage was held constant at 50% 

for all persons 18 years of age or older during 2005-2008) and MCV4 was 90% effective, there 

would be a 5% chance of observing 14 cases in vaccinated persons. If MCV4 were 85% 

effective, there would be a 47% chance 14 cases would be observed. Even with high estimates 

of coverage in the sensitivity analysis, MCV4 appeared to be between 80% and 90% effective.

To summarize, this is the first estimate of vaccine effectiveness for MCV4. The results of this 

analysis suggest that effectiveness of MCV4 is between 80% and 90%, which is similar to 

polysaccharide vaccine. It is also important to consider that all of the observed cases of 

meningococcal disease in MCV4 recipients occurred less than 3 years since vaccination 

therefore this estimate of vaccine effectiveness applies to persons less than 3 years since 

vaccination.

The ACIP Meningococcal Working Group expects more data to be available in 1 to 3 years to 

further evaluate vaccine effectiveness. Plans are to expand the MCV4 effectiveness casecontrol study to additional sites with the hope that this analysis will allow CDC to determine 

separate estimates of vaccine effectiveness for serogroup C and serogroup Y. Additionally, with 

the introduction of new conjugate vaccines, vaccine-specific analyses will be conducted. At this 

time, CDC is unable to evaluate duration of protection using this early data; however, they will 

continue to monitor for cases of disease in vaccinated persons through the case-control study 

and ongoing surveillance in the US.

Discussion 

Dr. Neuzil requested further rationale for why, with respect to effectiveness estimates, a straight 

case-control study using the ABC and MeningNet sites was not done.

Ms. MacNeil responded that CDC is in the process of conducting that study, but it is not 

complete. It has been slow because the incidence has been so low in the last few years. What 

was presented was simply an early estimate using that data. Eased on the case-control study 

are anticipated within the next year or two.

Dr. Pickering requested clarification between what was recognized and what was actually tested 

for. That is, were the 12 people who did not have an apparent immunity deficiency tested for 

terminal complement deficiency or any of the other conditions known to be associated with this 

disease?

Ms. MacNeil replied that the records reviewed were of the actual hospitalization for 

meningococcal disease. There were no additional indications of other cases that had 

complement deficiencies at the time of disease; however, CDC did not have any follow-up 

records regarding whether they were tested for complement deficiencies later.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

85

Rationale and Proposed Recommendations for Revaccination 

of Persons at Increased Risk for Meningococcal Disease

Amanda Cohn, MD

Division of Bacterial Diseases / NCIRD

Centers for Disease Control and Prevention

Dr. Cohn presented the rationale and proposed recommendations for revaccination of persons 

at increased risk for meningococcal disease. She acknowledged and thanked sanofi pasteur 

for providing CDC with much of the data to be presented during her presentation. She then 

explained the working group rationale for recommending revaccination with quadrivalent 

meningococcal conjugate vaccine (MCV4) for high risk groups, clarifying that at this time, there 

is still a single licensed vaccine, MCV4, to which she would be referring. However, these 

proposed recommendations are intended to apply to any quadrivalent conjugate vaccine used, 

and the language will be adjusted as new vaccines are licensed. In addition, she defined the 

group of persons at increased risk, reviewed the available data on safety and immunogenicity of 

revaccination, and reviewed the proposed recommendations.

In 2005, ACIP recommended that persons aged 2 to 55 years who are at increased risk for 

meningococcal disease be vaccinated with MCV4. MCV4 was licensed in 2005 only for a single 

dose, and there were no recommendations made for revaccination made at that time. There 

was an expectation that conjugate vaccines would provide longer lasting protection than 

polysaccharide vaccine. Since that time, it has become clear that data on duration of protection 

from primary vaccination and the safety and efficacy of revaccination are limited, and it is 

unlikely there will be more data available. Given that many individuals in this high risk group are 

at much greater risk for severe disease, the mortality among these high risk groups can be high. 

Therefore, the working group believes that protection should be optimized for these high risk 

groups. There is a precedent for revaccination with meningococcal vaccines as the 

recommendation to revaccinate with polysaccharide states:

“Revaccination might be indicated for persons previously vaccinated with MPSV4 who 

remain at increased risk for infection. 

– Children (age <4 years) should be considered for revaccination after 2-3 years 

– For older children and adults, revaccination might be considered after 5 years”

This recommendation was also made in the setting of limited data on duration of protection, and 

even some concern about blunted response of revaccination; however, revaccination of these 

groups has become a standard of care. Therefore, the burden of proof needed to be that 

conjugate vaccines provide substantially greater protection than polysaccharide vaccine five 

years after vaccination not to recommend revaccination. While these individuals may continue 

to be protected beyond five years, immunogenicity data are not strong enough for the working 

group to be assured.

With respect to why the working group believes high risk groups should be revaccinated, the 

group evaluated data on circulating antibody, but memory and herd immunity are also important 

benefits of conjugate vaccines. Serum bactericidal activity (SBA) is a measure of functional 

antibody or the ability of sera to kill a strain of Neisseria meningitidis in the presence of 

complement. Baby rabbits were used as the complement source. SBA is an accepted marker 

of immunogenicity, but no there is no clear cut off that indicates long-term protections for 

individuals after vaccination. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

86 

Dr. Cohn presented the percentage of persons with SBA titers greater than 1:128, because this 

was the cutoff that was used for licensure trials for MCV4. However, this may be an overestimate of titers needed for protection. Additionally, the assays are highly variable across 

laboratories. There are also properties of conjugate vaccines, such as the ability to mount a 

memory response, that are not quantitated in SBA titers. The contribution to protection of these 

conjugate properties versus levels of circulating antibody is not well-understood, but there is 

evidence from the meningococcal group C conjugate vaccine (MenC) experience in the UK that 

memory alone is not enough to protect against meningococcal disease, perhaps because there 

is not enough time to mount a memory response before infection becomes overwhelming. 

Finally, there is not high enough coverage with MCV4 that reduced transmission can be 

expected, so no additional protection can be presumed through herd immunity at this time.

SBA-BR seroresponse ≥1:128 post-vaccination at years 3 and 5 post-vaccination, serogroup C, 

Dr. Cohn presented data from studies of subjects in the initial clinical trials. The total number of 

subjects tested 3 and 5 years out is very small. The 3-year subjects were initially vaccinated at 

11 to 18 years of age, and the 5-year year subjects were initially vaccinated at 2 to 10 years of 

age. Three years after vaccination, the subjects vaccinated with MCV4 had substantially higher 

titers than those vaccinated with MPSV4 in naïve controls. At five years, only 50% of those 

vaccinated with MCV4 has titers at or above 1:128, which is greater than the 42% seen in the 

other two groups, but is still low. There is similar data at 5 years among subjects initially 

vaccinated at 11 to 18 years of age, but Dr. Cohn did not show that data because the number of 

subjects in that study was very small. However, the data is comparable and is very similar to 

the 2 to 10 year olds who were vaccinated 5 years previously [Data courtesy of sanofi pasteur, 3 

year follow-up of MTA02 (11-18 year-olds), 5 year follow-up of 603-02 (2-10 year-olds)].

In terms of the GMTs of the SBA, there is better persistence of SBAs in subjects vaccinated with 

MCV4 compared to MPSV4 and at 5 years. Titers are higher than age matched controls, which 

is not the case for subjects who were previously vaccinated with MPSV4, but the absolute 

values of these titers is still low. In the smaller study of 11 to 18 year olds at 5 years, the GMTs 

were similarly low. To summarize, the 5-year SBA persistence data do not convince the 

working group that protection, as measured by circulating antibody at 5 years, is substantially 

higher in subjects vaccinated with MCV4 than in unvaccinated individuals or in subjects who 

received MPSV4,[ Data courtesy of sanofi pasteur, 3 year follow-up of MTA02 (11-18 year-olds), 

5 year follow-up of 603-02 (2-10 year-olds)].

The proposed 2009 definition for persons recommended for revaccination includes the 

following:





Those at increased risk of infection

–

–

–

Persistent complement deficiency

Anatomic or functional asplenia 

Those with suboptimal response to vaccination

Anatomic or functional asplenia 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

87 



–

–

Those with prolonged or frequent exposure

Microbiologists who are routinely exposed to isolates of N. meningitidis 

Frequent travelers to or people living in areas with high rates of meningococcal 

disease (Meningitis belt)

Previous ACIP language implied that only persons with terminal complement component 

deficiencies are at increased risk. To clarify, the working group would like to change this 

language to state that persons with persistent deficiencies in the complement pathway are at 

increased risk, and those deficiencies would be listed in the recommendations. Late 

complement pathway deficiencies are highly associated with recurrent disease, but other 

deficiencies put persons at risk as well. For example, 70% of children with primary C3 

deficiency have an episode of invasive bacterial disease in a median age of 2 years, and 55% of 

this disease is caused by Neisseria meningitidis. There is a high risk for recurrent disease. In 

comparison, C1, C2, and C4 deficiencies are rarely associated with invasive disease. 

Properdin, factor D, and terminal complement deficiencies also cause a high rate of infections 

(50-60%). These occur in the teenage years, and almost all of this disease is caused by 

Neisseria meningitidis. Complement-independent, antibody-mediated phagocytic killing can 

occur with high levels of antibody. Therefore, maintaining high levels of antibody in this 

population is important.

The data on the risk of disease in persons with asplenia is from older case series and studies 

that showed risk for all encapsulated organisms, including, but not specifically for Neisseria 

meningitidis. So while the working group was unable to offer a precise risk for disease among 

asplenics, it is widely accepted that persons with asplenia are at risk for invasive infection from 

Neisseria meningitidis. There are also data to suggest that persons with asplenia have a 

suboptimal response to vaccination. A group of 130 persons with asplenia had a significantly 

lower response to one dose of MenC vaccine in the UK. Their SBA GMTs were 157 compared 

to 1448 among non-asplenics, and only 80% of those individuals had titers greater than 1:8 SBA 

[Balmer, P et al. Infection and Immunity, Jan 2004, 332-337]. 

In terms of exogenous exposures putting a person at increased risk, microbiologists exposed to 

isolates of Neisseria meningitidis are at increased risk with an estimated attack rate of 13 per 

100,000 microbiologists exposed to an isolate of Neisseria meningitidis during 1996-2001, 

compared to a rate of .3 per 100,000 among US adults. There is also a high risk of mortality, 

which was 50% among a small group of laboratory workers with an n of 16, which is possibly 

related to this group being exposed to a high bacterial load [Sejvar et al, J. Clin Micro, 2005].

The disease risk in travelers or to persons living in areas with the epidemic meningococcal 

disease, such as the African Meningitis Belt, is not known. It is likely to only be higher if that 

person is living in or working with local population; however, given the potential for limited 

access to medical care while traveling, the working group felt that this was important to include 

in these recommendations. Additionally, vaccination has a small, but possible ability to reduce 

risk of colonization and spreads to household contacts of travelers upon the return, such as 

occurred after the W 135 Hajj outbreak. 

In terms of how many people would be included in this recommendation, based on private 

claims data provided to the working group by sanofi, approximately 20,000 doses annually are 

given to groups for which vaccine is recommended only for high risk persons. Over the course 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

88

of five years, this would be about 100,000 persons in total who received vaccination, but not all 

of these individuals would necessarily need to be revaccinated. Travelers may not be included 

in these estimates, as vaccination is an out-of-pocket cost for travelers, but most travelers will 

unlikely be traveling five years after to the African Meningitis Belt, so they were unable to 

estimate how many travelers would be included. Although there are about 60,000 persons with 

sickle cell anemia in the US, the prevalence of complement deficiencies and other types of 

asplenia is unknown. So the working group recognizes that this recommendation is off-label 

use of the vaccine, but they are comfortable with this given the targeted and small number of 

individuals at increased risk included in these groups.

The working group discussed at length their preference not to include college freshmen living in 

dorms and military recruits in the groups recommended for revaccination at this time. This is a 

much larger cohort of individuals, more than 600,000 / year with much broader policy and 

programmatic implications. In 2009, very few persons in these groups were vaccinated greater 

than five years prior and coverage in the fall of 2006 was only 11%, so it was likely to even be 

lower. For the upcoming college year, the number of adolescents vaccinated more than five 

years ago will be very low. In most colleges, there is relatively high vaccination coverage 

among college freshmen, and there is close to 100% coverage among military recruits. 

Therefore, individuals no longer protected by vaccine may be protected by the potential for herd 

immunity in these institutions. The working group agreed that more time should be taken to 

assess the degree of transmission in these highly vaccinated populations, and the need for 

revaccination in these groups.

There are limited safety data available on revaccination. Dr. Cohn reported on data from two 

studies. The first was from subjects initially vaccinated at 11 to 18 years old and the second 

was in subjects initially vaccinated at 2 to 10 years of age. The proportion of subjects with local 

and systemic adverse events was similar whether they received MCV4 or they were vaccinenaïve prior to this initial vaccination. The reactions were similar and there were no serious 

adverse events in any of the groups. A strong boost response was observed with revaccination 

for both serogroup C and serogroup Y. In terms of the percentage of seroresponders after 

revaccination compared to age matched controls, 100% of subjects previously vaccinated with 

MCV4 had titers at or above 1:128. A strong boost response was also demonstrated by high 

GMTs among subjects previously vaccinated, compared to vaccine-naïve subjects. The same 

was true for serogroup Y. More subjects were able to retain titers at or above 1:128 five years 

after initial vaccination with serogroup Y, compared to serogroup C. A large portion of the 

vaccine-naïve individuals also had antibody titers above or at 1:128. This may be due to natural 

immunity due to nasal pharyngeal carriage or it may be related to the assay used. 

Nevertheless, a boost response to revaccination was clearly demonstrated for serogroup Y 

compared to the previously vaccine naïve group [Data courtesy of sanofi pasteur, 5 year followup of 603-02 (2-10 year-olds at dose 1)]. 

To summarize, even with the small number of individuals in these studies, the ACIP working 

group was convinced that revaccination would be safe and would induce a boost response.

The working group also evaluated this five year interval for revaccination among the young 

children aged 2 to 6 years. Regarding the SBA GMTs by single year of life for 2 to 10 year olds, 

there are very few persons in each of the age years where it is clear that the initial immune 

response in the very young children is similar to polysaccharide vaccine. It is known that 

protection in young children vaccinated with polysaccharide vaccine is not long-lasting 

[Pichichero M et al. Pediatr Infect Dis J. 2005;24:57-62]. Limited antibody persistence data with 

MCV4 suggests children vaccinated at age 2 to 3 years are not as well-protected three years 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

89 

post vaccination. Of children vaccinated at age 2-3 years, 14.6% (n=48) had an hSBA titer >1:4 

3 years after vaccination [Granoff, D et al. PIDJ 2005:24, 132-136]. Children at increased risk in

this age group are also likely to be asplenic or have complement deficiency, and may have a 

suboptimal response to vaccine. The working group agreed that an additional dose of vaccine 

three years after the first MCV4 may benefit this small group of children. 

Thus, the working group was proposing revaccination for high risk persons out of an abundance 

of caution. In the setting of demonstrated disease risk, which is very high in some of these age 

groups, and a low risk for serious adverse events, the working group felt that it would be useful 

to have limited off-label use in this small targeted group. There is evidence of waning functional 

antibody, which may or may not indicated lack of protection; however, it is known that high 

levels of circulating antibody is important for persons with complement deficiencies. Persons at 

increased risk are not protected at this point by herd immunity in the population. There is also 

strong evidence of a boost response. Therefore, the proposed recommendation is:

“Persons aged 2-55 years who remain at increased risk for meningococcal disease 5 

years after vaccination with MCV4 or MPSV4 should be revaccinated with MCV4. This 

includes:

–

–

–

–

Persons with persistent complement component deficiencies*

Persons with anatomic or functional asplenia 

Microbiologists who are routinely exposed to isolates of N. meningitidis 

Frequent travelers to or people living in areas with high rates of meningococcal 

disease (African meningitis belt)

*inherited or chronic deficiencies such as C3, properdin, factor D, or late complement 

components”

Two additional components of this recommendation would be stated as follows:

“At this time, college freshmen living in dorms who were previously vaccinated against 

meningococcal disease at age 11-18 years are not recommended to be revaccinated 

with MCV4. 

Children who received their first MCV4 or MPSV4 at age 2-6 years and remain at 

increased risk for meningococcal disease should be vaccinated with an additional dose 

of MCV4 3 years after their first meningococcal vaccine.” 

Discussion

Referring to the safety of revaccination [slide 15], Dr. Neuzil said it would be ideal to see a 

larger number of subjects who had received a repeat vaccination in the 11 to 18 year old group 

(n=17). Based on a power calculation, that would not be high enough to detect a difference. 

She wondered whether Dr. Cohn could tell them anything more about local reactions, even 

though the total number was close, in terms of whether there was any trend toward greater 

severity, et cetera.

Dr. Cohn responded that there is one additional study that she did not include in adolescents 11 

to 18 years of age who were revaccinated at three years rather than five years. The n in that 

study was greater and the proportions were similar. She requested that someone from sanofi 

further discuss the reactions as she did not have specific information beyond whether they fell 

into one of the specified categories.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

90

Dr. Hosbach (sanofi pasteur) responded that they have larger numbers at three years which he 

agreed to provide to the group, although he did not have it with him. There was nothing 

remarkable. 

Dr. Marcy expressed concern about the data Dr. Dull presented for Menactra®, given that 

subjects barely made it at 1:8 in some cases. Now they were viewing 1:128, and the levels 

were very high. He was trying to understand the difference, because simply attributing it to 

different assays was not sufficient.

Dr. Cohn responded that human complement was used in the other assays, while the sanofi 

and UK studies had used baby rabbit complement for the most part. There are also differences 

in assays in various laboratories. The level needed for licensure was based on baby rabbit 

complement, which seems to have changed in the process in that she believed human 

complement would be required for all future studies. She inquired as to whether anyone from 

FDA wanted to comment.

Dr. Hosbach (sanofi pasteur) responded that baby rabbit complement was utilized initially in 

comparing what was licensed for Menomune®, the polysaccharide vaccine. That was utilized 

as a standard. For studies in infants and toddlers, human complement was used as well. 

Referring to the second component of the proposed recommendation, James Turner (ACHA) 

thought they would find that there would be students coming to school who received 

polysaccharide when they were teens. The proposed recommendation seemed to state that no 

revaccination would be recommended if they had been vaccinated against meningococcal 

disease. He suggested an amendment to read, “Those who were previously vaccinated with 

MCV4, would not need to be revaccinated with MCV4.” 

Dr. Cohn responded that the change could be made to reflect MCV4, and a line could be added 

to indicate that persons with polysaccharide vaccine should be revaccinated if they have not 

been vaccinated in five years.

Amy Middleman (SAM) noted that the proposed recommendations indicated that persons aged 

2 to 55 who remained at increased risk from meningococcal disease should be immunized 

again five years later. However, the second component of the recommendation separated out 2 

to 6 year olds and indicates revaccination at three years. She wondered whether the first part 

should actually read “7 to 55 year olds.”

Dr. Cohn said that consideration was given to changing that, but the caveat is that if children are 

initially vaccinated at age 2 and then they are vaccinated at age 5, by the next time they would 

be over 7 years old. They did not want people to think that they continually needed to be 

vaccinated at three years. She agreed that they could change it if it seemed confusing.

Dr. Baker pointed out that the dashes needed to be replaced with “through.”

Dr. Sawyer was not clear whether the working group was proposing multiple revaccinations or a 

one-time revaccination.

Dr. Cohn answered that as currently written, the recommendation was that persons continue to 

be vaccinated every five years. This can be readdressed in the future, but the group was 

thinking that to simplify the recommendations, this language would work well. For this particular 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

91

group of individuals, this may have to be revisited every five years and would likely require the 

same recommendation given the high risk of disease.

Dr. Baker agreed that it was frustrating, given the limited data. There is a tremendous risk for 

the individuals to be included. The population and costs are small. Microbiologists are already 

covered by the Occupational Safety & Health Administration (OSHA) for vaccine, and travelers 

or their employers pay for the vaccine. The risk of not having protective immunity drove this 

recommendation. The poorest response in is ages 2 through 4 year. They are more likely to be 

vulnerable as they turn 5 or 6, depending upon when they have been vaccinated. The Red 

Book used to say 3-5, but people were confused about whether this meant 3 or 5. Moving to a 

five-year recommendation as routine for adolescents, but a three-year for children younger than 

that is consistent with the Red Book.

With regard to the lack of specific safety data, Dr. Sawyer wondered whether Vaccine Adverse 

Event Reporting System (VAERS) data were assessed to determine whether those who had 

been following this practice without recommendations had generated any reports to VAERS.

Dr. Cohn responded that there is a VAERS analysis of people who are vaccinated with MCV4 at 

all. There has not been a specific analysis to examine people who may have received two 

doses. Aside from the reports of Guillain-Barré Syndrome (GBS), there is nothing specifically 

about syncope in adolescents. In children who received many other vaccines, the adverse 

events are similar (e.g., local reactions in other vaccines).

Dr. Cieslak indicated that he had not seen any data on breakthrough cases because of waning 

immunity, nor had he seen data on the efficacy side suggesting that that population they were 

proposing to revaccinate was likely to be protected after the second dose. If I had to guess, 

because they did not respond to the first dose, they would probably be less likely to respond to 

the second dose.

Dr. Baker responded that the data Dr. Cohn summarized on asplenics led to the UK 

recommendation that adult asplenics receive two doses two months apart. They immunized 

and bled subjects one month. It is known that asplenics do not have a good primary response, 

so revaccinating them may be similar to giving them two doses, which is routine health policy in 

the UK. Even if one or two microbiologists died of meningococcal disease at five years, she did 

not want to be the one to find out. While there are very limited data regarding safety, this is 

driven by the incredible risk for these patients. The difference is 13 per 100,000 for 

microbiologists compared to .3 per 100,000.

Nancy Messonnier added that the working group discussed balance: Do you wait for 

breakthrough cases to occur before you make a recommendation? Part of the conclusion that 

the working group came to was that the standard of care was actually the polysaccharide 

vaccine recommendation for revaccination, which appeared to be based on a similar lack of 

data on breakthrough cases. As discussed in the working group, there was not convincing 

evidence that the conjugate vaccine behaved substantially differently in these age groups than 

polysaccharide vaccine such that a different recommendation would be warranted than would 

be made for polysaccharide vaccine.

Dr. Englund noted that there were some data showing that college freshmans’ re-immunization 

was not very robust. She wondered whether the working group was happy with that part of the 

recommendation.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

92 

Dr. Cohn responded that there are some data to show that individuals who initially received 

polysaccharide vaccine and were then give conjugate vaccine were able to overcome and 

boost. Though not to the same extent as persons who previously received conjugate vaccine, it 

was better than an additional dose of polysaccharide vaccine.

Dr. Judson inquired as to whether this would have to go back through the FDA for a change in 

indications or labeling, given that they were making a recommendation based on inadequate 

efficacy data that the FDA might not approve.

Dr. Cohn responded that the recommendation was for off-label use.

Dr. Baker replied that the current label is for one dose. There is no re-immunization labeling at 

this time, as has been the case for polysaccharide vaccine for years. The initial efficacy was in 

the military where human complement was used. In the military polysaccharide was developed 

because of the tremendous outbreaks and the high mortality. There was a great efficacy study 

in which efficacy was correlated with bactericidal activity in recruits. That was the history of a 

very bad disease versus a very safe vaccine. With regard to Dr. Englund’s question regarding 

whether the working group was happy, Dr. Baker said she was not happy but this was all the 

data they had and she was concerned about individuals at high risk.

Dr. Englund felt strongly that the lack of data was very concerning. This is a major problem that 

will affect a large segment of children who received the polysaccharide vaccine. There are 

mechanisms to get it funded that ACIP should be encouraging.

Dr. Baker thought the assumption that there is a large population of children who received 

polysaccharide vaccine who will need to be revaccinated was a tremendously wrong 

assumption.

Dr. Cohn thought that most children who received polysaccharide vaccine would have received 

it prior to going to college unless they were in one of the high risk groups. If they were in a high 

risk group, they would fall under the recommendation to continue to be revaccinated with MCV4. 

The polysaccharide recommendations were only made for children who were entering college 

and were living in dorms.

Dr. Hosbach (sanofi pasteur) stated that this is not in the package insert. The older package 

insert does indicate that the ACIP recommendation says to immunize these populations every 

three to five years. They do intend to generate additional data.

Motion: MCV4 Revaccination for Persons at Prolonged Increased Risk

Dr. Sawyer moved to approve the revised recommendations as stated in the presentation. Dr. 

Sumaya seconded the motion. The recommendation will include clarification again MCV4 and 

dashes with be changed to “through.” The motion passed with 13 affirmative, 1 negative, and 1 

abstention.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

93 

VFC Resolution Update: Meningococcal Vaccines

Jeanne M. Santoli

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention 

Dr. Santoli indicated that the purpose of this proposed resolution was to update the 

revaccination recommendations discussed during this session and to streamline the resolution 

through the use of links to published documents. 

The MPSV4 Component of the VFC Resolution, I are:







































Eligible groups

All children 2-18 years of age. 

Recommended Meningococcal Polysaccharide Vaccine Schedule 

The recommended schedule for meningococcal polysaccharide vaccine can found at: 

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm 

See Section B. Conjugate Vaccine to Prevent Meningococcal Disease for potential, 

limited use of MPSV4 for revaccination.

Dosage Intervals for Meningococcal Polysaccharide Vaccine 

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm 

See Section B. Conjugate Vaccine to Prevent Meningococcal Disease for potential, 

limited use of MPSV4 for revaccination.

Recommended dosage 

The recommended dosage can be found in the package inserts available at 

http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833 

Contraindications and Precautions

Contraindications and Precautions can be found in the package inserts available at 

http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833

MCV4 Component of the VFC Resolution, I are:

Eligible groups

All children 2-18 years of age. 

Recommended Meningococcal Polysaccharide Vaccine Schedule 

The recommended schedule for meningococcal conjugate vaccine can found at: 

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm 

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5631a3.htm

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5648a4.htm 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

94 



































Revaccination is recommended for children at increased risk of meningococcal disease, 

including: 

Persons with persistent complement component deficiencies (inherited or chronic 

deficiencies such as C3, properdin, factor D, or late complement components )

Persons with anatomic or functional asplenia 

Persons infected with HIV

Microbiologists who are routinely exposed to isolates of N. meningitidis 

Frequent travelers to or people living in areas with high rates of meningococcal disease 

(African meningitis belt).

Dosage Intervals for Meningococcal Conjugate Vaccine 

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm 

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5631a3.htm

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5648a4.htm 

Children through age 18 years who received their first dose of MCV4 or MPSV4 at ages 2-6 

years and remain at increased risk for meningococcal disease should receive an additional 

dose of MCV4 at 3 years after their first dose. 

Children through age 18 years who received a dose of MCV4 or MPSV4 after age 6 and 

remain at increased risk for meningococcal disease should receive an additional dose of 

MCV4 at 5 years after their previous dose. 

MCV4 is preferred for revaccination, but MPSV4 is an acceptable substitute for persons with 

precautions or contraindications to MCV4 vaccine.

Recommended dosage 

The recommended dosage can be found in the package inserts available at 

http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833 

Contraindications and Precautions

Contraindications and Precautions can be found in the package inserts available at 

http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833 

The underlined group, persons infected with HIV, was not a group that was discussed. 

However, that group was previously included in the VFC resolution for vaccination by the ACIP, 

so it was brought forward into this VFC resolution to give providers who are treating these 

children the flexibility of vaccinating VFC eligible children with this vaccine.

Then the resolution concludes with the following statement about making updates based on 

published documents:

“If an ACIP recommendation or notice regarding meningococcal vaccination is published 

within 12 months following this resolution, the relevant language above (except in the 

eligible groups sections) will be replaced with the language in the recommendation and 

incorporated by reference to the publication URL. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

95 

Motion: VFC Resolution Update for Meningococcal Vaccines

Dr. Baker moved to approve the revised recommendations as stated in the presentation. Dr. 

Sawyer seconded the motion. It was noted that all dashes should be replaced with “through.” 

The motion passed with 14 affirmative, 0 negative votes, and 1 abstention.

Introduction

Paul Cieslak, MD

Chair, ACIP JEV Vaccines Workgroup

Dr. Cieslak offered gratitude to the technical advisors the workgroup was able to obtain from the 

outside including, Christina Greenaway (International Society of Tropical Medicine), Tony Marfin 

(Washington Department of Health), David Shlim (ASTMH), and Tom Solomon (University of 

Liverpool).

He explained that the JEV Vaccines Workgroup was charged with reviewing safety and 

immunogenicity data for the new inactivated Vero cell-derived JEV vaccine, tradename Ixiaro ®; 

updating and revising the 1993 ACIP recommendations for the use of JE vaccines among US 

travelers; monitoring the availability of JEV vaccines for US travelers and working to mitigate 

possible supply issues (BIKEN’s production of JE-VAX ®); and addressing the availability of 

JEV vaccines for US children, with the new vaccine being labeled only for persons 17 years of 

age and above. 

Revised Recommendations for the Use 

of Japanese Encephalitis Virus Vaccines

Marc Fischer, MD, MPH

Arboviral Diseases Branch

DVBID, NCZVED, CDC

Dr. Fischer reminded everyone that Japanese encephalitis virus (JEV) is a mosquito-borne 

flavivirus. JEV is the leading cause of encephalitis in Asia, with an estimated 35,000 to 50,000 

annual cases. Of these, 20%-30% of patients die and 30%-50% of survivors have significant 

sequelae. There are no specific antiviral therapies, and treatment consists of supportive care. 

JEV is transmitted in an enzootic cycle between mosquitoes and amplifying vertebrate hosts, 

primarily pigs and wading birds. JEV is transmitted to humans through the bite of an infected 

mosquito, but less than 1% of infected people develop symptomatic disease. Humans are a 

dead-end host and do not develop a level or duration of viremia sufficient to infect mosquitoes.

Japanese encephalitis occurs primarily in rural agricultural areas, often associated with rice 

production and flood irrigation. The mosquitoes that transmit JEV feed primarily outdoors during 

the evening and night. In endemic countries, most adults have protective immunity and JE is 

Japanese Encephalitis Virus
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

96

primarily a disease of children. However, since travelers from non-endemic countries usually 

do not have JEV antibodies, travel-associated Japanese encephalitis can occur among persons 

of any age. In most temperate areas of Asia, JEV transmission is seasonal, and human disease 

usually peaks in summer and fall. In the subtropics and tropics, transmission patterns vary and 

human disease often peaks during the rainy season, but may occur year round.

From 1973 to 2008, there were 55 cases reported in the literature of travel-associated Japanese 

encephalitis among people from non-endemic countries, including the US. The median age of 

these cases was 34 years, patients ranged from 1 to 91 years of age, 53% of the patients were 

male, 34 of the travel-associated cases were tourists, 9 were expatriates living in Asia, and 6 

were soldiers or military personnel. The type of travel was unknown for another 6 cases. Ten 

of the reported cases were fatal, and 24 of the survivors had sequelae. None of these patients 

had received JEV vaccine. 

For 37 of the 55 travel-associated cases, more complete information was available regarding 

their itineraries and activities. Duration of travel for these cases ranged from 10 days to 34

years, and 65% of the cases were traveling for a month or longer. Of the 13 short-term 

travelers, 10 had a trip duration of 2 to 4 weeks, and 3 had traveled for 10 days to 2 weeks. 

Among these shorter-term travelers, 3 had known extensive rural exposures, and 8 stayed in 

resorts or coastal hotels with shorter trips into more rural areas. Two cases did not have any 

risk-related itinerary information available. No cases were reported among short-term travelers 

who visited only urban areas.

From 1943 to 1972, there were more than 300 cases of JE among U.S. military personnel. 

Between 1973 and 1992, 11 cases were reported among US citizens, including 5 among civilian 

travelers. Since December 1992, when a JEV vaccine was first licensed in the US, only 4 cases 

of Japanese encephalitis have been reported among US citizens, all among civilian travelers or 

expatriates. Three of these cases occurred among returning immigrants or travelers visiting 

family in Asia. 

Estimating the incidence of Japanese encephalitis for travelers to Asia is difficult. Extrapolating 

from the rates of disease among unimmunized US military personnel or resident children in 

endemic areas, the risk of Japanese encephalitis for travelers with prolonged stays in rural 

areas with active JEV transmission may theoretically be as high as 10 to 200 cases per 1 million 

travelers per week. However, most travelers do not have this type of itinerary or risk, and 

between 1973 and 2008, there were only 15 cases of JE reported among US travelers to Asia. 

In 2004, there were an estimated 5.5 million entries of US travelers into Japanese encephalitis 

endemic countries. Using these figures, for all travelers to Asia, an overall risk of less than 1 

case per 1 million trips would be estimated. 

Based on the available data, the workgroup concluded that the overall risk of Japanese 

encephalitis for most travelers to Asia is very low, but that the risk varies based on destination, 

duration, season, and activities. The risk of Japanese encephalitis among expatriates and 

travelers who stay for prolonged periods in rural areas with active JEV transmission, are likely 

similar to that of the susceptible resident population. Travelers on brief trips may be at 

increased risk if they have outdoor or nighttime exposures in rural areas, especially during 

periods of active transmission. Short-term travelers, whose visits are restricted to major urban 

areas, are at minimal risk for Japanese encephalitis.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

97

Two JEV vaccines are currently licensed in the US. JE-VAX®, an inactivated mouse brainderived vaccine, has been licensed since 1992 for use in travelers one or more years of age. In 

March 2009, the FDA approved IXIARO®, an inactivated Vero cell-derived vaccine, for use in 

travelers 17 years of age or older. The inactivated mouse brain-derived vaccine was first 

developed in the 1960s. It has been administered to millions of people worldwide and has been 

used effectively to control Japanese encephalitis disease in several Asian countries including 

Japan, Taiwan, South Korea, and Thailand. In December 1992, a formulation of this vaccine 

was first licensed in the US. The vaccine was manufactured by BIKEN in Osaka, Japan and is 

distributed in the US by sanofi pasteur. However, in 2006, BIKEN discontinued production of 

JE-VAX®, and remaining supplies are now limited. 

JE-VAX® is a formalin inactivated vaccine derived from wild-type Nakayama-NIH JEV strain 

grown in mouse brains. The final preparation is lyophilized and contains gelatin as a stabilizer 

and thimerosal preservative. The primary immunization series consists of three doses 

administered subcutaneously on days 0, 7, and 30. Efficacy of the mouse brain-derived vaccine 

was demonstrated in a randomized, controlled trial conducted among 65,000 Thai children. 

Study participants were randomized to receive two doses of JEV vaccine or tetanus toxoid. 

After 2 years, the vaccine had an efficacy of 91% [Hoke 1988]. The current 3-dose primary 

immunization series for travelers was established based on immunogenicity studies performed 

in adults from non-endemic countries.

Mouse brain-derived JEV vaccine results in mild injection site reactions in about 20% of 

recipients. Mild systemic side effects such as fever, headache, or diarrhea have been reported 

in approximately 10% to 30% of vaccinees. This vaccine has also been associated with allergic 

hypersensitivity reactions and rare, but serious neurologic adverse events. Allergic 

hypersensitivity reactions, including generalized urticaria and angioedema of the face and 

oropharynx, have been reported primarily among adult travelers and military personnel. The 

reported frequency of allergic reactions range from 10 to 260 cases per 100,000 vaccinees, and 

these risks vary by country, year, case definition, surveillance method, and vaccine lot [Plesner 

2003; Takahashi 2000; Berg 1997; CDC 1993]. The study with the highest incidence of allergic 

hypersensitivity reactions included active follow-up of over 14,000 US Marines in 1997 in which 

38 allergic reactions were identified, including 27 patients with urticaria, angioedema, and / or 

wheezing, and 11 patients with generalized pruritis. Two patients were hospitalized for 

observation. Although most of these reactions occurred within the first 24 hours after the first 

dose, when they occurred following a subsequent dose, symptom onset was often delayed with 

a median of 4 days and a range of up to 2 weeks [Berg 1997].

Gelatin, which is used as a vaccine stabilizer, may be responsible for some of these allergic 

reactions. In one study among Japanese children who received mouse brain-derived JEV 

vaccine, 10 children who developed an immediate hypersensitivity reaction all had measurable 

immunoglobulin E (IgE) antibodies against gelatin. By contrast, only 1 of 28 children developed 

a delayed hypersensitivity reaction, and none of 15 controls who had no allergic reaction had 

evidence of anti-gelatin IgE antibodies [Sakaguchi 2001].

The incidence of neurologic events reported following receipt of mouse brain-derived JEV 

vaccine has ranged from 0.1 to 2.6 per 100,000 vaccinees [Takahashi 2000; Plesner 1998]. 

These neurologic events have included paresthesia, seizures, encephalopathy, gait 

disturbance, and Guillain-Barre syndrome. In addition, there have been case reports of children 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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in Japan and Korea with acute disseminated encephalomyelitis (ADEM) following vaccination. 

In 2005, in response to these cases, Japan suspended routine immunization with mouse brainderived JEV vaccine. In reviewing this decision, the World Health Organization (WHO) Global 

Advisory Committee on Vaccine Safety determined that a causal link had not been 

demonstrated. The committee recommended that, although current use and policies should not 

be changed, the mouse brain-derived vaccine should be gradually replaced by new generation 

JEV vaccines [Matsukura 1980; Ohtaki 1992; Ohtaki 1995; Sohn 2000; Takahashi 2000; Matsui 

2002; Ferguson 2007; Plesner 2000; Plesner 2003].

The recently licensed inactivated Vero cell-derived JEV vaccine is manufactured by Intercell 

Biomedical and distributed in the US by Novartis Vaccines. This vaccine is now available in the 

US, Europe, and Australia, and the manufacturer anticipates having adequate supplies to meet 

US civilian traveler needs. IXIARO® is a formalin inactivated vaccine derived from the 

attenuated SA 14-14-2 JEV strain propagated in Vero cells. The final liquid preparation 

contains aluminum hydroxide as an adjuvant. It does not contain gelatin or thimerosal. The 

primary immunization series consists of two doses administered intramuscularly on days 0 and 

28. The vaccine is not licensed for use in children less than 17 years of age. 

Due to the availability of several effective JEV vaccines in Asia, randomized, controlled efficacy 

trials to evaluate new vaccines would now be logistically difficult and potentially unethical. As a 

result, there are no efficacy data for the new Vero cell-derived JEV vaccine. Instead, the 

vaccine has been licensed based on its ability to induce JEV neutralizing antibodies as a 

surrogate for protection, and based on safety evaluations in almost 5,000 adults [Hombach 

2005; Markoff 2000].

The pivotal non-inferiority study compared people randomized to receive two doses of the new 

Vero cell-derived vaccine to three doses of the existing mouse brain-derived vaccine. The study 

was performed among adults in the US, Austria, and Germany. The primary outcome measure 

was the proportion of vaccinees who developed JEV neutralizing antibodies based on a 50% 

plaque reduction neutralization test or PRNT50. The immunogenicity analysis was performed 

on 735 subjects who met all protocol criteria, including having no JEV neutralizing antibodies 

prior to vaccination. The safety analysis was performed on 863 subjects who had received at 

least one dose of either vaccine. Of the Vero cell-derived vaccine recipients, 98% developed a 

neutralizing antibody titer of 10 or greater, compared to 95% of the mouse brain-derived vaccine 

recipients, at 56 days after the first dose. This met the study criteria for non-inferiority. The 

geometric mean titers (GMTs) were significantly higher among recipients of the Vero cellderived vaccine. However, it is important to note that this study used SA 14-14-2 as the target 

strain in the neutralizing antibody assay and GMTs were higher for the mouse brain-derived 

vaccine when the Nakayama JEV strain was used in the assay. In this study, severe pain or 

tenderness at the injection site was uncommon and occurred in less than 2 percent of recipients 

of either vaccine. However, severe redness or swelling at the injection site was significantly 

less common among recipients of the Vero cell-derived vaccine. The frequency of systemic 

adverse events was similar between the two groups [Tauber 2007].

The pivotal safety study compared 1,993 subjects who received two doses of the new Vero cellderived JEV vaccine to 657 subjects who received two doses of a placebo adjuvant composed 

of phosphate buffered saline and aluminum hydroxide. Adverse events were monitored for 56 

days following the first dose. The proportion of vaccinees who reported any adverse event, 

medically attended adverse events, serious adverse events, or an adverse event that resulted in 

termination from the study, were similar between the two groups [Tauber 2008]. 
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99

Among the 12 (0.6%) subjects in the Vero cell-derived vaccine group who terminated the study 

prematurely due to adverse events, 2 (0.1%) of the events were classified as severe, including 

one case of gastroenteritis and one rash. Of the adverse events leading to termination, 8 

(0.4%) were considered possibly related to the study vaccine, including two subjects with 

headaches, and one subject each with influenza-like illness, injection site pain, nausea, fatigue, 

rash, and dermatitis. One case of generalized urticaria was reported in a patient at 8 days after 

she had received her 2nd dose of the Vero cell-derived vaccine. The urticaria was described as 

being of moderate intensity. It was treated with an antihistamine and resolved within 3 days. 

Angioedema was not observed. The event was assessed by the study investigator as being 

unlikely related to the vaccine and the subject completed the study.

Overall, the new inactivated Vero cell-derived JEV vaccine is a very promising vaccine for use in 

adult travelers, given its favorable immunogenicity and reactogenicity profile after a two dose 

primary series. In addition, because the vaccine does not contain gelatin or murine proteins, 

there are likely to be fewer vaccine-associated hypersensitivity or neurologic adverse events 

compared with the mouse brain-derived vaccine. However, because the new vaccine has been 

studied in less than 5,000 recipients, the possibility of these or other rare adverse events cannot 

be excluded. Post-licensure surveillance data will be important to further evaluate safety in a 

larger population.

The new Vero cell-derived JEV vaccine is currently approved for use in adults 17 years of age 

or older. As a result, the mouse brain-derived vaccine is the only JEV vaccine that is approved 

for use in children in the US. Although the mouse brain-derived vaccine is still approved for 

use in adults, sanofi pasteur will now restrict purchase of their remaining inventory of JE-VAX®

for use in children 1 to 16 years of age. All remaining doses of JE-VAX® will be available 

through this pediatric stockpile. One pediatric clinical trial with IXIARO® has been completed 

and others are planned, but it will likely be several years before the vaccine is approved for use 

in children in the US. 

Recommendations regarding the use of JEV vaccine for travelers must weigh the risks of travelassociated Japanese encephalitis, with the benefits and potential risks of JEV vaccine. The 

overall risk of Japanese encephalitis for most travelers to Asia is very low, but again varies 

based on destination, duration, season, and activities. When Japanese encephalitis does 

occur, it has a high morbidity and mortality, and there is no specific treatment. Safe and 

effective vaccines are available. However, the possibility of rare serious adverse events cannot 

be excluded. Given these considerations, the workgroup developed the following general 

recommendations for the prevention of JE among travelers: 

1. Travelers to JE endemic countries should be advised of risks of JE disease and the 

importance of measures to reduce mosquito bites

2. JEV vaccine is recommended for travelers who plan to spend a month or longer in endemic 

areas during the JEV transmission season

3. JEV vaccine should be considered for short-term travelers to endemic areas during the JEV 

transmission season if they will travel outside of an urban area and their activities will 

increase the risk of JEV exposure
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

100

4. JEV vaccine is not recommended for short-term travelers whose visit will be restricted to 

urban areas or times outside of a well-defined JEV transmission season

With regard to recommendations for the prevention of JE among travelers, the following 

language was crafted: 

“Travelers to JE endemic countries should be advised of the risks of JE disease and the 

importance of personal protective measures to reduce the risk of mosquito bites. For 

some travelers who will be in a high risk setting based on location, duration, season, and 

activities, JEV vaccine may further reduce the risk of infection.”

“All travelers should take precautions to avoid mosquito bites to reduce the risk of JE 

and other vector-borne infectious diseases. These precautions include using insect 

repellent, permethrin-impregnated clothing, and bed nets, and staying in screened or air 

conditioned rooms. Additional information on protection against mosquitoes and other 

arthropods can be found at [CDC Yellow Book website].”

Recommendations for the use of JEV vaccine are as follows: 

“JEV vaccine is recommended for travelers who plan to spend a month or longer in 

endemic areas during the JEV transmission season. This includes longer-term travelers, 

recurrent travelers, or expatriates who will be based in urban areas but are likely to visit 

endemic rural or agricultural areas during a high risk period of JEV transmission.” 

“JEV vaccine should be considered for the following:

 Short-term travelers (<1 month) to endemic areas during the JEV transmission 

season if they plan to travel outside of an urban area and have an increased risk 

of JEV exposure. Examples of higher risk activities or itineraries include: 1) 

Spending substantial time outdoors in rural or agricultural areas, especially 

during the evening or night; 2) Participating in extensive outdoor activities (e.g., 

camping, hiking, trekking, biking, fishing, hunting, or farming); and 3) Staying in 

accommodations without air conditioning, screens, or bed nets.

 Travelers to an area with an ongoing JE outbreak.

 Travelers to endemic areas who are uncertain of specific destinations, activities, 

or duration of travel.” 

“JEV vaccine is not recommended for short-term travelers whose visit will be restricted 

to urban areas or times outside of a well-defined JEV transmission season.” 

Dr. Fischer also presented the draft recommendations for laboratory workers, reporting that at 

least 22 laboratory-acquired JEV infections have been reported in the literature. JEV may be 

transmitted in a laboratory setting through needle sticks or theoretically through aerosol or 

mucosal exposure. Work with the wild-type JEV is restricted to laboratories with Biosafety Level 

3 (BSL-3) containment and select agent registration. Some well-characterized attenuated JEV 

strains may be handled safely at BSL-2. Based on this information, the workgroup developed 

the following recommendations, which he noted differed slightly from the original handout:

“JEV vaccine is recommended for laboratory personnel who work with live, wild-type 

JEV strains. Vaccinated, at-risk laboratory personnel should receive appropriate booster 

doses of JEV vaccine or be evaluated regularly for JEV-specific neutralizing antibodies 

to assure adequate titers.”
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

101

Discussion

Dr. Marcy inquired as to what had been the previous use annually of this vaccine, thinking about 

the 2500 to 4000 doses left in the stockpile and how long that was expected to last.

Dr. Fischer responded that this had varied over time and partially depended upon how much 

has gone to the military. 

Dr. Hosbach (sanofi pasteur) replied that while it was difficult to predict how long the stockpile 

was anticipated to last, based on their estimates, it probably would last approximately 2 to 3 

years. It was very difficult to calculate how many children were actually receiving the vaccine. 

In total, just over 100,000 doses were used annually, and about 80% to 90% of that went to the 

military. Thus, there was not a major marketplace for the use of this vaccine.

Dr. Marcy inquired as to whether Intercell planned to move along quickly to amass more data 

and whether the FDA would seek a fast track. He expressed concern that the vaccine supply 

would be depleted before the new one was available.

Dr. Katrin Dubischar-Kastner (Intercell) indicated that Intercell, the manufacturer and license 

holder of the vaccine, is progressing with its pediatric development plan. They are currently 

starting trials and expect them to begin in the 4th quarter of 2009. Pediatric licensure is 

expected within the next 2-3 years.

Dr. Fischer mentioned that the possibility had been discussed with FDA of setting up an 

investigational new drug (IND) that could be used in the event that the JE-VAX® supply was 

completely exhausted but no licensure had been issued on the new vaccine. That is the way 

this vaccine was administered in Europe for years. They did not have a licensed JE vaccine. 

They do believe that the supply should last for approximately 2 years. The number of children is 

small and the regimen is 3 doses. 

In terms of global warming, Dr. Marcy wondered whether attention was being given to changes 

in patterns of the viruses. For example, there have been changes in the dengue season. 

Dr. Fischer responded that there has definitely been a change in the geographic area that JEV 

covers over the past few decades. It is unclear how much of that is a surveillance artifact 

versus actual change. There has probably been change in agriculture practices, herd migration, 

and other things. There is no clear evidence of global warming or climate change playing a role 

in that. For vector-borne diseases, it is really very complex as to what global warming or climate 

change affects, because there will be changes in rainfall as well as warming. Therefore, it is 

very unclear for most vector-borne disease what the effect of climate change would be. With 

regard to season, it is less certain whether there have been changes. There has certainly been 

more recognition of classic outbreaks that occurred in Northern Asia where this disease was 

first recognized in the early 1900s, in which there are high peaks in very short periods of time 

(July through September) as is observed with West Nile Virus. There is certainly more 

recognition moving into South Asia and the Western Pacific that the disease occurs even more 

sporadically or year round. It is not clear whether that reflects a change over time or merely 

recognition of the disease.

Dr. Hosbach (sanofi pasteur) indicated that the doses stockpiled are due to expire in May 2011.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

102

Dr. Stanley Gall (ACOG) said he did not hear anything about use of this vaccine during 

pregnancy, although this is bound to occur. He wondered whether the assumption could be 

made that because it was non-live virus vaccine it would be safe during pregnancy.

Dr. Fischer responded that this would differ for the two vaccines. One vaccine is considered a 

category C, one a Category B. For the new vaccine, there have been some studies in rodents 

so the category is a little different. Basically, it is considered for both the vaccines to be a 

precaution; that is, because it is not a live vaccine, there is no known risk, but data are limited. 

Thus, the wording basically states that vaccination should be deferred unless the person has to 

travel to a high risk area and the risk of the disease outweigh the risks of the vaccination.

Dr. Meissner pointed out as a working group member that the group did discuss that the Vero 

cell-derived vaccine appears to be a significant improvement over the mouse brain-derived 

vaccine. Although it is still early, at least at this stage, it appear to have significant advantages. 

He thought that was a tribute to Intercell Biomedical for their production of this vaccine and 

Novartis for their plan distribute this vaccine. This vaccine does not have gelatin as a stabilizer, 

will not have nervous tissue proteins from the mouse brain, and appears to be more 

immunogenic. He thought that should be acknowledged. There have been only 4 cases of JEV 

in 15 years since the first set of recommendations were issued in 1993, which also weighed 

heavily on the working group deliberations.

Christine Hahn (CSTE) noted that this recommendation relied heavily upon knowing when JEV 

transmission season is. She wondered whether this appeared on the CDC travel site for quick 

reference.

Dr. Fischer responded that there is a table that has transmission seasons by country and areas 

that are endemic. The table is included in the current recommendations. The working group 

agreed that it could be updated more readily and changed to refer to the Yellow Book website, 

and would then be updated in the Yellow Book every other year. There is also a cautionary 

statement that there are limits to surveillance data, and that there are changes from year to 

year. A general idea is given of the seasons and the locations where JE occurs, but people 

must be careful in interpreting that data. Those caveats are included in the document.

An inquiry was posed regarding what the new vaccine product insert would say about 

revaccination for those who have continuing exposure over the years, and how often 

revaccination should occur.

Dr. Fischer responded that for the new vaccine, there are really no recommendations with 

regard to booster doses or revaccination. There are some data on the ration of neutralizing 

antibody, which cites two different studies, one which is published and one which has been 

presented at a meeting, in which Intercell is examining duration of neutralizing antibodies. One 

study shows as many as 83% of vaccinees having neutralizing antibodies at 12 months. The 

other study went out as far as 24 months and had a little less than 60% at 12 months, and 48% 

at 24 months. Currently, in both the package insert and the ACIP recommendations, there are 

basically no recommendations similar to what was done initially for meningococcal conjugate 

vaccine with regard to booster doses. It simply states that this will need to be determined.

Dr. Beck noted that at one point, the DoD had a back-up stock of JE-VAX®. He wondered 

whether that still existed and could serve as a potential back-up for the civilian population.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

103 

COL Cieslak (DoD) responded that he believed that stock was sold back to the company in 

advance of the Beijing Olympics. The DoD basically relinquished that supply. What is currently 

being held for pediatrics is in part some of that stock that was sold back by DoD.

Dr. Hosbach (sanofi pasteur) expressed gratitude to the military, the cooperating agencies, and 

Dr. Gellen for helping arrange this. A couple of times sanofi pasteur was able to buy back 

material from the military to supply to the private sector. However, the military still has a 

stockpile of JE-VAX®, of which sanofi recently repurchased another 5,000 doses to keep going 

so until IXIARO® is licensed.

Regarding cost considerations, Dr. Chilton indicated that there was a statement in the 

committee’s packages that were received prior to the meeting indicating that those who travel to 

rural areas or expatriates living in rural areas probably have roughly the same exposure to this 

disease as those who live in those areas, which is listed in that material at 0.1 to 2 cases per 

100,000 persons per week in those areas. He wondered if that was correct.

Dr. Fischer responded that those data are extrapolated significantly from military population 

data primarily during the Korean Conflict and Vietnam War. 

It seemed to Dr. Chilton that for those traveling to or living in one of these rural areas, 

preventing one case of JE would cost $5 to $100 million at the price quoted for this vaccine. 

That seemed high to make a recommendation as strong as the one pending a vote.

Dr. Fischer replied that two things needed to be taken into consideration. First, all of the cases 

reported have been in the context of vaccination. It is not clear exactly who is being vaccinated, 

but it is assumed that the vaccine is being somewhat appropriately targeted such that cases are 

being prevented. Second, the numbers presented were of cases reported in the literature. 

There are likely more cases that are not diagnosed and / or reported. He cautioned against 

making too many assumptions. While the disease is believed to be rare, he would not try to put 

a specific number on it. The working group did engage in discussions about cost, but this is a 

travel vaccine.

Dr. Sumaya pointed out that Recommendation #2 states that “JEV vaccine should be 

considered.” He wondered whether there was a reason it did not say “recommended,” 

particularly when one of the items is travelers to an area with an on-going JE outbreak.

Dr. Fischer responded that this was similar to the current recommendations, and they have the 

strongest evidence that these are the people at greatest risk. More thought really needs to be 

placed on the individual traveler and their itinerary. 

Dr. Cieslak said he thought the incidents cited were 100,000 per year and not per week, and the 

week extrapolation was different. He thought it was as high as 1 per 5000 per week.

Dr. Fischer replied that they were per week for the highest risk populations.

Motion: Revised JE Vaccine Recommendations

Dr. Meissner moved to approve the revised recommendations as proposed. Dr. Sawyer 

seconded the motion. The motion passed with 12 affirmative, 1 negative, and 0 abstentions. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

104 

Introduction

Dr. Mark Sawyer, Chair

Hepatitis Vaccines Work Group 

Dr. Sawyer indicated that the terms of reference for the Hepatitis Vaccines Work Group were to:









Determine the advisability and extent of hepatitis A vaccination recommendations for 

families adopting children from other countries

Review data from recent hepatitis B outbreaks among diabetics in institutional care to 

determine whether vaccination is appropriate 

Review data related to long-term immunity of hepatitis B vaccine to determine if additional 

vaccine doses are necessary; if so, what dosage and schedule

Review hepatitis A vaccine long-term immunity to see if updating recommendations is 

warranted

The first term of reference regarding hepatitis A recommendations was dealt with in the past. 

During this session, an update was presented on the work group’s deliberations pertaining to 

the second term of reference regarding recent hepatitis B outbreaks among diabetics in 

institutional care to determine whether vaccination is appropriate for this population.

Hepatitis B among Residents of Long-Term Care Facilities

Nicola D. Thompson, PhD

Division of Viral Hepatitis

NCHHSTP, CDC 

Dr. Thompson presented a summary of information the hepatitis vaccine work group has 

discussed in recent months with respect to the role of hepatitis B vaccine use among residents 

of long-term care facilities, specifically those with diabetes. While seemingly unrelated, these 

three issues had arisen which the work group was charged to address (e.g., hepatitis B virus, 

diabetes, and long-term care). During this session, she discussed hepatitis B virus transmission 

during delivery of health care, summarized hepatitis B virus infection outbreaks among people 

with diabetes, discussed diabetes epidemiology in the US, addressed long-term care, and 

raised possible prevention strategies for consideration.

Hepatitis Vaccines
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

105

There has been a dramatic decline in the incidence of acute HBV infection in the US last few 

decades. Much of this decline can be attributed to the implementation of vaccine 

recommendations for infants and children, and targeted high risk groups, such as injection drug 

users, persons with high risk sexual behaviors, healthcare workers, and chronic hemodialysis 

patients. The decline observed has been much more striking in younger age groups when 

compared to older adults when incidence is stratified at 50 years of age. In 2007, about 4500 

cases of acute HBV infection were reported, and the acute HBV infection fatality rate was 1.5%. 

It is important to note that due to under-reporting and the high proportion of asymptomatic acute 

infections, it is estimated the actual number of new cases in 2007 was around 43,000 [National 

Notifiable Diseases Surveillance System (NNDSS)].

There is an inverse relationship between the age at infection and the development of chronic 

HBV infection. The risk of developing chronic HBV is highest in those who are infected as 

infants and children, compared to healthy adults. [Shepard et al. Epidemiologic Reviews 

2006;28:112-125]. However, older adults and immune suppressed individuals are also at high 

risk for developing chronic HBV infection Studies have shown that this risk may be as high as 

59% in older adults [Kondo. Hepatology 1993;18:768-74], between 40% and 45% for 

hemodialysis patients [Hyams CID 1995;20:992-1000], and up to 22% for HIV-infected 

individuals [Alter MJ J Hepatol 2006; 44:S6–9].

The CDC estimates that between 800,000 and 1.4 million persons in the US have chronic HBV 

[CDC MMWR 2008;57 No. RR-8]. Other estimates suggest that it may be higher at around 3 

million, and that immigration plays an important role in chronic HBV infection in the US, with 

estimates indicating that approximately 46,000 cases are imported each year [Welch et al. 

Estimating Prevalence of chronic hepatitis B in Foreign-born persons in the US. Abstract 

OP059. ISVHLD 2009; Mitchel et al. Increasing burden of imported chronic hepatitis B – US, 

1973-2007. EIS Conference 2009]. Chronic carriers are central to the epidemiology of HBV, as 

they may be asymptomatically infected for many years and unknowingly provide a risk of 

transmission to susceptible persons. Chronic carriers are at increased risk of cirrhosis and liver 

cancer. It is thought that between 2000 and 4000 people die each year from HBV-related 

chronic liver disease [CDC MMWR 2008;57 No. RR-8].

The primary modes of HBV transmission are perinatal, sexual, and by percutaneous and 

permucosal exposures. This includes injection drug use, non-sexual household contact with 

HBV infected persons, and healthcare related transmission. While healthcare related 

transmission due to occupational exposures and through the receipt of blood and blood 

products has been decreasing, patient-to-patient HBV and hepatitis C (HCV) transmission 

during the delivery of healthcare has been increasingly recognized in the US [1:Thompson et al. 

Nonhospital health care–associated hepatitis B and C virus transmission: United States, 1998–

2008. AIM 2009;150:33-39].

With respect to the number and cause of HBV and HCV outbreaks that have been reported 

since 1998 in the US, all of these outbreaks have involved patient-to-patient transmission during 

the delivery of healthcare due to poor infection control practices. Both hepatitis B and C 

outbreaks have occurred in a variety of settings, including endoscopy clinics, nuclear imaging 

clinics, pain remediation clinics, oncology clinics and physician offices. One area of particular 

concern is the multiple and continuing outbreaks of HBV infection among long-term care 

residents that have repeatedly been associated with poor practices during diabetes care, 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

106

specifically during blood glucose monitoring [Thompson, Perz. JDST 2009;3:283-89; Thompson 

et al. AIM 2009;150:33-39]. 

While the prevalence of chronic HCV infection is higher in the US than chronic HBV infection, 

there are some important features of HBV that help facilitate its transmission; the high viral titer 

and high environmental stability. A virus can be present in tiny or invisible amounts of blood, 

and due to the environmental stability, dried blood on surfaces, equipment or devices can 

remain viable for at least seven days [Beltrami et al, Clin Microbio Reviews, 2000. MMWR 

2001;50(No. RR-11); Bond et al. Lancet 1981; 8219:550-1. Shikata et al. J Infect Dis 

1977;136:571–76; Shikata et al. J Infect Dis 1977;136:571–76; Kamilli et al. ICHE 2007;28:519-

24]. Together these characteristics play an important role in healthcare-related HBV 

transmission and specifically during diabetes care when equipment used for finger stick 

procedures and monitoring blood glucose levels are shared among multiple persons. HBV 

transmission has been associated with blood contamination of the end and barrel of springloaded finger stick devices, with blood contamination of blood glucose testing meters, and with 

failures by staff to wear or change gloves or perform hand hygiene between performing fingerstick procedures.

Preventing this type of transmission relies on consistent adherence to standard infection control 

recommendations. In 1990, CDC and the FDA published recommendations clearly stating that 

spring loaded finger stick devices should be restricted for individual use. Later, guidance on this 

issue came from the American Association of Diabetes Educators. In 2005, CDC again 

reinforced the 1990 recommendations and made specific recommendations for prevention of 

blood borne pathogen transmission during diabetes care in long-term care settings. This issue 

is also addressed in the 2007 Healthcare Infection Control Practices Advisory Committee

(HICPAC) Isolation Guidelines, which are applicable to all settings were healthcare is delivered. 

Just a few months ago, the FDA issued a health alert for the appropriate use of insulin pens in 

healthcare settings. This alert was issued after it was discovered that these devices, designed 

for individual use, were found to have been used on multiple patients in two US acute care 

hospitals.

In the US, the first recognized outbreak of hepatitis B associated with diabetes care was 

reported in 1990. Since then, and despite multiple comprehensive prevention 

recommendations, these outbreaks have continued to occur. A notable shift from acute care 

hospitals to the long-term setting appears to have occurred, first in nursing homes and then in 

assisting living facilities. In total, 19 outbreaks of HBV infection among diabetic persons have 

been reported since 1990, with 6 outbreaks occurring in the past 2 1⁄2 years. Given that most 

newly infected adults will be asymptomatic and that the diagnosis of acute hepatitis B is often 

not suspected or missed in older adults, it is likely that these outbreaks under represent the true 

number that have occurred.

From combined data from 13 seroprevalence surveys conducted during investigations of these 

outbreaks, in which 1308 persons were tested for HBV infection, persons with diabetes had a 

high prevalence of both past and chronic infection compared to those without diabetes. In these 

outbreaks, acute HBV infections occurred predominantly among persons with diabetes, 30.5% 

compared to 0.9% among those without diabetes. Overall, the prevalence of ever being 

infected with HBV (including those with past, chronic, and acute infection among non-diabetics) 

was 5.6%, but was 42.9% among persons with diabetes. The median age of people with acute 

HBV infection from these outbreaks was 75 years with a wide range from 42 to 92 years. The 

vast majority with acute HBV infection (92%) had diabetes and were monitoring their blood 

glucose levels. A small number of secondary cases have been reported in non-diabetic 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

107

roommates and family members of infected individuals, and among non-vaccinated staff 

members. About 1/3 of those with acute infection were symptomatic, and among those that 

were symptomatic, 37% were hospitalized. The acute HBV infection fatality rate was 5% among 

all people infected and was actually as high as 15% among those with symptomatic acute 

hepatitis B. Those who died from acute HBV infection had a median age of 85 years and 

ranged from 64 to 92 years [CDC. Unpublished Data 2009].

Among 29 people who were re-tested at least six months after their initial diagnosis of acute 

infection, 50% had developed chronic infection. As already noted, this is similar to rates that 

have been reported in the literature for older adults and immune suppressed individuals, such 

as hemodialysis patients, and is higher than that for HIV infected individuals [CDC Unpublished 

Data 2009; Kondo. Hepatology 1993;18:768-74; Hyams CID 1995;20:992-1000; Alter MJJ 

Hepatol 2006; 44:S6–9]. It has been well reported that the prevalence of diabetes has been 

and continues to increase rapidly in the US. Only about 5-10% of those with diabetes have 

Type 1, the vast majority have Type 2 diabetes. In 2006, just under 18 million people in the US 

had been diagnosed with diabetes [CDC available at: 

www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm]. 

This equates to about 5.8% of the total US population, but the prevalence is highest among 

people 65 years of age and older [Cowie et al., Diabetes Care 2009;32:287-94. CDC available 

at http://www.cdc.gov/diabetes/statistics/prev/national/tprevage.htm]. As the population 

continues to age, the number of people with diabetes will also continue to increase. By 2050 it 

is estimated that 29 million people will have diabetes, with most of them being older than 65 

years of age and our colleagues in the division of diabetes translation tell us that this 29 million 

is an underestimate of what the actual burden will be [Boyle et al. Diabetes Care 2001:24:1936-

40]. Daily blood glucose monitoring is a common practice among those with both Type 1 and 

Type 2 diabetes. Approximately 60% of all people with diabetes are estimated to self-monitor 

their blood glucose level at least once a day. This is in line with the Healthy People 2010 goal 

of 61% [CDC. Behavioral Risk Factor Surveillance System. MMWR 2007;56:1133-1137].

Long-term care provides both medical and non-medical care to people with chronic illnesses or 

disabilities. Long-term care is provided in many settings, but there are two main categories of 

residential long-term care and they have very different philosophies. Nursing homes provide 

care to people who cannot be cared for at home or in the community setting. They provide a 

wide range of personal care and health services that are medically oriented. Regulation and 

oversight of nursing homes occurs at the federal level. Assisted living is a group living 

arrangement that provides residents help with activities of daily living, such as eating, bathing, 

using the bathroom, and medication administration, this includes diabetes care. Social and 

recreational activities are usually provided and these facilities operate under a social model. 

There is no federal definition of assisted living and facility licensing and oversight occurs at the 

state level. 

It is important to point out that the data for nursing homes is much more robust than it is for the 

assisted living facilities. The nursing home data largely comes from the National Nursing Home 

Survey conducted by CDC. The data from assisted living comes from a couple of different 

sources, some of which is from 2002, and some of which is more recent data from non 

representative samples. In both nursing homes and assisted living facilities, the majority of 

residents are female and the median age is between 84 and 85 years. In both settings, a 

substantial number (10-12% or around 270,000 persons) of residents are less than 65 years of 

age. Memory and mental health disorders are common among residents of long term care. In 

nursing homes, it is estimated that about 25% of residents have diabetes, and between 15 and 
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20% in assisted living. Other common health conditions among residents include stroke and 

COPD or emphysema. About 2/3 of nursing home residents are considered to be in fair or poor 

health, compared to 50% of those in assisted living [National Nursing Home Survey, 2004, 

NCHS/CDC; US Dept of HHS Assistant Secretary for Planning and Evaluation Office of 

Disability, Aging and Long-Term Care Policy. November 2002; Overview of Assisted Living, 

2006. NCAL]. 

In long-term care settings, there are relatively few professional, licensed medical staff: 32% of 

direct care staff in nursing homes and only 15% in assisted living. The duties of licensed nurses 

include resident assessment, medication reviews, care plan development, staff monitoring, 

wound care, vital sign readings, oxygen administration, blood glucose monitoring, and delivery 

of injections. In some states, these activities can be delegated to unlicensed, paraprofessional 

staff that comprises the majority of direct care staff in both of these settings. Few states have 

minimum staffing ratios for assisted living. Some require that a registered nurse (RN) be 

available 24 hours a day, but they do not have to be on site, or they only have to come in when 

medications are administered. Few states require paraprofessional staff, such as personal care 

aides, to be certified. Most paraprofessionals have no formal healthcare or medical training and 

learn while they are on the job [American Health Care Association. Estimates of Current 

Employment in the Long-Term Care Delivery System and Bureau of Labor Statistics; National 

Nursing Home Survey, 2004, NCHS/CDC; Overview of Assisted Living, 2006. NCAL].

Recruitment and retention of staff is recognized as a major challenge in long-term care settings. 

The average annual staff turnover rates range from 36-41% for registered nurses, 44-50% for 

licensed practical nurses, and between 45-66% for paraprofessional staff. Compared to other 

healthcare workers, long-term care staff earns the lowest salaries, receive the fewest benefits, 

are less likely to have employer sponsored health insurance, and have few advancement 

opportunities. In one recent HBV outbreak investigation, when the public health department 

staff returned to the facility 6 months after the initial investigation to conduct follow-up 

assessments, the new nursing director and staff were unaware that hepatitis B outbreak had 

even occurred. The impact of training and education initiatives is hampered in settings with 

such high staff turnover [Sikorska-Simmons. Gerontologist 2005;45:196-205; Zimmerman et al. 

J Am Geriatr Soc 2002;50:1987-95; 2007 American Healthcare Association Survey: Nursing 

Staff Vacancy and Turnover in Nursing Facilities; 2007 AAHSA National salary and benefit 

surveys]. In addition, high nursing turn over and low staffing rates have been associated with 

incident of infections in long term-care. In this setting, infections have been recognized as the 

leading cause of morbidity and mortality among residents. This increase in risk is due to the 

vulnerable resident population and the institution environment where residents share bedrooms 

and bathrooms and group activities are encouraged [Zimmerman et al. J Am Geriatr Soc 

2002;50:1987-95; Richards. Infections in Residents of LTC Facilities: An Agenda for Research. 

Report of an Expert Panel. JAGS 2002;50:570-576].

Infection prevention and control programs have been poorly implemented in long-term care. 

Few resources or personnel are devoted to infection control activities, and there are no 

dedicated infection control staff. Staff charged with infection control duties often have many 

other duties and spend few hours on infection control issues. About half of the staff who are 

charged with infection control have no training in infection control themselves [Goldrick. 

Infection Control in skilled nursing LTC facilities: An Assessment. AJIC 1999;27:4-9]. There are 

few data on the effects of infection control interventions on resident outcomes and cost. This 

limits the uptake and implementation of infection control programs and dedication of resources 

to this issue [Richards. Infections in Residents of LTC Facilities: An Agenda for Research. 

Report of an Expert Panel. JAGS 2002;50:570-576]. 
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Two surveys have been conducted by CDC to assess routine diabetes care in non-outbreak 

situations. These surveys were used to assess the standard of diabetes care in these long term 

care facilities. Selected results from those surveys showed that, among facilities using spring 

loaded finger stick devices, between 16 and 24% of were sharing these among their diabetic 

residents despite there being recommendations in place since 1990. Among facilities sharing 

blood glucose testing meters among residents, 50-72% were not cleaning meters between each 

use. In both these surveys, the facilities were aware that the public health authorities had a 

planned visit to review diabetes care at their facility. In Virginia, the state health department had 

mailed educational packets and CDC safe diabetes care recommendations to each facility 

ahead of their visit. It is, therefore, likely that the prevalence of unsafe diabetes care practices 

may be higher than reported here [Virginia data: Patel et al. ICHE 2009;30; Florida data: CDC 

Unpublished Data 2008].

Currently, it is estimated there are about 2.5 million people residing in long-term care facilities in 

the US. Most of these residents are in nursing homes, although most growth in long-term care 

residency has occurred in the assisted living arena. This sector of long-term care has the least 

regulation and oversight, and the fewest medically trained staff [US Dept of HHS. Office of 

Disability, Aging and Long-Term Care Policy. November 2002; Overview of Assisted Living, 

2006. NCAL and National Nursing Home Survey, 2004, NCHS/CDC]. As the US population is 

aging and living longer, there will be an increasing demand for long-term care services among 

adults with disabilities. It is expected that over the next 30 years, there will be a doubling of the 

number of people with moderate or severe disability [Johnson et al. Meeting the LTC needs of 

the Baby Boomers: How Changing Families will affect paid helpers and intuitions. 2007. The 

Urban Institute].

In summary, the reported incidence of acute HBV has been declining dramatically in the US; 

however, this decline has been much less dramatic among people greater than 50 years of age. 

Patient-to-patient HBV and HCV transmission due to poor infection control practices during the 

receipt of healthcare has been increasingly recognized in the US. This type of transmission has 

occurred in a variety of healthcare settings. However, persons receiving diabetes care in longterm care facilities have emerged as one risk group. In these settings, multiple people undergo 

daily and often multiple daily percutaneous exposures during blood glucose monitoring. Despite 

long-standing and comprehensive prevention recommendations, HBV infection outbreaks 

continue to be reported in long-term care. These outbreaks have shown that HBV is not an 

insignificant disease in this population of older adults with diabetes, with a high rate of acute 

HBV deaths and chronic infection being reported. Improving infection control, oversight, and 

regulation of long-term care is an increasing public health priority, although many challenges 

remain. Without change, the number of people placed at risk for infection will increase as the 

prevalence of diabetes and utilization of long-term care both increase.

CDC is addressing the prevention of hepatitis B among diabetics in three ways: 1) by improving 

the implementation and adherence to existing infection control recommendations; 2) by working 

with equipment manufacturers to develop technology and safety engineered devices to help 

prevent sharing of equipment, by developing and designing and marketing equipment for 

institutional use, and by developing equipment that reduces or eliminates blood borne pathogen 

transmission; and 3) by assessing the role of hepatitis B vaccine in prevention, which is the 

current charge of the Hepatitis Vaccines Workgroup.

Future workgroup meeting topics include examining the epidemiology of HBV infection, focusing 

on older adults without traditional risk factors; reviewing data on hepatitis B vaccine 
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immunogenicity and safety by age, focusing again on older adults and people with diabetes; and 

assessing feasibility, programmatic issues, and cost-effectiveness. 

Discussion

Dr. Judson found it amazing that 50% of the facilities surveyed were not following even the most 

basic or reasonable prevention techniques. He thought states regulated these facilities closely. 

His 92 and 94 year old parents live in such a facility and tell him that state inspectors come by to 

review practices, and everyone is very tense. 

Dr. Thompson replied that most people who work with infection control in this area would agree 

that oversight and regulation is sorely missing in long-term care facilities, particularly assisted 

living facilities. While surveys are conducted, these may only be done once every three years 

and often they are assessing non-infection control issues.

Dr. Baker indicated that inspections are every three years in Texas, and facilities are notified in 

advance. Because facilities are forewarned, they look great on paper for one day.

Dr. Judson wondered whether facilities were directly violating the regulations that pertain to 

them or were simply undertrained with no one really in charge.

Dr. Thompson thought the latter was the case most of the time. While she did not know 

whether there specific regulations were in place for this issue, there are certainly 

recommendations from CDC. Unfortunately, there are 50 states with 50 different sets of 

regulations, oversight, and licensing. For example, in Pennsylvania, to work in an assisted 

living facility and perform blood glucose monitoring and administer insulin injections, you would 

only need to have to have a high school diploma and attend a four-hour training class. Undertraining and under-staffing are definitely issues, and there are very few professional staff. There 

are infection control recommendations that some facilities follow, but this is certainly not 

happening in all of them.

Dr. Judson thought that from a public health standpoint, this situation ought to be fixable with 

the proper regulations and enforcement.

Dr. Thompson agreed. The working group plans to address infection control in terms of 

implementation of the existing recommendations, technology (e.g., safe devices), and vaccines. 

Ken Schmader (AGS) noted that nursing homes are highly regulated by various federal and 

state organizations; however, infection control practices are not addressed amongst all the 

quality measures and regulations. Many issues need to be addressed (e.g., delirium, pressure 

sores, weight loss, depression, et cetera) within quality measures. Quality infection control can 

occur in the nursing home, for which there is evidence from the VA. The Department of 

Veterans Affairs is the largest single provider of nursing home care in the US, with over 130 

nursing homes and 11,000 patients. The VA has put into practice infection control training 

practices, practitioners, programs, et cetera. There is very good evidence that this works. In 

fact, in the American Journal of Infection Control in 2008, there was an article published on that, 

which could serve as a model for the work group. Dr. Chesley Richards of CDC is one of the 

authors [Prevalence of nursing home-associated infections in the Department of Veterans 

Affairs nursing home care units; AJIC: American Journal of Infection Control. 36(3):173-179, 

April 2008]. 
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Dr. Thompson added that the Study on the Efficacy of Nosocomial Infection Control (SENIC)

study was instrumental in showing that there is a cost benefit to implementing infection control, 

and that savings can be made by the facility. However, there is no such equivalent study or 

data for long-term care. 

Alexis Elward (HICPAC) emphasized that infection control implementation is very resourceintensive and requires a considerable amount of education—repeatedly. There is a large 

proportion of paraprofessional staff, as high as 65%-85% in some of these facilities. This raises 

further challenges. With the lack of consistent regulatory oversight and dedicated resources, 

the problem is further compounded. Hepatitis B vaccination would only be one arm of a 

comprehensive program to address this issue.

Dr. Baker thought it would be beneficial to have some data pertaining to immunity. She agreed 

that infection control is extremely labor-intensive and education must be repeated regularly. 

Even certified nursing assistants who require more than four hours of training do not know 

anything about infection control and blood borne precautions. They are paid $8 an hour in most 

assisted living facilities with no benefits, so the minute there is a better place down the street, 

they move on. It is all about money.

Introduction

Carol J. Baker, MD, Chair

ACIP Yellow Fever Work Group

Dr. Baker indicated that the Yellow Fever Work Group was charged to update and revise the 

2002 recommendations based on new evidence. Many organizations were involved in the 

process of a rigorous review of the literature. The following Yellow Fever Work Group meetings 

were held, with the topic areas addressed shown for each:

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September 16, 2008

Introduction and background YF disease and vaccine

November 10, 2008

Vaccine presentation, dose and booster

Simultaneous Administration of Other Vaccines

December 9, 2008

General Safety

Requirements for vaccination before international travel

Upcoming changes to yellow fever risk areas

Yellow Fever Vaccine
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January 12, 2009

Hypersensitivity

Yellow fever vaccine-associated viscerotropic disease

February 9, 2009

Thymic disease and use of vaccine

Yellow fever vaccine-associated neurotropic disease

March 9, 2009

Travelers and individuals living in endemic areas

HIV

Elderly 

April 14, 2009

Pregnancy

Breastfeeding

Young children

May 11, 2009

Cancer and cancer treatments

Immunomodulatory drugs

Additional topics

The resulting proposed revisions were reported to the full committee during this session for the 

purpose of information. 

Proposed Updates to the ACIP Yellow 

Fever Vaccine Recommendations 

J. Erin Staples, MD, PhD

CDC / CCID / NCZVED / DVBID

During this session, Dr. Staples reviewed yellow fever disease, the vaccine used to prevent it, 

and the proposed updates to the 2002 yellow fever recommendations the work group is 

considering.

Yellow fever disease is caused by yellow fever virus which is the prototypic flavivirus. It is 

transmitted to humans predominantly by Aedes mosquitoes, though other mosquitoes are 

involved in rural settings. However, in urban areas, Aedes aegypti mosquitoes can effectively 

spread the disease from human to human leading to large outbreaks of the disease. Yellow 

fever disease is endemic to 47 countries in equatorial Africa and South America. It can cause a 

range of disease in humans from mild illness to jaundice and hemorrhage. The WHO estimates 

there are approximately 200,000 cases and 30,000 deaths per year due to yellow fever; 

however, most cases go unrecognized by the current surveillance systems.

Yellow fever vaccine was developed in the 1930s. It is a live-attenuated viral vaccine produced 

in eggs (e.g., chicken embryos). From 1937-2008, over 500 million doses have been given to 

humans. Currently, one vaccine licensed for use in the US, YF-VAX®, produced by sanofi 

pasteur. It is derived from 17D-204 vaccine strain, so it is often referred to as a 17D vaccine. 
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There are two primary reasons to vaccinate someone against yellow fever, which are to: 1) 

protect travelers and endemic populations against the disease; and 2) limit the introduction and 

spread of the disease into new areas. Many countries require proof of vaccination for all 

travelers. Yellow fever vaccine is the only vaccine exclusively covered under International 

Health Regulations, which were updated in 2005. Countries have the right to detain a traveler 

without proof of yellow fever vaccine for up to 6 days (e.g., the incubation period of the disease).

Multiple factors must be weighed when deciding whether to vaccinate someone against yellow 

fever (e.g., country requirements, risk of disease, and risk of vaccine adverse events). The risk 

of illness and death for yellow fever in an unvaccinated traveler traveling 2 weeks to endemic 

area in West Africa is 50 and 10 per 100,000 population, respectively. For South America, that 

risk is estimated to be about 10 times lower at 5 illnesses and 1 death per 100,000 population 

[Monath Clin Infect Dis. 2002;34:1369-1378]. Risk for vaccine adverse events must be taken 

into consideration as well. Risk for general adverse events is approximately 43 per 100,000 

doses and for serious adverse events is approximately 4.7 per 100,000 doses [Based on US 

VAERS data 2000-2006; Lindsey et al. Vaccine. 2008; 26: 6077-6082].

The potential serious adverse events following yellow fever vaccination fall into three categories. 

The first is anaphylaxis. Individuals who are allergic to eggs, chicken proteins, and gelatin are 

at increased risk at a rate of 1.8 per 100,000 doses. Neurotropic disease / neurologic disease is 

a conglomerate of various presentations that are due to one of two mechanisms. The first is 

direct vaccine viral invasion of the central nervous system resulting in encephalitis or meningitis. 

The other is autoimmune-mediated phenomenon such as Guillain-Barré Syndrome (GBS) or 

acute disseminating encephalomyelitis. The rate for all neurologic disease following yellow 

fever vaccination is 0.8 per 100,000 doses. Another serious adverse event is viscerotropic 

disease in which the vaccine virus, as a live attenuated virus, proliferates and causes a disease 

similar to natural infection with multi-system organ failure. This occurs at a rate of 0.4 per 

100,000 doses, with a case fatality of over 50%.

The Yellow Fever Work Group took two general approaches for revising the yellow fever 

recommendations that were published in 2002. The first was that the group wanted to provide 

more specific information when possible based on published literature, unpublished reports, or 

expert opinions. They also wanted to further clarify the risks of disease versus the vaccine to 

help better guide travel practitioners in advising their patients about whether to be vaccinated. 

The work group also wanted to align the yellow fever ACIP recommendation with other ACIP 

documents. For example, there are pregnancy and breastfeeding guiding principles, so that 

language would be used to help unify the way breastfeeding and pregnancy are put forth. 

When there is a lack of evidence for yellow fever vaccine specifically, the group plans to adhere 

to the general recommendations for live viral vaccines with respect to timing intervals and 

Immunocompromised individuals. 

Anticipated revisions to the 2002 recommendations for the upcoming 2009 recommendations 

fall into broad categories, which are to: update the epidemiology of yellow fever disease, 

include information on International Health Regulations (2005), update vaccine safety data, 

add / improve wording for vaccine precautions and contraindications based on new data; and 

outline research priorities. In terms of the updated epidemiology of yellow fever disease, a new 

risk map was created in 2008 which harmonizes the WHO and CDC areas at risk: 
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Disease activity has been increasing in the last couple of years in terms of the areas affected, 

specifically for South America where areas in which yellow fever disease has been dormant for 

the last 30 years now have disease activity. That includes Northern Argentina, Paraguay, the 

Eastern edge of the endemic area for Brazil, and Trinidad. In Africa, there has been an 

increase outside of their normal endemic area of West Africa in the central African countries.

In terms of vaccine safety data, the work group wants to update the incidence rates. This 

information will come from more recent VAERS data, which includes the serious adverse event 

rate of 4.7 for all comers. Specific age group incidents will also be highlighted, particularly for 

serious adverse events. For individuals 60-69 the rate will be 6.3 serious adverse events per 

100,000 doses, and for those greater than 70 the rate goes up to 12.6 per 100,000 doses. 

More information will also be provided on serious adverse events. When the last 

recommendations were published in 2002, viscerotropic disease had just been recognized. 

There have been more cases, so those data will be summarized to present key clinical 

characteristics that are observed. The neurologic disease observed will also be characterized. 

Specific testing that can be conducted for vaccine adverse events will be described to assist in 

determining whether the event that is noted is potentially related to the vaccine. Potential 

treatments will as be discussed which would apply for events such as GBS. More information 

will also be provided on yellow fever vaccine precautions. For breastfeeding, updated 

information will be included on transmission and vaccine-associated adverse events. For those 

≥ 60 years, the risk of the disease versus serious adverse event will be clarified. For HIV, risk 

will be further defined based on CD4 counts and anti-retroviral therapy.

In terms of contraindications, in 2004 thymic disease was recognized as a risk factor for 

viscerotropic disease. Language was subsequently added to package inserts. Thus, language 

needs to be added to the ACIP recommendations to clarify thymic conditions that will place 

someone at risk. Immunomodulatory drugs are a relatively new class of drugs that alter 

immune response. There are many different groups of immunomodulatory drugs, some of 

which include tumor necrosis factor-alpha (TNF-α) blockers, Interleukin1 (IL1) blockers, and 

monoclonal antibodies (Mab). Many of the package inserts contraindicate the use of live viral 

vaccines, so that language will be added to the 2009 yellow fever recommendations.

During the next couple of months, the work group plans to craft specific language for the revised 

yellow fever vaccine recommendations. It is anticipated that final recommendations will be 
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presented for an ACIP vote in October 2009, with the final document expected to be submitted 

to the MMWR in November 2009.

Discussion

Dr. Temte inquired about the methodology for doing conducting assessments, noting that 

VAERS had been mentioned a couple of times. In his experience, many patients receiving 

yellow fever vaccines are typically receiving several other vaccines simultaneously. In addition, 

increasing numbers of patients in older age groups are travelling internationally. Thus, it seems 

that it would be extremely difficult to determine adverse events caused by yellow fever vaccine 

versus other vaccines, and / or the potential synergistic effects of yellow fever vaccine coadministered with other vaccines.

Dr. Staples responded that in the VAERS analysis, the work group examined whether other 

travel vaccines were co-administered. For the cases specifically classified as the most serious 

adverse events being considered (e.g., viscerotropic disease and neurotropic disease), many of 

the cases had diagnostic testing to confirm that yellow fever vaccine was the source of their 

adverse event. This issue can be further considered.

Dr. Baker added that the statement will include information about how to test to confirm whether 

there is an association with yellow fever vaccine.

In terms of safety, Dr. Neuzil pointed out that this vaccine is frequently given in other countries 

as part of campaigns. They may be able to acquire additional safety data from some of these 

sources. She also inquired as to whether any other vaccines are available or in development.

Dr. Staples responded that as far as she knew, there were no other vaccines available or in 

development. There are other routes of administration, and there have been some preliminary 

studies examining inactivation of the current vaccine. Until recently, when viscerotropic disease 

was discovered to have been a risk of the vaccine, it was considered to be very safe and 

effective. It is still a fairly safe and effective vaccine, particularly for endemic areas. 

Dr. Katz (IDSA) asked what was known about boosters and what the International Health 

Regulations state says about them.

Dr. Staples responded that the International Health Regulations, as well as the WHO, state that 

boosters should be given every 10 years. Most of the serious adverse events observed have 

been reported after primary vaccination, so it is not believed that boosters increase the risk of 

serious adverse events. There are some data to suggest that immunity lasts longer, but when 

the WHO conducted a comprehensive review about the booster interval, they still thought that 

10 years was a reasonable timeframe for this vaccine.

Ms. Stinchfield (NAPNAP) inquired as to whether it was correct that special certification was 

required to serve as a yellow fever vaccine clinic, and if so what the rationale was for that 

requirement.

Dr. Staples responded that a certificate is regulated through CDC’s Division of Migration and 

Global Quarantine (DMGQ). However, much of the regulation also requires state health 

department involvement. This was linked to the International Health Regulations, which prior to 

the 2005 recommendations, emphasized yellow fever disease as one of the immediately 

notifiable diseases considered important. However, the specific regulations for yellow fever 
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vaccine and proof of yellow fever vaccine have been sustained in the 2005 regulations. She 

believed that it was the International Health Regulations and the requirements for proof of 

vaccination that supported detainment for lack of proof of vaccination.

No public comments were offered during the first day of the meeting.

June 25, 2009

Call to Order

Dr. Dale Morse

Chair, ACIP

Dr. Larry Pickering

Executive Secretary, ACIP, CDC

Dr. Dale Morse welcomed the group to the second day of the meeting. He turned the floor over 

to Dr. Larry Pickering to address unfinished business.

Dr. Pickering offered a few comments about Dr. Morse on the occasion of his final meeting 

serving as an ACIP member and Chair of ACIP. He reflected on the time and energy that Dr. 

Morse had spent on ACIP and with CDC, and enumerated Dr. Morse’s many accomplishments 

as Chair of ACIP. Dr. Pickering expressed appreciation to Dr. Morse for his many contributions 

to the committee, which include the following ACIP recommendations made during his 

chairmanship:

CDC. Prevention of Rotavirus Gastroenteritis Among Infants and Children; recommendations of the 

Advisory Committee on Immunization Practices (ACIP). MMWR 2009;58 (No. RR-2)

Recommended Adult Immunization Schedule—United States, 2009. MMWR 2009;57 

Recommended Immunization Schedules for Persons Aged 0 Through 18 years --- United States, 2009. 

MMWR 2009;57

CDC. Prevention and Control of Influenza; recommendations of the Advisory Committee on 

Immunization Practices (ACIP). MMWR 2008;57 (No. RR-7)

CDC. Prevention of Herpes Zoster; recommendations of the Advisory Committee on Immunization 

Practices (ACIP). MMWR 2008;57 (No. RR-5)

CDC. Prevention of Pertussis, Tetanus, and Diphtheria Among Pregnant and Postpartum Women and 

Their Infants; recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 

2008;57 (No. RR-4)

CDC. Human Rabies Prevention - United States, 2008; recommendations of the Advisory Committee 

on Immunization Practices (ACIP). MMWR 2008;57 (No. RR-3)

Dr. Morse thanked Dr. Pickering and those present, offering a wrap-up of his time with ACIP. 

He noted the rapid growth that ACIP saw during Jon Abramson’s leadership from 2005 to 2007, 

Public Comments Day 1

Unfinished Business
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including: 1) voting to recommend rotavirus vaccine for children and the HPV vaccine for young 

females; 2) recommending a second dose of the varicella vaccine; 3) zoster vaccine for adults; 

4) conjugated meningococcal vaccine for adolescents and college students; 5) Tdap vaccine for 

adolescents and adults; 6) expanded adult recommendations for hepatitis B vaccine and 

expanded recommendations for hepatitis A vaccine for all children over 12 months; and 7) 

expansion of use of influenza vaccine to include children age 24 through 59 months.

Dr. Morse then turned to 2007 to 2009, when ACIP entered a maintenance phase. This phase 

did not bring less work for the committee, however. Vaccine guidelines were updated for 

children, adolescents, and adults; anthrax; meningococcal; HAV for prophylaxis; HAV for foreign 

adoptee contacts; pneumococcal; combination vaccines; and second dose of rotavirus. Further, 

ACIP has prepared for October 2009 votes on PCV 13, bivalent HPV for females, quadrivalent 

HPV for males, and novel H1N1 influenza. He noted that 12 votes were pending for this June 

meeting: rabies, polio, JE, MMR, influenza antivirals, meningococcal, MMRV safety, and 

combination vaccines.

Dr. Morse noted the important progress toward universal flu immunization, with expansion of 

recommendations for children through 18 years of age. While flu recommendations for adults 

have not yet been completed, he anticipated that these recommendations could be achieved in 

the near future. He pointed out that a change in leadership is a good time to assess where the 

committee has been, where it is currently, and where it is going. It is also a good time for the 

committee members to share in their combined accomplishments and to recognize the 

individual contributions of their colleagues. In particular, he recognized the efforts of Jean 

Smith, Antonette Hill, Larry Pickering, and all ACIP staff. Further, Dr. Morse acknowledged the 

importance of science in ACIP’s work. He cited David Axelrod, former New York Commissioner 

of Health who said, “We must remain devoted to the canons of science that are so much part of 

the practice of medicine and the practice of the allied arts. To do otherwise would be to build 

public policy on quicksand.” Knowledge without application is useless. ACIP must also 

remember the faces behind the numbers and the people who are served by their work, as Dr. 

Jules Richmond, Former Surgeon General, said: “statistics are people with their tears wiped 

dry. As Xenophon in Cryopaedia, 400 BC said, “As there are persons who mend torn garments, 

so there are physicians who heal the sick; but your duty is far nobler and one befitting a just 

person – namely to keep people in health.” Collectively, they have been able to accomplish 

more than they could individually. The cause of keeping people healthy is noble, and Dr. Morse

thanked ACIP for allowing him to be part of the process.

General Recommendations on Immunization

Dr. Andrew Kroger

CDC.CCID/NCIRD/ISD

Dr. Morse asked Dr. Andrew Kroger to present revised language for the General 

Recommendations on Immunization for the committee to consider. Dr. Kroger reminded the

group of Option Two from the previous day’s discussion, which stated: 
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“The use of a combination vaccine generally is preferred over separate injections of its 

equivalent component vaccines if licensed and indicated for the patient’s age, but 

depends on the vaccination status of the patient, provider preference, patient 

preference, the potential for adverse events, and vaccine availability.”

Discussion regarding this option led to a consensus that it was the best of those offered, but the 

language needed streamlining. The term “licensed” is redundant, and concern was expressed 

about describing vaccines as recommended for a specific age. There was an affirmative vote 

by ACIP for this option. The General Recommendations Working Group of ACIP met and 

discussed how best to incorporate feedback from the general group into the recommendation. 

Their deliberations resulted in the following clarification:

“The use of a combination vaccine generally is preferred over separate injections of its 

equivalent component vaccines. Considerations should include provider assessment*, 

patient preference, and the potential for adverse events,” with a footnote to state: 

“*Provider assessment should include storage costs, number of injections, vaccine 

availability, vaccination status, likelihood of improved coverage, and likelihood of patient 

return visits.”

Discussion:

Dr. Englund felt that storage cost was not the most important thing for practitioners to consider, 

so she suggested that the order of the items in the superscript list be revised. She commended 

the working group on this clarification.

Dr. Neuzil said that the potential for adverse events is part of the provider assessment, and she 

wondered about the rationale for putting that element in the first part of the statement rather 

than in the second part.

Dr. Kroger replied that from a public health point of view, the potential for adverse events is 

important to add because vaccine safety stakeholders play an important role along with 

providers and patients and this issue will be revisited in future decisions about combination 

vaccines.

Dr. Temte added that in current practice situations, the largest barrier to immunization is 

concern over adverse events. Placing it in the first statement highlights its significance and the 

degree to which ACIP considers it to be an important issue.

Dr. Sumaya said that the working group debated whether to include the issue in the body of the 

recommendation or in its annotation. Because the issue will be critical in monitoring, they 

concluded that it should be in the body of the recommendation.

Dr. Baker asked for clarification about where the annotated text would be placed. Dr. Kroger 

answered that in recent history of MMWR publications, this information has gone at the bottom 

of the page.

Dr. Stinchfield noted that storage and cost are two different issues, so they should be separated 

by a comma. She agreed with rearranging the order of the items.
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Dr. Ehresmann commented that some of the issues fall under “patient preference,” and she 

wondered whether providers consider patient preference in their assessment. The phrasing 

could state, “considerations should include provider assessment and the potential for adverse 

events” and note patient preference as part of the assessment.

Dr. Judson agreed that patient preference is a subset of the provider assessment.

Dr. Englund disagreed, stating that physician offices do not carry every vaccine combination, so 

the language should remain as written.

Dr. Cieslak said that the general recommendation stated too much. He suggested “the use of 

combination vaccines generally is preferred,” leaving physicians to consider what they usually 

consider.

Motion: General Recommendations on Immunization

Dr. Chilton made a motion to approve the recommendation of the work group to accept the 

newly-written clarification for Option Two as written, with the exception of moving “storage” and 

“cost” to the end of the statement and to separate them with a comma. Dr. Judson seconded 

the motion. The motion carried with 14 affirmative votes, 0 abstentions, and 1 negative vote. 

Centers for Disease Control and Prevention

Dr. Anne Schuchat presented updates on CDC’s work in international use of vaccine. The 

WHO recently recommended global use of rotavirus vaccine. CDC is part of a consortium 

working to provide scientific and technical support to introducing both rotavirus and 

pneumococcal conjugate vaccines around the world. CDC is also completing the Hib Initiative, 

a four-year Global Alliance for Vaccines and Immunization (GAVI)-supported initiative, with the 

mandate to promote evidence-informed decisions in resource-poor countries about the use of 

Hib vaccine. More than 90% of the birth cohort in developing countries is now living in countries 

that have decided to use this vaccine. This initiative has the potential to reduce global deaths 

substantially. The last part of CDC’s major global effort regarding vaccines is the Measles 

Initiative. Last January, CDC announced a 74% reduction in worldwide measles deaths since 

2000. The work that ACIP does on these vaccines has a direct link to these global efforts.

Center for Medicare and Medicaid Services (CMS)

Dr. Linda Murphy reported that in February 2009, the Children’s Health Insurance Program

Reauthorization Act (CHIPRA) and the American Reauthorization and Recovery Act (ARRA) 

were approved. As a result, many programs and changes are anticipated. Grants under 

CHIPRA will be announced in July 2009, and the funds will be awarded by September 30, 2009. 

These grants are aimed at schools and a range of local and religious groups, which are not 

typical outreach groups. The groups include coalitions and other agencies that will reach rural 

and tribal children that state and federal entities may not be able to reach. Six million children 

are uninsured, and grants are available to reach out to them to enroll them in CHIP or Medicaid. 

Agency Updates
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Once the children are reached, the states must be able to take the new enrollments. When the 

grants are posted on www.grants.gov, applicants will have 30 days to submit grant proposals. 

CMS is focusing on outreach and enrollment, quality, and information technology as they work 

to improve healthcare to Medicaid- and CHIP-eligible children.

CMS is always seeking to improve in the area of pandemic planning. They are considering 

ways to be flexible with Medicaid, given the H1N1 situation. As it stands, Medicaid works well in 

an epidemic situation. CMS will work with each individual state when new plans are written.

The Vaccines for Children (VFC) rates were put on hold in the absence of a Secretary of Health 

and Human Services (HHS) or a Director of Medicaid. Now that Cindy Mann has been named 

the Director of Medicaid and Kathleen Sibelius as Secretary of HHS, they are able to rewrite 

and update the Federal Register notice for VFC, with more developments on the horizon.

Department of Defense (DoD)

Dr. Wayne Hatchey explained that DoD is focusing on influenza. A mandatory influenza 

immunization requirement is in place for active duty service members. They began mandatory 

immunization for healthcare workers providing direct patient care last year. This year, services 

must report compliance with the program. DoD is preparing for two simultaneous (or 

overlapping) influenza immunization programs with seasonal influenza and novel H1N1. They 

are collaborating with CDC and FDA to track vaccine effectiveness through the Armed Forces 

Health Surveillance Center (AFHSC), as well as vaccine safety through the Military Vaccine 

Agency (MVA). DoD is developing an immunization strategy that is based on variable disease 

virulence. The strategy will be adjusted by target groups, based on the epidemiology of novel 

H1N1.

Department of Veterans Affairs (DVA)

Dr. Linda Kinsinger reported that on April 25, 2009, the DVA activated an operations center to 

coordinate communications to and from the field. They instituted case reporting for the VA 

based on CDC policies. Reporting occurred daily at first, and then occurred weekly as of midMay. Based on evolving CDC recommendations, and with input from VA subject matter

experts, DVA issued seven clinical advisories to the field. They held a series of five VA-wide 

teleconferences over a three-week period to allow the field to ask questions, and they have 

participated in a number of inter-agency working groups and policy committees.

Food and Drug Administration (FDA)

Dr. Norman Baylor noted that most of FDA’s activity updates involved H1N1 work; therefore, he 

presented an update later in the meeting agenda.

Heath Resources and Services Administration (HRSA)

Dr. Geoffrey Evans updated the group on the autism hearing. Decisions were made regarding 

the Theory One combination of MMR vaccine and thimerosal. Theory Three was also decided 

upon, as there was no new evidence for the MMR vaccine-only theory. Decisions for three 

cases are in, and are under appeal. The first-level appeal decisions should be in later in the 

year. Theory Two, the thimerosal-only decision, is awaiting the end of briefing. He expressed 

hoped that the briefing would end in the next few months, with decisions later in the year. The 

Institute of Medicine (IOM) contract project to review vaccines and adverse events, which 
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started in September 2008, held an organizational meeting in April and a Biologic Mechanisms 

Workshop in Washington the previous day. The committee is adding varicella vaccine, 

influenza vaccines, HPV, and hepatitis B. If additional funding is obtained, then four additional 

vaccines will be added.

Indian Health Services (IHS)

Ms. Amy Groom reported that IHS instituted influenza-like illness surveillance using its 

electronic health records system. The system receives daily feeds from approximately 300 

facilities, and compile the data weekly for their sites and administrative areas. The trends of 

influenza-like illness in Indian Country mirror national trends. They are, however, investigating a 

cluster of severe H1N1 disease resulting in hospitalizations in a group of Indians in Arizona. 

IHS will determine whether this is an unusually high hospitalization rate or a result of 

widespread transmission in the area.

National Institutes of Health (NIH)

Dr. George Curlin stated that influenza research advances in seasonal influenza as well as in 

novel H1N1. He assured them that seasonal influenza has not been forgotten, despite 

concerns regarding H1N1. Enrollment has begun in a study of influenza vaccines for pregnant 

women, and basic research also continues.

National Vaccine Advisory Committee (NVAC)

Dr. Gus Birkhead presented an update on NVAC’s recent accomplishments: 1) input into draft 

National Vaccine Plan; 2) RAND study of the effectiveness of NVAC; 3) completion; 4) Adult 

Vaccination Report release in June 2009; 5) Vaccine Safety Working Group Report on the CDC 

ISO Scientific Agenda in June 2009; and 6) NVAC’s role in the H1N1 vaccination program.

The National Vaccine Plan is being updated for the first time since 1994. The IOM and NVAC 

have both been involved. Over 450 public comments have been received, and five public 

sessions have been conducted by IOM. NVAC has provided comments directly to IOM. NVAC 

held three public engagement sessions in St. Louise, Missouri; Syracuse, New York; and 

Columbus, Ohio. A public stakeholders’ meeting was held in Washington, DC. These sessions 

examined population values pertaining to vaccinations. The final report is due in November. 

Additional information is available at: http://www.hhs.gov/nvpo/vacc_plan/.

Dr. Birkhead described the RAND Corporation’s study of the effectiveness of NVAC. A draft 

report of the study was presented during ACIP’s last meeting. The report consisted of a 

literature review, reviewing past recommendations to NVAC, and interviews with key 

stakeholders. The report concluded that NVAC has a broad mission and there may be 

confusion in the minds of the general public and of healthcare professionals regarding the 

mission of each of the HHS advisory committees relating to vaccines. There are at least four 

other agencies in addition to NVAC. Further, the report states that NVPO is under-resourced to 

fully support its broad mission. The study highlighted gaps in representation on the group, 

including public members, economists, communication experts, and others. The report’s 

recommendations focus on these areas and on engaging in more active follow-up and seeking 

feedback from the Assistant Secretary of Health (ASH).

The Adult Vaccine Working Group completed the first part of its charge to review federal agency 

activities relating to adult immunizations. The working group created the following
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recommendations: 1) Better assess immunization coverage; 2) Conduct health services 

research; 3) Emphasize adult immunization with grantees; 4) Update immunization guidance; 

5) Health care worker immunization; 6) Secure funding support, in particular including all ACIP 

vaccines in Medicare Part B; 7) Develop incentives; 8) Conduct outreach and promotional 

campaigns; and 9) Improve safety monitoring.

Regarding the fourth recommendation, it was noted that many federal programs do not operate 

on the current ACIP guidelines, so the group recommended that all federal agencies dealing 

with adult immunization examine their internal program guidance. The report will go to the ASH 

and will be posted soon. The working group is moving to its second charge, which is to broadly 

consider vaccine financing in the public and private sectors.

In June 2009, NVAC’s Immunization Safety Working Group issued a report on its review of the 

CDC Immunization Safety Office Scientific Agenda. The report contains advice on the content 

of the research agenda, adding draft topics and providing a framework for prioritizing research

topics. The report also details possible barriers to implementing the research agenda and 

suggestions for addressing them. It was adopted during the June 2009 meeting, and a draft is 

available on the NVAC website. The process of reviewing the agenda was extensive, and 

included community meetings and keystone and stakeholder meetings.

The Vaccine Safety Working Group’s second charge is to review the current federal vaccine 

safety system. Over the next year, they will review the current federal vaccine safety system. 

Further, the working group will develop a White Paper describing the infrastructure needs for a 

federal vaccine safety system, which are to: 1) fully characterize the safety profile of vaccines in 

a timely manner; 2) reduce adverse events whenever possible; and 3) maintain and improve 

public confidence in vaccine safety. The membership of the working group has expanded. Its 

three chairs are Andy Pavia, Marie McCormick, and Tawny Buck. Three new members have 

been added to the group: Vicky Debold, PhD, RN, Health Administration and Policy Department 

at George Mason University, VRBPAC Public Representative; Robert Beck, JD; ACIP Member 

Public Representative; and Bill Raub, PhD, Former Deputy Director of the National Institutes of 

Health and Science Advisor to the Secretary, Department of Health and Human Services.

Current plans for NVAC include a kick-off working group meeting on July 15 – 16, 2009, in 

Washington, DC. The meeting will include presentations and discussion on five panels: 

1) Principles and policy alternatives for a robust vaccine safety system; 2) Identifying innovative 

ways of overcoming gaps in vaccine safety science infrastructure; 3) The ideal system to meet 

the needs of the public, public health, and healthcare professionals for confidence in vaccine 

safety; 4) Lessons from other safety arenas; and 5) Enhancing the adoption and implementation 

of the NVAC white paper.

Dr. Birkhead also described NVAC’s role in the response to novel H1N1 influenza. The June 2, 

2009 NVAC meeting included informational presentations from a number of advisory 

committees and partner organizations. He emphasized that NVAC’s role in the response 

includes maintaining partner input. NVAC will focus on the implantation of a vaccination 

program; ensuring stakeholder input; maintaining coordination among vaccine advisory 

committees; and contributing to vaccine safety and post-marketing. They plan to hold two 

public teleconferences and to submit recommendations to the ASH. A subgroup of the Safety 

Working Group will work with CDC and ISO concerning surveillance and vaccine safety issues.

NVAC made a series of recommendations to the new ASH regarding response to novel H1N1. 

The recommendations include accelerating the urgency of the response. While response has 
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begun, state and local planning must begin before it is too late. Further, resources are needed 

at the state and local levels, where health departments have lost 10,000 staff in the past year 

and expect similar losses this year. State and local health departments will bear the brunt of 

H1N1 response, and pandemic response will be occurring simultaneously with response to 

seasonal influenza. Further, pandemic influenza funding for state and local entities was 

terminated in 2008, and other preparedness funding has declined. NVAC’s recommendations 

noted that while the $350 million in supplemental funding was helpful, at a cost per dose of $15, 

the vaccination program will cost $9 billion dollars. Finally, vaccine safety monitoring is a critical 

piece of the response effort.

National Vaccine Program Office (NVPO)

Dr. Bruce Gellin noted that Dr. Howard Koh had been confirmed as the ASH. Before he came 

to HHS, he was the Harvey Feinberg Professor of the Practice of Public Health.

Introduction: Overview of Session

Abigail Shefer, MD

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Shefer reported that a nationwide shortage of Hib vaccine began in December 2007 when 

several lots of the vaccine produced by Merck were recalled voluntarily and production was 

temporarily suspended. To address the limited supply of Hib vaccine, CDC recommended that 

the Hib booster dose at 12 to 15 months be temporarily deferred for healthy children. Since 

then, there has been enhanced surveillance for Hib disease to identify any increase in incidence 

of cases. Using sentinel site registry data in select states, there has been some indication that 

the third dose of the primary series may have declined due to programmatic issues as well as a 

mismatch between local supply and demand, she said. Some information on both of these 

issues has been presented at past ACIP meetings. The shortage has been on-going for 

approximately 1.5 years.

Haemophilus Influenzae b (Hib) Vaccine
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Glaxo-Smith Kline (GSK) Monovalent Hib Vaccine

Remon Abu-Elyazeed MD, MPH, PhD 

Head, Pediatric Vaccines

Clinical and Medical Affairs, North America

GlaxoSmithKline 

Dr. Abu-Elazeed thanked ACIP for the opportunity to present clinical data highlights of 

GSK’s Hib conjugant vaccine. GSK has been working closely with CDC and FDA to 

make HIBERIX®, its Hib vaccine, available in the US as quickly as possible to help 

alleviate the Hib vaccine shortage that has become a public health concern.

HIBERIX® is reconstituted at the time of use before intramuscular administration. Each 

0.5mL single dose contains 10 micrograms of purified capsular polysaccharide 

conjugated to approximately 25 micrograms of inactivated tetanus toxoid. It contains no 

thimerosal and is latex-free. HIBERIX® was first licensed in Germany in 1996 and is 

currently licensed in 98 countries. From its launch until November 2008, approximately 

55 million doses of HIBERIX® have been distributed worldwide. A Biologic License 

Application (BLA) was submitted to the FDA on March 17, 2009, and it is being 

reviewed under accelerated approval. License of HIBERIX® in the US will provide an 

additional source of vaccine to the US market for booster dose. The proposed indication 

under review by the FDA is active immunization as a booster dose for the prevention of 

invasive disease caused by Hib in children ages 15 months through 4 years of age, and 

prior to their first birthday.

The clinical package to support approval of HIBERIX® contains data from nine studies. 

Seven studies provide core data when HIBERIX® was administered as a booster dose. 

These include 1008 subjects. Two additional studies focus on administration of 

HIBERIX® as a primary vaccination series. These studies provide supportive safety 

data and include 1396 subjects. The studies were chosen in consultation with FDA as 

the most relevant to evaluation of HIBERIX® use in the US.

In all of the trials, HIBERIX® was administered to children between 11 and 25 months. 

All seven studies support the safety of HIBERIX®. Six studies support immunogenicity, 

and three of them study administration of HIBERIX® as a booster in children who 

received primary vaccinations with HIBERIX® according to a 2-4-6 month schedule, or 

according to a 3-4-5 month schedule. Four studies provided data on the 

interchangeability when a booster dose of HIBERIX® was administered to children 

previously vaccinated with another vaccine. These four studies provided safety and 

immunogenicity data of HIBERIX® following priming with other Hib vaccines that are 

licensed in the US.

Polyribosyl ribitol phosphate (PRP) immune responses after a booster dose of 

HIBERIX® following priming in infancy with HIBERIX® were studied in children aged 14 

to 23 months. They received HIBERIX® co-administered with a combination DTaPHBV or DTaP-IPV vaccine. In a series of studies after booster vaccination with 
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HIBERIX®, 100% of the subjects achieved seroprotection at both 0.15 microgram per 

mL and at 1 microgram per mL cutoffs. In all three studies, HIBERIX® elicited a marked 

increase in GMCs from pre- to post-vaccination. In three additional studies, children 

were primed in infancy with either HIBERIX®, ActHIB®, HibTITER®, or PedvaxHIB®. 

After a booster vaccination with HIBERIX®, 100% of the subjects achieved protection at 

the 0.15 microgram per mL cutoff. Further, between 96.4% and 100% of subjects 

achieved anti-PRP antibodies concentration greater than or equal to 1 microgram per 

mL. In all three studies, HIBERIX® elicited a marked increase in GMCs from pre- to 

post-booster vaccination.

Regarding the immunogenicity of co-administered vaccines, in one study a booster 

dose of HIBERIX® was co-administered with DTaP and OPV. In the second study, a 

booster dose of HIBERIX® was co-administered with DTaP-HBV-IPV. The studies are 

not meant to be comparative, but both measure immunogenicity with co-administered 

vaccines. All subjects in both studies achieved seroprotective antibody levels against 

diphtheria, tetanus, and polio. At least 95% of the subjects demonstrated pertussis 

vaccine response. The group who received the Hepatitis B vaccine achieved 

seroprotective antibody levels against Hepatitis B, demonstrating that HIBERIX® does 

not interfere with immune response to concomitantly administered vaccines.

In terms of safety, solicited local and general adverse events were reported in all seven 

studies within four days after the booster dose was administered. Two representative 

studies include Study DTaP-HepB-IPV 010 and Study DTaP-IPV 026. In one study, 

children 12 to 25 months of age received HIBERIX® and a combined DTaP-HepB-IPV 

vaccine. This study included 371 subjects. The second study included 65 children 

aged 15 to 19 months of age who received HIBERIX® and DTaP. In both studies, 

HIBERIX® was administered concomitantly at a separate site. Relatively few local and 

general adverse events were reported, and there were very few cases of Grade 3 

symptoms.

Three serious adverse events were reported in 1008 subjects in the seven booster 

studies. All subjects recovered with no sequelae. No deaths were reported in any of 

the seven clinical studies. It was concluded that the safety of HIBERIX® was clinically 

acceptable. From the launch of HIBERIX® in 1996 until 2008, approximately 55 million 

doses have been distributed worldwide. Evaluation of post-marketing adverse events 

reports since the product launch have not revealed safety concerns, and HIBERIX® has 

not been withdrawn in any country due to safety concerns or regulatory issues.

Regarding immunogenicity, a booster dose of HIBERIX® provides strong immune 

response in children previously primed with Hib vaccine, regardless of the priming 

vaccine or the priming schedule. HIBERIX® is immunogenic when administered 

following primary vaccination with another US-licensed Hib conjugate vaccine. Further, 

HIBERIX® is immunogenic when co-administered with other commonly-used pediatric 

vaccines.
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Dr. Abu-Elazeed reiterated that the BLA was submitted on March 17, 2009 and is 

awaiting accelerated approval. As a post-license commitment, GSK plans to conduct a 

confirmatory trial for the booster dose in US infants, with HIBERIX® given at months 2-

4-6 and 15 to 18 months as scheduled. This trial will include co-administration with 

commonly-used pediatric vaccines.

Discussion

Dr. Ehresmann asked about the timeframe for an accelerated FDA review. Dr. AbuElazeed replied that the maximum time is six months from the submission date.

Dr. Baylor added that there is no specific time for accelerated review. Priority review 

timeframes are six months, where the criteria for accelerated approval allow for vaccine 

approval on a surrogate, which in this case is immunogenicity. A confirmatory study is 

required post-licensure. FDA’s goal is to complete this process as soon as possible.

Hib Surveillance

Michael L. Jackson, PhD, MPH

Meningitis and Vaccine Preventable Diseases Branch

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Jackson reported on Hib surveillance during the Hib vaccine shortage. In October 2008, 

when Merck announced that they would not be able to return to market until mid-2009, CDC

began enhanced surveillance for Hib. They worked to raise awareness among clinicians and 

laboratorians of the on-going vaccine shortage, the need for testing of suspected H. influenzae

cases, and for reporting to local health departments. CDC disseminated messages through a 

number of venues, including an MMWR report; notices through organizations such as PIDS and 

NACCHO and the Epi-X system; and presentations at national meetings. 

Since November 2008, CDC has actively followed up with state health departments on all 

reported cases of invasive H. influenzae in children less than five years of age. This follow-up is 

to make sure that CDC has the best available information on serotype, vaccination history, and 

disease outcome. For this evaluation, the focus is on invasive Hib, defined as isolation of Hib 

from a normally sterile site such as blood or cerebrospinal fluid.

Using enhanced surveillance data, CDC began testing for an increase in Hib incidence. The 

pre-shortage baseline was defined as the years 2000-2007, as these were years during which 

the incidence of Hib in the US was relatively stable. Fairly good surveillance data are available 

for that timeframe. Using the 2000-2007 data, the expected number of annual cases of Hib 

during the baseline period were calculated, with 95% confidence intervals. Starting from 

January 2009, each month the number of Hib cases reported in children less than five years for 

the past twelve months is compared with the upper confidence limit of the expected cases from 

baseline. This analysis tests whether the cases have exceeded the expected counts. These 

analyses were conducted for the US as a whole and for each state or jurisdiction individually.
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For the US as a whole, the expected cases of Hib for each calendar month, with confidence 

limits, were also calculated. They then compare the monthly number of reported Hib cases with 

the upper confidence limit of the expected monthly cases. This calculation is repeated for Hib 

plus untyped H. influenzae. The analysis of Hib plus untyped H. influenzae is needed to 

account for possible differences in the proportion of cases that were serotyped during the 

shortage compared to the baseline period.

Another question of interest is whether the population at risk for Hib has changed as a result of 

the Hib vaccine shortage. In particular, it is important to learn whether there have been shifts in 

the age distribution or the vaccination history of Hib cases among children less than five years 

of age. To address this, CDC compared Hib cases occurring since November 2008, when the

active follow-up started, with Hib cases reported through the ABC system from 1995 through 

2007, prior to the vaccine shortage. 

For the twelve month period of May 2008 through April 2009, a total of 43 cases of invasive Hib 

in children less than five years were reported to CDC. For comparison, the annual average 

during the baseline period was 31.4 cases per year. Although somewhat higher than average, 

this difference was not statistically significant.

Hib cases reported in each state or jurisdiction from May 2008 through April 2009 in children 

less than five were compared with the state-specific annual averages. Overall, 32 states or 

jurisdictions reported as many or fewer cases than average during baseline. Twenty states or 

jurisdictions reported more cases than average during baseline. Despite media reports of 

clusters of Hib in a few places, none of the increases were statistically significant. Hib case 

counts for the US as a whole exceeded the historical limits during February of 2009, but not in 

the subsequent months. Dr. Jackson reminded the group that the period from November 2008 

through April 2009 represented a timeframe during which CDC worked to enhance Hib 

surveillance, so some of this increase may be a surveillance artifact. The combined counts of 

Hib and untyped H. influenzae have remained within the historical limits during the shortage.

Age and vaccination histories for Hib cases during the vaccine shortage were compared with 

cases from the pre-shortage era for whom age and vaccination history are available. During the 

shortage, cases tended to be younger and were more commonly un- or under-vaccinated than 

pre-shortage cases. However, the differences were not statistically significant.

Dr. Jackson concluded that CDC has not observed a sustained, statistically significant increase 

in Hib cases in children less than five years of age either for the US as a whole or for any 

individual state, despite enhanced surveillance efforts. In addition, there has been no apparent 

change in the population at risk for invasive Hib. Hib cases in children less than 5 years of age 

during the shortage are not significantly different from cases prior to the shortage in terms of 

age distribution or vaccination history. There has not been a substantial impact on invasive Hib 

in children less than five years of age in the US during the Hib vaccine shortage. CDC will 

continue to monitor Hib incidence as the booster dose is reinstated and as new Hib vaccines 

are introduced.
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Discussion

Dr. Schuchat found the data to be reassuring. When the shortage began, they discussed a 

“cushion of protection,” given the herd effect of the vaccine. She expressed her hope that 

people would not interpret these data to mean that the shortage has not been a concern or that 

additional cases are not possible. They have learned from other countries with similar 

difficulties that problems can emerge over time. They are probably in the “cushion of protection” 

and a long delay for booster doses would present a problem.

Dr. Pickering asked for clarification on the untyped cases and how typing rates might be 

improved, as well as what the demographic differences were between untyped cases and Hib 

cases.

Dr. Jackson replied that the enhanced surveillance efforts have included contacting the states to 

verify serotype information. They have better serotype information available now than they did 

prior to the shortage. An average of 40% of cases were untyped before the shortage, and now 

about 12% of cases are untyped. He did not have information regarding distribution of age 

among untyped influenza cases since the start of the shortage, though he noted that these were 

a small proportion of the Hib cases.

Dr. Ehresmann confirmed that these cases are untyped, not untypable. Dr. Jackson agreed.

Vaccine Supply

Jeanne Santoli, MD

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Santoli presented information regarding the anticipated 2009 supply to support 

reinstatement of the Hib booster dose. 

Sanofi pasteur will supply at least 18 million doses of Hib-containing vaccine, including both 

monovalent and combination product, to the US market during 2009. The increased supply will 

be available beginning in July 2009. This volume will support return to the fourth dose and to 

begin catch-up efforts.

GSK has applied for licensure of their monovalent Hib vaccine, HIBERIX®. They have the

capacity to produce more than 4 million doses for the US during 2009. The regulatory review 

response is anticipated no later than mid-September, and the indication sought is for the 

booster dose.

Merck is working with FDA toward the following goals: 1) a limited supply of PedvaxHIB® to be 

available in the fourth quarter of 2009; and 2) full availability of PedvaxHIB® is expected in the 

first quarter of 2010. The return of COMVAX®, the combination with hepatitis B and 

PedvaxHIB® will be dependent upon the supply situation for both the Hib and hepatitis B 

vaccine components.
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Hib Vaccine Implementation Plan

Abigail Shefer, MD

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Shefer presented plans for the implementation of the Hib booster dose. The currently 

available Hib-containing vaccines include monovalent Hib (ActHib®) and DTaP-IPV/Hib 

(Pentacel®). Both are manufactured by sanofi pasteur. An increased number of doses of both 

vaccines will be available starting July 1, 2009. The increased number of doses will be 

sufficient to reinstate the booster dose of Hib vaccine to be administered on time at 12 to 15 

months for all children who completed the primary three-dose series. However, there will only 

be enough supply for limited catch-up at this time.

Limited catch-up means that older children whose booster dose was deferred should receive a 

dose of Hib vaccine at their next routinely scheduled visit or medical encounter. Supply 

constraints do not permit mass recall of all children whose booster dose was deferred. This

means that CDC does not recommend that practices institute an active notification process to 

contact all children with deferred booster doses at this time. Rather, CDC recommends that 

practices target children presenting for their next scheduled appointment or who have a medical 

encounter for any reason.

The current availability of Hib vaccine means that providers will be able to order some additional 

doses of Hib vaccine each month based on previous purchasing patterns or on practice birth 

cohort and estimates of additional needs. This applies to both private and public vaccine 

supplies. Practices need to develop a tailored plan that best suits their office environment, 

taking into account such elements as staffing, responsibilities, and clinic setup. The plan will 

likely include a review of electronic or paper records or registries or IIS prior to a physician 

encounter; screening children during scheduled visits; and discussing and sharing immunization 

schedules with parents.

Most of the challenges at the practice level are related to the use of combination products and 

the goal of minimizing extra immunization. This might lead to a mismatch between patient 

vaccination needs and the available stock of different vaccine formulations available in a local 

provider’s office. For example, practices using Pentacel® for Hib vaccination need to ensure 

that adequate supplies of monovalent Hepatitis B vaccine are available to complete the 

Hepatitis B vaccine series. Further, children who have already received four doses of DTaP 

should be prioritized to receive monovalent Hib vaccine.

In collaboration with several partners, CDC has prepared a number of educational materials 

about reinstating the booster dose and limited catch-up. The June 26, 2009 MMWR will include 

an article on the topic. Q & As for providers and patients are in the clearance process and may 

be ready for posting in early July 2009. Additionally, a one-page provider letter will be placed in 

all McKesson vaccine shipments and will alert providers to the reinstatement of the booster 

dose and limited catch-up. Another resource is an algorithm table on “Protecting Infants against 

Hepatitis B Virus Infection When Using Pentacel® Vaccine during the Hib Vaccine Shortage.” It 

outlines the issues and thinking that a practice needs to undergo when considering Hepatitis B 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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and Hib-containing vaccines. It is posted on the CDC website: 

http://www.cdc.gov/vaccines/vac-gen/shortages/default.htm. 

Plans for monitoring the situation are under discussion. They will continue to monitor Hib 

vaccine use through the registry sentinel sites. These registries are located in eight states 

throughout the country that have higher-quality data and are able to provide more timely data. 

This information will give CDC an idea of provider compliance with the recommendation. They 

are also considering conducting a provider survey to assess knowledge and practices related to 

administration of the booster and catch-up. The survey can be targeted through the registry 

sentinel sites, which will allow validation of actual vaccine delivery. A national survey of 

pediatricians and family physicians is also possible. The monitoring plans will depend on 

several factors, including vaccine supply and any new Hib-containing vaccines that come to 

market and affect that supply.

Discussion

Dr. Morse complimented all of the individuals who worked to manage the shortage. A 

tremendous amount of work took place, from surveillance to allocation and education. 

Professional agencies and manufacturers worked to help increase supply.

Dr. Ehresmann clarified that the booster will be reinstated as of July 1, 2009. Dr. Shefer 

confirmed that the recommendation will be to reinstate the booster dose on time for children 12 

– 15 months old, with limited catch-up for children during a regular visit or other encounter.

Dr. Ehresmann shared comments from a listserv of state grantees, who expressed concern 

regarding vaccine supply and concerns pertaining to the reinstatement of the booster dose. 

She was encouraged to hear about the GSK product.

Dr. Leonard Friedland (GSK) said that all manufacturers need to adequately plan for vaccine 

supply. He asked about sanofi pasteur’s distribution plans for July between monovalent Hib and 

combination Hib vaccines as they reintroduce additional supply. This information will help them 

at GSK understand their supply constraints.

Dr. Phil Hosbach (sanofi pasteur) replied that while he could not share that information in this 

forum, they have shared detailed information with CDC so they have a month-by-month supply 

for Pentacel® and Hib. They are pleased to have kept supply in place for at least three doses 

for the last year and one half. They have been able to adjust their supplies to provide a fourth 

dose.

Dr. Shefer said that AAP and AFP will communicate with their members about the reinstatement 

of the booster dose in various ways.

An inquiry was posed regarding why HIBERIX® is indicated for 15 months and why it could not 

be given at 12 months.

Dr. Schuchat replied that GSK would need to submit infant information.

Dr. Abu-Elazeed said that the clinical package submitted for approval of HIBERIX® as a booster 

dose includes children less than 15 months, but the numbers are not sufficient to expand the 

indication for less than 15 months.
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Dr. Pickering requested further information about plans to expand HIBERIX® in the future.

Dr. Abu-Elazeed answered that GSK has committed to a post-approval study. The primary 

series will be administered at two, four, and six months with a booster at 15 to 18 months.

Nancy Messonnier (NCIRD) said that the indication for Hib, the ACIP recommendations, and the 

Red Book start at 12 months for the booster dose. However, sanofi pasteur’s vaccine is not 

licensed for 12 to 15 months. The only vaccine with this licensure is produced by Merck. 

Because sanofi’s vaccine is not licensed for 12 to 15 months, GSK’s vaccine, which is based on 

a comparison with sanofi’s, will have the same indication as Sanofi’s—only 15 months. 

Physicians are likely to administer it anyway.

Dr. Friedland (GSK) added that GSK is in late development with a combination HiBmeningococcal-CY vaccine for infants. The fourth dose in that schedule will be at 12 months. 

They look forward to presenting data on that vaccine during the October 2009 ACIP meeting.

Claire Hannon (Association of Immunization Managers) echoed concerns that grantees have 

about the supply of Hib. She has heard from programs that are waiting for supplies to maintain 

the 3-dose series. The supply for July has only recently been sent, and it is difficult for grantees 

to know where they will be in the middle of July. They are happy to get additional vaccine in 

July and glad to have details about monovalent and combination products, but not knowing how 

much will be in the future is difficult. Some providers use a combination of a different type, so 

they need monovalent and need information about the future.

Dr. Santoli said that they have given grantees quarterly information about their allocation, 

recognizing the need for them to plan ahead. They were not able to give that information the 

first time because of a need to understand reactions to the first allocations. They adopted a 

different approach to be more equitable across states. She agreed that grantees need as much 

information as possible in advance.

Tom McCubbins (Merck) announced that Merck has restarted its Hib process. The data are 

very promising, and they should have supply available in the fourth quarter of 2009. They 

anticipate a return to full supply in 2010.

Dr. Mark Netoskie (AHIP) said that AHIP supports these recommendations. A survey of their 

member organizations indicated that they would not require changes to their current vaccine 

policies.
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132 

Dr. Jeanne Santoli

CDC/CCID/NCIRD/ISD

Dr. Santoli offered updates on the supply of vaccine for pediatric and adult hepatitis B, hepatitis 

A, and MMR-V. 

In February 2009, CDC analyzed available pediatric supply data from both United States

manufacturers of pediatric hepatitis B to assess sufficiency over the remainder of 2009. This 

assessment would help them understand the situation and how to proceed. In conjunction with 

the Vaccine Supply Stakeholder Group, which includes representatives from AAP, AAFP, 

ASTHO, NACCHO, AIM, FDA, and ACIP, CDC determined that there was no need to adjust 

routine pediatric vaccine recommendations. Following that analysis, in March 2009, CDC and 

its partners communicated broadly to encourage providers to continue routine ordering practices 

and to avoid placing larger-than-normal orders or stockpiling. Some delays had occurred in 

January and February, which could have caused ordering behavior to change and therefore 

create a situation that they hoped to avoid. Both manufacturers and CDC’s 64 immunization 

grantees are currently managing provider orders to support judicious vaccine ordering. This 

endeavor takes a great deal of work, but the process is critical to moving forward without issuing 

interim recommendations for this vaccine.

The analysis showed that the summer months of June, July, and August were anticipated to 

have the tightest vaccine supply. At this point, both manufacturers are supplying vaccine to the 

United States market. GSK will supply additional product to the United States beginning in 

September 2009 to assure sufficient supply. Merck expects supplies to be limited during the 

remainder of 2009, although supplies are still forthcoming, and they do not expect to return to 

full supply until 2010. 

She then addressed adult hepatitis B vaccine. Merck is not currently distributing its adult or 

dialysis hepatitis B vaccines. These products will not be available for the remainder of 2009, but 

will return to full supply in 2010. Fortunately, the supply of GSK’s adult hepatitis B vaccine and 

adult hepatitis A/hepatitis B combination vaccine is sufficient to meet national demand at this 

time. The supply will meet increased demand that comes from CDC's High Risk Adult Hepatitis 

B Initiative.

Regarding adult hepatitis A vaccines, Merck is not currently distributing this product currently 

and does not anticipate doing so during 2009. Merck will provide additional information 

regarding the availability of adult hepatitis A vaccines when it becomes available. GSK’s 

production and supply of adult hepatitis A vaccines and adult hepatitis A/hepatitis B combination 

vaccine are currently in good supply to meet national demand, said Dr. Santoli. 

MMR-V vaccine has not been, and will not be, available during the remainder of 2009. Merck 

expects MMR-V to return to the United States market with full availability in the first half of 2010. 

Vaccine Supply
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Finally, she addressed monovalent vaccines for measles, mumps, or rubella. Merck is not 

distributing these products at this time. They plan to resume production of these monovalent 

vaccines in the future, based on available resources and capacity. However, Merck does not 

expect that these vaccines will be available for at least two years. They are making customers 

who inquire aware of that longer time frame.

Discussion

Mr. John T. McCubbins (Merck) thanked his colleagues at GSK and sanofi for helping with the 

shortage issues that Merck has experienced. They understand the shortages’ significance to 

public health. He offered apologies to ACIP, public health providers, and patients for Merck’s 

difficulties. They have a two-fold plan to resolve their issues. An acute plan will address issues 

with specific vaccines that are in short supply, and long-term infrastructure issues will be 

addressed so that when temporary issues arise, they are not translated into supply issues. 

Progress has been made on that front. For example, Merck has produced 25% more varicellacontaining product in the first five months of 2009 than they have produced in any previous 

year. They have restarted Pedvax, and the supply should be available at the end of 2009 and 

the beginning of 2010. Merck has been producing its hepatitis B product, and they expect full 

supply in 2010. Additionally, they are investing in expanding infrastructure and in building new 

facilities in Ireland and North Carolina. They anticipate licensure for the North Carolina facility in 

2010, which will improve the supply situation. They are investing in the future to ensure that 

they will get where they want to be and not have a recurrence of this situation. Merck is in the 

vaccine business for the long haul, and they commit to greater transparency on their supply 

situation, including progress and setbacks. He understood that the only appropriate apology 

was to put these vaccine products back on the market, and Merck is committed to that effort.

Dr. Sawyer asked for comments from Merck regarding the rationale for returning to production 

of monovalent measles, mumps, and rubella, given that there are no recommendations from 

ACIP to use those vaccines.

Mr. McCubbins replied that the monovalent M, M, and R have been given a lower priority than 

the combination product. This prioritization is due to a capacity issue and the belief that better 

coverage is achieved with the combination product. Merck will return to monovalents, but not 

for at least two years.

Margie McGlynn (President, Merck Vaccines) responded that Merck has heard mixed feedback 

from the marketplace. There is no clear, good answer regarding production of monovalent M, 

M, and R. They feel that if providers are interested in using the monovalent vaccines, it is their 

obligation not to make that decision on behalf of the providers. They understand the on-going 

public health debate and the feelings of physicians who believe in using monovalents because 

of fears of problems with co-administration of combination vaccines. The concerns are not 

valid, but could affect penetration rates and utilization rates of the vaccine. They also 

appreciate that some providers and patients want monovalent products. For these reasons, 

Merck decided not to make the choice. At the same time, MMR has priority to immunize the 

greatest possible number of children on a global basis. They welcome additional input. She 

stressed that this decision was one of her most difficult as President of Merck Vaccines.

Dr. Birkhead stated his belief that Merck had made a mistake by proceeding with monovalents.
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Dr. Temte said that the Wisconsin Council on Immunization Practices (WCIP) has heard that 

various hospitals and health systems have been using the pediatric hepatitis B vaccine off-label, 

giving two doses to adult employees for cost savings. He asked about broad communication 

efforts to avoid this practice.

Dr. Santoli answered that CDC is in the process of clearing a set of hepatitis B Q & As about 

supply challenges on the pediatric and adult sides. This Q & As will state clearly that to make 

the best use of pediatric vaccine supply during a time when supply is limited, that supply should 

not be used to vaccinate adults. She agreed that the cost incentive may cause people not to 

heed that guidance.

Dr. Sumaya asked about communication or agreement between the pharmaceutical companies 

that supply the vaccines and the information that reaches providers via a number of advisory 

groups that make decisions and plans. He wondered whether the pharmaceutical companies 

have strategic plans for the next few years, and whether CDC has a sense of time frames and 

the availability of vaccines.

Mr. Phil Hosbach (sanofi pasteur) replied that they in close contact with CDC and the ACIP 

working groups as they work on vaccine development. They also work with NVAC and share 

information about their plans for vaccine development to target infectious diseases in the US 

and around the world. Information is shared at this working-group level.

Dr. Santoli added that when there is an issue or a challenge, the Vaccine Supply Stakeholders 

Group shares proprietary information as part of their discussions. They use this information to 

make decisions and recommendations. The involved organizations share a great deal of 

information that is not always made public. For example, the information used to make the 

decision about pediatric hepatitis B was based on month-by-month supply projections from each 

of the manufacturers, plus stockpile data.

Dr. Stan Grogg (AOA) expressed concern about Merck’s decision to produce monovalents, and 

his concern about delays in immunizations.

Dr. Schuchat reminded the group that pediatric vaccine shortages are addressed with a 

pediatric vaccine stockpile, which is part of the VFC program. There is a six-month supply of 

pediatric vaccines. With all of the new vaccines and combination vaccines, and with some 

formulations going out of production, the stockpile is undergoing re-evaluation and assessment. 

It has helped in some shortage situations and fallen short in others.

Dr. Christine Hahn (CSTE) recalled a discussion about combination vaccines in which it was 

concluded that MMR is not a combination vaccine because the individual antigens are not 

available. The vaccine recommendations were used to support combination vaccines, but the 

newly-approved statement is softer and includes patient preference as a prominent 

consideration. She felt that this statement could be interpreted as support for moving to 

monovalents for MMR. This interpretation seems to be in conflict with the committee’s 

sentiments.

Ms. Stinchfield (NAPNAP) echoed concern for single-antigen vaccines for measles, mumps, 

and rubella. Science should drive ACIP’s decisions, and it seems that producing these vaccines 

is not a good use of resources or efforts when the call for them comes from a small minority of 

parents and providers who will give in to the “too many, too soon” or “too young” arguments. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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Science disproves those assertions. To make single-antigen vaccines available goes against 

science and toward public opinion, which is sometimes erroneous.

Dr. McGlynn (President, Merck) indicated that there is a two-year time period between now and 

a point at which Merck would be able to reintroduce these vaccines. She welcomed and 

encouraged clear and specific ACIP recommendations. The physician community places orders 

for vaccines, and these calls influence Merck’s decision. Clearly, the physician community is 

most influenced not by Merck’s statements as a manufacturer, but by clear and strong 

recommendations from ACIP and other stakeholder groups. She expressed hope that they 

could work together to assure that the right outcome takes place.

Dr. Schuchat suggested that since an upcoming session of the meeting would focus on MMRV, 

they should delay their discussions about formulations until that session.

Dr. Birkhead said that ACIP has issued clear guidance on the MMR and monovalent issue. He 

pointed out that ACIP “holds the strings” to the VFC program, and he was not sure that

monovalents would automatically be included in the program when they became available, or 

whether it would require an ACIP vote to include them.

Dr. Lance Rodewald noted that monovalents were previously available from Merck, but were 

never in the VFC program.

Dr. Temte said that before the measles vaccine, the rate of febrile seizure with measles was 70 

per 10,000 people. The rate with the monovalent measles vaccine is about 9 seizures per 

10,000. The rate with MMR is 3 to 4 per 10,000. The perception that the measles vaccine by 

itself is safer than measles mixed with mumps and rubella is not supported by data. He 

suggested that they take a proactive approach to keep this information in front of physicians and 

the public.

Ms. Hannon (AIM) was grateful that manufacturers share information with CDC and the 

Stakeholders Group, which includes an AIM representative. This information cannot be shared 

further than those groups, however. Some grantees were informed about the hepatitis B 

vaccine situation either by providers or by McKesson’s announcement that the product was on 

back order. Even given the numerous legal issues, it is possible to make significant 

improvements in planning if more information about supply is available. Grantees are 

sometimes the last to find out even though they are engaged with CDC, and CDC makes 

decisions with information from manufacturers.

In light of the request from Dr. McGlynn, Dr. Ehresmann suggested that ACIP make a strong 

statement in opposition of Merck’s approach to producing monovalents, based on the current 

status of the science and ACIP statements. She suggested that a future meeting could 

generate a formal resolution to express the committee’s concern.

Dr. Keyseling (SHE) pointed out a limited use of monovalent vaccines during epidemic 

situations of mumps or measles for healthcare personnel and community coverage. If a limited 

supply of monovalent vaccine were controlled by the government and available for release, then 

it could be a cost-effective method for handling epidemics.

Dr. Schuchat said that one of the uses of the stockpile is for outbreak response, but CDC’s 

recommendation for outbreak response in the US is MMR.
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Mr. Hosbach (sanofi pasteur) recalled discussions from the previous day regarding policy 

decisions and their influence and impact on manufacturers. Many manufacturers were 

surprised at the direction of the committee regarding combination vaccines, as the 

manufacturers were not involved with the Combination Working Group. Knowing that the 

committee no longer prefers a type of vaccine will change manufacturers’ plans. Manufacturers 

try to share their development plans. A policy change has a significant impact on what they 

have done previously and their future directions. Manufacturers should not drive policy, but 

should be part of the process. If manufacturers participate, then they can help committees 

make well-informed decisions and understand complete impacts. Further, the public is also 

included in decision-making processes. ACIP is concerned about maintaining public 

involvement, and the manufacturers are also seeking guidance and information from providers 

and the public. He asked that manufacturers stay involved as much as possible.

Jane Quinn (GSK) supported Mr. Hosbach’s comments and elaborated on the collaborative 

efforts and willingness of manufacturers to work closely with CDC and all stakeholders. Issues 

of global planning capacity and supply constraints on particular antigens, as well as combination 

vaccine planning versus monovalent use, are important for all to consider. GSK has produced 

monovalent vaccines on a number of occasions, but they realize the breadth and 

interconnectedness of vaccine supply planning, especially around infant immunization 

schedules and combination vaccines. The process is difficult, and they take as many inputs into 

account as possible. They wish to remain open with CDC and all stakeholders in this effort. 

Vaccines must be brought forward in appropriate volumes and are readily available to all who 

need them. GSK is supportive of continued collaboration and supports Merck’s comments 

regarding transparency, especially in public health crises.

Dr. Katz (IDSA) said that the Measles Partnership, which administers the measles vaccine 

throughout resource-poor nations, uses monovalent measles vaccine. Some countries have 

now been able to switch to measles-rubella. MMR is not necessarily the international product. 

The Serum Institute in India, which makes most of the vaccine used for the Measles 

Partnership, makes monovalent measles vaccine. International use of monovalent vaccine 

does not mean that the US should change its preferences, but serves to point out that from the 

manufacturers’ point of view, different markets demand different products.
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137 

Introduction

Jonathan Temte, MD, PhD

University of Wisconsin

ACIP, Working Group Chair

Dr. Temte opened the MMRV Vaccine Safety Working Group session, first offering background 

information pertaining to the group’s process. They have worked on MMRV vaccine safety 

issues for approximately 16 months. In February 2008, preliminary data were presented to 

ACIP suggesting an increased risk for febrile seizures following the first dose of MMRV vaccine

among children aged 12 through 23 months in the first to second week after vaccination. 

Therefore, ACIP recommended removing the preference for the combination MMRV vaccine 

over separate administration of MMR and varicella vaccines and forming and ACIP MMRV 

Vaccine Safety Working Group [Morbidity and Mortality Weekly Report (MMWR), March 2008].

The group’s first term of reference was risk assessment being lead by the CDC Immunization 

Safety Office (ISO). The group was charged with a careful review of post-licensure studies and 

suggesting any additional analyses that might be needed to fill data gaps. Further, the group 

was to review encephalitis cases following the MMRV vaccine, and to communicate vaccine 

safety findings in a clear and transparent manner. The second term of reference concerned risk 

management and the formulation of policy options for ACIP’s consideration, taking into account 

both the benefit of vaccination and risks of vaccine adverse events. Additionally, the group was 

charged to identify and reconcile potential inconsistencies in previous ACIP statements related 

to measles, mumps, rubella, varicella vaccination, and febrile seizure prevention. 

In June 2008, the work group presented the terms of reference and other process information 

to ACIP. In October 2008, they presented results from the Vaccine Safety Datalink MMRV 

Febrile Seizure Study and heard final results from the Merck-sponsored febrile seizure study. 

October’s report also included work group’s interim synthesis of risk for febrile seizures after 

MMRV. In February 2009, ACIP heard preliminary results from a physician survey regarding 

opinions for MMRV vaccine use and was presented the elements of the policy framework that 

would be assessed to formulate options for MMRV vaccine use. Dr. Temte stressed that the 

group’s overall procedure had been intensive. They have had the benefit of great expertise of 

the work group members, as well as input from various other federal, state and local 

organizations and programs. They have also benefited from two unpublished studies providing 

detailed information on MMRV vaccine safety. Physician and mother opinion surveys and 

studies and the ethics consultation had an important impact on their work. An abundance of 

data has filtered through the work group in over 50 hours of teleconference meetings.

He reminded everyone of the social context in which they are dealing with discussing febrile 

seizure as a vaccine adverse event. Over the last few years, there has been a substantial 

increase in the number of vaccines recommended for usual use. Because of the effectiveness 

of vaccines, we are now in a situation in which many parents express more concern and fear of 

a vaccine and its potential adverse events than of the disease the vaccine has been so 

successful in preventing. Public trust in the safety and efficacy of vaccines is key at this point to 

Measles-Mumps-Rubella-Varicella Vaccine Safety 
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138

the on-going success of immunization programs. Also, communication and influence from 

multiple media sources is rapid (e.g., internet). These sources of information may or may not be 

factual. In conclusion, Dr. Temte reminded everyone that the recommended schedule in the US 

in 2009 is for the first dose of measles, mumps, and rubella for persons aged 12 through 15

months of age followed by a second dose at 4 to 6 years of age. The same schedule applies for 

varicella vaccine. MMRV vaccine is approved for use among healthy children aged 12 months

through 12 years [http://www.cdc.gov/vaccines/recs/schedules/child-schedule.htm].

 

 

Parental Perceptions of MMRV Vaccine

Alan P. Janssen, MSPH

Health Communication Specialist

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Mr. Janssen provided preliminary results of a qualitative study conducted with mothers and 

pediatricians regarding the MMRV vaccine. The objective of the study was to explore 

perceptions regarding the risks and benefits of the MMRV vaccine with pediatricians and with 

mothers. In addition, the study tested draft communication materials regarding the MMRV 

vaccine with mothers.

Regarding the methodology of the pediatrician survey, data collection included in-depth, thirtyminute interviews conducted one-on-one with 21 pediatricians. The interviews addressed dose 

one and dose two of the MMRV vaccination. The pediatricians were provided with an MMRV 

product profile. Studies were conducted in a commercial market-research facility in New York 

City and Kirkland, a suburb of Seattle, Washington, from May 9 - 15, 2009. They encouraged a 

diverse panel of respondents from the pediatric community, all of whom were board-certified. 

Of the panelists, 6 were male and 15 were female; 14 were White, 4 were African-American, 

and 3 were Asian. The pediatricians surveyed spend 70% of practice time in direct patient care 

and self-reported giving at least 5 MMR vaccines per month.

Pediatrician perceptions of MMRV vaccine were generally favorable. Common comments 

included the following: 

“We loved having it.”

“I have no reservations about ProQuad.”

“I miss it. I wish it would come back.”

“I’m definitely in the ProQuad pack.” 

A few pediatricians expressed reservations, such as the following:

“I’m not that comfortable with it, really.”

“I don’t like it that much.”

Pediatricians were asked to rank the significance of the MMRV vaccine to their armamentarium

on a scale of 1 to 7, with 1 representing no significant contribution to the practice and 7 

representing a highly significant addition to the practice. Most of the 17 pediatricians 

interviewed were very favorable toward the MMRV vaccine, with 9 respondents rating the 

vaccine’s significance at a 7, and 5 at a 6.
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When provided with data regarding the rates of fever and febrile seizures following MMRV 

vaccine, several pediatricians remarked on the data, but were not alarmed by them. 

Some of their remarks were as follows:

“I don’t think [fevers, febrile seizures] are numerous or serious enough to not use [ProQuad].”

“It makes sense. If you have more fevers, you’ll have more seizures.”

“...of significance to the patient, not clinically...I’d still use it.”

Pediatricians considered that for parents fever and febrile seizures are important and distressful 

events. Some of the comments were as follows:

Fever

“Fever is worrisome [for parents] and it’s across the board.”

Febrile Seizure

“The kids are fine and it takes the parents years to recover.”

“It’s really not a big deal. I talk the parents down.”

“Really scary for the parents; really harmless for the child.”

“It’s a very, very scary thing for parents to observe.” 

“That’s what freaks them out. Then they get fever phobia.”

“[Parental trauma] – that’s the big one.”

Regarding acceptance of the MMRV vaccine, most pediatricians reported that they would stock 

the MMRV vaccine as well as MMR and varicella vaccines. The top four factors rated as “very 

important” in influencing the decision to use MMRV vaccine were: 1) ACIP and AAP 

recommendations; 2) the potential for the MMRV vaccine to improve coverage for varicella 

vaccine; 3) parental preference for fewer injections at a visit; and 4) parental concerns for risk of 

febrile seizure. Another factor considered for decision-making was pediatricians’ support for 

flexibility to be able to meet the needs of their patients.

The interview included this question: “What do you think ACIP should recommend for dose 1 

MMRV at ages 12 to 15 months?” Of the 21 responding pediatricians, 11 said that they wanted 

provider choice between the MMRV vaccine and separate MMR and varicella vaccines, 5 stated 

a preference for separate MMR and varicella vaccines with an option to permit the use of 

MMRV, and 5 stated a preference for the MMRV vaccine. Some of their comments were

“We want families to have choices.” 

“There are families that want to unbundle vaccines and some who want to bundle. It would be 

nice to have a choice.”

“It makes our lives a little bit easier.”

“I just want to keep it simple. MMRV for both would simplify our conversation.”

The interview also asked pediatricians’ opinions regarding ACIP recommendations for dose 2 of 

MMRV vaccine at ages 4 to 6 years. Again, 11 pediatricians recommended provider choice 

between the MMRV vaccine and separate MMR and varicella vaccines, 10 had a preference for 

the MMRV vaccine for the second dose, and none supported separate MMR and varicella 

vaccines for dose two. Some of their comments were:

“It’s a much bigger deal with 5-year olds.”

“I think it’s more distressing with older kids.”

“Four-to-six year olds really, really, really don’t like shots”
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140

In summary, among the 21 pediatricians interviewed in two cities, approximately 50% stated a 

preference for provider choice between the MMRV vaccine and the separate MMR and varicella 

vaccines for both doses. Consistent with other studies, pediatricians reported less concern for 

fever and febrile seizures, but they also perceived that parents were likely to have greater fever 

and seizure concerns.

With respect to the methodology utilized in the Mother study, data were collected by means of a 

series of “mini focus groups” in Kirkland, Washington and New York City. The sessions 

included up to six participants per group, lasted about one hour and were moderated by a 

professional moderator who provided the mothers with background material about the MMRV 

vaccine and febrile seizures. The study assessed the mothers’ views about combination 

vaccines in general and about dose one of the MMRV vaccine for children aged 12 through 15 

months. The participants all had children aged 7 months to 3 years of age. Their children had 

neither experienced seizures nor had a condition which compromised the child’s immune 

system and thus their ability to receive certain vaccinations. The participants also expected 

their child to receive all or most of the recommended childhood vaccinations. A total of 16 focus 

groups were conducted with 82 respondents. The median age was 31 years, with a range of 20 

through 46 years. Of the 82 participants, 63 had at least one college degree. Respondents 

were White (n=58), African-American (n=10), Hispanic (n=6), Asian (n=5), and mixed race 

(n=3).

When asked about combination vaccines in general, the mothers produced a modest list of 

advantages, a longer list of disadvantages, and an even longer list of questions. The list of 

advantages included the chance for fewer shots and less pain and trauma; protection against 

several diseases at once; fewer doctor trips; and potentially lower costs for vaccination. The list 

of disadvantages associated with combination vaccines included an inability to pinpoint a source 

of allergic reaction; the potential for increased side effects; the concern that the combination 

shot may be too great a challenge for the child’s immune system; and less parental choice

regarding how children receive vaccines. The mothers’ questions focused on the side effects of 

the combination vaccines, whether the combination is as effective as separate vaccines, and 

how combination vaccines fit into the immunization schedule, including the catch-up schedule.

The degree of acceptance of the MMRV vaccine varied substantially among the mothers. After 

reviewing information about the MMRV vaccine, mothers were asked if their physician 

recommended MMRV for dose 1 for their child aged 12 to 15 months, to rank their acceptance 

of that recommendation on a scale of 1 to 7. Of the respondents, 18 gave a rank of 1, or “no 

way / no how” and 18 gave a rank of 7, or acceptance without reservations.

Comments of mothers who were acceptors of the MMRV vaccine centered on their trust of their 

pediatrician. They also liked the idea of giving one less shot. The non-acceptors of the MMRV 

vaccine determined that the risks were not worth the benefit of the combination vaccine, and 

there was a great deal of concern regarding seizures among this group. 

Mothers were generally less concerned about fever than they were about seizures, although 

some respondents did express strong concern about fever. Their assessment of the importance 

of the difference between the separate and combination vaccines varied. Some mothers 

spontaneously reported that fever and seizures could be prevented by using TylenolTM. The 

mothers’ perception of post-vaccination fever in general appeared to be affected by their 

experience. One mother commented, “That just comes with the territory, but you still worry.” 

Regarding seizures, there was general agreement among the mothers that seeing their child 
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have a febrile seizure would be a harrowing experience. For some, information on the rates of 

febrile seizure was of significant concern; for others it was not. A number of the mothers 

responded that they did not know what a febrile seizure was. After receiving information on the 

rates of seizure and the MMRV vaccine, some mothers responded that the numbers were not 

alarming.

In summary, the Mothers study was conducted with a small sample of mothers who reported 

that they have their children vaccinated. They generally expressed a high degree of trust in 

their pediatricians. Mothers can differ in their conclusions regarding the data about MMRV 

vaccine and the rates of fever and febrile seizures and, thus, in their acceptance of MMRV 

vaccine. After reviewing and discussing risks and benefits of MMRV and separate MMR and 

varicella vaccines, almost one-third of the mothers reported that they would be resistant to 

having their child receive the MMRV vaccine; about one-quarter of the mothers were neutral, 

and about 40% of them would accept it.

Discussion

Dr. Neuzil thought that it might be helpful to put these surveys into perspective with the 

perception survey reviewed at the February 2009 meeting. That survey included 300 

pediatricians and family practitioners. The physician interviews and mothers’ focus groups have 

very small numbers, and there could be different types of biases.

Dr. Temte answered that two different methodologies were used. The first survey was a 

randomized sampling of family physicians and pediatricians to have a general overview. Focus 

groups and interviews are not intended to be representative, but rather to determine common 

themes that occur across clinicians. In this case, they involved a multi-modal approach. Some 

themes were fairly consistent. They were not necessarily looking for percentages, but at 

themes that could be followed up with questions. Taken as a whole, the comments were 

consistent.

Mr. Janssen said that an advantage of a qualitative study is the ability to explore in more depth 

and to learn what is behind decisions. The combination of both methods is helpful in the 

decision-making process.

Dr. Dixie Snyder noted that the group of mothers had no major concerns about vaccines, as 

they planned to have their children vaccinated. A large proportion of the mothers were 

concerned when they received information about fever and febrile seizures after the MMRV 

vaccine. All studies have limitations or biases, but it is striking that this group of respondents 

were vaccine-friendly, yet expressed these concerns.

Dr. Baker echoed Dr. Snyder’s comment, adding that the “vaccine acceptable” group is not 

concerned about safety and is generally “pro-vaccination.” She asked about the methodology 

behind the selection of cities for the study.

Mr. Janssen replied that the Seattle area population has numerous questions about the safety 

and use of vaccines. Mothers in this area were recruited via their play groups and asked a

series of questions about vaccines. The New York City area has more concerns with disease 

because of the crowded nature of the city, so mothers there are likely to have opinions 

regarding vaccines. In contrast, focus groups in the center of the country showed that parents 

tend to follow physician recommendations. They chose areas in which they were likely to 

receive a range of responses. He has conducted studies like these for 10 years and was struck 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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by the number of questions and concerns raised, even among groups of vaccine acceptors. 

They trust their physicians, but many are going to other sources for information about vaccines 

that they then discuss with their physicians.

Dr. Baker commented on the finding that many parents do not know what a febrile seizure is, or 

that there is a risk for one with any vaccines. When counseling their patients, practitioners need 

to be aware of these gaps in knowledge and of reluctance on the part of parents.

Dr. Temte observed the New York City focus groups and noted the following: 1) fevers were of 

concern to parents; 2) in general, parents were not aware of febrile seizures until they heard a 

description of them, and the description alarmed them; and 3) almost all of the focus groups 

mentioned a risk of thimerosal exposure with MMR, even though that does not exist. The 

amount of misinformation is immense, making it even more important to ensure that patients 

receive clear information.

Dr. Sumaya agreed with the utility of the methodology that assesses perceptions. At the same 

time, these studies need to be supplemented by studies with multiple providers and populations 

with broader demographic characteristics.

Evaluation of MMRV and Febrile Seizures: 

Updated VSD Analyses with Chart Review Results

Nicola Klein, MD, PhD

Northern California Kaiser Permanente

and the Vaccine Safety Datalink MMRV Team

Dr. Klein reported on the updated VSD analyses with chart review results from the Vaccine 

Safety Datalink (VSD) / MMRV Rapid Cycle Analysis (RCA) study evaluating MMRV and febrile 

seizures. The VSD is comprised of 8 HMOs: Group Health Cooperative, Kaiser Permanente

Colorado, Kaiser Permanente Northwest, Harvard Pilgrim Health Care, Health Partners, 

Northern California Kaiser Permanente, Marshfield Clinic and Southern California Kaiser 

Permanente. Data are available on more than 8 million members.

Over the last few years, following the licensure of new vaccines, the VSD has undertaken RCA 

studies for each new vaccine. RCA utilizes data which are updated weekly on all vaccines and 

all outcomes. Analyses on outcomes specific for each vaccine are conducted every week. 

Each RCA study has a lead principal investigator from one of the VSD sites. Dr. Klein is the 

principal investigator at Northern California Kaiser Permanente, which is the lead site for the 

MMRV RCA Study.

Dr. Klein reviewed the MMRV seizure results, which were presented at the February 2008 ACIP 

meeting. The study monitored for seizures, among other outcomes, after the first dose of 

MMRV for patients presented in the emergency room and inpatient settings during post-vaccine 

days 0 to 42 among 12 through 23 month olds. A signal for seizures was detected in the 42-day 

period following MMRV compared with historical rates in MMR recipients. Upon further 

evaluation, the study found significant clustering of seizures on days 7 through 10 after both 

MMRV (N= 43,353) and MMR + varicella (V; N= 314,599) vaccines using temporal scan 

statistics. VSD reviewed charts to confirm febrile seizures during the seven to ten days after 

vaccination for both MMRV (N=45) and MMR + V (N=132) through 2007. Based on those 
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reviews, the study calculated an odds ratio of 2.3 (95% CI 1.6, 3.2), which translates to one

additional febrile seizure for every 1,923 MMRV doses administered instead of MMR + V.

Following this presentation, ACIP voted to change the recommendations from a preference for 

MMRV to no preference for MMRV or MMR + V. In addition, an MMRV Work Group was 

formed. One of the terms of reference of the Work Group was to evaluate additional data that 

would be helpful. A few questions remained after the preliminary work: 1) chart confirmation of 

febrile seizures outside the 7- to 10-day risk period; 2) the risk for seizures after MMRV versus

MMR + V in different time windows: 0 to 42 days, 0 to 30 days, 5 to 12 days, and 13 to 30 days 

to directly compare with the Merck-sponsored Phase 4 study in a post-hoc analysis; and 3) to 

conduct further investigations of risk for seizures in 4- to 6-year-olds, particularly evaluating for 

excess risk.

To address these questions, the investigators took advantage of the fact that the VSD had a 

supply of MMRV through most of 2008, so they utilized those data to conduct additional studies. 

The investigators considered seizures among 12 through 23 month olds after the first dose of 

vaccine administered during 2000 – 2008. There was a strong peak and clustering between 

days 7 and 10 for MMRV, MMR + V, and MMR alone. Further, there are no obvious clustering 

or peaks outside this window. Temporal scan statistics show that for MMRV, MMR + V, and 

MMR, there is significant clustering between 8 and 10 days, 7 and 10 days, and 7 and 11 days, 

respectively, depending on the vaccine. No clustering was identified for varicella alone.

The investigators also considered the question of detecting outpatient visits for fever. They 

collected data on outpatient fever visits among 12 through 23 month olds after the first dose of 

vaccine from 2000 – 2008. The results were similar to the seizure conclusions in that there was 

a peak in days 7 through 10. Temporal scan statistics of fever showed remarkable clustering 

between days 7 and 10 for all three measles-containing vaccines. Again, no significant 

clustering was identified for varicella alone.

Using these data, the investigators evaluated chart confirmation of febrile seizures outside the 

7- through 10-day risk period. In consultation with the VSD investigators and the ACIP MMRV 

Working Group, a chart review plan was devised to include all seizures 0 to 42 days after

MMRV, all seizures 7 to 10 days after MMR + V, and a sample of seizures at 0 to 6 and 11 to 42 

days after MMR + V. That sample was equivalent to the number of MMRV seizures during days 

0 to 6 and 11 to 42.

A total of 491 charts were sampled, and 451 were reviewed. The review confirmed that an 

acute seizure of any type had occurred in 94% of the charts (n=424). One of the study 

questions concerned whether there is a differential confirmation between MMRV versus MMR + 

V. There was no difference in confirmation rate between MMRV and MMR + V, with 94% of the 

charts being confirmed as an acute seizure of any type for both vaccines (n=424). Further, 87% 

of the total charts reviewed were febrile seizures (n=392), and there was no difference between 

the MMRV and MMR + V groups. Another question concerned whether there was a differential 

confirmation rate between cases that occurred within the 7- to 10-day risk period or outside it. 

Of the cases, 90% were confirmed in the 7- to 10-day window as febrile seizures, versus 83% 

outside the 7-10 day risk window and these two confirmation rates are significantly different 

from each other. More importantly, there is no differential in terms of the confirmation rate in the 

MMRV versus MMR + V groups either during the 7-10 day window or outside this risk period. 

However, because there was a difference between the confirmation rates of the two windows, 

when the sampling scheme was applied to a regression analysis, 90% was applied to any case 

in the window (7-10 days), and 83% to cases outside the window. In the chart review findings 
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among febrile seizure cases in 12 through 23 month olds, no difference was detected between 

whether it was a first seizure event between MMRV versus MMR + V, or whether there was a 

positive family history for seizures between recipients of MMRV versus MMR + V. Given that 

data pertaining to family history were missing from nearly half the charts, the results should be 

interpreted with caution.

The study next sought to evaluate the risk for seizures after MMRV versus MMR + V in the time 

windows of 0 - 42 days, 0 - 30 days, 5 - 12 days, and 13 - 30 days to directly compare with the 

Merck-sponsored Phase 4 study. When the study compared the risk of seizures 7 to 10 days 

after MMRV compared to MMR + V, the automated data showed a relative risk of 1.98 with 

confidence intervals of 1.43 and 2.73. These results were similar to Dr. Klein’s presentation to 

ACIP in February 2008. Chart-confirmed febrile seizures are similar, with approximately a twofold increase in relative risk (RR=2.04). These data translate to risk difference of 4.3 per 10,000 

doses; that is, for every 2,300 MMRV doses given rather than MMR + V, one more febrile 

seizure will occur 7 to 10 days after vaccination. A similar analysis for seizures 0 – 42 days 

after MMRV showed an increased relative risk of 1.42 in the automated data, with confidence 

intervals of 1.11 and 1.81. The chart-confirmed febrile seizure case data were very similar, with 

a relative risk of 1.46 and confidence intervals of 1.11 and 1.92. The risk difference for this 

window was 6.2 per 10,000 doses.

The data from 2000 – 2008 include mostly historical data for controls. While the investigators 

controlled for confounders as best they could, there are issues associated with using historical 

controls. Therefore, a case-centered logistic regression analysis was conducted. This analysis 

is a variation of the self-controlled case series method. Given that a seizure occurred, this 

analysis compares MMRV to MMR + V and determines whether the patient was more likely to 

have received the vaccine 7 to 10 days before the seizure, or during the control window of 43 –

180 days before the seizure. This analysis showed an increased odds ratio for febrile seizures 

of 1.92 and significant confidence intervals of 1.39 and 2.66 for the MMRV compared with MMR 

+ V for the 7-10 day postvaccination period. When the analysis was conducted for the window 

of 0 – 42 days, there was an increased odds ratio of 1.3 and confidence intervals of 1.03 and 

1.65. Thus, the previous analyses were confirmed, and there is increased risk for febrile 

seizures in these windows. Using regular regressions, post-vaccination risk was considered for 

days 5 through 12; 13 – 30; and 0 – 30 days. Using chart-confirmed cases only, increased

relative risk was found for having a febrile seizure during the 5 – 12 and 0 – 30 day periods. 

However, no difference in risk of febrile seizures in the MMRV versus MMR + V group was 

detected in the 13 – 30 day window. The automated data results were very similar to the chartconfirmed data. 

Further investigations were also conducted on risk for seizures in 4 - 6 year olds, particularly 

evaluating for excess risk. In this group, there were 4 seizures during days 7 – 10 after the 

MMRV vaccine. Zero occurred during that time for MMR + V. There is no significant difference 

between the 4 versus zero split. Further, only 1 of the 4 cases was diagnosed as a febrile 

seizure. In evaluating risk for 4 – 6 year olds, the investigators adopted a conservative 

approach. Instead of evaluating excess risk as before, in this case they evaluated for absolute 

risk. When evaluating absolute risk for MMRV for one case out of approximately 85,000 doses 

given, the upper limit of the confidence interval was one per 15,194. At most, therefore, for 

every 15,000 MMRV doses given, 1 febrile seizure will occur 7 to 10 days after vaccination, 

even if all of the risk is due to the MMRV vaccine. Similar calculations for MMR + V show one 

febrile seizure per approximately 17,000 doses.
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In summary, among 12 - 23 month olds after the first vaccine dose, fever and seizure are 

elevated 7 - 10 days after all measles-containing vaccines. MMRV increases fever and seizure 

about twice as much as does MMR + V. Analyses of chart-reviewed febrile seizures confirmed 

a two-fold increase risk of febrile seizures on days 7 - 10 following MMRV as compared to MMR 

+ V. The increased risk for seizures observed during other time windows is due to the risk 

during the 7 - 10 day window. Among 12 - 23 month olds after the first vaccine dose, for every 

2,300 MMRV doses given instead of MMR + V, one additional febrile seizure will occur 7 - 10 

days after vaccination. Among 4 - 6 year olds, no evidence of elevated seizure risk was found 

during the six weeks after MMRV. For the 7 - 10 days after vaccination, an absolute risk greater 

than 1 febrile seizure per 15,000 doses of MMRV can be ruled out. Among 12 – 23 month olds 

after vaccination, there is a sharp peak for seizures between days 7 and 10 for MMRV. The 

graph demonstrates that the increased risk for seizures detected during the longer windows is 

due solely to the increased risk in the 7- to 10-day window.

Synthesis of Evidence for Febrile 

Seizure Risk after MMRV Vaccination

Karen Broder, MD

CDC / CCID /NCPDCID / DHQP / ISO

Dr. Broder presented the final synthesis of the evidence for febrile seizure risk after MMRV 

vaccination on behalf of the MMRV Vaccine Safety Work Group. She reminded everyone that 

an interim synthesis was presented in October 2008. The framework for her presentation 

included a review of the evidence framework used to assess risk for febrile seizures after 

MMRV vaccine; risk assessment for Doses 1 and 2 of MMRV; the clinical importance of febrile 

seizures assessment; and a discussion of other terms of reference, including an encephalitis 

case review, additional analyses, and communication of findings.

In October, the work group presented an evidence framework that they developed to assess the 

risk for febrile seizures after MMRV. The framework was based on frameworks used by IOM, 

WHO, and the draft ACIP evidence-based work group guidance. The framework contains three 

lines of evidence, and all lines were evaluated for Doses 1 and 2. The first line is populationbased risk, or epidemiologic risk. The second is biologic plausibility, which in this case is the 

plausibility of having a febrile seizure after MMRV vaccination. The last line is clinical 

importance of the adverse event, which the group divided into two assessments: 1) the medical 

importance of febrile seizures, and 2) the psychosocial importance of febrile seizures as an

adverse event.

The analysis used quality of evidence grading definitions from the draft evidence-based work 

group guidance. One modification has been made since the October 2008 presentation in that 

evidence ratings no longer include the impact of further research. They are specific to the 

nature of the evidence. Four levels were used: high, moderate, low, and very low.

The approach to evaluating the evidence across all lines included a thorough review of two 

unpublished post-licensure studies of febrile seizure risk after MMRV: VSD (principal 

investigator: N. Klein), and a Merck-sponsored study (principal investigator: S. Jacobsen). In 

addition to these studies, the group reviewed literature and other data sources, including 

unpublished data. They consulted with numerous experts and held multiple discussions. Two 

work group surveys assessed and graded the quality of evidence for MMRV and febrile seizure 

risk. As noted, the group presented its first assessment in October 2008.
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With respect to the synthesis of the Dose 1 MMRV risk assessment, Dr. Broder summarized the 

data available in October 2008 from the VSD and Merck-sponsored studies. Both studies 

considered rates of confirmed febrile seizures after MMRV and compared them with rates after 

MMR and varicella vaccines administered in separate injections at the same visit (MMR + V) in 

children aged 12 through 23 months. Both studies found an increased risk for febrile seizures in 

the 1 to 2 weeks after vaccination with MMRV compared to MMR + V. No chart review data 

were available in the VSD study outside the 7- to 10-day period at the time. The results in the 

Merck-sponsored study were final. In the Merck-sponsored study, no difference in risk was 

noted in the 0 – 30 days after MMRV compared to MMR + V. A non-statistically significant 

decrease in febrile seizure risk was observed after MMRV compared to MMR + V in the 13 – 30 

day window after vaccination, with a relative risk of 0.6.

Since October 2008, the VSD has provided data from the expanded chart review study of 

children aged 12 through 23 months receiving Dose 1 of MMRV compared with MMR + V. They 

enrolled more children, employed additional methods, and reviewed charts in time periods 

outside the 7- to 10-day window. The work group assessed the evidence for the early and late 

risk windows after MMRV compared with MMR+V to determine whether there is a decreased 

risk for febrile seizures after MMRV compared with MMR+V in the 13 to 30 days after 

vaccination that might compensate for the increased risk observed after MMRV in the 5 to 12 

day period. Both studies compared rates of confirmed febrile seizures after dose 1 MMRV with 

rates after separate injections of dose 1 MMR + V in children aged 12 to 23 months. Both 

studies used a largely historical comparison cohort for the MMR + V cases. The VSD study 

included about 83,000 MMRV and about 376,000 MMR + V subjects. The Merck-sponsored 

study included about 31,000 subjects in each vaccination group.

The primary interval of interest in the VSD study was 7 to 10 days after vaccination on the basis 

of the temporal scan analysis. The primary interval of interest in the Merck-sponsored study 

was 5 to 12 days after vaccination, on the basis of pre-licensure data for fever. With the 

exception of one additional analysis in the 7 to 10 day period, which was not statistically 

significant, the Merck-sponsored data have remained unchanged since October 2008. Similar 

to the October 2008 data, the updated VSD study continues to show about a two-fold increase 

in risk for febrile seizures in the 7 to 10 days after MMRV vaccination compared with MMR + V. 

The VSD results in the later window showed a significant increased risk for febrile seizures 

during the 6 weeks after vaccination and observed no decreased risk in 13 to 30 days after 

vaccination for MMRV compared with MMR + V.

In terms of the previous experience regarding biological plausibility, the increased risk for febrile 

seizures in the 1 to 2 weeks after MMRV vaccination compared with MMR + V vaccination is 

biologically plausible. A study in the VSD of approximately 137,000 children under age 7 years

showed that vaccination with MMR is associated with an increased risk for febrile seizure during 

the 8 to 14 days after vaccination. About one additional febrile seizure occurs per 3000 to 4000 

children vaccinated [Barlow, Davis et al. NEJM, 2001]. A population-based study of about 

35,000 children aged 12 through 23 months who were vaccinated with varicella vaccine 

identified no increased risk for febrile seizures during the month after vaccination, after 

controlling for co-administration of MMR vaccine. Pre-licensure trial rates of vaccine-related 

fever and measles-like rash were higher in children aged 12 through 23 months receiving Dose 

1 MMRV than those receiving Dose 1 MMR + V, in the 6 weeks after vaccination [Black S et al. 

NEJM, Pediatric Infectious Diseases Journal, 1999]. In the trials, 22% of MMRV recipients had

fever, compared with 15% of MMR + V recipients. The fever was clustered in the 5 to 12 days 

after vaccination. Among subjects who had fever after vaccination, the proportion who had 
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147

fever during the 5 to 12 days was 45% for MMRV and 36% for MMR + V. Among subjects who 

had measles-like rash after vaccination, the proportion who had this rash during the 5–12 days 

was 82% for MMRV and 81% for MMR + V [Source: Package insert 2-2008 and unpublished 

data from Merck on 10-20-08]. Rates of outpatient fever visits after different patterns of MMR 

and varicella vaccine administration show that the medically-diagnosed fevers in all of the MMRcontaining groups are clustered in the 7 to 10 days after vaccination, and MMRV rates are 

higher than MMR + V rates [N. Klein, ACIP presentation, June 25, 2009; excludes KPSC site].

The work group used the evidence scores to grade population-based risk and biological 

plausibility. The survey of the work group addressed two questions: 1) the quality of evidence 

supporting an increased risk for febrile seizures after MMRV versus MMR + V in the 1 to 2 

weeks after vaccination; and 2) the quality of evidence supporting whether there is a decreased 

risk for seizures after MMRV compared with MMR + V in the 13 to 30 days after vaccination. 

The work group felt that the quality of evidence was high for the increased risk after MMRV in 

the early window, and that the quality of evidence was low to support the notion of a 

compensatory risk of MMRV compared with MMR + V.

In summary, two post-licensure studies assessed rates of febrile seizures in children aged 12

through 23 months who received Dose 1 MMRV vaccine and compared these rates with 

children who received separate Dose 1 injections of MMR and varicella vaccines at the same 

visit. The studies used different methods and populations of children. Despite using different 

methods and populations, the two studies showed remarkable consistency during the 1 to 2

weeks after vaccination.

On the basis of this review, the work group made two conclusions regarding the evidence for 

febrile seizure risk after Dose 1. First, among children aged 12 through 23 months, during the 1

to 2 weeks after vaccination (5 to 12 or 7 to 10 days, depending on the study) compared with 

separate Dose 1 injections of MMR and varicella vaccines administered at the same visit (MMR 

+ V), the evidence supports a causal relationship between receipt of Dose 1 MMRV vaccine and 

an increased risk for febrile seizures; the magnitude of the risk is about two-fold. After 

vaccination, 7 to 9 febrile seizures occur per 10,000 children vaccinated with MMRV and 3 to 4

febrile seizures occur per 10,000 children vaccinated with MMR + V. After Dose 1 MMRV 

vaccine, 1 additional febrile seizure is expected to occur per approximately 2,300 to 2,600 

children vaccinated, compared with MMR + V.

Additionally, among children aged 12 through 23 months, after considering multiple lines of 

evidence, the MMRV Work Group concluded that the body of evidence suggests that during the 

6 weeks after vaccination (0 to 30 or 0 to 42 days, depending on the study), an increased risk 

for febrile seizures after Dose 1 MMRV compared with MMR + V is only present during the 1 to 

2 weeks after vaccination (7 to 10 or 5 to 12 days, depending on study). The risk of febrile 

seizures occurring during other periods after vaccination is similar between Dose 1 MMRV and 

MMR + V. Therefore, the risk of febrile seizures occurring during the 1 to 2 weeks after Dose 1

MMRV compared with MMR + V is not offset by a decline in risk after MMRV in the later period 

after vaccination.

Regarding Dose 2 MMRV vaccine, the pre-licensure safety experience during Days 0 to 42 after

vaccination, showed lower fever rates in children aged 15–26 months receiving dose 2 MMRV 

compared with dose 1 MMRV (N=1035) [ProQuad® Package Insert, February 2008]. There 

were similar fever rates in children aged 4–6 years receiving dose 2 MMRV (N=397) compared 

with MMR and varicella vaccines (N=193) (children received dose 1 MMR and varicella at least 

once month earlier) [Reisinger et al. Pediatrics, 2006]. Fever >102o F or warm to touch was 
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10% in the MMRV group versus 9% in the MMR+V group. No febrile seizures were reported in 

pre-licensure study subjects receiving Dose 2 MMRV vaccine [Personal communication with Dr. 

Kuter, Merck on 10-20-08].

In terms of the summary of evidence for febrile seizure risk after Dose 2 MMRV vaccination, 

among children aged 4 to 6 years, epidemiologic and clinical data suggest adverse event 

experiences, including fever, are similar after vaccination with MMRV or separate injections of 

MMR and varicella vaccine administered at the same visit. Febrile seizures are much less 

common in the age range when Dose 2 MMRV is recommended (age 4 to 6 years) than when 

Dose 1 MMRV is recommended (age 12 to 15 months). Post-licensure studies were not 

designed to assess risk for febrile seizures after Dose 2 MMRV; however, in light of findings 

from the Dose 1 studies regarding febrile seizure risk in the early window, the MMRV Work 

Group assessed the evidence for febrile seizure risk in children aged 4 to 6 years. Information 

about Dose 2 MMRV febrile seizure risk was inferred from data on febrile seizure rates in 4 to 6 

year olds.

Regarding the summary results from VSD and Merck-sponsored studies for confirmed febrile 

seizures in children aged 4 to 6 years after MMRV versus MMR + V vaccines, in the VSD study, 

there was one febrile seizure in the MMRV group of almost 85,000 subjects, and no febrile 

seizures in the MMR + V group of about 65,000. The VSD study did a calculation showing that 

given these observations, at most, one febrile seizure will occur after vaccination per 

approximately 15,000 doses of MMRV and 17,000 doses of MMR + V in children aged 4 to 6 

years. The Merck-sponsored study identified no febrile seizures in the 5 to 12 days after MMRV 

or MMR + V in approximately 50,000 subjects [Sources: 2008-09 ACIP presentations; personal 

communication N. Klein 6/22/09; Personal communication with Merck-sponsored study 

investigators on 12-16-08].

In conclusion, regarding the risk of febrile seizure after Dose 2 vaccination, among children 

aged 4 to 6 years, the available data do not suggest that children who receive Dose 2 MMRV 

have an increased risk for febrile seizures after vaccination compared with those who receive 

separate MMR and varicella vaccine injections at the same visit; however, less information is 

available regarding the risk for febrile seizures after Dose 2 MMRV at ages 4 to 6 years than 

Dose 1 MMRV at ages 12 to 23 months.

Clinical importance of febrile seizures. Febrile seizures are defined in the medical literature as 

seizures that occur in febrile children who do not have an intracranial infection, metabolic 

disturbance, or history of afebrile seizures [AAP. Pediatrics. 2008; Johnston M. Nelson 

Textbook of Pediatrics. 2007]. They can occur in any setting of fever. They usually occur at 

ages 6 to 60 months, with a peak age of 14 to 18 months. This peak overlaps with the age of 

recommendation for the first dose of MMRV. Febrile seizures affect about 2% to 5% of young 

children in the US [AAP. Pediatrics. 2008; Baulac. The Lancet Neurology. 2004]. Other 

countries provide similar estimates. Febrile seizures generally have an excellent prognosis. 

More than 90% of children who have a febrile seizure will not develop epilepsy; however, certain 

factors and genetic predisposition can increase the risk for future development of epilepsy after 

a febrile seizure. One third of children with a first febrile seizure will have recurrent febrile 

seizures [Baulac. The Lancet Neurology. 2004].

The first conclusion of the Work group regarding the medical importance of febrile seizures is 

that children who have a first febrile seizure for any reason are likely to seek medical attention, 

which commonly includes a visit to the emergency department. The evidence from two 

population-based studies suggests that children who have a febrile seizure shortly after MMR 
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149

vaccination are not more likely than children who have febrile seizures for other reasons to have 

future epilepsy or neurodevelopmental disorders [Barlow, NEJM 2001 and Vestergaard, JAMA 

2004]. The evidence from one study in Denmark suggests that children who have a febrile 

seizure after Dose 1 MMR vaccination may have a higher risk for having another febrile seizure 

than children who had a febrile seizure for other reasons. The magnitude of this risk is likely 

small, estimated by this study at about a 19% increased risk. Although data on sequelae of 

febrile seizures after MMRV vaccine are not available, experts believe it is likely that the findings 

described above for MMR vaccine would be applicable to MMRV. The medical assessment is 

the same for Doses 1 and 2 of MMRV, except that febrile seizures in the 4 to 6 year age group 

occur less frequently than in the 12 to 15 month age group. Experts believe that the risk for 

recurrent febrile seizures would be lower for a child aged 4 to 6 years who has a febrile seizure 

after Dose 2 MMRV than a child aged 12 to 23 months who had a febrile seizure after Dose 1

MMRV [Vestergaard, JAMA 2004].

The second conclusion, pertaining to the psychosocial importance of febrile seizure, a national 

survey of physicians, which was presented to ACIP in February 2008, as well as interviews and 

focus groups of physicians and mothers, suggest consistently that parents and caregivers 

generally consider febrile seizures to be a more severe adverse event than is perceived by 

physicians [ACIP Presentations, Kempe 2/09 and Janssen 6/09]. Multiple studies across 

various cultures show that when a child experiences a febrile seizure, it may have a negative 

effect on the family, including adverse mental and physical health consequences in the parents 

and caregivers [Literature review presented to the WG by Dr. Skillen on 2/11/09].

One of the work group’s terms of reference was a clinical review of the encephalitis cases 

identified in the VSD study and the Merck-sponsored general safety study. The VSD study 

assessed for outcomes other than seizures, and encephalitis and meningitis were among those 

outcomes. The VSD study detected 2 cases of possible encephalitis after MMRV using ICD-9 

codes. These cases were presented by Dr. Klein in February 2008. Both cases were in 

children who also had febrile seizures 7 to 10 days after vaccination. When the cases were 

presented to ACIP, some clinicians raised questions about whether they were true encephalitis 

cases. The Merck-sponsored study detected 1 possible case of encephalitis after MMRV 

vaccine. This child did not have a febrile seizure. The work group then coordinated an expert 

review by two independent pediatric neurologists. They applied the Brighton Collaboration case 

definition [Sejvar, Vaccine 2007]for encephalitis to these three cases. Remarkably, both 

neurologists had the same assessment: 1 of the VSD cases met the criteria for encephalitis, 

and the other 2 cases were ruled out.

The work group was also charged to consider additional analyses that should be conducted 

regarding MMRV and febrile seizure risk. Over the last year, many of these analyses were 

completed, either by the VSD Study, focus groups, or special data requests. The work group 

believes that routine adverse event monitoring, which is done for all recommended vaccines,

should continue when MMRV returns to the market. Further, an area of potential research 

might include studies regarding health outcomes in MMRV recipients who have febrile seizures 

shortly after vaccination. The work group also worked under the terms of reference to 

communicate its findings regarding risk assessment in a clear and transparent manner. To this 

end, materials are under development by CDC communication experts to communicate the risk 

of febrile seizures after MMRV vaccine, as well as the benefits of MMRV vaccine in a clear and 

transparent manner. Additionally, the Vaccine Information Statement (VIS) will be updated to 

reflect updated data.

Discussion after Drs. Klein and Broder’s presentations
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Dr. Judson congratulated all those involved in the exhaustive investigation, complimenting their 

thorough approach to a large problem. He felt that the work made causal relationships clear, 

and he was glad that they were in a position to achieve closure on the subject.

Dr. Marcy concurred and added a perspective from the point of view of a pediatrician. The 

average pediatrician has approximately 1500 patients in his or her cohort. If 10% of them are 

changing every year, if there is 1 seizure per 2300 injections, then it will be 15 years before one 

additional seizure is observed. During this time, if 4% of patients have febrile seizures due to

viral infections, the pediatrician will have seen 92 first febrile seizures, and a total of 120 if a 

third of those patients have a second seizure. Therefore, they are comparing 120 seizures over 

15 years in a pediatric practice with 1 in 15 years. To him, that was a “small price to pay” when 

considering the probable increase in compliance. Parents frequently do not return for a varicella 

shot for many months, creating an increased period of risk. The minority opinion in the MMRV 

Work Group regarded the risks and benefits of vaccine and raised the point, “First, do no harm.” 

If one seizure every 15 years is used in that principle, then no vaccines would be administered, 

as every vaccine has adverse events. While the MMRV vaccine may result in additional office 

and / or emergency room visits due to febrile seizures, most emergency rooms can handle that 

volume. Public trust in vaccines is only a problem when there is a lack of transparency. If 

parents are not informed of the possibilities, then public trust will be lost. But if parents know 

the risks up front, and if they have the option to decline, the approach is reasonable, and the 

public trust will not be an issue. He believed that vaccine coverage would suffer and children 

would be put at risk for periods of time if MMRV was not used and if parents were not given the 

option to use it as much as possible.

Dr. Amy Middleman wondered about the existence of data regarding the difference in fever 

rates in those older than 6 years of age, since the vaccine is indicated for use up to age 12.

Dr. Broder answered that there are no safety data available beyond ages 4 to 6, but in the area 

of biological plausibility, similar adverse events were seen in 4- to 6-year-olds receiving the 

second dose as MMRV or as separate MMR and varicella vaccines. From a biological 

standpoint, it is fair to extrapolate that this would apply to older children. They do not have data 

to support this idea, however.

Dr. Klein said that they did consider fever in 4- to 6-year-olds, and those seem to be background 

seizure visits. There are 20-fold fewer overall visits than for children aged 12 to 23 months.

Dr. Harry Keyserling inquired about data on injection site risk. By giving a second injection, are 

there local site reactions, such as a localized infection at the injection site. Data were presented 

on thousands of doses, and he wondered whether infection is an issue.

Dr. Klein replied that they did not specifically look at injection sites, as they were monitoring for 

6 outcomes following the RCA study. Injection site is not typically used in RCA studies for a 

variety of reasons. They tend to focus on outcomes that would not be evaluated in prelicensure studies, but rather on outcomes that are more serious or rare.

Using the model by which the pathogenesis of varicella was developed, Dr. Mercy said after the 

injection is given there is a local, minor infection and a primary viremia. Then, the virus is 

disseminated throughout the body, and there is a secondary viremia, when the fever occurs. 

For this reason, he did not feel that the injection site was important. Rather, the secondary 
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viremia is important, if the model for attenuated virus immunization is the same as natural 

varicella.

Dr. Judson asked whether the question concerned bacterial infection.

Dr. Harry Keyserling clarified that if there is an infection in 1 out of 10,000 injections, or one out 

of 100,000 injections, then the risk of a local infection is compared to the risk of excess febrile 

seizures. But if data support that giving 100,000 injections does not cause an increased local 

problem, then the information would be useful.

Dr. Dixie Snider responded that bacterial infections after vaccinations are relatively uncommon.

Clearly, injection safety is an important issue, particularly in developing countries. He wondered 

about data on frequency of injection site infections, although Chesley Richards indicated that 

they did not have those data.

Barbara Kuter (Merck) addressed some of the conclusions based on the pre-licensure safety 

data that was collected in Merck’s clinical trials. Regarding fever in the pre-licensure studies, 

she noted that in a study in which children were vaccinated with 2 doses of MMRV (first at 12 

months and second at 15 months), the rates of fever were considerably lower with the second 

dose at a rate of 23% with the first dose, versus 8% with the second dose. In addition, Merck 

conducted studies in 4- to 6-year-olds. In these studies, children were either given MMR + V or 

MMRV. The fever rates were identical between the two groups. Further, there were no serious 

injection site reactions related to the MMRV vaccine. In fact, overall rates of injection site 

complaints were lower with MMRV than they were with MMR + V, with the exception of the rate 

of injection site rash, which was 1% higher for MMRV than for MMR + V.

Dr. Ehresmann commented that while she agreed with Dr. Mercy’s comments, in Minnesota, 

with a birth cohort of 67,000 children, 30 febrile seizures would be expected per year. Even 

though the increase might not be significant to an individual practice, it may have a bigger 

impact on a population basis.

Dr. Joe Bocchini (APA) asked Dr. Klein whether the chart review, which indicated that 16% and 

22% of two groups had a first febrile seizure, implied that this was the only group for which data 

were available, or whether a significant percentage had a prior febrile seizure.

Dr. Klein said that of all the reviewed charts, 16% for MMRV had a prior febrile seizure, and 

22% for MMR + V had one. Data were available in 85% of the charts. The children were aged 

12 through 23 months. The study did not exclude someone who had a febrile seizure from the 

study unless the second seizure did not occur within 42 days of the event. In that case, they 

were excluded when they were identified from automated data.

Dr. Bocchini followed up, asking if the patients had a febrile seizure prior to that period, what 

percentage included in the study may have had a febrile seizure that was their second or third. 

Dr. Klein clarified that they were excluded if their seizure occurred within 42 days.

Dr. Patricia Whitley-Williams asked for verification that the population studies reflected the 

heterogeneity of the US population.

Dr. Klein replied that VSD covers a large geographical area. This study included patients from

Kaiser Permanente’s Center in northern California. This population is representative of the 
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underlying population of California, which is quite diverse. However, it is slightly underrepresentative of the very poor and of the very rich.

Policy Options for Use of MMRV Vaccine

Mona Marin, MD

CDC / CCID / NCIRD / DVD

Dr. Marin described the MMRV Vaccine Safety Work Group assessment of the elements of the 

policy framework and presented the work group’s proposed policy options for MMRV vaccine 

use. The elements of the policy framework were presented to ACIP in February 2009 and 

include vaccine safety; efficacy / effectiveness and immunogenicity; burden of disease to 

prevent (i.e., measles, mumps, rubella, and varicella); program implementation; equity in access 

to vaccines and use of public funds; and social context. 

The work group offered the following assessment of these elements for Dose 1 at ages 12 to 15 

months, which is the age at which Dose 1 vaccine is routinely recommended. Regarding 

vaccine safety, Dr. Marin reiterated Dr. Broder’s summary and emphasized that the safety 

summary describes an increased risk for febrile seizures during the first to second weeks (5 to 

12 or 7 to 10 days, depending on the study) after Dose 1 MMRV vaccine compared with Dose 1

MMR and varicella vaccines administered at the same visit (MMR + V); one additional febrile 

seizure is expected to occur per approximately 2,300 to 2,600 children vaccinated with Dose 1

MMRV, compared with MMR + V. During the 4 to 6 weeks after vaccination, an increased risk 

for febrile seizures after Dose 1 MMRV compared with MMR+V is only present during the 1 to 2 

weeks after vaccination [Adapted from presentation by Dr. Karen Broder, CDC. ACIP meeting, 

June 25, 2009].

Regarding the efficacy / effectiveness and immunogenicity, MMRV was licensed on the basis of 

non-inferior immunogenicity of the antigenic components compared with simultaneous 

administration of MMR and varicella vaccines, based on the results of four randomized, 

controlled clinical trials [FDA, ProQuad clinical review, available at 

http://www.fda.gov/cber/review/proquadR.pdf]. Efficacy was inferred on the basis of non-inferior 

immunogenicity. Effectiveness of MMRV was not evaluated in clinical studies. Based on this 

evidence, the work group assessment was that the quality of evidence for non-inferiority was

high and that MMRV and MMR + V had equal immunogenicity. Equal effectiveness was 

assumed.

Dr. Marin reminded the committee that the burden of disease prevented is a function of vaccine 

effectiveness and vaccine coverage. The current burden of disease in the US for measles, 

rubella, and mumps is eliminated or very low 1-3. The burden of varicella is low, with the 10-year 

vaccination program having had an important impact of approximately 90% reduction in disease 

incidence during 1995-20053. There are still an estimated 400,000 varicella cases per year. 

These disease levels were achieved in the absence of MMRV. The current low levels of 

disease are due to high population immunity achieved through high vaccine coverage. The 

coverage of MMR vaccine among 19 to 35-month-olds has been between 90% and 93% since 

19965. All states had second dose measles-containing vaccine school entry requirements in 

2005 – 2006. These requirements are an important tool for ensuring high vaccination rates. 

Coverage of varicella vaccine among 19 to 35 month-olds reached 90% in 2007. Forty-six 

states had one dose school entry requirements in 20087 [1. Katz SL and Hinman AR. J Infect 

Dis, 2004; 2. Reef SE and Cochi SL. J Infect Dis, 2006; 3. Barsky A et al. IDSA abstract, 2008; 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

153

4. Guris D et al. J Infect Dis, 2008; 5. NIS, www.cdc.gov/vaccines/stats-surv/default.htm#nis; 6. 

http://www.cdc.gov/vaccines/vac-gen/laws/downloads/izlaws05-06.pdf; 7. CDC, unpublished 

data (courtesy of Jessica Leung, MPH)].

For burden of disease to prevent, the work group concluded that MMRV as a first dose likely 

has a similar impact to that of MMR + V for prevention of measles, mumps, rubella, and 

varicella. MMRV may lead to more children vaccinated against varicella at age 12 months 

rather than 15 to 18 months. An important burden of disease for varicella is not seen among 

children aged 12 to 18 months. The quality of evidence for this conclusion was expert opinion 

and the benefit of MMRV and MMR + V for preventing measles, mumps, rubella, and varicella 

for the first dose was assessed as equal.

Regarding program implementation, the work group discussed differences in storage conditions. 

MMR is stored in the refrigerator, where varicella and MMRV must be stored frozen. Further, 

many discussions focused on the impact of the number of injections, given that 9 or 10

vaccinations are recommended either routinely at age 12 to 15 months or for ages that overlap 

ages 12 to 15 months1. The work group also discussed the known parent and provider 

preference for fewer injections per visit 2-4. The group examined the current experience with 

vaccine administration using data from two immunization information systems5. These data 

showed that the majority of children receive Dose 1 MMR and varicella vaccines at age 12 

months. A minority receive them at 15 – 18 months. Among children who receive varicella 

vaccine, about 84% receive the first dose at 12 months, and the percentage increases to 97% 

by 18 months. The Immunization Information Systems also showed that one-third to one-half of 

children received four or more injections at one visit at ages 12 to 14 months

[1.http://www.cdc.gov/vaccines/recs/schedules/child-schedule.htm; 2. Meyerhoff A. Clinical 

Pediatrics, 2004; 3. Lieu TA et al. Vaccine, 2000; 4. Freed GL et at. Pediatrics, 2006; 5. Source: 

Immunization information Systems, MI and OR sentinel sites].

Information was available from the 2006 – 2007 National Immunization Survey1. Regarding 

timeliness of vaccination among 24 to 35 month-olds, 20% of children fell behind in their 

vaccinations during the interval from the 6-month to the 15-month vaccines schedule, 67% of 

children were not fully vaccinated by age 16 months, including about 28% who did not receive 

MMR. The work group discussed multiple factors that could lead to delayed vaccination or 

under-vaccination. The group also discussed the potential impact of combination vaccines. 

There was expert opinion agreement that combination vaccines may offer benefit in terms of 

overall coverage or timeliness, but the literature is limited to quantitate the benefit2-4 [1. Luman 

ET et al. Am J Prev Med, 2009; 2. Marshall GS et al. Pediatr Infect Dis J, 2007; 3. Happe LE et 

al. Pediatr Infect Dis J, 2009; 4. Allred NJ et al. PAS abstract, 2009].

In their consideration of program implementation, the work group discussed additional 

information from focus groups with mothers which indicated that mothers had questions and 

concerns related to safety of vaccines1. If MMRV were recommended by their physician, 41% 

of mothers would accept and 31% would refuse. Several different studies on physician use and 

opinions of MMRV vaccine were considered as well. These studies found good uptake when 

MMRV was available. Physicians interviewed reported no differences in experience using 

MMRV compared with MMR1. Regarding intended use of MMRV given post-licensure safety 

data, one study found that 9% of family physicians and 21% of pediatricians would give MMRV 

to a healthy 12- to 15-month-old, where 20% to 24% would let parents decide2. Another study 

indicated that about half of prior users and about 20% of non-prior users expect their patients 

aged 12 to 15 months to receive Dose 1 MMRV3 [1. A. Janssen, CDC. ACIP meeting June 25, 
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154

2009; 2. Dr. A. Kempe, Univ of Colorado. ACIP meeting February 26, 2009; 3. J. Kramer, Merck 

& Co. Presentation to the WG, May, 2009].

Examining all of this evidence, the work group considered the general preference among 

parents and providers for fewer injections at one visit and that it is likely that vaccination against 

measles, mumps, rubella, and varicella at ages 12 to 15 months would be preferred as one 

injection instead of two, assuming that the safety profile is similar. MMRV potentially can have a 

favorable impact on the on-time administration of other vaccines recommended for ages 12 to 

15 months. However, for some parents and providers, the benefit of the reduced number of 

injections is outweighed by the increase in febrile seizure rate after MMRV.

Based on expert opinion, the work group concluded that there was insufficient evidence to 

assess the difference in benefit between MMRV and MMR+V in terms of program 

implementation. Available data from the National Immunization Survey suggest that in terms of 

coverage for Dose 1, there was no difference for measles, mumps rubella and varicella 

vaccines coverage by age 19 months with the use of MMRV. This is likely due to the alreadyhigh coverage rates prior to MMRV introduction [Zhen Z, CDC, communication to the WG, May, 

2009. Source: NIS Q307-Q208]. A minority of work group members expressed concerns that 

use of MMR + V could adversely affect the overall vaccine coverage rates and incidence for 

other vaccine-preventable diseases. Also, the impact of the recommendation on acceptance by 

parents is unknown.

Regarding access to vaccines and the use of public funds, ACIP has issued recommendations 

for MMR, MMRV, and varicella vaccine use. These vaccines should be covered similarly by 

insurance companies. There are VFC resolutions, and the price of the vaccines per dose is 

similar [Available at http://www.cdc.gov/vaccines/programs /vfc/cdc-vac-price-list.htm. 

However, MMR + V includes two administration dose fees as opposed to one. MMRV and 

varicella are stored frozen, so there is no difference in availability due to storage requirements. 

The work group concluded that there is high quality of evidence for no difference in access and 

use of public funds between MMRV and MMR + V.

Besides the social context in general presented by Dr. Temte in the introduction, the work group 

consulted with CDC and academic ethicists regarding possible ethical aspects associated with 

the MMRV vaccine recommendations. The key question explored was whether the increased 

protection for the population offsets any increased risk for the individual. Considering the ethical 

principles of risk / benefit analysis, parental and provider preferences, and justice and fairness 

considerations, the ethics group recommended an approach that makes safety the default, 

therefore favoring a preference for separate MMR and varicella vaccines for Dose 1. The 

choice to use MMRV vaccine should be made available if the physician and parents decide it is 

the best option. Additionally, if future data show that a preference for separate vaccines has a 

larger-than-expected impact on coverage, then the option should be reconsidered.

In terms of the policy options for Dose 1, of the four options discussed by the work group and 

presented to ACIP in February 2009, three policy options received support from at least one 

group member. The work group proposes for a vote two of those options: 1) preference for 

separate MMR and varicella vaccines over MMRV vaccine; and 2) no preference for MMRV 

vaccine over separate MMR and varicella vaccines (current interim recommendation) [CDC. 

Update: Recommendations from the Advisory Committee on Immunization Practices (ACIP) 

Regarding Administration of Combination MMRV Vaccine. MMWR. 57(10);258-260]. The third 

option was: MMRV not recommended for ages one to two years; always use separate MMR 

and varicella vaccines, and was supported by one work group member.
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155

With respect to the work group’s assessment of the elements of the policy framework for Dose 2 

at ages 4 to 6 years, regarding vaccine safety the conclusion presented by Dr. Karen Broder 

indicated that there was no increased risk after Dose 2 MMRV vaccine for children 4 to 6 years. 

For efficacy / effectiveness and immunogenicity, as mentioned, MMRV was licensed on the 

basis of non-inferior immunogenicity of the antigenic components. The geometric mean titer 

(GMT) was the primary end point to demonstrate similar antibody responses. For measles, 

mumps and rubella the GMT fold rises were comparable between MMRV and MMR + V groups 

[Reisinger KS et al. Pediatr Infect Dis J, 2006]. However, for varicella, the GMT fold rise was

higher after MMRV than MMR + V (difference statistically significant) but there were no tests 

done to show superiority. Therefore, the work group concluded that the evidence supports that 

MMRV and MMR + V are at least equal in terms of immunogenicity and effectiveness. Some 

experts felt that because GMT is higher after Dose 2 MMRV compared with Dose 2 MMR + V or 

varicella vaccine, the effectiveness may be higher after MMRV, but there are no data on 

possible superior protection against varicella provided by MMRV. The quality of evidence for 

non-inferiority was high, and the benefit of MMRV and MMR + V was equal in terms of 

immunogenicity. Equal effectiveness was assumed.

The burden of disease prevented was considered similar to that for Dose 1 at ages 12 to 15 

months, with several differences in coverage for varicella. The second dose for varicella was 

recently recommended in 2006, compared with 1989 for MMR. In 2008, only 12 states had 

school entry requirements for two doses of varicella vaccine, compared with all states for 

measles-containing vaccine [CDC, unpublished data (courtesy of Jessica Leung, MPH)]. There 

are currently no good ways of measuring coverage for the second dose of varicella, so 

estimates are relied upon based on the number of states that have school-entry requirements. 

The work group concluded that MMRV as a second dose has the potential to have a greater

impact on the control of varicella disease than MMR + V through increasing second-dose 

varicella coverage until states implement school entry requirements. There will likely be similar 

impact to that of MMR + V for prevention of measles, mumps, and rubella. The quality of 

evidence for this conclusion is expert opinion. For the difference in benefit between MMRV and 

MMR + V, the Working Group concluded that MMRV is potentially more beneficial for varicella 

than MMR + V.

Regarding program implementation, storage conditions for Dose 2 are similar to those 

discussed for Dose 1. In terms of the number of injections, 5 vaccines are routinely 

recommended at ages 4 to 6 years1. Anecdotal reports indicate that it is more difficult to 

administer multiple injections at one visit to children aged four to six years. Data from two 

immunization information systems indicates that the routine age for Dose 2 MMR vaccine is four 

years, and 37% to 48% of children aged 4 to 6 years received 4 to 5 injections at one visit2. 

One physician opinion study on the use of MMRV showed that 20 percent of family physicians 

and 38% of pediatricians would give MMRV to a healthy 4- to 6-year-old, and 21% to 25% 

would let parents decide3. Another study found that two-thirds of prior users and one-third of 

non-prior users expect their patients aged 4 to 6 years to receive Dose 2 as MMRV4 [1. 

http://www.cdc.gov/vaccines/recs/schedules/child-schedule.htm; 2. Source: Immunization 

information Systems, MI and OR sentinel sites; 3. Dr. A. Kempe, Univ of Colorado. ACIP 

meeting February 26, 2009; 4. J. Kramer, Merck & Co. Presentation to the WG, May, 2009].

The work group reached a conclusion regarding program implementation that it is likely that 

vaccination against measles, mumps, rubella, and varicella at ages 4 to 6 years is preferred as 

one injection (MMRV) instead of two (MMR + V) by both parents and providers, provided that 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

156

the safety profile is similar. A potential benefit for MMRV is a more rapid increase of coverage 

for Dose 2 varicella vaccine and improved coverage for other vaccines recommended at this 

age. The quality of evidence for this conclusion is expert opinion, and in terms of difference in 

benefit, it was concluded that MMRV is more beneficial than MMR + V. 

Regarding equity in access to vaccines, use of public funds, and social context, the evidence 

and assessment for Dose 2 are similar to those for Dose 1 at age 12 to 15 months. The ethics 

consult did not address recommendations for Dose 2. 

In terms of the policy options for Dose 2, after the previous day ACIP meeting when a vote 

occurred on the general recommendations for combination vaccines, the MMRV Work Group 

held a conference call. The group proposes to defer the recommendation for Dose 2 MMRV at 

ages 4 to 6 years to the ACIP General Recommendations for combination vaccines with the 

same language adopted by the committee.

In terms of evidence for Dose 1 and Dose 2 of MMRV vaccine at ages other than routinely 

recommended, no safety data are available for Dose 1 MMRV among children aged older than 

23 months1. It should be noted that febrile seizures usually occur at ages 6 to 60 months, with 

the peak age being 14 to 18 months. Some data are available regarding the MMR experience: 

a study in Denmark showed a decreased risk for febrile seizures with increasing age at 

vaccination within the age group 15 to 23 months1. For Dose 2 MMRV at ages less than 4 

years, data are available for ages 15 to 26 months. There is a lower incidence of fever and 

measles- and varicella-like rash than post-Dose 12,3. In clinical trials, among approximately 

2,700 subjects, two febrile seizures occurred (of which one in a setting of roseola) after Dose 2 

when Dose 2 was administered 3 months and 6 – 9 months after Dose 14. The immune 

response after dose 2 is primarily anamnestic response, of measles-containing vaccine 

recipients 95% have antibodies after Dose 1 administered at age 12 months. Immunogenicity 

was not inferior when the second dose was administered at ages younger than 4 years2,3. No 

safety or immunogenicity data are available for Dose 1 or Dose 2 MMRV at ages 7 to 12 years. 

However, febrile seizures occur almost exclusively among children aged 6 to 60 months [1. 

Vestergaard M et al. JAMA, 2004; 2. Shinefield H et al. Pediatr Infect Dis J, 2005; 3. Shinefield 

H et al. Pediatr Infect Dis J, 2005; 4. Merck & Co. Presentation to the WG, December, 2008].

With this evidence and in light of the recent ACIP General Recommendations on combination 

vaccines, the work group proposes that the Dose 1 recommendation apply to children aged 12 

to 47 months. Supporting evidence for using 47 months, or 3 years, as the cutoff age: 1) the 

two post-licensure studies found an increased risk for febrile seizures 5 to 12 days after Dose 1

MMRV compared with MMR + V among children aged 12 - 23 months, 2) In the absence of 

safety data, the group recommended adopting an approach that favored safety during the 

period of risk for febrile seizures, and 3) The first febrile seizure is uncommon after age four, 

with 94% of seizures occurring in children aged younger than 4 years in a population-based 

study in Finland [Sillanpaa M et al. Population based study of febrile seizures in Finland. J 

Pediatr Neurology, 2008]. Further, the work group proposes that for Dose 1 at other ages 

besides 12 - 47 months and Dose 2 at any age up to MMRV’s license of 12 years, the 

recommendation should be that from the ACIP General Recommendations on combination 

vaccines.

Regarding other MMRV vaccine-related guidance from the work group, studies suggest that 

children who have a personal or family history of febrile seizures or family history of epilepsy are 

at increased risk for febrile seizures compared with children who do not have such histories (see 

table in the slide presentation). The MMRV (ProQuad®) package insert lists individual or family 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

157

history of convulsions as a warning. The work group therefore proposes that ACIP includes a 

personal or family history of seizures as a precaution for MMRV vaccine use. “Family” is 

defined as a first-degree relative. The ACIP General Recommendation document’s definition of

“precaution” was presented in the footnote [“A precaution is a condition in a recipient that might 

increase the risk for a serious adverse reaction or that might compromise the ability of the 

vaccine to produce immunity (e.g., administering measles vaccine to a person with passive 

immunity to measles from a blood transfusion). A person might experience a more severe 

reaction to the vaccine than would have otherwise been expected; however, the risk for this 

happening is less than expected with a contraindication. In general, vaccinations should be 

deferred when a precaution is present. However, a vaccination might be indicated in the 

presence of a precaution because the benefit of protection from the vaccine outweighs the risk 

for an adverse reaction.” ACIP General Recommendations on Immunization. MMWR

2006;55(No. RR-15)].

One of the work group’s terms of reference was to reconcile the guidance for use of antipyretics 

for prevention of febrile seizures. In its 2008 guidance for long-term management of the child 

with simple febrile seizure, the American Academy of Pediatrics (AAP) states that no studies 

have demonstrated that antipyretics, in the absence of anticonvulsants, reduce the risk of 

simple febrile seizures [American Academy of Pediatrics. Clinical practice guideline for the longterm management of the child with simple febrile seizure. Pediatrics, 2008]. Although 

antipyretics may improve the comfort of the child, they will not prevent febrile seizures. Based 

on a literature review presented to the work group, there is insufficient evidence to recommend 

either ibuprofen or acetaminophen prophylaxis to prevent simple febrile seizures [Dr. R. 

Baumann, Univ of Kentucky. Literature review, presentation to the WG, December, 2008]. The 

work group therefore proposes to adopt the AAP guidance regarding use of antipyretics to 

prevent febrile seizures to the MMR and MMRV situations. The proposed wording is as follows: 

“MMR or MMRV vaccines may cause fever after vaccination. Most fevers after a 

measles-containing vaccine occur during the five to 12 days after vaccination. Parents 

and caregivers should be counseled about the possibility of fever after a measlescontaining vaccine and educated on timing and measures to control it. Studies have not 

demonstrated that antipyretics (e.g., acetaminophen or ibuprofen) prevent febrile 

seizures. Guidance on diagnosis and management of febrile seizures has been 

published elsewhere.” 

The new language is proposed because the language regarding the use of antipyretics to 

prevent febrile seizure in the 1998 MMR statement is vague. It says that antipyretics may 

prevent febrile seizures, but notes that preventing febrile seizure is difficult due to the sudden 

onset of fever.

Dr. Marin then presented options for ACIP to consider for a vote. She began with a summary 

for Dose 1 at routine ages 12 to 15 months. To protect against measles, mumps, rubella, and 

varicella, two vaccine options are available: MMRV vaccine or MMR and varicella vaccines. 

The two options are considered equivalent in terms of disease protection. Use of MMRV 

vaccine results in one fewer injection compared with use of separate MMR and varicella 

vaccines and may improve the on-time coverage for the vaccines recommended at ages 12 to 

15 months. Use of MMRV vaccine results in a higher risk for fever and febrile seizures 5 to 12 

days after the first dose when administered during the second year of life compared with use of 

separate MMR and varicella vaccines at the same visit. There is about one extra febrile seizure 

for every 2,300 - 2,600 MMRV doses. The risk for febrile seizures after MMRV can be reduced, 

but not eliminated, by administering separate injections of MMR and varicella vaccines. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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Children who have febrile seizures generally have an excellent prognosis; however, febrile 

seizures often require a medical visit to the emergency room for the child and are distressing to 

parents and caregivers.

Therefore, the work group’s first option proposed to the ACIP for a vote, which was supported 

by the large majority of the group, was as follows: 

“For the first dose of measles, mumps, rubella, and varicella vaccines at ages 12 to 15 

months, separate MMR and varicella vaccines are preferred to MMRV vaccine. 

However, providers may choose to administer MMRV vaccine after discussing the 

benefits and risks of each option with the parents or caregivers.” 

The pros of this option include: 1) it considers evidence-based criteria for decision-making, 

including vaccine safety; 2) in the setting of language barriers, sets the default for the alternative 

with the lower risk for febrile seizure; and 3) leaves open the possibility of administering MMRV 

in situations in which its use provides a benefit. The cons of this option include: 1) it might 

negatively affect the on-time coverage for other vaccines recommended for ages 12 to 15 

months and the control of the respective diseases; and 2) it might lead to more complex 

recommendations.

Dr. Marin then presented the work group’s second policy option, which was supported by a 

sizeable minority of the group: 

“For the first dose of measles, mumps, rubella, and varicella vaccines at ages 12 to 15 

months either MMRV vaccine or separate MMR and varicella vaccines can be used. 

The benefits and risks of both vaccination options should be discussed with the parents 

or caregivers.” 

The pros of this option are: 1) it allows physicians and parents to make a decision that best suits

the child’s individual situation; 2) it could result in simpler, more streamlined recommendations 

for all age groups, depending on the option chosen for Dose 2; and 3) it might be perceived 

favorably by the category of providers who prefer to be given the facts and let them make the 

decision. The cons of this option are: 1) it might mean more time for providers to counsel the 

parents about the options, weigh the evidence, and make a decision; 2) in practice, the choice 

could stop at the provider level, and not all children or parents would have access to the two 

options; and 3) it could potentially be perceived as a less pro-active role taken by the public 

health community for a vaccine safety issue.

Discussion

Dr. Chilton offered his comments as a practicing pediatrician in private practice in a state where 

there is universal purchase. He was in favor of recommending separate MMR and varicella 

vaccines for 5 reasons: The cost of inventory was one of his reasons. If he had to maintain an 

inventory of both MMRV and MMR + V, without knowing which one would be picked by patients, 

then he would prefer to have only one available. Second, if both vaccine options were 

available, then extra time would be needed to counsel parents about the available vaccines and 

the relative risks and benefits of both. Third, if he were to give the MMRV vaccine, his office 

would receive one fewer administration fee. He would be giving more counseling for less 

money. Fourth, he felt that there is an over-emphasis on the number of vaccines given. He did 

not feel that babies cried more when given four vaccines as opposed to three vaccines, and he 

hoped that they would downplay this aspect, given that they administer three or more vaccines 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

159

at each visit at two, four, and six months. Fifth, taking his personal experience into account, he 

said that with each child that has a febrile seizure in his practice, he spends a fair amount of 

time counseling the family about the fact that febrile seizures are not important. He then 

schedules another visit for a week later, knowing that the family is worried at their initial 

conversation and the family will have more questions in the week following the seizure. Finally, 

he commented that his daughter has a child who has had three febrile seizures. Each time, his 

daughter calls him from the emergency room. Even when parents have a pediatrician in the 

family, febrile seizures are important. He recognized that the additional risk of febrile seizure 

may not add excessively to his overall “quotient,” but he hoped to avoid any febrile seizures that 

he could. He added that the work group had done a great deal of epidemiological work on this 

problem, and he hoped that they would consider doing similar work on another problem, that of 

whether the availability of measles, mumps, and rubella as monovalent vaccines actually 

increases or will decrease the amount of vaccine uptake. They have time to consider this 

question before they issue a statement opposing the reappearance of these monovalent 

vaccines.

Dr. Temte thanked Dr. Marin and Dr. Broder for their work, as well as CDC, VSD, and Merck. 

There is a great deal of very good evidence, which was carefully reviewed by the work group. 

Their votes came out of this careful consideration. In essence, there is one clear signal that the 

MMRV first dose at young ages has a higher rate of febrile seizures. The evidence does not 

inform regarding differences in coverage rates depending on the two options. Until February 

2008, ACIP expressed a clear preference for MMRV. Yet in actual practice, physicians still had 

the ability to choose between two options. They chose the separate vaccines at a high rate of 

30% to 40% despite ACIP’s preference. Therefore, expressing a preference did not close off 

other options.

Dr. Ehresmann expressed her personal preference for Option 1, based on the epidemiological 

data. For MN that would mean 30 extra febrile seizures per year. She also pointed out the 

“con” for Option 2, a potential perception as a less proactive role taken by the public health 

community. With all of the parental concern about vaccine safety, she felt that they should take 

a strong stance.

Dr. Marcy responded to Dr. Chilton’s observation about febrile seizures. Parents perceive 

vulnerability. He estimated that, based on the patient population of a pediatrician and the rate of 

febrile seizures after MMRV and MMR + V, a pediatrician would see one more seizure every 15 

years and reiterated that that is not many. Further, 30 extra seizures in a state is not many for 

an entire state. He would have liked more data to make a decision, but they have to consider 

the frequency of seizures, not only the fact that they occur. He did not know what the VIS would 

say, but presumed that it would be modified to include the finding of the increased risk for febrile 

seizures after MMRV. This will make it easier to present the situation to patients. He favored 

Option 2.

Dr. Marin replied that the VIS is going to present the increased risk information and include the 

rates of febrile seizure after MMR and MMRV.

Dr. Sawyer identified himself as a member of the work group and one of the “significant 

minority” who favored Option 2. His concern stemmed from data from the physician and parent 

interviews and focus groups. A significant minority of physicians and parents feel that the 

combined MMRV vaccine is a valuable option. Option 1 may effectively take that choice away, 

even though the language said that the choice was still there. If the ACIP statement clearly 

preferred separate vaccines, only a small number of pediatricians would choose the 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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combination vaccine due to concerns regarding liability issues. They should weigh that 

possibility carefully. Further, there is a lack of clear evidence that a separate vaccination 

recommendation will lead to decreased coverage or decreased disease prevention; however, 

these decreases would be certain. There is a potential for 8 or 9 injections at a 12- to 15-

month-old visit. Data from the Immunization Information Systems show that less than half of 

children will receive more than 4 doses at a single visit. It is inevitable that multiple visits and 

therefore failed visits and failed immunizations will occur. He feared that a separate 

recommendation would ultimately lead to decreased coverage. Regarding storage issues, he 

noted that the physician focus group participants did not indicate concern about stocking both 

vaccines.

Dr. Judson agreed with Drs. Sawyer and Marcy, clarifying that his focus was on the absolute 

risk of an adverse event, which is not terribly consequential in the overall perspective of febrile 

seizures. He recognized the effects of seizures, but he supported the minority opinion.

Dr. Meissner was a member of the work group who favored Option 2. He commented that there 

is an increased risk of 3 to 4 per 10,000 for febrile seizures for MMR + V. The conversation 

regarding seizure possibility will take place with parents if MMRV is administered, when the rate 

increases to 7 to 9 per 10,000, but it still needs to take place for MMR + V. Secondly, regarding 

storage, the recommendation for Dose 2 is unknown. If there is a preference for MMRV for 

Dose 2, then there will be a need for 3 different vaccines. Regarding the idea of ensuring that 

the recommendation is perceived as proactive, he did not feel that an ACIP recommendation 

should be based on concern of what the anti-vaccine group might say. The decision should be 

based on what is best for the child. He then offered a theoretical advantage for administering 

MMRV. MMRV may lead to more children vaccinated against varicella at age 12 months, rather 

than waiting until 15 to 18 months. The varicella vaccine has been available for approximately 

15 years, and females who were vaccinated are entering their childbearing years and will likely 

have lower titers, and the antibodies that they will pass to their babies will be lower. If there is a 

later administration of the varicella vaccine, then there may be a longer window of vulnerability 

to varicella among children of these women. While the consideration is theoretical, it may 

become an issue as the years go by.

Dr. Marin responded that they do not see an important burden of varicella among young 

children or varicella outbreaks in preschool children. The virus tends to circulate among schoolage children, so they do not see a burden of disease now in the younger children. Dr. Meissner

agreed, reiterating that this situation may change as these women begin to have children.

Dr. Englund agreed with her fellow pediatricians, who in her experience do a good job of 

explaining the risks and benefits of the vaccines. The explanation process is part of the 

standard of care, and she felt that Option 1 took away choice; whereas, Option 2 preserved 

choice. Further, she was concerned about clinical significance versus statistical significance.

Dr. Morse recognized compelling arguments existed on both sides. ACIP’s charge is to make 

science-based decisions, and the science shows an increased risk. Science alone is not the 

determining factor, though, and there are a number of other benefits to combination vaccines, 

as mentioned in the session that discussed the general recommendations on combination 

vaccines voted that morning. Other considerations, such as safety, are paramount.

With regard to storage, Dr. Judson indicated that for several decades, he was responsible for 

the Denver Public Health Immunization Program and Clinic. They found problems within clinics 

and other administration areas in the area of storage. For live virus vaccines, there is a greater 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

161

chance that something will go wrong with a refrigerator door or in a general refrigerator where 

the temperatures get too warm or too cold than there is for a vaccine that is stored in the 

freezer. A number of early reports of measles and rubella vaccine failures were associated with 

potential failures with vaccine holding temperatures in refrigerators.

Dr. Joseph Bocchini reported on discussions at AAP concerning this issue. They addressed the 

issue most recently in April 2009 to keep up-to-date with ACIP and to provide input. AAP had a 

similar debate with strong opinions on both sides. Overall, there was favor for what would be 

considered Option 1.

Dr. David Kimberlin was the AAP liaison to the work group. Throughout their yearlong 

deliberations, the work group heard from numerous public health physicians regarding provider 

choice of either MMRV or MMR + V, Option 2, versus a recommended preference for separate 

MMR and varicella vaccines, phrased as Option 1. In addition, he had spoken with practicing 

pediatricians about the issue of provider choice versus a recommended preference. 

Overwhelmingly, the physicians strongly requested that provider choice be allowed for Dose 1. 

They want to make the decisions that they and the parents think are best for each child. This is 

consistent with the majority of the 21 pediatricians, and Mr. Alan Janssen’s presentation, which 

requested that choice be allowed. Speaking for himself, Dr. Kimberlin added that the main 

issue for ACIP is whether a concern over a 0.05% increased chance of febrile seizures, which 

have no lasting medical consequence, is great enough to justify ACIP inserting itself into the 

physician-parent communication process in a way that limits the physician’s options as a Dose 1 

preference for MMR + V, as Option 1 would do. An option with provider choice for MMRV or 

MMR + V would allow physicians the flexibility that they request. Additionally, stating a 

preference for MMR + V for Option 1 put them on a slippery slope, especially when they heard 

of plans to make available monovalent measles, mumps and rubella vaccines.

Dr. Temte said that physicians and care providers see febrile seizures retrospectively; that is, 

they see them after the fact and after the child has recovered. Parents see the seizures

prospectively and perceive the seizures as their children are perhaps dying. This common 

theme emerged from numerous cross-cultural studies. The parents see the children “doing 

something very scary.” It does not affect them only for a day, week, or month—they may see 

the effects for years. Secondly, the focus groups made it apparent that the lay public does not 

understand what a febrile seizure is. When it is stated that a febrile seizure is a vaccineinduced neurologic event that is not significant, he felt that the approach from a committee 

standpoint was questionable. Third, there was a clear difference in fever between MMRV and 

MMR +V in the first dose. The parent focus groups showed high concern on this issue, which 

could set off a chain of medical events for the child.

Dr. Beck commented on the strong arguments on both sides, and he expressed his appreciation 

to the work group for using the draft document of the ACIP Evidence–based recommendation 

work group and for the evidence base. He felt that in the real world, the choice has to focus on 

the best interest of the child. At this age, the best interest of the child is only spoken through the 

parents. Therefore, the parental thoughts and feelings are important, including the factors that 

contribute to their decisions and to the physicians that help them make decisions. He admitted 

that the focus group was very small, but it was also very telling in how the physicians had similar 

concerns to the parents when faced with the issue of a child who might experience a seizure, 

albeit an event that is not medically life-threatening. In the mind of the parent, the event was 

serious. His experience in working with parents in the autism community and beyond, with a 

range of those who may be misinformed and those who are well-informed, shows a parallel. It 

is important that ACIP take into consideration the real concerns of parents, as the parental 
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concerns are in the best interest of the child. He was persuaded by the economic issues 

created by stocking more than one vaccine and by other similar issues; however, he set these

issues aside to focus on the best option for the child. The choice element seemed to address 

the interests of the child better than the “non-choice” element.

Dr. Schuchat expressed her appreciation of the discussion and the perspectives of practitioners

and state public health programs. She added that CDC has conducted research in vaccine 

hesitancy with parents, learning about the issues on parents’ minds. Repeatedly they hear that 

an adverse event is real to a parent, while a vaccine-preventable disease is theoretical. She 

reminded them that they are talking about a real 1 in 2000 risk of a febrile seizure from a 

vaccine. That parent is also thinking about the risk of measles, mumps, rubella, or varicella for 

their child. The 1 in 2000 may not seem like a lot for a practice, but it may be more than the 

child’s risk for one of the conditions, as they have reduced rates. 

Dr. Morse added that Susan Lett called in to express her support for Option 1.

Dr. Doug Campos-Outcalt added his support for Option 1, which preserved choice. AAFP 

members are increasingly moving toward evidence-based medicine and asking evidence-based 

medicine questions. He could defend an ACIP decision based on expert opinion when no other 

evidence existed, but he would have difficulty explaining an expert-opinion-based decision by 

ACIP that countered high-level evidence that there was distinct harm from a vaccine. There are 

adverse reactions at significant rates, and evidence against it is hypothetical or based on expert 

opinion. If they use evidence-based methodologies, then they should follow where it led.

Motion: Dose 1 at Ages 12 – 15 Months (Option 2)

Dr. Baker moved to accept Dose 1 at Ages 12 – 15 Months (Option 2) as stated. Dr. Meissner 

seconded the motion. The motion carried with 10 affirmative votes, 0 abstentions, and 5

negative votes.

Dr. Marin then presented policy options regarding Dose 2 at routine ages 4 to 6 years. She 

reminded the group that to protect against measles, mumps, rubella, and varicella, two vaccine 

options were available: MMRV vaccine, or separate MMR and varicella vaccines. The two 

options were considered equivalent in terms of disease protection. Use of MMRV vaccine 

results in one fewer injection compared with the use of separate MMR and varicella vaccines 

and has the potential to improve the coverage for Dose 2 varicella vaccine as well as for other 

vaccines recommended at this age. Available data do not suggest an increase in risk for fever 

or febrile seizure after the second dose MMRV vaccine at ages four to six years compared with 

second dose administered as separate MMR and varicella vaccines at the same visit.

The work group offered one proposed option. For the second dose of measles, mumps, rubella, 

and varicella vaccines at ages 4 to 6 years, the recommendation was deferred to the ACIP 

General Recommendations on combination vaccines (June 2009). The pros of this approach 

are: 1) currently no safety concerns; 2) the recommendation is simpler and harmonized with the 

General Recommendations on combination vaccines; 3) the option results in one fewer 

injection, which can reduce pain and pain anxiety and will likely be better accepted by patients, 

parents and providers; and 4) it could lead to a more rapid increase of coverage for Dose 2

varicella vaccine in the current context of incomplete school entry requirements. The con of this 

option is that it could create difficulties for providers ensuring their clinics have adequate 

supplies of all three vaccines.
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The policy option was worded to reflect the ACIP General Recommendations: For the second 

dose, 

“The use of a combination vaccine generally is preferred over separate injections of its 

equivalent component vaccines. Considerations should include provider assessment, 

patient preference, and the potential for adverse events.” 

A footnote, agreed upon that morning by ACIP, would read: 

“Provider assessment should include number of injections, vaccine availability, likelihood

of improved coverage, likelihood of patient return, cost, and storage considerations.”

Motion: Dose Two at Ages 4 to 6 Years

Dr. Baker moved to approve the option for Dose 2 at Ages 4 to 6 years as stated. Dr. Chilton 

seconded the motion. The motion carried unanimously with 14 votes in the affirmative, 0

abstentions, and 0 negative votes. 

Dr. Marin then presented the work group recommendations for Dose 1 and 2 at ages other than 

those routinely recommended. For Dose 1 at ages 12 to 47 months (12 months to 3 years), the 

recommendation be that for Dose 1 at routine ages (12 to 15 months). For Dose 1 at ages 4 

years and older and for Dose 2, the recommendation is deferred to the ACIP General 

Recommendations on combination vaccines, approved in June 2009.

Discussion

Dr. Pickering noted that the recommendation approved before was for administering Dose 1 at 

ages 12 to 15 months.

Dr. Marin clarified that the work group proposes that the recommendation approved for Dose 1 

at the routinely ages of 12 to 15 months apply for 12 to 47 months.

Dr. Ehresmann felt that the recommendation was moot, since the ACIP had chosen Policy 

Option 2.

Dr. Neuzil expressed concern that Policy Option 2 was distinct from ACIP’s General 

Recommendations, which indicate a recommendation to use combination vaccines in a majority 

of circumstances. She agreed with the 12 – 47 month age group in this recommendation, 

noting that more education would be needed for parents and providers.

Motion: MMRV Vaccine for Dose 1 and Dose

2 at Ages Other Than Routinely Recommended

Dr. Neuzil moved to approve the option for MMRV vaccine for Dose 1 and Dose

2 at ages other than routinely recommended as presented. Dr. Sawyer seconded the motion.

The motion carried unanimously with 14 votes in the affirmative, 0 abstentions, and 0 negative 

votes. 
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164

VFC Resolution Update: Measles, 

Mumps, Rubella, and Varicella Vaccine

Dr. Jeanne Santoli

CDC/CCID/NCIRD/ISD

Dr. Santoli presented an update to the VFC resolution pertaining to measles, mumps, rubella, 

and varicella. She explained three components of the resolution. The first focuses on MMR. 

Eligible groups are children 12 months through 18 years of age, and the group may include 

those as young as 6 months of age in an outbreak or prior to international travel. She referred 

to the primary MMR statement from ACIP for recommended doses and contraindications. The 

recommended vaccine schedules, dose intervals, and precautions can be found at the following 

url: 

http://www.cdc.gov/mmwr/preview/mmwrhtml/00053391.htm; 

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5049a5.htm; and 

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5522a4.htm?s_cid=mm5522a4_e

Recommended dosage can be found in the package inserts available at the following url: 

http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833

She then turned to the varicella portion of the resolution. Eligible groups include children at 

least 12 months through 18 years of age. Recommended schedules for varicella vaccine can 

be found at the following url: 

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5604a1.htm

This page also includes information regarding dosage intervals, contraindications, and 

precautions for varicella vaccine. Recommended dosage can be found in the package inserts 

available at the following url: 

http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833

Next, Dr. Santoli addressed the MMRV component of the VFC Resolution. Eligible groups 

include children at least 12 months through 12 years of age. Recommended schedules for 

combined measles, mumps, rubella, and varicella vaccine can be found at the following url: 

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5604a1.htm

The second element of the MMRV component of the VFC resolution would mirror ACIP’s 

recommendations regarding Dose 1. For the first dose of MMRV vaccines given at 12 - 47 

months of age, either MMRV vaccine or separate MMR and varicella vaccines can be used. 

The potential benefits and risks of both vaccination options should be discussed with the 

parents or caregivers. For the first dose of MMRV vaccines given at 4 years of age or older, the 

use of a combination vaccine is generally preferred over separate injections of its equivalent 

component vaccines. Considerations should include provider assessment, patient preference, 

and the potential for adverse events. For the second dose given at any age, the use of a 

combination vaccine is generally preferred over separate injections of its equivalent component 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

165

vaccines. Considerations should include provider assessment, patient preference, and the 

potential for adverse events. Dr. Santoli called attention to a footnote to mirror the ACIP 

General Recommendations, which reads: 

“Provider assessment should include the number of injections, vaccine availability, 

likelihood of improved coverage, likelihood of patient return, and storage and cost 

consideration.”

She indicated that dosage intervals, contraindications, and precautions for MMRV vaccine could 

be found at the following url: 

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5604a1.htm 

Recommended dosage can be found in the package inserts available at the following url: 

http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833. 

In addition, a personal or family history of seizures is a precaution for MMRV vaccine use.

In conclusion, Dr. Santoli noted that if an ACIP recommendation or notice regarding measles, 

mumps, rubella, and / or varicella vaccination was published within 12 months following this 

resolution, the relevant language above (except in the eligible groups sections) would be 

replaced with the language in the recommendation and incorporated by reference to the 

publication URL.

Dr. Beck wondered whether rather than restating the ACIP recommendation in the VFC 

Resolution, the VFC Resolution could simply refer to the ACIP recommendation. This way, 

there would be no questions regarding language.

Dr. Santoli replied that the VFC Resolution would be published on the following Monday, so 

there would be no document to which it could refer. The ACIP General Recommendations 

would not yet have been published. When they are published, then the VFC statement will refer 

to where the General Recommendations are published.

Dr. Snyder noted that by law, they are required to vote on the VFC Resolution, as Congress has 

given appropriations authority. Once the vote was complete, the resolution would become 

effective, and they would share the message quickly.

Motion: VFC Resolution: MMRV Vaccine

Dr. Sawyer moved to approve the VFC resolution for MMRV vaccine. Dr. Meissner seconded 

the motion. The motion carried unanimously with 15 votes in the affirmative, 0 abstentions, and 

0 negative votes. 
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166 

Stephan L. Foster, Pharm.D., FAPhA

CAPT (Ret) U.S.P.H.S

Professor and Vice Chair

University of Tennessee College of Pharmacy

Liaison Member

CDC Advisory Committee on Immunization Practices (ACIP)

Dr. Foster indicated that he had been a member of ACIP since approximately 2001, and was 

the first pharmacists to sit on the committee as a liaison member. In addition, he has a history 

with the US Public Health Service from which he is a retired Commissioned Health Officer. 

He reported that pharmacists have been involved in the distribution of vaccines since the early 

1900s. The American Pharmacists Association Program began in 1993 when HHS Secretary 

Donna Shalala asked the American Pharmacists Association (APhA) to help define the role of 

pharmacists in a national vaccine program for Children. By 1995, the Health Care Financing 

Administration (HCFA) recognized pharmacists as providers. In 1996, Mississippi recognized

pharmacists as immunizers and convened the first APhA’s training program, which was three 

days in length. Also in 1996, APhA then said through their House of Delegates that pharmacists 

should have three roles in the area of immunizations: 1) advocate (educating and motivating 

patients); 2) facilitator (hosting others who vaccinate (e.g., in most cases nurses)); and 3) 

immunizer(giving vaccinations themselves). 

The APhA presented courses to state associations and colleges of pharmacy over next two 

years. The program was first licensed in 1999. The program is currently structure as a two-part 

program. The first component is a home self-study of approximately 12 hours on the following 

topics:

 Module 1: Pharmacists as Vaccine Advocates

 Module 2: Immunology

 Module 3: Vaccine-Preventable Diseases

 Module 4: Establishing a Pharmacy-Based Immunization Program

 Module 5: Administering Vaccines 

 Self-Study Assessment

The second component consists of a one-day live seminar, which includes the following topics:

 Importance of Vaccines

 Shortfalls in Vaccine Delivery and Opportunities for Pharmacists

 How Vaccines Prevent Disease

 Vaccine-Preventable Diseases

 Identifying Vaccination Needs

 Establishing a Pharmacy-Based Immunization Program

 Practice Implementation

 Adverse Events Following Vaccination and Emergency Preparedness

 Vaccine Administration Technique

Pharmacy-Based Immunizations
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This program probably has more training for pharmacists than most other health care 

professions receive in this particular area. This program has been accepted by the majority of 

states in the US as a requirement before pharmacists can actually administer vaccines. 

In 2002, the American College of Physicians (ACP) and the American Society of Internal 

Medicine (ASIM) published the following statement regarding pharmacist’s scope of practice 

[Ann Intern Med.2002;136:79-85]: 

Position 4

“ACP-ASIM supports the use of the pharmacist as immunization information source, host 

of immunization sites, and immunizer, as appropriate and allowed by state law. ACPASIM will work with pharmacy organizations to increase immunization awareness.”

Most pharmacists in the country disagreed with physicians determining pharmacists’ scope of 

practice, but those who had been involved in vaccinations were relieved that they supported

pharmacists as immunizers, as appropriate based upon state law. The American Society of 

Health-System Pharmacists (ASHP) developed guidelines based upon what they thought the 

standards of practice should be with respect to legal authority, training, program structure, and 

reimbursement [ASHP. Am J Health-Pharm. 2003; 60: 1371-7]. As of June 9, 2009 Maine 

became the 50th state to authorize pharmacists to administer immunizations. Over 60,000 

pharmacists have been trained and have delivered over 3 million influenza vaccinations. 

Given that vaccines are prescription drugs, pharmacists must have the legal authority to 

administer them. State law governs health care practice. Each state has specific prescribing 

regulations, so it is imperative to know what the laws are. In the State of Tennessee, 

pharmacists can operate under written or verbal prescriptions, but can administer vaccines 

under standing orders. Most states operate under standing orders. Even in many states that do 

not have the laws, a physician can send a prescription to a pharmacy and the pharmacists can 

fill it as they would any other type of prescription. A standing order written by a physician can 

state that a pharmacist is permitted to administer only a particular vaccine and to whom it may 

be administered. Protocols can be written into standing orders for emergency administration. 

This is typically done in partnership with a physician in the community, through a cooperative 

agreement. In the case of an emergency / pandemic, a governor may sign a declaration to 

expand authority. During Hurricane Katrina, pharmacists in Tennessee were given prescriptive 

authority to immunize those who were coming into Tennessee. An immunization protocol / 

standing order identifies the individual who has delegated activity; identifies the pharmacist 

authorized to administer vaccine; indicates the types of vaccines the pharmacist is authorized to 

administer; describes the procedures, decision criteria, or plan the pharmacist should follow, 

including when to refer patient; delineates the procedure for emergency situations; and outlines 

record keeping and documentation procedures.

With regard to the variation in state limits to pharmacists’ authority, 17 states have no age 

restriction, 22 restrict administration to those > 18 years of age, 1 restricts administration to 

those > 16 years of age, 4 restrict administration to those > 14 years of age, et cetera. Many 

states stipulate which antigen may be administered. Two states permit influenza only, two 

permit influenza and pneumococcal, one permits adult vaccines only, 33 have no restrictions, et 

cetera. These limitations are built into the state laws as they are written. 
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Another major issue with respect to pharmacists administering vaccinations regards 

professional liability. The physician’s liability does not encompass the pharmacist’s scope of 

practice. The physician is not liable for pharmacist’s error in dispensing. Therefore, it is 

recommended that all pharmacists have liability insurance that covers all professional services. 

Pharmacists are also afforded the same protection under the federal Vaccine Injury 

Compensation Program (VICP) for the same types of things other practitioners are, but are 

protected only if documentation and event reporting occurs. 

Pharmacies are in a position to make a unique contribution for a number of reasons: access, 

proximity, extended hours; ability to identify high-risk patients easily based upon their 

medications; the public’s trust; and the public’s enthusiastic acceptance. In general, 

pharmacists realistically want to be part of the health care team. Pharmacies are an ideal place 

to distribute medications and vaccinations during an emergency to avoid having patients 

congregate. Tennessee’s pandemic flu laws stipulate that everyone will present to a central 

high school or other location where their medication will be dispensed to them by volunteers. It 

would be much easier for social distancing to have the medications disseminated to pharmacies 

in the state for distribution. This is likely to become a much easier process with the electronic 

medical record.

Discussion Points

Kenneth Schmader (AGS) recognized that pharmacists have been life savers for vaccines 

covered under Medicare Part D, and were indeed a very important part of the health care team.

Stanley Grogg (AOA) inquired as to what the protocol would be for patient who experience 

anaphylaxis.

Dr. Foster responded that they have Epinephrine. They had one physician who said he would 

not write a standing order for Epinephrine; however, the pharmacist refused to administer 

vaccines without it. The training program includes an emergency component. In addition to the 

training program, to administer vaccines in Tennessee, pharmacists are also required to 

maintain CPR certification.

Alan Hineman (Formerly from the National Vaccine Advisory Committee) stressed that 

pharmacists were going to play an important role in expanded immunization services, 

particularly with adolescents and the notion of annual influenza immunization for children. He 

pointed out that every state has an immunization registry and immunization information system; 

however, not all pharmacists who administer immunization are reporting them. He encouraged 

that this be a routine part of pharmacists’ activities.

Dr. Foster responded that this is included in the training program. The training program 

stresses that pharmacists should not be engaging in routine pediatric vaccines, because they 

firmly believe in the pediatric home. This is not a course for pediatric vaccines.

With regard to increasing immunization rates, Christine Hahn (CSTE) wondered whether any 

health departments had reached out to pharmacies as a site through which to increase 

childhood immunization access. 
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Dr. Foster responded that San Antonio, Texas has been particularly avid. Dr. Fernando Gurrera 

had signed standing orders for his entire area. There has been a great deal of difficulty in 

convincing health departments to write standing orders. There are still areas in Tennessee in 

which pharmacists do not administer vaccines because they cannot find physicians to write 

standing orders. Yet other areas are very much involved.

Dr. Cieslak indicated that a concern in his state was potential “cherry picking” of paying patients. 

With that in mind, he wondered if the national organization had any recommendations with 

regard to accepting Medicaid or VFC.

Dr. Foster responded that he was not aware of any pharmacies that had been in the VFC 

programs. Many pharmacies are involved in Medicaid programs since it pays for drugs also. It 

has been very difficult to convince pharmacists to administer more than influenza vaccines. 

That is typically not difficult to get reimbursed. Many patients who present on their own are

willing to pay for the vaccine themselves. A few rural health departments in a few states have 

asked pharmacists to help with pediatric vaccines due to the shortage of physicians within the 

area. However, that is very rare.

Dr. Ehresmann noted that she did not see the issue of storage and handling addressed, which 

is an important part of the vaccine program.

Dr. Foster responded that there is a major component that addresses storage and handling, and 

pharmacists are accustomed to dealing with storage and handling issues.

Dr. Judson inquired as to whether there were any examples in which pharmacists have been 

able to play a continuing viable role in providing vaccines, meaning that they are reimbursed, 

build up a clientele, and have a volume business. In many places, pharmacy currently seems to 

be a very low margin / high volume operation that could not do very well on seasonal, shortterm, one-time administration.

Dr. Foster responded that certain pharmacists have been involved in vaccine programs; 

however, it is really not an on-going patient situation. Vaccines probably make more of a 

margin for pharmacists than any other drug they fill. In most cases, the hesitancy for 

pharmacists in administering vaccines is that they are too busy and it takes too much time. 

Otherwise, he was not aware of any pharmacies / pharmacists building up a practice. 

Pharmacists are encouraged to partner with physicians. Many independent pharmacists in 

Tennessee send records to the patients’ physicians. Most patients present for influenza and 

shingles vaccine because they are Medicare Part D reimbursable. Pharmacists administer only 

about 7% of the influenza vaccines in the country, which is not a major percentage.

Dr. Morse inquired as to what the capacity of pharmacies might be, and whether they could 

solve the problem for the fall.

Dr. Foster responded that he did not know how many pharmacies had pre-filled their orders for 

influenza vaccine. Most chains have routine ordering departments that order / distribute 

vaccines for pharmacies. Several pharmacies, particularly independent ones, order vaccine for 

physicians’ office as well. This can be a partnership at any point. Pharmacists would very 
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much like to be a part of this and really enjoy doing it. It is nice to be able to get out and touch a 

patient. 

Session Introduction / Overview

Kathy Neuzil, MD, MPH

Chair, Influenza Vaccine Workgroup

Anthony Fiore, MD, MPH

Influenza Division, NCIRD, CDC

Dr. Neuzil acknowledged the influenza workgroup members, pointing out their wide diversity of 

expertise and significant liaison representation. She reported that workgroup activities in 2009 

have included a review of seasonal vaccine safety data updates; presentations from vaccine 

manufacturers on adjuvanted seasonal and H5N1 vaccines; discussions of antiviral issues (e.g., 

antiviral resistance among seasonal H1N1; interim guidelines for pandemic H1N1 treatment; 

and annual treatment and chemoprophylaxis recommendations); and discussions of pandemic 

H1N1 with respect to immunology, epidemiology, vaccine development, and program planning. 

This was the first year in which the recommendations for vaccines and antivirals for influenza 

were separated. The vaccine recommendations and vote occurred in February, while the 

antiviral recommendations were to be voted upon during this session. 

The goals of this special ACIP influenza session were to discuss and vote on antiviral guidance 

for both seasonal and pandemic H1N1 virus infections; and provide background on pandemic 

H1N1 issues for ACIP in preparation for activities and decisions in summer and fall 2009. Dr. 

Neuzil noted that some considerations to keep in mind for the pandemic A/H1N1 vaccination 

program included: 1) The need for clear program goals, roles, and responsibilities; 2) Timelines 

for a vaccine program must consider the possibility of an “early wave.” What vaccines are likely 

to be available, when, and in what quantities? What basic information is needed to inform 

recommendations on use of a vaccine, preferably a licensed vaccine? When will it be 

available?; and 3) How might a pandemic influenza vaccine program co-exist with a seasonal 

program?

To orient the panelists to this session, Dr. Fiore reviewed the agenda, enumerated the 

presentations, and introduced the presenters.

2008-09 Influenza Epidemiology: 

Seasonal and Novel Influenza A (H1N1)

Lyn Finelli, DrPH, MS

Lead, Influenza Surveillance and Outbreak Response Team

Epidemiology and Prevention Branch, Influenza Division, NCIRD

Referring to the US WHO / NREVSS Collaborating Laboratories Summary (2008-09), Dr. Finelli 

pointed out that within the regular influenza season during, H1 was the predominant virus with a 

sweep through of B at the end of the season. When the H1N1 pandemic strain occurred, there 

was co-circulation of all of the seasonal virus with H1N1. During the week ending May 2, 2009 

when novel H1N1 first appeared, there was a major increase which represented a surge in 

Influenza
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testing by state health departments. The circulation of seasonal viruses declined as the season 

went on, with novel H1N1 increasing to represent 97% of all influenza viruses tested. 

With regard to the percentage of visits for influenza-like illness (ILI) reported by the US 

Outpatient Influenza-like Illness Surveillance Network (ILINet) for 2008-09 and the previous two 

seasons, seasonal influenza was mild in 2008-2009. However, at the end of April there was a 

sudden surge in ILI. That activity had declined and probably represents those who presented to 

the doctor to be checked, as well as the worried well who may not normally have presented to 

care but did when they hear the press regarding novel H1N1. The following map illustrates how 

focal novel H1N1 was as of May 2009:

There has been a major concentration of disease in the Southwest in California and Texas, in 

the Pacific Northwest, and in the Northeast in Illinois and Wisconsin. The disease has remained 

focal, although it is now in different areas. As of June 2009, there was a great deal of ILI activity 

in Massachusetts, Minnesota, New Jersey, and New York. There was also widespread activity 

in 11 states during this time in the Northeast, West, and Southwest as reflected in this weekly 

influenza map:

 
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During Week 18 (week ending May 9, 2009) there was a solid band of activity in several states, 

with the affected area changes dramatically over time.

Regarding pneumonia and influenza mortality for 122 US, the 2008-09 season was fairly mild 

without a lot of mortality. The percentage of pneumonia and influenza deaths did not exceed 

the epidemic threshold for week ending June 6, 2009. With respect to influenza-associated 

pediatric deaths for the 2005-06 season to the present, seasonal influenza deaths reported 

totaled 46 in 2005-2006, 78 in 2006-07, 88 in 2007-08, and 83 in 2008-09 of which 17 were 

attributable to H1N1. Given the rather mild 2008-09 seasonal flu, there would have been only 

about 66 deaths if not for the 17 deaths attributed to novel H1N1 in children under the age of 18. 

In terms of the antigenic characterization data for 2008-09 influenza viruses in the US, between 

October 1, 2008 and June 12, 2009 CDC characterized 1626 influenza viruses as follows:

Seasonal influenza A(H1N1) [n=947]: 

• 947 (100%) similar to A/Brisbane/59/2007 (2008-09 vaccine strain)

• Includes H1N1 resistant to oseltamivir

Influenza A(H3N2) [n=162]

• 162 (100%) similar to A/Brisbane/10/2007 (2008-09 vaccine strain)

Influenza B [n=517]

• 65 (13%) in B/Yamagata lineage

– Similar to B/Florida/04/2006 (2008-09 vaccine strain)

• 452 (87%) in B/Victoria lineage and not similar to the B strain 

Pandemic influenza A (H1N1) [n=125]

• 125 (100%) similar to prototype a/California/07/2009, which is the proposed pandemic 

influenza vaccine strain

With respect to the epidemiology of the H1N1 outbreak, the triple-reassortant swine virus has 

been circulating since about 2000-01 and has caused 13 sporadic cases over the past three to 

four years that CDC and its partners in health departments have investigated. Compared to the 

novel or pandemic H1N1 strain, this virus is triple-reassortant because it has swine, avian, and 

human genes. The pandemic strain genes are very different in that they have the same avian 

and human genes, three of the same swine genes, and two new genes that have never been 

seen before in either humans or swine in North America. 

To summarize the events of the pandemic, between April 15 to17, 2009, two cases of febrile 

respiratory illness occurred in child residents of adjacent counties in Southern California. These 

cases were initially identified as swine influenza A (H1N1) virus and later as unusual variants of 

swine influenza. Both viruses were genetically closely related to each other and both were 

resistant to amantadine and rimantadine. Both viruses contained a unique combination of gene 

segments not previously recognized among swine or human influenza viruses in the US. 

Neither child had contact with pigs. However, this did not deter CDC from comprehensively 

investigating animal contact in the beginning of the outbreak. Approximately one week to 10 

days into the outbreak, 10 cases were reported from three states. Ten days into the outbreak, 

investigations were underway in six states. One week into the outbreak, nine states were 

affected. Data for week ending 06 Jun 2009 have been updated. Since the 24 Jun 2009 

briefing, cases reported for this week had increased by 1,749, to 3,164. This is a relatively 

steep increase, but represents in part cases reported by several states which had not reported 
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for several days previously. As of 17 Jun 2009, there were 27,717 cases reported to CDC. Of 

these, there were 3065 (11%) hospitalizations; 127 (0.4%) deaths; and 50% male / female. The 

median age in all cases was 12 years, in hospitalized cases 20 years, and deaths 37 years. 

The overall percentages of hospitalizes cases increased, probably due to testing practices. 

State health departments, which have been conducting much of the testing, are now screening 

primarily severely ill people because they are so overwhelmed. Thus, the proportion being 

screened from hospitalized people was greater over the previous few weeks.

CDC has conducted a number of epidemiologic investigation studies, and has developed 

secondary attack rates in households from those studies. In addition, CDC has engaged with 

their mathematical modeling partners who have modeled the secondary attack rate. The 

estimates for secondary attack rates in households are fairly consistent from all of the studies 

and the models. The secondary attack rate for a household member of a confirmed case is 

18% to 19% for those with acute respiratory infection, and between 8% to 12% for those with ILI 

(e.g., fever with cough or sore throat). Generation time is used as a surrogate for incubation 

period. The generation time for acute respiratory infection is 2.0 to 3.1 days and for ILI is 2.4 to 

3.1 days. A number of community incident studies have been conducted. One of the most 

difficult things about this outbreak is that when pandemic planning was done, severe morbidity 

and mortality were planned for. This is also what they thought they would do in terms of 

tracking the outbreak with surveillance. However, given the mild to moderate outbreak to date, 

information is being sought about the bottom of the pyramid—those who may be ill but who 

have not sought care. Several surveys have been conducted in an attempt to assess this. A 

telephone survey was conducted in New York City in May 2009, during which the proportion of 

people ill with ILI during that month was 6.9%. In Chicago a door-door survey was conducted, 

with the median percent of people ill in households was 6%, which was somewhat lower for ILI 

and somewhat higher for acute respiratory infection. A university survey was conducted in 

Delaware with two different groups, with 6% to 11% ill. The overall proportion of people sick in 

households was 6%. As of 24 Jun 2009, the rates of probable and confirmed H1N1 cases by 

state were as follows:

 

 
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CDC no longer receives date of onset for cases. Over the past few weeks 3000 to 4000 cases 

were report, but the week prior to the ACIP meeting over 6000 cases were reported. With the 

exception of one state that had not reported in a couple of weeks, all of these cases were fairly 

recent.

With respect to age distribution of cases reported as of 18 Jun 2009 (n=21,449), there were 

2146 cases (10%) in the 0 to 4 age range; 11,720 (55%) in the 5 to 24 year age range; 4041 in 

the 26 to 64 year age range; 219 (1%) > 65 years of age; and 3324 (15%) of an unknown age. 

In terms of cases rates per 100,000 population by age group as of 18 Jun 2009 (n=18,125 

excluding 3324 cases with missing ages), 2146 (10.2) were reported in 0 to 4 year olds; 11,720 

(14.2%) in 5 to 24 year olds; 4,041 (2.5%) in 25 to 64 year olds; and 318 (.6%) in those > 65 

years of age. Pandemic H1N1 hospitalizations by age group based on data reported as of 18 

Jun 2009 (n=2228) included 445 (20%) ages 0 to 4; 859 (39%) ages 5 to 24 years; 756 (34%) 

ages 25 to 64; 86 (4%) ages > 65 years of age; and 82 (4%) of unknown ages. Rates of 

hospitalization by age group per 100,000 population as of 18 June 2009 included 445 (2.1%) 0 

to 4; 859 (1%) 5 to 24; 756 (0.5%) 25 to 64; and 86 (0.2%) > 65.

In terms of differential rates of hospitalizations for various cities as of 18 Jun 2009, the US rate 

overall is very low. Arizona and Illinois are intermediate for those states that are heavily 

affected. In Massachusetts there were high rates of hospitalization, in Utah they were even 

higher, and hospitalizations were extremely high in New York City. The hospitalization rates in 

New York City approximately those for cumulative hospitalization for seasonal few, while others 

are lower.

Based on data from the Emerging Infections Program (EIP) sites, cumulative hospitalization for 

2007-08 for seasonal influenza were approximately 42.8 per 100,000 population in the 0 to 4 

age range and 75.6 in those > 65. In 2008-09, seasonal flu was predominantly H1N1. During 

that season, the highest rate was in the youngest age group of 0 to 4 years (36.6) and lowest in 

those > 65 (14.6). Every season is a mixed season, so the increase rates among those over 

age 65 during 2007-08 could also be due to influenza B and H3. The hospitalization rates were 

much higher cumulatively that they were thus far for novel H1N1.

Regarding the characteristics of those hospitalized, at the time of this ACIP meeting there were 

3,065 hospitalizations among 27,717 cases. Detailed clinical data were available on 

approximately 268 patients, 21% were admitted to the ICU, 13% were placed on mechanical 

ventilation, and there were 17 deaths. The median time from onset of illness to hospital 

admission was 3 days, with a range of 1-14 days. The median length of stay was 3 days, with a 

range 1-53. The median length of stay for seasonal influenza is approximately 2 days. The 

gender distribution is approximately 50 / 50, with 128 females (48%) and 140 males (52%). The 

median age in this cohort is 22 years (range 21 days-86 years), which is slightly older than the 

median age for all those hospitalized. In terms of the age distribution of those hospitalized in 

this cohort, the highest percentage of people hospitalized is in the 19 to 49 year age group 

(n=95; 35%) followed by 10 to 18 years of age (n=55; 20%).

Underlying conditions among those hospitalized included the following: Asthma or COPD

(32%), Diabetes (16%), immunocompromised (12%), chronic cardiovascular disease excluding 

hypertension (11%), neurocognitive disorder (8%), neuromuscular disorder (8%), current 

smoker (10%), pregnant (7%), chronic renal disease (8%), seizure disorder (6%), and cancer 

(3%). The definition for “immunocompromised” is a catch-all and represents not only those with 

HIV infection, but also people on long-term steroid or chemotherapy. Clinical information on 

those who were hospitalized reflected the following: chest radiographs demonstrating 
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pneumonia at admission (35%), ARDS (16%), diagnosed with sepsis at admission (12%), 

mechanical ventilation (13%), treated with antivirals (73%), treated with antibiotics (78%), 

treated with steroids (35%), and recovered (94%). Among this cohort, approximately 180 blood 

cultures were done. Of Those 179 were negative and 1 was positive in an elderly man with E. 

coli.

Regarding pandemic H1N1 deaths by age group (n=87), as of 18 Jun 2009 5 (6%) deaths were 

reported in the 0 to 4 year old age group; 19 (22%) in the 5 to 24 year old age group; 55 (63%) 

in the 25 to 64 year old age group; 5 (6%) in the > 65 year old age group; and 3 (3%) of an 

unknown age. The pandemic H1N1 case fatality ratio by age group as of 18 Jun 2009 was 5 

(0.23%) in the 0 to 4 year old age group; 19 (0.16%) in the 5 to 24 year old age group 5 to 24 

year old age group; 55 (1.36%) in the 25 to 64 year old age group; 5 (2.29%) in the > 65 year 

old age group; and 3 (0.09%) in those of an unknown age.

With respect to the pandemic (H1N1) deaths reported to CDC by states as of 25 Jun 2009, 

limited data were available on 99 of the 111 deaths in 20 states. Of these, 49 (53%) were 

female and 44 (47%) were male. Race / ethnicity was known only for 47 subjects because it is 

not being collected at the state level, of whom 6 (13%) were non-Hispanic Black; 19 (40%) were 

non-Hispanic White; 19 (40%) were Hispanic; and 3 (6%) were other. The median time from 

illness onset to death was 7.5 days (range 0 - 40 days). The median age range was 37 years 

(range 2 months-72 years), broken down as follows: 0-23 months 5 (6%); 2-4 years 0 (0%); 5-9 

years 7 (8%); 10-17 years 10 (11%); 18-29 years 11 (13%); 30-49 years 35 (40%); 50-64 years 

18 (21%); and ≥65 years 1 (1%).

Of the 99 pandemic (H1N1) deaths reported to CDC by states as of 25 Jun 2009, 12 (12%) of 

persons had no underlying conditions. Some conditions may have overlapped for individual 

cases for the following breakdown: Asthma 11%, Other Pulmonary Disease 24%, Diabetes 

13%, Chronic Cardiovascular Disease 14%, Neurocognitive Disorder 15%, Neuromuscular 

Disorder 11%, Pregnant 8%, Seizure Disorder 7%, Morbid Obesity 11%, Obesity 34%, Other 

Serious (hepatic, cancer, immunosuppressed) 13%. There have also been 5 deaths among 

pregnant women, of whom 4 were in their 20s. They died at various stages in their 

pregnancies: 1 in the first trimester, 1 in the second trimester, and 3 in the third trimester. For 

the most part, underlying conditions in these women are unknown. However, several of them 

had no underlying conditions. 

In conclusion, on April 15, 2009 a novel swine-origin influenza A H1N1 virus was identified in a 

boy in California. At the time of this meeting, there were 27,717 reported cases in the US and 

55,000 reported worldwide. The majority of persons hospitalized and who died had underlying 

conditions. Given the rapidly evolving outbreak, more cases are expected and transmission will 

likely continue into the influenza season. At this point, it did not appear that transmission was 

declining at all. Surveillance plans include continuing enhanced surveillance throughout the 

summer; convening a CSTE and CDC working group to solidify surveillance plans for fall and 

winter; focusing less on case counts as they grow larger and become less representative 

because of testing practices; focusing on more severe outcomes, syndromic surveillance data, 

and laboratory data; continuing enhanced virologic surveillance; and developing revised 

screening recommendations and guidance for prioritization of laboratory testing with CSTE and 

APHL.
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Discussion 

In terms of reporting out for the greatest percentage in the last couple of weeks, Dr. Morse 

inquired as to whether there was bias toward testing, given that selective testing was being 

conducted more for H1N1 and not as much for other strains. 

Dr. Finelli responded that CDC conducted a survey of state health departments in May, at which 

time it did not appear that there was a bias. This survey does need to be repeated, but it 

appeared at the time of this meeting that laboratories were preferentially testing for H1N1 and 

not testing as widely for the other seasonal viruses. That could be responsible for the 97% 

positive rate for H1N1 and very little seasonal flu. However, little season flu occurs during the 

summer. Therefore, it could be a combination of both. 

When age is corrected for, Dr. Judson wondered if diabetes (13%) and obesity (34%) were 

over-represented in the deaths.

Dr. Finelli responded that this appeared to be true. There were so many children in the 

hospitalization cohort, the rate of obesity appeared to be very low. She did not show that

percentage during the presentation because she thought it should be stratified by age to 

determine a clear percentage. Most of those with diabetes were adults. 

Dr Temte thought the information presented underscored the lack of good community-based 

surveillance in the US for issues outside of fairly significant events. He also observed that 

obesity stood out as a fairly new risk factor that had not been a characteristic risk factor for 

influenza in the past. There is very little data in the literature to explain why that could be a risk 

factor, other than the possibility of some cytokine interactions. He inquired as to whether CDC 

had examined immunization status for seasonal influenza vaccine in these patients in terms of 

whether there is any potential for cross-reactivity. In addition, he wondered how much 

confirmed disease was acute infection. In Wisconsin, primary care is seeing many people with 

mild illness. They are not testing, but he suspects a lot of it is respiratory viruses. 

Dr. Finelli responded that through surveys, CDC in the process of examining the bottom of the 

pyramid of people who are mildly ill and may not seek care. With those data and other data 

combined from the surveillance systems, CDC is developing a model with multipliers to give 

them an idea of the disease burden. They will be able to update that model on a regular basis 

to have an overall picture. Currently, CDC is estimating over a million cases in the US from that 

model. When there are more confirmed data, they will have more solid confidence limits. CDC 

initially examined vaccination status in these data, finding that the proportion of people 

vaccinated among those hospitalized looks like the proportion of people vaccinated among 

those hospitalized for flu every year. Among those with underlying conditions, it is higher than 

those with no underlying conditions. A couple of vaccination effectiveness studies were 

conducted, one among healthcare workers in Ohio and one among healthcare workers in 

Chicago in two Epi Aids. With very wide confidence limit, there appeared to be no protection 

from seasonal vaccine for H1N1. Regarding obesity, among the deaths, an extraordinary 

number of people with morbid obesity died. These individuals were in excess of 340 pounds. 

Lately, when CDC has been contacting the states to find out about deaths, they have been 

asking specific questions about obesity. In some studies going into the fall, CDC plans to 

examine height and weight on all patients hospitalized and patients with pneumonia to 

determine a quantitative measure of obesity. The data collected so far on hospitalization has 

just included a check box. It may be checked if the chart indicates that a patient is obese. 
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Obesity is probably differentially ascertained and transcribed by providers. Thus, body mass 

index (BMI) should be used as a good measure of obesity, which CDC plans to do in the fall. 

Dr. Baker was impressed by the burden of seasonal influenza, which can be prevented. She 

expressed her hope that the ACIP and public health in general would emphasize the need to 

prevent seasonal influenza by starting early as soon as vaccine supply is available and thinking 

about novel ways to get the message out to providers and the public.

Dr. Meissner asked Dr. Finelli to speculate on when H1N1 first began to circulate. The first 

confirmed isolates were in mid-April; however, testing is not usually conducted at the end of the 

influenza season.

Dr. Finelli responded that she preferred not to speculate on that, given that it was not her area 

of expertise. However, there was a late influenza season this year and there was more testing 

in April than usually because the season did not get into full swing until the second week of 

February. The two cases were picked up in ILI Net in CDC sentinel surveillance system. In 

examining syndromic surveillance data, there did not appear to be widespread disease 

anywhere else before these two cases were picked up. Therefore, she thought CDC’s 

surveillance system did do its job. Both of these cases were picked up in sentinel providers that 

are part of the Navy. They have very good labs and conduct a great deal of testing. Because 

Novel Influenza A Virus is a reportable disease, state health departments do typing for Influenza 

A on a routine basis and send CDC data on any that are not sub-typable. CDC received several 

of these over approximately six months that were triple-reassortant swine, which CDC 

investigated. However, they received no viruses in the lab that were never typed that were not 

sub-typable in January or February. They heard about focal outbreaks of ILI and viral syndrome 

in Mexico the week preceding the discovery of the two cases and were curious with regard to 

whether the two cases were related to what was occurring in Mexico. At that time, CDC has 

information from its colleagues that there were organisms or viruses identified for the various 

outbreaks, so the agency had a “stay tuned” attitude.

In the 0 to 4 age group, Dr. Neuzil encouraged CDC to separate out some of the younger ages, 

particularly those under 6 months of age because that has a policy implication. For seasonal 

vaccine, there is no vaccine license. Potentially for the new vaccine, studies could be 

conducted to examine whether that younger age group is important. In addition, there will not 

be any maternal antibody for newborns. Therefore, even if they have some protection from 

seasonal flu, they are unlikely to have any protection from the novel influenza. With that in 

mind, she asked Dr. Finelli to comment on whether there was heterogeneity in the 

hospitalization rates for the 0 to 4 age group. 

Dr. Finelli responded that CDC has some data on children under 6 months of age; however, she 

did not recall whether they had any significant underlying conditions. Certainly, children less 

than 24 months of age had very few underlying conditions. 

Dr. Neuzil clarified that she also wondered whether the rates were higher. For seasonal flu, 

dividing 0 to 4 by finer age strata would result in a 10 times difference. That is, those younger 

than 1 year of age have 10 times higher rates than 3 to 4 year olds. She was curious whether 

this was also true with respect to H1N1. 

Dr. Finelli responded that CDC had conducted such an analysis, and that as she recalled the 

highest rates were in children less than 6 months of age.
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Dr. Beck noticed that the age distribution for H1N1 was somewhat different than for seasonal 

influenza. He wondered if CDC had any comparative data from outside the US regarding 

whether the flu in other locations was following the same pattern as in the US, and how the 

clinical characteristics were similar or different. 

Dr. Finelli replied that she did not have data with her pertaining to other countries.

Regarding the secondary attack rate, Ms. Stinchfield (NAPNAP) requested additional 

information regarding the definitions being used to distinguish the respiratory component in ARI 

versus ILI.

Dr. Finelli responded that ILI includes fever with cough or sore throat, while ARI was any two of 

five symptoms (rhinorrhea, cough, fever, sore throat, coryza).

Influenza Antiviral Medications

Anthony Fiore, MD, MPH

Influenza Division, NCIRD, CDC

With regard to information from other countries, Dr. Fiore shared the following map from the 

World Health Organization (WHO) website illustrating cumulative cases according to country. 

North America had over 500 cases as of 24 Jun 2009, while across the Southern Hemisphere 

there were many cases in countries entering their typical influenza seasons (e.g., Argentina, 

Australia, Chile, et cetera).
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In terms of epidemiologic data that could be expected from countries with June to September 

influenza seasons, there are respiratory syndrome surveillance systems with influenza 

programs in 32 countries that have been built over last five years with pandemic preparedness 

funding. Most of these countries have improved laboratory capacity, and CDC has provided 

reagents to them to assist them in laboratory testing. The types of disease surveillance 

information they are capable of providing to CDC include ILI, severe acute respiratory illness 

(SARI), and ILI or SARI with lab confirmation. The following map illustrates where CDC 

personnel and influenza study sites are located throughout the world in 2009. A number of sites 

are located in the Southern Hemisphere in tropical areas where there is influenza circulation 

during June through September. CDC hopes to be able to use the existing platforms in these 

areas to acquire information over the next few months:

The most established information CDC receives from countries throughout the world come from 

the WHO Global Surveillance Network, which is a viral surveillance network that was 

established in 1952. The backbone of this system is the four WHO Collaborating Centres 

(WHO CCs), which are located in Atlanta, Japan, Australia, and the United Kingdom. These 

collaborating centres receive information from the National Influenza Centres (NICs). Currently, 

there are 126 NIC institutions in 97 countries that are recognized by WHO. NICs collect 

specimens in their country of approximately 175,000 patient samples annually according to the 

WHO website; perform primary virus isolation and preliminary antigenic characterization; and 

ship newly isolated strains to WHO CCs for high level antigenic, genetic, and antiviral sensitivity 

analyses (n=approximately 2,000 viruses sent annually to the WHO CCs). There are 25 NICs in 

the Southern Hemisphere, which are expected to receive viruses over the next several months. 

Additional NICs in countries in the Northern Hemisphere with circulation during June through 

September include Thailand, Bangladesh, and Central America.
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Pertaining to information expected from surveillance in countries with June through September 

influenza virus circulation, the most important questions six weeks before this meeting regarded 

whether the pandemic virus would continue to circulate. The answer to this question is a 

resounding “yes.” Preliminary, it appears that pandemic viruses are circulating at the same time 

as other influenza viruses. Information has been received from Australia that H3N1 circulation 

has been observed. Regarding whether viruses are changing, CDC will be using the viral 

surveillance plans that are in place to collect these and characterize them. No changes had 

been observed at this time among the pandemic H1 viruses examined to date. This will be an 

on-going focus of study. In terms of whether the epidemiologic parameters are changing (e.g., 

attack rate, incubation period, et cetera), it will be difficult to obtain representative data in most 

countries observing current circulation. It is important remember that with on-going outbreaks in 

the US, there could still be a considerable amount of good data. Concerning whether the 

clinical manifestations are changing (e.g., severity, secondary infections), data are difficult to 

acquire in the US and other countries given different healthcare parameters. Obtaining viruses 

from unusual or severe cases is feasible to determine whether the viruses are changing. It will 

be possible to study whether community mitigation interventions are working in the US and 

other countries. These will be ecologic studies and they will be challenging to interpret. The 

bottom line is that there are a lot of data to examine in the US and CDC will do their best to 

acquire data from countries that have influenza viruses in circulation, especially from countries 

with co-circulation. 

Turning to the ACIP antiviral recommendations, Dr. Fiore reviewed previous discussions and 

workgroup considerations, presented an antiviral resistance update, and explained the draft 

treatment and chemoprophylaxis recommendations for seasonal and pandemic influenza. In 

most previous years, vaccine and antiviral recommendations were approved and published 

together as a package. The vaccination recommendations were voted on during the February 

2009 ACIP meeting and were soon expected to be published in the MMWR. The workgroup 

recommendation in February 2009 was that further assessment was needed of emerging 

oseltamivir resistance among seasonal influenza A (H1N1) viruses. The workgroup’s 

recommendation was to separate the antiviral recommendations from the vaccine 

recommendations for the 2009-10 season and a vote was proposed for the June 2009 ACIP 

meeting.

The workgroup discussions from February to June 2009 examined a variety of topics. Dr. Fiore 

explained that the proposed recommendation reflected the workgroup’s consideration of the 

experience with the 2008-09 influenza season and patterns of antiviral susceptibility; recent 

recommendations from other groups (e.g., Infectious Diseases Society of America, American 

Academy of Pediatrics, World Health Organization); information from antiviral experts and FDA 

colleagues who participated in workgroup calls; and pandemic influenza A (H1N1) clinical and 

epidemiologic features.

Regarding resistance to antivirals among seasonal influenza viruses in the US since October 

2009, 970 of 975 (>99%) seasonal influenza A (H1N1) viruses tested were resistant to 

oseltamivir. All influenza A (H1N1) viruses were sensitive to zanamivir, while >99% of H1N1 

viruses that were resistant to oseltamivir were sensitive to adamantanes (e.g., rimantadine and 

amantadine). All 169 influenza A (H3N2) viruses were sensitive to oseltamivir and zanamivir 

and were resistant to adamantanes. All 508 influenza B viruses tested were sensitive to 

oseltamivir and zanamivir. With respect to antiviral resistance among novel influenza A (H1N1) 

viruses in the US since April 17, 2009 all pandemic H1N1 viruses tested were sensitive to 

oseltamivir and zanamivir (n=184) and resistant to adamantanes (n=141). A summary of 

antiviral resistance during the 2008-2009 season is reflected in the following table:
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

181

INFLUENZA VIRUSES

Antiviral Seasonal 

H1N1

H3N2 B Pandemic 

H1N1

Adamantanes Susceptible Resistant Resistant Resistant

Oseltamivir Resistant Susceptible Susceptible Susceptible

Zanamivir Susceptible Susceptible Susceptible Susceptible

A number of key assumptions went into the development of the draft recommendations for 

antiviral agents for the prevention and control of influenza: Seasonal influenza viruses and 

pandemic H1N1 might have overlapping seasons. There is an inability to determine virus 

subtype or antiviral susceptibility in clinical settings, which makes clinical management 

challenging. Most antiviral treatment is empiric, given that clinicians cannot determine virus 

sub-type or antiviral susceptibility in a clinical setting in a way that helps with clinical 

management, at least in the first few days. Oseltamivir resistance among influenza seasonal 

A(H1N) is not associated with differences in clinical presentation or risk factors for illness. 

Influenza testing might be helpful, particularly if influenza B is identified. Viral surveillance data 

that includes influenza A subtypes might be helpful, but are often unavailable or not timely. 

Additional revisions of antiviral recommendations might be needed depending upon influenza 

virus susceptibility, influenza epidemiology and virus surveillance data, and antiviral supply.

Regarding the antiviral treatment recommendations, antiviral treatment should be started as 

soon as possible after illness onset. Persons for whom antiviral treatment should be considered 

include: those hospitalized with influenza, those with influenza viral pneumonia, those with 

influenza and complicating bacterial pneumonia, and those with influenza who are at higher risk 

for influenza complications, regardless of illness severity. Situations that merit consideration of 

chemoprophylaxis, and persons who should be considered for antiviral chemoprophylaxis in 

these situations, when influenza viruses are circulating in the community, include: Persons at 

higher risk for influenza complications for whom influenza vaccine is contraindicated, 

unavailable, or expected to have low effectiveness (e.g., persons who are significantly 

immunocompromised); persons at higher risk for influenza complications during the two weeks 

after influenza vaccination (after the second dose for children aged <9 years who have not 

previously been vaccinated) when influenza viruses are already circulating in the community; or 

unvaccinated family members and close contacts (including health care workers) of persons at 

risk for influenza complications when influenza viruses are circulating. During an influenza 

outbreak in a closed institutional setting with high-risk residents (e.g., extended-care facilities) 

antiviral treatment should be considered for all residents, regardless of vaccination status, and 

unvaccinated staff. When one or more family members in a household develops suspected or 

confirmed influenza and chemoprophylaxis can be started within 48 hours of last exposure, this 

should include unvaccinated family members who are at higher risk for influenza complications. 

These chemoprophylaxis recommendations are somewhat reworded from last year, but are 
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essentially the same groups of persons who have been recommended for chemoprophylaxis in 

the past several antiviral recommendations from ACIP. These boxes have footnotes, given that 

some information needs to be further explained. 

The footnote for the Treatment Recommendations Box would include the following:

 Recommended antiviral medications (neuraminidase inhibitors) are not licensed for 

chemoprophylaxis of children aged <1 year (oseltamivir) or aged <5years (zanamivir).

 A recent Emergency Use Authorization provides information on use of oseltamivir for 

children aged younger than 1 year (see Table 4). There has been recent Emergency 

Use Authorization directed at use for pandemic H1N1 that provides information on use of 

oseltamivir for children younger than 1 year of age. 

 Some experts prefer weight-based dosing for children aged <1 year, particularly for very 

young or premature infants. 

 When using weight-based dosing for infants aged <1 year for chemoprophylaxis, those 

aged 9-11 months should receive 3.5 mg/kg/dose BID, and those aged <9 months 

should receive 3.0 mg/kg/dose BID.

 Updates or supplements to these recommendations (e.g., expanded age or risk group 

indications for currently licensed vaccines) might be required.

 Healthcare providers should be alert to announcements of recommendation updates and 

should check the CDC influenza website periodically for additional information.

The footnote for the Chemoprophylaxis Recommendations Box would include the following, with 

differences from treatment recommendations noted in bold:

 Recommended antiviral medications (neuraminidase inhibitors) are not licensed for 

chemoprophylaxis of children aged <1 year (oseltamivir) or aged <5 years (zanamivir). 

 A recent Emergency Use Authorization provides information on use of oseltamivir for 

children aged younger than 1 year (see Table 5). 

 Some experts prefer weight-based dosing for children aged <1 year, particularly for very 

young or premature infants. 

 When using weight-based dosing for infants aged <1 year for chemoprophylaxis, those 

aged 9-11 months should receive 3.5 mg/kg/dose QD, and those aged <9 months 

should receive 3.0 mg/kg/dose QD.

 Updates or supplements to these recommendations (e.g., expanded age or risk group 

indications for currently licensed vaccines) might be required. 

 Healthcare providers should be alert to announcements of recommendation updates and 

should check the CDC influenza website periodically for additional information.
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183

The recommendations for the selection of antiviral treatment are reflected in Table 3. The looks 

exactly like the guidance that was provided by CDC in December 2008 when first dealing with 

the problem of oseltamivir resistance. The footnote recommends consulting local virus 

surveillance data. For example, in the current situation just seeing pandemic H1N1 practitioners 

are selection oseltamivir or zanamivir and not using amantadine because there are no seasonal 

viruses being seen at this point. 

Table 3. Recommendations for the selection of antiviral treatment 

using laboratory test results, United States, 2009-10 season*

RAPID ANTIGEN, RT-PCR OR 

OTHER LABORATORY TEST

PREFERRED 

MEDICATION(S)

ALTERNATIVE 

(COMBINATION 

ANTIVIRAL 

TREATMENT)

Not done or negative, but 

clinical suspicion for influenza

Zanamivir Oseltamivir + 

Rimantadine

Positive A Zanamivir Oseltamivir + 

Rimantadine

Positive A+B Zanamivir Oseltamivir + 

Rimantadine

Positive seasonal A(H1N1) Zanamivir Oseltamivir + 

Rimantadine

Positive A(H3N2), pandemic 

A(H1N1), or B

Oseltamivir or 

Zanamivir

None

Local virus surveillance data should be consulted. Amantadine can be substituted for rimantadine but has increased risk 

of adverse events. Data on the effectiveness and safety of combination antiviral treatment of influenza are limited. 

Table 4 provides the information from the Emergency Use Authorization that was intended for 

use with novel influenza H1N1 now called pandemic H1N1. This describes the 

recommendation for treatment according to age.

TABLE 4. DOSING RECOMMENDATIONS FOR ANTIVIRAL 

TREATMENT OF CHILDREN YOUNGER THAN 1 YEAR WITH 

SUSPECTED OR CONFIRMED NOVEL INFLUENZA A (H1N1) USING 

OSELTAMIVIR.*

Age Recommended treatment dose for 5 days

<3 months 12 mg twice daily

3-5 months 20 mg twice daily

6-11 months 25 mg twice daily

*This Emergency Use Authorization was issued by the Food and Drug Administration on April 28, 2009, for a period of 1 

year. While this EUA was intended for use as guidance to clinicians who were considering treatment of infants aged <1 

year. However, seasonal influenza A(H3N2) and B viruses have similar sensitivity to oseltamivir. As of June 2009, nearly 

all seasonal influenza A(H1N1) viruses were resistant to oseltamivir. 
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184

Table 5 addresses antiviral chemoprophylaxis recommendations, which are essentially half the 

frequency of the same dose (e.g., given once per day versus twice per day). For 3 month olds, 

FDA did not give a dose because so little data were provided and the risk-benefit for 

chemoprophylaxis as compared to treatment is somewhat different. 

TABLE 5. DOSING RECOMMENDATIONS FOR ANTIVIRAL 

CHEMOPROPHYLAXIS OF CHILDREN YOUNGER THAN 1 YEAR WITH 

SUSPECTED OR CONFIRMED NOVEL INFLUENZA A (H1N1) USING 

OSELTAMIVIR.*

Age Recommended prophylaxis dose for 10 days

<3 months Not recommended unless situation judged 

critical due to limited data on use in this age group

3-5 months 20 mg once daily

6-11 months 25 mg once daily

*This Emergency Use Authorization was issued by the Food and Drug Administration on April 28, 2009, for a period of 1 

year. While this EUA was intended for use as guidance to clinicians who were considering treatment of infants aged <1 

year. However, seasonal influenza A(H3N2) and B viruses have similar sensitivity to oseltamivir. As of June 2009, nearly 

all seasonal influenza A(H1N1) viruses were resistant to oseltamivir. 

The last component of the recommendations that are proposed to be somewhat different this 

year compared to last year is that some consideration is given to treatment considerations for 

severely ill patients. Altered regimens might be required in terms of longer duration, higher 

dosage, and / or alternative routes of administration. In the recommendations, none of these is 

endorsed, but references are provided for further guidance. In addition, information is provided 

to indicate that investigational drugs or alternative formulations of licensed medications might be 

available.

Dr. Fiore summarized that pandemic influenza H1N1 viruses have the same susceptibility profile 

as influenza A (H3N2) and influenza B (sensitive only to oseltamivir or zanamivir). Oseltamivir 

resistance among seasonal influenza A(H1N1) viruses limits antiviral options. All currently 

circulating viruses are sensitive to zanamivir, although various considerations limit its use. Most 

treatment is empiric. Zanamivir OR oseltamivir + an amantadine are recommended when 

oseltamivir-resistant viruses are circulating. Empiric treatment recommendations are the same 

as current CDC guidance (December 2008) and current IDSA guidance (March 2009) for 

seasonal influenza. There is a focus on treating hospitalized patients or those with an age or 

medical risk factor for more severe illness. The recommendations may require revision as the 

season progresses.
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185

Discussion 

Dr. Baker found it very ironic that infants 6 to 12 months of age are never evaluated for certain 

vaccines / antivirals, but then suddenly there is an Emergency Use Authorization and dosing 

schedule. With that in mind, she suggested that in the future perhaps they could be more 

thoughtful in that area. She expressed her hope that the dosing recommendations were not 

made up, and requested further information regarding what pharmacokinetic and safety studies 

had been conducted to provide assurance that there will be very safe treatments or 

chemoprophylaxis for infants less than 1 year of age. 

Dr. Fiore responded that David Kimberlin would be the best resource for this, given that he is 

one of the principal investigators on the studies from which the weight-based dosing was 

derived.

Dr. Kimberlin (AAP) replied that there are on-going studies being conducted by the National 

Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group that 

have been evaluating treatment doses of oseltamivir using an age de-escalation weight-based 

approach with targeted AUCs. These studies have been underway for three seasons. There 

are data for children between 3 months through 11 months of age. Until the Emergency Use 

Authorization was published, they had not gone down to the 0 to 2-month age group, so there is 

definitely extrapolation in that recommendation. The way CDC and FDA used those data, which 

were provided to them in the full dataset, and adjusted it to an age-based as compared to 

weight-based type approach had implications of how it would be applied across a programmatic 

scale. Certainly, there are data available. The data that were provided to CDC, FDA, and 

agencies throughout the world have been submitted to IDSA and are expected to be presented 

there. As more data are gathered, they may soon be able to publish a more comprehensive 

preliminary picture. For example, there is a recent dataset of babies in a neonatal ICU who 

were exposed to novel H1N1. The investigators were able to acquire blood samples, which 

these will soon be examined for an oseltamivir concentration determination. 

Dr. Baker requested further information about the N in each of the boxes (e.g., how many 

patients have been studied for pharmacokinetic and safety).

Dr. Kimberlin (AAP) responded that no problems have been observed with safety. However, the 

numbers are relatively small. For the 6 month through 8 month age group, 15 subjects have 

been studied; 7 for the 9 month through 11 month age group; and 5 or 6 for the 3 month through 

5 month age group. Since the ages were opened up through the Emergency Use Authorization 

and all cohorts by age were enrolled, there are also several 0 through 2 month olds. This is an 

AUC-targeted design, so the investigators knew what the target range was. For all of the 

children under 1 year of age, they began with 3 mg/kg/dose given twice per day as the dose 

being evaluated. The 9 month through 11 month age group were below the target range, which 

is why they were adjusted up to 3.5 mg/kg/dose. This is an on-going study, so at this time this 

is the best information available but it is probably not the final answer. 

Dr. Baker stressed that she was not making a criticism about the Collaborative Antiviral Study 

Group, but was instead merely pointing out that this spoke volumes about the insufficient data 

available. 
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186

With regard to novel H1N1, the chemoprophylaxis recommendations struck Dr. Cieslak as being 

impractical or obsolete. Based on the recommendation, a major percentage of the American 

public would be prophylaxed indefinitely into the future. Even for the highest risk people, it 

seems to say that while the virus is circulating, unlike the usual season there does not appear to 

be any end in sight with H1N1, so it could be interpreted as prophylaxis for a year. 

Dr. Fiore responded that the preamble in the box outlines circumstances under which this would 

be done. They are not a full recommendation to always use chemoprophylaxis. This is 

somewhat a backing down from the pandemic H1N1 recommendation currently posted on the 

web. They are faced with a situation in which they have to balance between recommending 

prophylaxis for a very narrow group with a drug that is licensed that works quite well, with the 

desire to provide the option for prophylaxis in situations that are somewhat difficult to predict 

from a recommendations point of view. The attempt here was to prioritize the types of situations 

in which chemoprophylaxis might be considered. He agreed that if taken literally as a full-scale 

recommendation to provide prophylaxis to every person, it would involve a significant number of 

people. There are no safety data for a year of prophylaxis, and as the recommendations were 

developed, they probably did not fully anticipate that the virus would continue to circulate as 

much as it has over the summer. 

Dr. Cieslak suggested that this needed to be addressed before voting for the recommendation.

Dr. Fiore requested suggestions for how to narrow this down. This was a very challenging 

recommendation for the workgroup to develop (e.g., to specifically recommend prophylaxis for 

one small group or to open it up to other situations in which prophylaxis might be considered). 

As part of the workgroup and director of a bone marrow transplant unit with multiple people in 

the hospital, multiple people on ventilators, and H1N1 circulating, Dr. Englund was not willing to 

put a stop to prophylaxis in high risk patients. However, she thought that these antiviral issues 

needed to be re-addressed in August or September before it is anticipated that the flu season 

will begin again. She agreed with Dr. Cieslak, but was not willing to recommend stopping 

treatment in high risk groups while the virus continues to circulate. Perhaps they could add the 

phrase “while virus is circulating” because prophylaxis should not be used when virus is not 

circulating. 

Dr. Neuzil agreed that it was very challenging for the workgroup. In the same way that ACIP 

likes to make recommendations early so that providers can order vaccine and prepare, the 

workgroup wanted to get something out for that same reason. They fully expect that this 

situation will have to be continually re-assessed and interim guidance will have to be offered. 

CDC set a very good precedent from the beginning with the communication message that this 

outbreak is evolving and with it the guidance must evolve. She said that while the workgroup 

was open to revision of the language, she did not think the workgroup thought that people would 

be receiving prophylaxis for 8 to 9 months at a time. Bone marrow transplants are a very 

specific, very high risk group. 

Related to the potential volume for whom prophylaxis might be used, Dr. Sawyer requested 

information about what the status of the supply of antivirals was expected to be.
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187

Christine Hahn (CSTE) expressed confusion with regard to what would be used for prophylaxis 

(e.g., seasonal flu, pandemic flu, or both). She did not see any drug recommendations, nor was 

it clear what the intent was for the antiviral recommendation. Given that some people may not 

be able to tolerate long-term prophylaxis, she wondered if there would be a table just for 

chemoprophylaxis to address the preferred antiviral in various situations. For example, a 

household is probably going to be treated based on how the contact has been treated. If the 

contact is determined to have seasonal influenza, it would seem that the prophylaxis would be 

switched to match that to protect against a particular household exposure. Thus, there seemed 

to be considerations with respect to contacts that might need to be considered.

Dr. Fiore responded that if both viruses were circulating and there continued to be oseltamivir 

resistance in the seasonal H1N1s, prophylaxis would preferentially be done with zanamivir. It 

sounded to Dr. Fiore that some language needed to be added with regard to how one might 

approach a prophylaxis situation and might change it over time if the virus is identified for the 

original source patient, such as in an outbreak. 

It seemed to Dr. Judson that there was a clear understanding of what antivirals are available, 

what the costs-benefits are, and that there are almost dichotomous outcomes for the various 

drugs against the sizable group of viruses that were tested. Therefore, he thought they had 

most of the information they were likely to have for the next few months. 

Dr. Cieslak thought that as written, the guidelines were a “dead letter” and that Oregon would 

certainly not follow them. With the situation in flux, he thought it would be preferable at this 

point to say that chemoprophylaxis is up to the provider and that the CDC website should be 

monitored for further guidance. He thought something that vague and non-leading would be 

preferable to the recommendation suggested. 

Amy Middleman (SAM) inquired as to whether there were any cost-effectiveness analyses that 

could help to guide which groups would be the most important to target.

Dr. Fiore responded that there are some cost-effectiveness analyses for seasonal viruses. He 

reiterated that the chemoprophylaxis recommendations before the committee at this time were 

essentially the same that had been in place for the last couple of years, although pandemic 

H1N1 did not have to be dealt with. However, there were certainly situations in which large 

numbers of people might be affected in an early influenza season, with an uncertain vaccine 

match, groups of people not expected to respond to the vaccine or who did not receive it, et 

cetera. Chemoprophylaxis is probably used infrequently and with the new focus on pandemic 

H1N1, chemoprophylaxis would be considered much more than in the past. 

James Turner (ACHA) indicated that a consideration in the college health setting with their living 

conditions is perhaps being more aggressive treating an index case with antivirals, hoping to 

keep them from shedding the virus and then not having to chemoprophylax the entire dormitory. 

He wondered if discussion about index cases would be beneficial. While he understood that 

they wanted to limit chemoprophylaxis to high risk groups, depending upon the living 

environment, it may be more cost-effective to treat index cases aggressively. In addition, his 

impression was that the rapid antigen tests currently available at the point of care were not FDA 

approved for novel H1N1 testing. 

Dr. Fiore replied that the rapid antigen tests were approved for seasonal influenza, not H1N1. 

In terms of prophylaxing an entire dorm, that would not be a recommendation because most 

would not likely have underlying illnesses that would put them at risk.
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188

James Turner (ACHA) pointed out that these students may have elderly frail parents who they 

could expose, they volunteer in nursing homes and schools, et cetera. The concentric circles 

become enormous around these students. 

Dr. Julie Morita (Chicago Department of Public Health) pointed out that Chicago, being a 

relative hotbed of novel influenza activity, would find the chemoprophylaxis recommendations to 

be very useful. They had to create their own recommendations, so it would be beneficial to 

have ACIP’s recommendations in support of their own. They do not have the sense that novel 

influenza is declining in Chicago. She extended Chicago’s gratitude to CDC for all of the 

support they received in the beginning phases of this pandemic. There were several teams of 

EIS Officers and other medical epidemiologists who were extremely helpful and valuable to 

Chicago. 

Dr. Baker disagreed with Dr. Cieslak, recognizing that Oregon and other states would be likely 

to do whatever they believe is best. However, given the media attention ACIP needs to make 

some recommendations with a strong caveat that these will probably be changing. If they do 

not continue to give guidance, they will not being doing their job.

Dr. Morse requested that the issue of supply be addressed.

Andrew Leone (GSK) indicated that at this point, GSK had reactivated all of its global sites. 

They have annual capacity of approximately 55 to 60 million courses of RELENZA ®. In the 

US, they have the capacity to produce approximately 1.6 million courses per month and is 

committed to producing throughout 2009. Thus, they anticipate ample supply for the upcoming 

influenza season.

Dr. Fiore indicated that there has not been a shortage in supply of oseltamivir through Roche 

and that the predominant drug in the US stockpile is also oseltamivir. 

With respect to the issue of increasing resistance, Dr. Meissner requested information on the 

status of Peramivir and whether it was expected to be active against oseltamivir-resistant H1N1 

season strain and the novel strain. 

Dr. Fiore responded that the neuraminidase inhibitor, Peramivir, from BioCryst Pharmaceuticals 

is currently in Phase 2 trials and is currently available under an investigational new drug (IND). 

The advantage of this drug is that it can be given intravenously or intramuscularly. There are 

several thousand treatment courses available. It is active against the circulating influenza 

viruses. He thought it might have intermediate to full activity against the resistant seasonal 

H1N1s. The activity is different from zanamivir. Further information can be acquired from the 

FDA’s and manufacturers’ websites. Intramuscular Peramivir might come into play if severe 

infections are observed in the fall or winter for which the licensed drugs are not effective or 

cannot be used for some reason.

Regarding the chemoprophylaxis considerations, Dr. Sumaya said he could understand 

beginning prophylaxis when a member in a household has influenza or in the closed institutional 

setting. However, he was somewhat unclear what was encompassed by the statement “when 

influenza viruses are circulating in the community” and what parameters would trigger the 

recommendation should provide prophylaxis. 
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189

Dr. Fiore responded that the recommendations do not include a trigger point for beginning 

chemoprophylaxis. Instead, practitioners should look to their state health departments for data 

on ILI visits, et cetera. It is very difficult to write recommendations to fit all scenarios. The 

purpose of the chemoprophylaxis box, which certainly had attracted the most attention during 

this meeting, was to offer permission as it were for people to think about the use of 

chemoprophylaxis in certain situations. 

Danuta Skowronski (Canada) suggested that because the chemoprophylaxis recommendation 

was causing so much angst whether a compromise might be to provide a prescription for early 

treatment for those at high risk that they could have filled at the earliest sign of symptoms. That 

would reduce the amount of drugs required and conserve them for those who really need them. 

Dr. Neuzil responded that she did not recall the working group discussing this specifically, but 

they discussed it extensively in the group who co-wrote the IDSA recommendations. Certainly, 

other professional groups have weighed in against that because there are a number of 

problems with this (e.g., potential supply problems, potentially using the prescription at the 

wrong time). She referred everyone to the IDSA and other documents to answer the question 

regarding why the ACIP working group did not consider that option. 

Jane R. Zucker, MD (New York City Department of Health) commented about the availability of 

antivirals, specifically as it related to the different formulations. New York City Department of 

Health’s experience was that there was an ample supply of the 75 mg capsules of oseltamivir, 

but not of the 30 mg and 45 mg capsules. They had particular problems with the availability of 

pediatric suspension with either short dating or pharmacies having difficulty with the supply and 

distributors. New York City sent communications out to pharmacies about the compounding of 

the capsules into the pediatric suspension. They also conducted a survey among their 

pharmacies, in which they learned that many of the pharmacies were not prepared to 

compound, although it is part of their training. Therefore, the specific request for CDC / ACIP in 

terms of looking at the antiviral supply is to ensure that there are ample plans in place with 

distribution and oversight of that, particularly for the pediatric formulations. Communication with 

pharmacists about compounding capsules into the correct suspension dosage is a very 

important part of the planning as well. 

Regarding prophylaxis, it seemed to Alan Hinman that one of the issues may be that there are 

highly limited data pertaining to the efficacy or safety of prolonged administration of 

chemoprophylaxis.

Dr. Fiore responded that this was correct.

Dr. Cieslak said his issue was that the recommendations were written with the understanding 

that most high risk people would be vaccinated, and they call for prophylaxis either in the 

absence of vaccination or until a vaccine can take effect. The recommendation seems to 

presuppose a typical influenza season. Neither of those is operative currently. 

Alan Hinman thought it sounded as though there was a desire to have a statement that one 

should consider chemoprophylaxis, which is a statement that has been issued in the past, and 

also a concern that with the continuing circulation of the novel H1N1, the circumstances are 

different—the virus is not necessarily passing through a community over a three to four week 

period. He wondered whether it would be feasible to leave the box as is and add to it a 

statement that “there are no or limited data on the safety or efficacy of chemoprophylaxis carried 

out over X period of time.”
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Samual Katz (IDSA) indicated that all of the data were reviewed with regard to the IDSA 

guidelines, and the efficacy data for prophylaxis were found to be quite robust and consistent. 

One issue regards emergence of amantadine or rimantadine resistance when the index case is 

treated, which probably does not need to be addressed specifically. The safety data go up to 

six weeks for all four drugs, based on several hundred patients in randomized controlled trials 

(RCTs). Beyond that, there are no data although there are some on-going trials in Southeast 

Asia. 

Dr. Pickering relayed the following comments for Dr. Lett: 1) she agreed with Dr. Cieslak’s 

comments regarding prophylaxis recommendations; and 2) she felt that Bullet 5 for treatment 

regarding persons with influenza at higher risk for influenza complications regardless of illness 

severity should receive antiviral treatment, which may have changed or morphed somewhat 

since the workgroup discussed it.

Dr. Robin Robinson (BARDA Director HHS) reported that HHS is in almost daily 

communications with the antiviral and vaccine manufacturers regarding their supplies. The 

numbers given by GSK were representative of what they communicated to HHS. Roche has 

communicated to HHS that they can provide 8 million treatment course per month through the 

remainder of 2009 from their Nutley, New Jersey facility. They have a larger global supply, but 

accessibility and availability of that could be problematic with the global needs going forward in 

the fall. BARDA also supports the contract for development of Peramivir with BioCryst 

Pharmaceuticals. The data thus far for Phase 2 clinical trials for intramuscular administration 

are not favorable to go forward. However, for intravenous administration BARDA is supporting 

their Phase 3 studies to go forward. They do not have a large amount of data that are 

supportive of severe cases thus far, although they will have data from a trial they have been 

conducting with BioCryst’s partner in Japan, Shionogi & Co., Ltd., in August. That would be 

critical to consider that drug in infected individuals as opposed to uncomplicated cases. 

Dr. Neuzil acknowledged that Dr. Cieslak had identified a very important discrepancy that 

originally they had a set of recommendations for antiviral use during seasonal influenza in which 

the assumptions is that the majority of the US population actually receives influenza vaccine, 

and that influenza vaccine is available in a timely manner. Looking at the pandemic plan, there 

is a separate set of recommendations on pandemic influenza treatment, prophylaxis, and 

vaccine that relates to availability. Perhaps what they had was a confluence of both of these in 

an unclear situation. Unlike the vaccine recommendations made for specific groups, the 

headline here is situations that merit consideration. Therefore, it was not a recommendation so 

much as it was a guidance. What is done in the fall will depend upon a number of factors that 

cannot be examined in isolation (e.g., vaccine and antiviral availability in relation to an 

outbreak). Perhaps they should craft the language around this to indicate that “the use of 

antivirals for chemoprophylaxis are dependent upon the availability of vaccines that match the 

circulating strain and the availability of antivirals.” Further into the season, that would allow 

CDC and others involved in pandemic response to monitor these factors and then perhaps 

publish more definitive recommendations. 
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Litjen Tan (AMA) pointed out that one thing which helped the working group get past this was 

the recognition that for the remainder of the summer it would be likely that what they would be 

dealing with would be the H1N1 pandemic strain. Therefore, these recommendations would be 

appropriate. However, they also discussed that as data begin to emerge, the guidelines would 

have to be revised. The group recognized that these guidelines would have to shift as the 

season moved forward.

Dr. Morse noted that most of the discussion had focused upon prophylaxis. With that in mind, 

he pointed out that there seemed to be a couple of options at this point: 1) they could proceed 

to approve the recommendations as proposed with some minor adjustments in the wording 

regarding prophylaxis on an interim basis and perhaps reconsider a time during which the 

issues could be revisited (perhaps during a summer meeting), or 2) address treatment only and 

leave prophylaxis in limbo for the remainder of the summer.

Dr. Neuzil clarified that there currently is guidance on the website, and that nothing in the 

proposed guidance contradicted that. Thus, there was no urgency to change it. 

Dr. Fiore showed a slide indicating that it reflected the current guidance.

Dr. Cieslak pointed out that the slide said that this was “Interim guidance for infection control for 

care of patients” versus a broader recommendation about prophylaxis. 

Dr. Fiore clarified that what he was showing was the antiviral recommendations and that the link 

in red was for healthcare personnel exposure to refer them to the guidance to determine 

whether they experienced significant exposure. 

Dr. Cieslak indicated that he could support the recommendation if some language was included 

to the effect of “Typically prophylaxis is recommended for these persons in the setting of novel 

influenza for which there is no vaccine, and for which the season is not well-defined. Physicians 

will need to consider duration of prophylaxis and supplies.”

Dr. Englund thought the information on Table 3, which she thought was a new table, was very 

useful for those working in a clinic or hospital setting, as well as for anyone who has access to 

knowing whether their patient has influenza. While some practitioners would disagree because 

it suggests giving two antivirals, that is the protocol until the virus is identified. Many sites, 

centers, and state health departments do let physicians know what is going on on a regular 

basis, so she knows what is occurring in her community. 

Dr. Fiore responded that the table was developed from interim guidance CDC published in 

2008, which was adapted by adding pandemic A(H1N1) to the bottom of the first column.

Dr. Morse suggested potentially moving ahead with the treatment vote at this time, and further 

developing the wording for the prophylaxis recommendation offline. 

William Schaffner (NFID) suggested putting “pandemic A(H1N1)” on a separate line as it was 

somewhat buried on the table as it stood. 
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Motion: Treatment Guidelines Recommendation

Dr. Sawyer made a motion to approve the treatment guidelines as stated and for the group to 

develop compromise language for the prophylaxis recommendation by the next morning. The 

motion was seconded. The motion carried with 13 affirmative votes, 0 abstentions, 2 not 

present (Lett, Baker), and 0 negative votes.

At the end of the day, the committee revisited the antiviral prophylaxis issue. Dr. Neuzil 

indicated that during the break further information was obtained. As a model, the Red Book 

addresses treatment for influenza. It has only a very short paragraph regarding 

chemoprophylaxis, in which a website is referred to. Perhaps this is a good option, given that it 

is user-friendly and adaptable. If the group generally agreed, the working group would draft 

language that refers to a CDC website and disseminate to members separately for review. 

Discussion 

After discussion with Dr. Campos-Outcalt, Dr. Temte suggested that the prophylaxis section be 

divided into post-exposure and general chemoprophylaxis because they are separate issues 

and there is better evidence for one than the other. 

Dr. Sawyer inquired as to whether ACIP or CDC would be responsible for the content of the 

website.

Dr. Fiore responded that upkeep of the website would be CDC’s responsibility.

Dr. Neuzil stressed that it was termed as “guidance” versus “recommendation.” 

Motion: Antiviral Prophylaxis Guidelines Recommendation

Dr. Meissner made a motion to include a brief paragraph that defers the reader to CDC’s 

website. The paragraph should also address the issue of chemoprophylaxis in the absence of a 

vaccine and in the absence of an anticipate cessation of influenza virus circulation. Dr. Baker 

seconded the motion. The motion carried with 13 affirmative votes, 0 abstentions, 2 not present 

(Lett, Judson), and 0 negative votes.

Novel Influenza A (H1N1) Vaccine Development and Progress

Robin Robinson, PhD

HHS / ASPR / BARDA Director

Dr. Robinson explained the 2009 US H1N1 vaccine strategy. The epidemiology of H1N1 

suggests that it can be expected to persist throughout the summer, fall, and winter along with 

what is observed for seasonal influenza. The moment that the novel influenza virus became 

apparent, the US went into the normal pandemic preparedness mode of vaccine development of 
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the strain. CDC engaged in isolating the strains, preparing the virus reference strains, and 

engaging in master virus seed preparation. Those strains (e.g., classical reassortants and 

reverse genetics reassortants) were essentially manufactured the last week of May, within a 

couple of days of the designated time and with the original plans and estimates for pandemic 

preparedness that had been done for H5N1. From there, the manufacturers began developing 

investigational lots to be moved into clinical studies in July. Vaccine manufacturing began at the 

same time the manufacturers received the reference viruses because they needed to start with 

commercial scale. It is known with new viruses that it takes a number of passages at 

commercial scale to move forward. 

Through numerous inter-departmental discussions, the decision was made to use Tier 1 

manufacturers, which are those manufacturers that have licensed seasonal influenza vaccine 

products, 4 which are inactivated and 1 which is live attenuated. In addition, if the severity of 

the pandemic were such that the transmissibility was so increased that a vaccine was needed 

for everyone as soon as possible, the adjuvant and bulk antigen would need to be made sooner 

than September. In anticipation of that and as part of the preparedness plans, they have gone 

forward with adjuvants. On May 27, 2009 Secretary Sebelius announced that HHS was moving 

forward not only with the vaccine development with the clinical studies, but also with the 

purchase of bulk antigen and bulk adjuvant for vulnerable populations, critical workforce, et 

cetera. Also needed are syringes and needles to move forward with a campaign, and vaccine 

administration activities must be addressed. Thus, some decisions have already been made 

while others will be made moving forward through the summer. 

For H1N1 vaccines, HHS has been working from the National Strategy for Pandemic Influenza

(Nov. 2005), the goal of which is to provide influenza vaccine to everyone in the US within 6 

months of pandemic onset. The H1N1 Vaccine Strategy follows the pandemic playbook for 

vaccine development, production, and administration with multiple decisions and on / off ramps. 

With two exceptions, the playbook is in tact: 1) The pandemic did not begin in Southeast Asia 

or some other part of the world, but began in the Northern Hemisphere in North America; and 2) 

It was not clear whether there would be a distribution system or what that would be. An earlier 

advisory group from NVAC worked with state and local health officials to point out problems with 

the vaccine distribution system that was in place. Clinical studies will inform vaccine formulation 

and safety profile. The vaccine could be licensed as an antigen-alone formulation, which may 

be afforded as strain changes, or under pre-EUA packages in preparation for the vaccine with 

adjuvant. Unfortunately, manufacturers who worked very hard on this had not filed their BLAs 

yet with their H5N1 vaccines, so they are not licensed. While these are mature in their 

development, but they are not currently licensed in the US. Key decision issues include 

prioritization of vaccine for special populations (e.g., children, critical workforce, et cetera), 

vaccine type, Thimerosal preservative, oil-in-water adjuvant, and post-immunization adverse 

event safety monitoring. 

The products from different manufacturers would include a standard antigen-alone formulation 

that would be in a multi-dose vial or a single dose syringe that would be Thimerosal-free or 

mixed with an adjuvant, either oil-in-water emulsion or with GSK (3.4%) it would be a 

combination of two vials with the adjuvant in one vial and the antigen to add to the vial from CSL 

(18.7%). From MedImmune (5.8%) would come the standard sprayer inhalation type of delivery 

system without adjuvant or Thimerosal. From GSK there would be a combination vaccine with 

their own antigen and adjuvant mixed at the beside. From sanofi pastuer (26.4%) there would 

be standard multi-dose vials, single dose syringes, Thimerosal-free without adjuvant. The 

adjuvant they would use is GSK ASO3 adjuvant mixed with their antigen. Novartis Vaccines 

(45.7%) will have a multi-dose vial standard without adjuvant or a single dose vial with the 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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adjuvant pre-formulated. If the virus continues as it has thus far, Scenario A for licensed 

vaccine is anticipated for H1N1 vaccine products and output, illustrated as follows (although this 

had changed four times in the last few days):

If the pandemic is more severe and morbidity and mortality warrant the use of an adjuvant, 

Scenario B will be followed. In this case, the licensed vaccine can be available early and then 

shift to use of the adjuvant when support by clinical data: 

Regarding H1N1 vaccine distribution options, CDC working with HHS, manufacturers, and 

others, is building the seasonal influenza vaccine distribution system already. With this 

systems, states order through a central CDC ordering system and then place orders with 

manufacturers moving forward. This was an adaptation that resulted from the 2004-05 

influenza vaccine shortage. The five vaccine manufacturers would produce the product, send it 

to McKesson (with whom CDC currently has a contract), from which it would go to states. An 

attractive aspect of this model is that McKesson could receive vaccine, syringes, needles, and 

fact sheets from different manufacturers, package it all together, and send it each “ship to site.” 

Recipients would then receive everything ready to go to begin vaccinations. McKesson has 

approximately 30 to 50 distribution sites available throughout the country, and could be more if 

they contract with other wholesale distributors. Capacity is about 40,000 to 90,000 parcels per 

U.S. H1N1 Vaccine Production Options: Scenario A

0

50

100

150

M doses 

Scenario A - Licensed Vaccine 60 100 80 80 80 80 80

Sept Oct Nov Dec Jan Feb Mar

U.S. H1N1 Vaccine Production Options: Sceanrio B

0

20

40

60

80

100

120

140

160

180

M doses

Scenario B - EUA (Adjuvant) 0 0 160 160 120

Scenario B - Licensed Vaccine 60 100 0 0 0

Sept Oct Nov Dec Jan Feb Mar
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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day. Part of this set-up was in response to assisting states in the current crunch. Ultimately, 

the desire would be to have this system available for 300 million people. Prioritization will 

depend upon severity of the disease, transmissibility, and whether drug resistance occurs. 

FDA Recommendations for Clinical 

Evaluation of Novel H1N1 Vaccines

Norman W. Baylor, Ph.D.

Director, Office of Vaccines Research and Review

Center for Biologics Evaluation and Research

Food and Drug Administration

Dr. Baylor presented a high level overview of FDA evolution of novel H1N1 vaccines. He 

emphasized that the FDA is examining all options in an effort to provide a flexible regulatory 

approach, which allow availability of H1N1 vaccine as rapidly as needed. At the same time, the 

FDA must ensure safety and public confidence in the vaccines licensed by the FDA or permitted 

for use under Emergency Use Authorizations. FDA actions to address H1N1 vaccine have 

included developing needed pathways and regulatory processes to speed vaccine availability; 

assuring safety and public confidence; facilitating vaccine manufacturing and availability; 

addressing scientific and related technical needs (e.g., growing H1N1 virus and preparing 

reagents needed for production); enabling current and evolving technologies; and working with 

other global national regulatory authorities and the World Health Organization.

With respect to regulatory guidance, the regulatory pathway for H1N1 vaccines is similar to that 

of annual influenza vaccine. Dr. Baylor emphasized that a guidance document is posted on the 

FDA website. What this document was based upon in terms of evaluating pandemic influenza 

vaccines began with H5N1. Because there is more experience with H1 subtypes historical, the 

FDA believes that there can be somewhat more flexibility with H1N1. For H1N1 vaccines 

manufactured using US licensed processes, applicants must submit a new BLA for 

administrative purposes, but can cross-reference their existing BLA for the seasonal vaccine. A 

data package is required that is similar to a “strain change” with the addition of limited data from 

dose-ranging studies. Under a declared emergency, an Emergency Use Authorization may be 

pursued for products manufactured by an unlicensed manufacturing process, but whose 

benefits likely outweigh risks. Currently, none of the US-licensed influenza vaccines contain 

adjuvants. 

The objectives for clinical evaluation of H1N1 vaccines primarily include: 1) dose-finding; rapid 

dose-finding necessitates a sample size adequate to assess the proportions of subjects that 

achieve the study endpoints; 2) safety evaluation (e.g., reactogenicity) and immunogenicity; and 

3) investigational adjuvant evaluation to provide data on their utility in dose sparing and 

enhanced immunogenicity.

Concerning the clinical evaluation of H1N1 vaccines, the FDA recommends that subjects 

include healthy adults 18 to 64 years of age and >65 years of age, and children 6 months to 3 

years of age and 3 years to 9 years of age. Also under discussion is whether an age group of 

10 to 17 should be included or whether extrapolation can be done from the 3 to 9 year olds. 

Additionally, FDA is open to investigators who are considering conducting clinical studies 

involving children less than 6 months of age. The design must be randomized, double-blind, 

and controlled. The interventions include two intramuscular doses of H1N1 separated by 21 

days and studying 7.5 mcg, 15 mcg, and 30 mcg doses. The endpoints include safety (e.g., 
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solicited and unsolicited adverse events) and immunogenicity (e.g., neutralizing titer of 1:40, 

which has historically been the target).

In terms of special considerations for clinical studies with adjuvants, manufacturers may 

consider multiple dose-ranging adjuvant arms: 3.8, 7.5, 15 mcg of hemoglobin antigen. FDA is 

trying to emphasize the added benefit of the adjuvant in that if there is no added benefit, there is 

no reason to include the adjuvant. Clinical studies may be conducted concurrently in the adult 

and pediatric age groups, with some exceptions. Subjects should be monitored for 12 months 

for serious adverse events (SAEs), deaths, and new onset of chronic medical conditions. This 

is primarily for those products with the novel adjuvants. Safety laboratory evaluations should be 

assessed at baseline and at early and late time points post-vaccination. The emphasis here is 

also on the adjuvanted products. 

Regarding international collaboration, FDA is working with EMEA, Health Canada, and other 

international regulatory agencies to harmonize approaches to vaccine development, multiple 

regulatory requirements for vaccine manufacturing (e.g., “Consensus” Protocol), and postauthorization surveillance and risk management plans.

In summary, development of monovalent H1N1 inactivated or live attenuated vaccines using 

licensed manufacturing processes is the most straightforward approach; however, the FDA will 

evaluate other vaccine types. The FDA is using flexible regulatory approaches to expedite the 

availability of H1N1 vaccines. Given the unpredictable nature of the pandemic, the FDA will 

evaluate adjuvants and other antigen sparing strategies.

H1N1 Vaccine Trials: NIH Update

George Curlin, MD

OD / DMID / NIAID

Dr. Curlin explained that NIAID is the vaccine development extramural part of the NIH. With 

their institute, the Division of Microbiology and Infectious Diseases, is the principal focus for 

vaccine development and extramural funding to control and prevent infectious agents except 

HIV. Vaccine and Treatment Evaluation Units (VTEUs) is a consortium of individual contracts. 

NIH’s VTEUs were established in 1962. These are a ready resource for the conduct of clinical 

studies, which are located in academic centers and other organizations. There are eight sites 

throughout the US, including: Group Health Cooperative in Seattle, Children’s Hospital Medical 

Center in Cincinnati, University of Maryland in Baltimore, University of Iowa in Iowa City, Baylor 

College of Medicine in Houston, St. Louis University in St. Louis, Vanderbilt University in 

Nashville, and Emory University in Atlanta. There is a broad range of capabilities in the VTEUs: 

phase I, II, III, and IV trials; bacterial, viral, parasitic vaccines (novel delivery systems, compare 

formulations / dosing schedules), therapeutics, immunotherapeutics; and targeted surveillance 

studies. They also have access to a wide range of populations: healthy adults, elderly, 

pediatric populations, and special populations (e.g. immunocompromised, pregnant women). 

The VTEUs have conducted over 160 Phase I, II, and III clinical trials since 1995 of seasonal 

vaccines, pre-pandemic vaccines, and antivirals. 

The initial steps in the H1N1 outbreak were for FDA, DMID, and BARDA to begin discussions 

on vaccine issues immediately. FDA engages in active discussions with manufacturers to 

develop core elements for clinical trials, receive proposals, and provide feedback. BARDA 

addresses the vaccine supply issues. NIAID’s role in the consortium is to provide the clinical 
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trial data that supplements the large Phase III trials, which are the principle element and source 

of information for the products that they hope will be deployed in advance of the next epidemic.

NIAID’s area of support specifically for H1N1 Vaccine Trials I is to assist licensed vaccine 

manufacturers in generating clinical data needed for licensure for more rapid availability of data 

in populations within a company’s license, and to generate data in groups for which H1N1 

vaccines may be used under Emergency Use Authorizations. NIAID is standing by to 

supplement the large scale trials with special trials to generate data in “special populations” 

(e.g., infants < 6 months of age, pregnant women, immunocompromised subjects). For H1N1

Vaccine Trials II, NIAID’s role is to generate clinical data to help inform policy decisions and / or 

address “gap” areas: more efficient use of vaccines in different populations, compare different 

H1N1 vaccines using a standard assay, and assess “real world” scenarios for mass vaccination. 

For example, do shorter versus longer dosing intervals result in comparable immune responses 

presuming two doses are needed? Co-administration of TIV with H1N1 vaccines raises a series 

of issues that must be address (e.g., adjuvanted, unadjuvanted; inactivated, live-attenuated). 

NIAID will also address prime / boost with adjuvanted vaccines from different companies (AS03-

H1N1, MF-59-H1N1). Another NIAID area of support for H1N1 Vaccine Trials III is to generate 

data on mixing stockpiled vaccine antigen and adjuvants from different manufacturers (e.g., 

GSK’s AS03 adjuvant mixed prior to administration with CSL or sanofi H1N1 antigen vs. GSK 

antigen). Pre-clinical data are likely to be required prior to clinical trials.

Negotiations with FDA are on-going, as are discussions with other global regulatory groups and 

companies. NIAID has initiated contact with companies directly regarding vaccine availability 

and regulatory documents needed to mount clinical trials. NIAID is also developing the new 

assays and preparations are underway with the VTEU sites to address capacity, access to 

populations, et cetera. The first set of vaccine protocols were expected to be finalized within 

two weeks, with other sets to follow. The VTEUs had already developed specimen collection 

protocol, enrolling patients, positive control samples, assay development, research reagent, 

clinical outcome, sequencing, shedding, humoral and cellular responses, et cetera. The VTEU 

protocol to assess safety and immunogenicity of TIV in pregnant women enrolled the first 

subject the week before this ACIP meeting. 

NVPO’s Role and the Guidance on Allocating 

and Targeting Pandemic Influenza Vaccine

Dr. Bruce Gellin

National Vaccine Program Office

Dr. Gellin reported that last week when Secretary Sebelius met with Margaret Chan, one of her 

requests was that the information that is coming out of these clinical trials and the system (e.g., 

surveillance, biologic) be shared with WHO and others who will have to make similar decisions. 

Needless to say, the Secretary readily agreed to this. Many decisions have already been made, 

such as the decisions to begin vaccine production, the clinical trials, and a potential 

immunization program. 

On May 22, 2009 the Secretary announced the purchase of an allotment of over $1 billion to 

begin the production of the vaccine ingredients to have an ample supply for the clinical trials, 

and to have the ingredients for antigens and adjuvants. On June 11, 2009 Secretary Sebelius 

and Secretary Duncan (Secretary of Education) sent a letter to Superintendents to begin to work 

with the Department of Education about what may occur in the fall. The letter addressed some 

of the contingencies schools need to deal with in the fall (e.g., dealing with ill children and 
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faculty, conducting education if schools are disrupted, et cetera). On June 24, 2009 President 

Obama signed the supplemental appropriation for $7.65 billion to better prepare the country for 

what might occur in the fall. Broadly, those funds are to support the purchase of additional 

vaccine and antigen, prepare for a potential immunization program and its execution, and to 

broadly support public health measures to better prepare for preparedness and response. 

There are a number of federal advisory committees within HHS and other departments that 

have a piece of this. There have been a number of regularly scheduled meetings to address the 

issues, with many of the discussions addressing what each of the committees brings to the table 

given their process and expertise.

NVAC will examine overall program implementation and will take a specific look at the vaccine 

safety monitoring pieces of this. NCAC will convene monthly calls that will be considered official 

public meetings. A special working group will assess vaccine safety monitoring, looking at the 

national system—not just the HHS component, but also the components of the DoD and the VA. 

The National Biodefense Science Board has been in existence for approximately a year and a 

half. This advisory committee reports to the Secretary essentially on preparedness issues, and 

it has a Pandemic Influenza Working Group. This group will also be convening conference 

calls. Dr. Gellin encouraged people to participate in these calls to better understand everyone’s 

roles and responsibilities, as well as the advice that they are giving to the departments. The 

DoD has its own system, the Defense Health Board and a subset of that. They have had a 

similar set of discussions about their preparedness for the military. The Department of 

Homeland Security has a committee called the National Infrastructure Advisory Council, which 

advises the President on critical infrastructure. This endeavor was begun by the Secretaries of 

HHS and the Department of Homeland Security who went jointly to this advisory council to ask 

them for help in identifying critical parties within the critical infrastructure, particularly in the 

setting of a severe pandemic when there would likely be absenteeism and disruption of schools, 

the economy, and society at large. The Department of Homeland Security provided a report 

that fed into this process “Guidance on Allocating & Targeting Pandemic Influenza Vaccine.”

The “Guidance on Allocating & Targeting Pandemic Influenza Vaccine” speaks to some degree 

on the goal of developing and implementing a vaccine program. It is important to distinguish the 

goals to ensure vaccine preparedness and the amount of vaccine that has been sent forth that 

might potentially be needed as a country from the goals pertaining to an immunization program. 

Obviously, there cannot be an immunization program without a vaccine, but just because there 

is a goal of making a substantial amount of vaccine does not necessarily mean that it will be 

used.

Referring to the following chart, Dr. Gellin stressed the importance of becoming familiar with the 

“Guidance on Allocating & Targeting Pandemic Influenza Vaccine,” particularly with regard to 

the Severity of Pandemic chart reflecting the various tiers of severity. He explained that the 

idea of chart was that based on the severity of a pandemic, every American would find their 

place on this chart regarding where they would get in line. What is important about this is the 

preamble. This is part of the preparedness activity because there was no crystal ball. A lot of it 

was driven by the experience with H5N1 and the concern that should that become transmissible 

what it might mean. Moreover, pandemics past do not all look like 1918. Hence, there must be 

a range of different responses appropriate to pandemic severity. With that in mind, Dr. Gellin 

shared the following passages: 

“...it is important that plans are flexible as the guidance may be modified based on the 

status of vaccine technology, the characteristic of pandemic illness, and risk groups for 

severe disease – factors that will remain unknown until a pandemic actually occurs.”
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“At the time of a pandemic, national leaders will obtain advice from scientific and public 

health experts to determine whether the guidance should be modified based on the 

characteristics of the emerging pandemic.”

“Guidance on pandemic vaccine allocation and targeting will be reassessed periodically 

before a pandemic occurs to consider the new scientific advances, changes in vaccine 

production capacity, and advances in other medical and public health response 

measures.”

The final piece of this was the recognition that this effort needs to engage many people outside 

the Beltway and conference rooms to talk to real people about their expectations and values. 

There was a long process in which input was obtained from stakeholders and the public, out of 

which came the following four goals of a program: 1) Protecting those who are essential to the 

pandemic response and providing care for those who are ill; 2) Protecting workers who are at 

greater risk of infection due to their job; 3) Protecting those who maintain essential community 

services; and 4) Protecting children.

Review of Existing Vaccine Prioritization Guidance

Tom Shimabukuro, MD

Centers for Disease Control and Prevention

Dr. Shimabukuro reviewed the existing pandemic vaccine priority groups, the process that went 

into generation the document titled, “Guidance on Allocating and Targeting Pandemic Influenza

Vaccine,” and what work was done previously and how the work was conducted. He 

emphasized that the guidance was an initial starting point for developing a prioritization process 

and for determining priority groups for receipt of vaccine during an influenza pandemic. 

Although the guidance covered various severities of a pandemic, it focused primarily on a 

severe pandemic with H5N1 in mind. This document was released in July 2008 prior to the 

emergence of the pandemic H1N1 virus. 

The US pan flu vaccine strategic goals in the HHS pandemic plan are to: 1) establish and 

maintain a dynamic pre-pandemic influenza vaccine stockpile available for 20 million persons 

(2 doses / person) or more persons depending on vaccine manufacturing capacity and results of 

dose-sparing adjuvant studies and prime-boost immunization studies: H5N1 vaccine stockpiles; 

and 2) provide pandemic vaccine to all US citizens within 6 months of a pandemic declaration: 

pandemic vaccine (600 million doses) [National Strategy for Pandemic Influenza (Nov 2005) 

and HHS Pandemic Influenza Plan (Nov 2005) www.pandemicflu.gov]. Under the current 

guidance, the goal of pandemic influenza vaccination program is to vaccinate all persons in the 

US who choose to be vaccinated. However, the vaccine supply will not be available all at once. 

Therefore, decisions regarding who will be vaccinated first will have to be made. The 

overarching objectives are to reduce the impact on health and minimize disruption to society 

and the economy.
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With respect to the process, this guidance was drafted by a federal interagency working group 

whose members represent all sectors of the government. This group received input from 

federal, state, and local public health agencies; other public sector agencies; and private sector 

partners as well. This was an 18-month long systematic process that included a historical 

analyses of previous pandemics, public engagement and stakeholder meetings, and a formal 

decision making process. Though not part of the development process, there was a provision 

for review and reassessment during a pandemic in the context of the current epidemiologic data 

and a provision for periodic review in general.

The specific objectives of the vaccination program would be to protect those who are essential 

to the pandemic response and provide care for persons who are ill (e.g., primarily healthcare 

workers); protect those who maintain essential community services; protect workers who are at 

greater risk of infection due to their job (e.g., emergency responders); protect those who 

maintain homeland and national security; and protect children (based primarily on feedback 

from public engagement and stakeholder meetings). Again, this is focused on a severe 

pandemic.

With respect to general principles, the guidance takes into account a “pandemic severity index” 

(PSI); provides for pro rata allocation of vaccines to states that is allocated and distributed 

according to population; strongly recommends state and local governments follow national 

recommendations; includes provisions that vaccine priority groups will be evaluated in the 

context of current epidemiologic data; and specifies that the guidance will be reassessed 

periodically in general. The framework of the document is organized around four categories, the 

first three of which are occupationally defined: homeland and national security, health care and 

community support services, critical infrastructure, and general population. Within each 

category there are specific target groups, which include: specific occupations / occupational 

groups, and age / risk-based groups (general population). There are 5 Tiers, with Tier 1 being 

the highest priority, follow by 2, 3, 4, and 5. The guide recommends vaccinating sequentially by 

tier and simultaneously within a tier. That is all target groups within a tier should be vaccinated 

simultaneously both within the categories and within the target groups. The primary objective of 

vaccination of critical infrastructure / key resources workers is not to reduce absenteeism in 

general, but is rather to protect workers with critical skills, knowledge, and licensure or 

certification whose absence would create bottlenecks or collapse of critical functions; and to 

protect workers at especially high occupational risk (e.g., direct patient care, first responders). 

The following is the main table in the guidance: 
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http://www.pandemicflu.gov/vaccine/allocationguidance.pdf

The table includes a column of the estimated number of individuals in each of the target groups. 

These numbers were determined in cooperation with the industry sector, councils, HHS, and 

DHS. A tier is assigned to each target group within each category. The estimated numbers add 

up to $300 million residents, which is the total population of the US. As noted, vaccination is 

done sequentially by tier and simultaneously within a tier. The blank boxes represent the “not 

targeted” category, which does not mean not included. Instead it means in a moderate or less 

severe pandemic, those specific occupationally defined groups will move into the general 

population category and will then be reassigned to those tiers and target groups within the 

general population. There is a balance act between critical infrastructure and security goals 

(e.g., maintaining key services, preventing societal disruption, preventing damage to the 

economy, maintaining homeland and national security) and public health goal (e.g., protecting 

the public’s health and preventing morbidity and mortality). In a severe pandemic, a vaccination 

program would be more weighted toward critical infrastructure and security needs. In a less 

severe pandemic in which critical infrastructure and security goals may not be compromised by 

disease, logically the goals would be re-weighted more toward the public health goals. These 

are not necessarily mutually exclusive. For instance, keeping school children healthy and in 

school may prevent a lot of societal disruption. So, there is really a mix of goals within the two 

broader goals. 

The following table illustrates that assigning a tier to a target group is not just a blanket 

statement in which healthcare workers are Tier 1. Included in Tier 1 are healthcare and 

emergency services. In working through the Industry Sector Councils, DHS, and HHS the 

determination was made that of all healthcare workers roughly 60% would be considered Tier 1. 

Some healthcare workers would not fall into Tier 1, 2, or 3. Of emergency service workers, the 

determination was made that approximately 90% would fall into Tier 1 primarily because of the 

increased risk burden. For Tier 2 target groups, the determination was made that 25% would be 

critical to maintaining services. 
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Tier Infrastructures Allocation Rationale

1 Healthcare

Emergency services

~60%

 90%

• High risk exposures

• Increased burden

2 Communications/IT

Electric & Nuclear

Oil & Gas

Water

 25% • Products/services 

essential to all sectors

• Products cannot be stored

• Little fungibility

3 Banking & Finance

Chemical

Food & Agriculture

Pharmaceutical

Postal & Shipping

Transportation 

7.5% • Products may be stored

• Demand may decrease

• Greater fungibility

Discussion

Dr. Morse inquired as to whether assessment was being done of the potential for 1 dose in the 

older age groups due to the potential for protection, such that they may not require 2 doses in 

certain age groups.

Dr. Baylor responded that FDA has recommended examining the data for adults when it is 

ready. They will attempt to review the data early so that decisions can be made early if 

possible. If they observe a robust immune response, some decisions can be made at that point 

that can be extrapolated to all of the groups. In some of the studies, the data will be reviewed 7 

days post dose 1; 14 days post dose 1; and the same for post dose 2 to have an early idea of 

effectiveness. 

After hearing the list of all of the committees that will be working on this, Dr. Baker inquired as to 

what committee would be responsible for deciding the recommendations for novel H1N1 

influenza vaccine. Until now, this has always fallen with the purview of the ACIP. 

Dr. Gellin replied that the idea behind this was that the guidance was created based upon the 

assumptions that were observed with the recognition, and then they had to gauge it as they saw 

it at the time. To him, this was what ACIP did all of the time. That is, ACIP looks at the vaccine, 

the epidemiology, and then makes recommendations on how to match that. Because the 

members have seen novel H1N1 information in pieces, the purpose of this session was to put 

all of this in front of the ACIP so that they could begin to think about the data needs ACIP has to 

fulfill their role. The short answer was that CDC was asking ACIP to consider how to manage 

the situation, particularly with an emerging epidemiological pattern. In some ways this may be 

similar to ACIP’s role in the management of vaccine shortages. ACIP would continue to make 

recommendations.

Dr. Baker noted that all of the information pertaining prioritization included children at the 

bottom; however, the boxes do not stipulate all children. It is children by age or youngest 

children and pregnant women are left off every time in Tier 1. With regard to the severity index, 

she asked whether there was a scoring index for severity. 
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Dr. Gellin responded that this was part of the difficulty WHO had in ratcheting up their pandemic 

phases, because that is a geographic determination versus a severity determination. The 

recognition along the way was that a response should be tailored to the magnitude of the 

problem and that while there was endless discussion about 1918, there was also discussion 

about 1957 and 1968. Hence the idea of a modulated response appropriate to the problem. 

The Pandemic Severity Index was the construct for that. 

Dr. Schuchat added that the general pre-pandemic planning attempted to use a framework with 

graded severity because decisions on short supply would be different in different circumstances. 

Clearly, what has been observed thus far is not a 1918 scenario. WHO has talked about what is 

being observed as a moderately severe pandemic. That does not necessarily correlate with the 

Pandemic Severity Index included in many of the documents submitted to ACIP. The principle 

issue for ACIP was that as they often consider influenza vaccinations in terms of who should be 

vaccinated, whether recommendations should be strong or permissive, et cetera. It is likely that 

vaccination would be carried out in a setting of limited supply, at least initially, which would 

require input from ACIP about the target populations for an initially limited supply. The NVAC 

committee will focus on how safety would be monitored. They have a Safety Working Group 

that has been considering that type of issue for years, and they are going to take on that piece 

of the larger pie. 

Dr. Baker asked for clarification with respect to whether the Severity Index was a quantitative 

trigger or if it was 15 committees’ debating a trigger.

Dr. Schuchat replied that ACIP did not really need to worry about the Severity Index. The 

Severity Index was helpful for planning purposes. Based on what is observed as the season 

goes forward, ACIP will considering who is most at risk, the rates, potential for increased illness 

in a second wave, et cetera. ACIP will be examining actual data from the pandemic.

With respect to seasonal influenza, William Schaffner (NFID) pointed out that there was an army 

of providers in place monitoring what is occurring and wondering how much they are going to 

have to revise their usual activities. With that in mind, he wondered who would decide whether 

an H1N1 program was going to be started, when, whether it would be early, and when this 

would be made known. 

Dr. Neuzil replied that one of the principles from her introduction pertained to how a pandemic 

influenza vaccine might co-exist with a seasonal vaccine program. The first step was to 

understand the timelines for when pandemic vaccine might be available. She proposed that this 

issue be put off until the next day at which time they would hear more detailed plans on vaccine 

program implementation. Then they would have all the pieces to weigh in.

Regarding the FDA presentation, Dr. Ehresmann noted that McKesson is the distributor used for 

the Vaccines for Children program. With that in mind, she expressed concern that if there is an 

overlap between seasonal influenza and the H1N1 vaccine, there may be volume issues with 

McKesson. 

Dr. Santoli agreed that this is a critically important question. In addition to seasonal influenza 

vaccine, half of the nation’s pediatric vaccine supply goes through the centralized distributor. 

CDC is happy with this and wants to protect it. CDC is wrestling with this question, and has 

asked McKesson to help them understand how risks to the routine seasonal flu and routine 

childhood distribution program and can be mitigated because these matter greatly, even in the 

midst of a novel response. 
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Regarding the clinical studies for adjuvants and the statement that subjects should be monitored 

for 12 months for serious adverse events, Dr. Ehresmann wondered whether that meant to have 

licensed vaccine with adjuvants it would take at least a year. 

Dr. Baylor replied that there will be surveillance post-license as well with the adjuvanted 

products. Most likely the products with novel adjuvants will be available through an Emergency 

Use Authorization. They probably will not be licensed vaccines.

Dr. Curlin indicated that two of the manufacturers that produce the adjuvants have already 

presented plans for long-term clinical studies that would span several years and would include 

hundreds of thousands of subjects, beginning in Summer 2009. 

Dr. Neuzil stressed that a key issue regarded the timelines. Looking at Dr. Robinson’s timeline, 

the critical piece pertains to when ACIP will be able to acquire the first clinical trial data in a 

variety of age groups following one dose of vaccine. 

Dr. Baylor responded that they would have to know when the vaccine would be available, which 

it was not at the time of this meeting. As soon as vaccine is available, the FDA’s goal is to 

begin the clinical trials. Although he did not have a calendar date, if they attempt to collect early 

data 7 to 14 days post dose 1 in a small group, that could possibly be three to four weeks after 

the trial begins. However, he stressed that no clinical trials could be conducted until the 

manufacturers produce a vaccine.

Dr. Neuzil was pleased to hear that the goal was to get a minimal dataset as quickly as 

possible. Along those lines, she wondered if there was a clear pathway for the live attenuated 

vaccine to be licensed and whether that would be considered a strain change.

Dr. Baylor responded that the pathway is the same. However, it is a strain change as defined in 

his presentation, with a limited amount of dose ranging data. In the US, no clinical data are 

required for annual strain changes. That would be the difference.

Dr. Meissner raised the issue of Guillain-Barré Syndrome, pointing out that in 1976 when the 

vaccine was recommended the association with Guillain-Barré Syndrome was not appreciated. 

He wondered whether this might be a generic problem with swine influenza, and whether 

anything was known about the degree of homogeneity between the hemoglobin molecule of the 

1976 swine strain and the California 2009 H1 strain.

Dr. Neuzil indicated that there would be presentations the next day regarding virus 

characteristics and the safety monitoring plans.

Phil Hosbach (sanofi pasteur) stressed that a reality check was needed, given that the 

discussion was focused on all things working perfectly, on time, moving quickly, aggressive 

plans, et cetera. Even if they do add to the protocols a 7- or 14-day blood draw, they will have 

to go back to their IRBs, draw the blood, bring it back in house, run it through assays, make 

sure that they have the right reagents for formulation of the vaccine, et cetera. Many 

assumptions had not been discussion, so he wanted to ensure that people understood that 

things would have to go perfectly in all of the groups, organizations, agencies, manufacturers, et 

cetera. 
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Dr. Morse agreed, noting that Dr. Robinson had outlined potential production capabilities that 

seemed much more optimistic than what he had heard previously.

Dr. Robinson replied that there are always assumptions. One important component that was 

built into preparedness is redundancy. They have five vaccine manufacturers that are going to 

produce different amounts to support what is available to the US. In 2004, this would have been 

a much different situation. With redundancy, they are now able to engage in conversations as 

to what is available. They took a very conservative estimate on many of the production yields 

and other assumptions, and would see over the next 30 days how those play out. It is not clear 

yet whether there will be more or less than needed.

Once the tiers are reviewed and fine-tuned and production is underway, Dr. Morse wondered 

how decisions to move successfully through the tiers would be managed. 

Dr. Gellin responded that they had to analyze the situation as it unfolded and not focus on the 

tiers specifically. The construct of the tiers is a helpful starting point, but the unfolding 

epidemiology must also be examined carefully from the data coming out of the clinical trials to 

consider how to direct certain products to certain populations. 

Dr. Sawyer wondered how, given the recent history of vaccine supply, manufacturers could 

suddenly turn out 600 million doses without blinking an eye and whether money was usually the 

missing ingredient. 

Dr. Robinson responded that basically, the $5.6 million has been appropriated and used over 

four years has permitted them to be in this situation. Four years ago, these adjuvants were not 

available. Similarly, there were just one or two manufacturers at that time and now there are 

five. The manufacturers have also increased their facility production. For example, GSK has 

two facilities that are producing influenza vaccine—one is producing seasonal and the other is 

producing H1N1 currently. Facilities have been retrofitted to enhance their capabilities so that 

existing facilities can produce larger amounts.

Doug Campos-Outcalt (AAFP) requested that someone address the issue of prioritization in 

terms of how that will be enforced and how much leeway states may have to deviate from that.

Dr. Gellin replied that this is like guidance that ACIP gives all of the time. It is guidance for 

those who are implementing the programs to follow. It is not enforced. When this process 

began, there was a desire by the states for such guidance so that not everyone had to do this 

on their own. Determining who should be in line first is not an easy task. Thus, this large 

national process was put in place to provide guidance for providers to follow as best they can 

depending upon the situation. While the guidance is important, following the implementation 

plan is also essential. The idea is for the guidance to be read by states and localities in concert 

with a range of others. 

Dr. Ehresmann said from a state perspective, the guidance is welcomed because consistency is 

very important. Using Minnesota as an example, the Twin Cities border Wisconsin; the 

Morehead area borders directly with Fargo, North Dakota; and in the Southeast corner of the 

state the healthcare system is centered in South Dakota. For Minnesota not to be consistent in 

other states would be highly problematic. While each state will face different issues in terms of 

their decisions, Minnesota will follow the guidance, and she believed other states would very 

much value and follow the guidelines as well for the importance of consistency throughout the 

country. 
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Danuta Skowronski (Canada) noted that if the situation continued to evolve as it had been over 

the summer, it is likely that a substantial part of the population will already have been affected, 

infected, and rendered immune by the fall. To what extent will that be taken into account in 

planning for immunization programs, perhaps through planned population sero surveys to 

assess population susceptibility moving into the fall.

Dr. Schuchat responded that the concept of everyone being immune has been discussed but is 

not considered to be very likely. A number of studies are underway, including serologic surveys 

to understand asymptomatic infection and how often that is occurring. H1N1 has a very focal 

nature. Even in locations such as New York City, the burrough-specific attack rates are not the 

same and it is likely that the vast majority of people have not yet been exposed to this virus.

Andy Pavia said he was still hearing to some degree that the guidance document on 

prioritization is being viewed as if it were “carved in stone.” He stressed the importance of ACIP 

thinking about the document as preparatory work that identified the size of the groups at risk 

and obtained some sense of public values, but does not consider the epidemiology of the H1N1 

outbreak which does not match the scenarios that were constructed or the reality of what 

vaccine there will be. Instead, ACIP should be considering how to fine tune prioritization 

because everyone would be looking to ACIP’s prioritization.

Dr. Gellin said that ACIP should review the epidemiology of what is in front of them, which is 

what they do every time they make a decision about a vaccine use.

Dr. Schuchat suggested that ACIP think about target populations, given that they may or may 

not recommend any tiering. There are a number of ways recommendations may evolve in 

terms of groups that might be recommended for vaccine, expected vaccine availability, timing of 

ability to deliver vaccine, et cetera. ACIP’s role was to be fully briefed on the particular real 

world scenario, factoring in uncertainties of how this might change by the time 

recommendations are being implemented, and then engaging in the committee’s usual work of 

determining target population recommendations for what might be a licensed vaccine. 

With regard to consistency between states, Christine Hahn (CSTE) reminded ACIP that unlike 

the earlier discussion about physicians wanting a choice, if novel H1N1 escalates many others 

will jump in to tell states where to direct vaccine. Given the uncertainties, she suggested 

strongly worded recommendations from ACIP to help states keep their priorities the same.

Dr. Chilton thought they were appropriately concerned about the coming 2009-10 influenza 

season, but he wondered if any consideration was being given beyond that to the next season 

with respect to a quadrivalent or pentavalent vaccines.

Dr. Gellin replied that this issue has arisen at the last two strain selection Vaccines and Related 

Biological Products Advisory Committee (VRPAC) meetings. As noted, several vaccine 

manufacturers now have greatly enhanced capacity such that consideration is being given to 

producing a seasonal vaccine that may provide broader protection. In the licensure of the H5N1 

vaccine, there was only a licensure pathway for a vaccine that had 90 mg to be given twice. So, 

there is a pathway through which a vaccine can be licensed. 

Dr. Baylor responded that it is not simple when adjuvants are added or quadrivalent products 

are being produced. This gets into supply issues because the vaccine virus that grows the least 

is going to dictate how much vaccine can be manufactured. Conceptually it may seem like a 
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207 

straight path, but in reality it not necessarily that simple. With respect to the regulatory 

mechanism data can be considered from a chemistry manufacturing and control perspective 

and a clinical outline, but there are other issues involved as well.

Dr. Schuchat noted that regarding the virologic surveillance, as well as the strain selections that 

occur twice every year, Dr. Cox would be presenting the next day. For decades, Dr. Cox has 

been helping to select the strains that go into seasonal influenza vaccine for the Northern and 

Southern Hemispheres. At this point, it is not know how many seasonal strains will be 

circulating this year, what the long-term circulation of the novel H1N1 will be, et cetera. It is very 

immature to determine how many strains will actually be needed. While it is exciting that there 

is greater capacity and better virologic surveillance worldwide, it is far too soon to understand 

what the formulation of vaccine would be for future Northern and Southern Hemisphere 

seasons. 

Dr. Sumaya inquired as to whether there was any possibility that the focus on influenza vaccine 

may hamper work on other vaccine programs.

Dr. Robinson responded that considerable effort has been made to ensure that H1N1 

production does not affect seasonal vaccine production, and that influenza production as a 

whole does not affect other vaccine programs. An attempt was made to build the infrastructure 

such that influenza vaccination production would be independent of production of other vaccines 

or other biological products. 

Dr. Englund pointed out that the epidemiology CDC provides ACIP will help them direct where 

they believe the priorities are. As a pediatrician she recommended that there be more specific 

age group definitions, particularly in children less than 4 years of age and in children less than 

12 months and 6 months. In her hospital, 30% of H1N1 cases that have been diagnosed are 

under 4 years of age. Because this epidemic is not as severe overall as was first thought, she 

believes that the cases affecting medical care and tying up the medical system need high 

priority. Once they have the data, ACIP can base their decisions based not only on severity and 

mortality, but also on cases that present to physicians’ offices and hospitals. 

Claire Hannan, MPH

Association of Immunization Managers (AIM)

Ms. Hannon reported that AIM continues to have on-going concerns about the Hib vaccine 

supply and reinstatement of the fourth dose. AIM represents the 64 immunization grantees of 

50 states, 8 territories, and 6 cities. AIM convened a conference call earlier in the day, during 

which the grantees had an opportunity to discuss their supply situations and the new Hib 

vaccine allocation that they received for July. While the overall supply has increased for July, 

the supply of monovalent Hib vaccine appeared to be decreasing. Many states indicated that 

their allocation of monovalent Hib vaccine decreased in July, which they were not expecting. 

This is important because providers may not choose to use the combination vaccine in children 

who only need the Hib component. At least 10 states reported that they do not have sufficient 

Hib vaccine to meet their needs and are not ready to move to the 4-dose series. Thus, there is 

a need to monitor this issue closely at the program and provider levels, not just at the aggregate 

Public Comments Day 2
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208 

or national levels. It is as if an announcement had been made about a product, but the product 

remained at the factory. In a supply situation, the overall number of available doses is not the 

only determining factor in deciding whether there is enough vaccine. It is also important to take 

into account how those doses are spread across providers, and the providers’ ability to use and 

manage the doses. More information is needed from the manufacturers about the individual 

products and the presentations they are planning to release. There is a major difference 

between monovalent Hib vaccine and the combination Pentacel® vaccine. If there is a 

significant shift in the ratio of one to another, immunization programs need to prepare and to 

work with the providers to change ordering and practice behaviors.

 

June 26, 2009

Virology and Immunology

Nancy J. Cox, Ph. D.

Director, Influenza Division

Director, WHO Collaborating Center for Influenza Reference and Research

Influenza Division, NCIRD

Dr. Cox reported on the laboratory characterization of the novel H1N1 viruses and vaccine 

development, given that these have been such a critical piece of the influenza response. 

Events unfolded very quickly, with the first US case of novel H1N1 detected on April 15, 2009. 

By about April 29, 2009, real time polymerase chain reaction (PCR) kits had already been 

assembled and were being distributed to US labs. This was possible because there was 

already a five-target real time PCR assay that could detect influenza A, influenza B, H1, H3, and 

H5. CDC had this assay because the agency was preparing for an H5 pandemic, with a 

considerable amount of response preparation predicated on the potential for an H5N1 

pandemic. Referred to as “swine flu” at the outset of the pandemic, novel H1N1 was a surprise. 

Nevertheless, CDC was able to develop primers and probes rapidly, acquire an Emergency Use 

Authorization, and obtain permission from FDA so that those primers and probes could be 

included in the five-five target assay. 

By about the middle of May, CDC had already developed a number of vaccine candidate

viruses that had been generated by reverse genetics or by classical reassortment, tested for 

their antigenic properties, and sequenced. The necessary safety testing had still not been 

conducted; however, CDC was permitted by all regulatory authorities and agreement of the 

World Health Organization (WHO) to ship these vaccine candidates to the manufacturers who 

could work under Biosafety Level 2 (BSL-2) conditions with BSL-3 enhancements. Thus, 

numerous efforts were being made in parallel to respond rapidly. By mid-June, real time PCR 

kits had been distributed to over 230 US laboratories and well over 300 international 

laboratories. 

Dr. Cox shared the following example to illustrate the very complex picture of the number of 

influenza A viruses currently circulating in pigs in North America:

Novel Influenza A (H1N1)
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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INFLUENZA 

DIVISION

Reassortant Events Among Swine Influenza 

Viruses (SIV) in North America

1930

Slide courtesy of Dr. Amy Vincent, NADC, USDA

This does not take into account the diversity of influenza viruses circulating in Europe, Asia, or 

the rest of the Americas—this is just in the US where H3N2, H1N2, reassortant H1N1, classical 

H1N1, and human H1N1 and H1N2 viruses are circulating. Dr. Cox reported that Dr. Amy 

Vincent of NADC / USDA and her colleagues have found that this internal gene cassette 

consisting of PB1, PB2, PA, NP, M, and NS were very stable. This cassette of genes seemed 

to accept hemagglutinins and neuromitidaises of a variety of different subtypes with no problem 

whatsoever. Dr. Cox emphasized that this was important to keep in mind moving forward, given 

that this stable replication complex plus cassette could accept, for example H5N1.

In the last few years, CDC has been concentrating on wild birds introducing their viruses into 

domestic poultry. Those viruses were subsequently transmitted to humans and there was a fear 

that there would be reassortment in humans between human influenza viruses and avian 

influenza viruses. But then, “out of left field” came the novel H1N1 viruses which combine a 

variety of gene segments from human influenza viruses, swine influenza viruses, and classical 

swine influenza viruses. Thus, it is extremely important to keep this total picture in context and 

focus carefully upon what is occurring with novel H1N1.

When the first novel influenza H1N1 case was recognized in California, CDC quickly knew that 

there was something different about this virus. The agency obtained a number of isolates of the 

triple reassortant H1N1 viruses from humans that had been transmitted from pigs in a variety of 

settings, and began developing primers, probes, and sequencing protocols so that these viruses 

could be examined rapidly to determine whether there had been any changes that might 

indicate that they would be more transmissible to humans. When the triple reassortant H1N1 

viruses were transmitted to humans, they did not transmit beyond one or possibly two 

generations. Humans appeared to be a dead end host. However, it was immediately apparent 

that the novel H1N1 virus did not behave in the expected manner with the real time primers and 

probes that the agency had been using to characterize triple reassortants. Much to their 

surprise, CDC found a gene type for this new virus that had not been described elsewhere in 

the literature. 

And if you look at the origin of the various genes, you can see that the PB2 and the PA genes 

were introduced in about 1998, were circulating in swine, they’re present here. The PB1 gene 

was introduced into humans in about 1968, introduced into swine in 1998, and that’s the origin 

of the PB1 gene. The HA, NP and NS date back to the 1918 virus and have been evolving in 

pigs during the period from 1918 to the present time. And the NA and M interestingly were the 

two new genes in this virus, and their original was avian influenza viruses that were introduced 

into swine at about 1979. First identified in Belgium and then they evolved this lineage of avian 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

210

H1N1 viruses became established in pigs and evolved until the current time. So in this new 

virus, we have this novel gene constellation that had not been seen before. People have been 

digging through their freezers, very carefully looking for the predecessors of these viruses 

among their swine influenza virus collections and so far, no one has been able to find the 

predecessor. 

Looking at the evolutionary tree, Dr. Cox pointed out a number of things about this particular 

evolutionary tree for the hemagglutinin gene; she noted in one place there was the 1918 virus. 

South Carolina/1 1918 H1N1, this is one of the viruses that was sequenced from preserved lung 

tissue by Jeffery K. Taubenberger. Everyone working on influenza is very familiar with older 

viruses such as Puerto Rico/34, Weiss/43, Denver/57, et cetera. The human seasonal influenza 

viruses have evolved. 

INFLUENZA 

DIVISION

A/Ohio/07/2009 H1N1

A/New York/18/2009 H1N1

A/California/05/2009 H1N1

A/Texas/04/2009 H1N1

A/Mexico/4108/2009 H1N1

A/California/04/2009 H1N1

A/Swine/Indiana/P12439/00 H1N2

A/swine/Guangxi/13/2006 H1N2

A/Wisconsin/10/1998 H1N1

A/Wisconsin/87/2005 H1N1

A/Swine/Ohio/891/01 H1N2

A/swine/Korea/PZ14/2006 H1N2

A/swine/Korea/CAS08/2005 H1N1

A/Iowa/CEID23/2005 H1N1

A/swine/Iowa/00239/2004 H1N1

A/swine/Memphis/1/1990 H1N1

A/swine/Ratchaburi/NIAH1481/2000 H1N1

A/Ohio/3559/1988 H1N1

A/swine/Indiana/1726/1988 H1N1

A/Philippines/344/2004 H1N2

A/swine/Iowa/2/1985 H1N1

A/swine/Chonburi/05CB1/2005 H1N1

A/Thailand/271/2005 H1N1

A/swine/Ontario/4/1981 H1N1

A/New Jersey/8/1976 H1N1

A/swine/Wisconsin/2/1970 H1N1

A/swine/Wisconsin/1/1957 H1N1

A/swine/Iowa/15/1930 H1N1

A/swine/Jamesburg/1942 H1N1

A/Minnesota/01/2009 H1N1

A/Brisbane/59/2007 H1N1

A/Solomon Islands/03/2006 H1N1

A/New Caledonia/20/1999 H1N1

A/New York/630/1995 H1N1

A/USSR/90/77 H1N1

A/Memphis/16/1983 H1N1

A/Fort Worth/50 H1N1

A/Denver/57 H1N1

A/Weiss/43 H1N1

A/Puerto Rico/8/34 H1N1

A/South Carolina/1/18 H1N1

0.02

Phylogenetic Tree of Hemagglutinin H1: Swine vs. 

Seasonal

Seasonal H1

Swine H1

Novel H1N1 Outbreak

Human cases of swine H1

Seasonal H1

(Garten, et al Science 2009)

Looking at the phylogenetic tree of hemagglutinin H1 with respect to swine versus season 

influenza, the hemagglutinins for novel H1N1 are on a long branch on the evolutionary tree. 

Many data points are missing because very little surveillance is being conducted for novel 

H1N1. While there is more surveillance in the US and Europe than in any other part of the 

world, and there is some surveillance being conducted in Asia (particularly in Hong Kong), much 

of the rest of Asia and most of world do not currently conduct any surveillance. 

Referring to the following table, Dr. Cox made several points about the importance of 

conducting haemagglutination-inhibition tests in terms of vaccine development and seeking 

cross-reactivity with seasonal vaccines: 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

211

INFLUENZA 

DIVISION

STRAIN DESIGNATION NJ/8/76 WI/10* IL/9* CA/07 MX/4108 NY/18 TX/15 AS/59

A/NEWJERSEY/8/1976 640 10 10 5 5 5 5 5

A/WISCONSIN/10/98* 80 1280 1280 640 640 640 640 5

A/ILLINOIS/9(33304)/2007* 160 1280 5120 2560 2560 1280 1280 5

A/California/07/2009 10 320 1280 2560 1280 1280 1280 5

A/Mexico/4108/2009 10 320 1280 2560 640 640 640 5

A/New York/18/2009 5 320 640 1280 640 640 640 5

A/TEXAS/15/2009 FATAL 10 640 2560 5120 2560 1280 1280 5

A/BRISBANE/59/07 5 5 5 5 5 5 5 160

TEST ANTIGENS

A/CALIFORNIA/7/09 X-179A 5 640 2560 2560 1280 1280 2560 5

A/TEXAS/5/2009 XPR8-IDCDC 

RG15 5 640 1280 2560 1280 1280 1280 5

Utah 249817 FATAL 5 160 1280 2560 1280 1280 1280 5

Washington V19-4347 FATAL 5 160 1280 1280 640 640 640 5

Arizona PV09124151 FATAL 5 320 1280 2560 2560 2560 2560 5

Montana 723335 10 320 1280 1280 1280 1280 1280 5

Maine VSP-001799 10 640 2560 2560 2560 2560 2560 5

Nevada 1050 5 640 1280 2560 1280 1280 1280 5

Utah 243727 5 640 1280 2560 1280 1280 1280 5

A/NONTHABURI/102/09 10 640 2560 2560 2560 1280 2560 5

Guatemala 450 5 320 1280 2560 1280 640 1280 5

Colombia 330 5 640 2560 2560 2560 2560 2560 5

El Salvador 351 5 320 1280 2560 1280 1280 1280 5

Mexico/4593/2009 40 1280 2560 5120 2560 1280 2560 5

A/AUCKLAND/1/2009 5 640 1280 2560 1280 640 1280 5

A/ENGLAND/195/2009 10 640 2560 5120 1280 1280 2560 5

The A/New Jersey/8/1976 ferret antiserum and its homologous antigen have a nice homologous 

haemagglutination-inhibition titer of 640. With respect to how this antiserum inhibits these 

viruses, novel H1N1 viruses are really quite different from A/New Jersey. A/Wisconsin/10/98 

and A/Illinois/9(33304)/2007 are triple reassortant swine influenza viruses that were isolated 

from humans. There is more similarity between the current strains and these two viruses than 

with the A/New Jersey/8/1976; there is a lot of homogeneity. The reference strain, California/7, 

has a homologous titer of 2560. If within 2- to 4-fold in terms of titer, the conclusion is that the 

virus is not varying from the referent virus. The reference strain from Mexico likewise has a lot 

of homogeneity in terms of the titers represented, as do A/New York/18/2009 and 

A/Texas/15/2009. With regard to the seasonal H1N1 virus, A/Brisbane/59/07, there is really no 

inhibition of this virus by any of the swine influenza ferret antisera and likewise antiserum to this 

virus does not inhibit any of the novel influenza viruses. 

Of the two top candidates (A/California/7/09 X-179A; A/Texas/5/2009 XPR8-IDCSC REG15), 

the A/California/7/09 X-179A is perhaps the leading contender among the various vaccine 

candidate viruses that have been produced, given that it seems to grow the best. It certainly 

has very similar antigenic properties to all of the novel swine influenza viruses. It is always 

possible to check whether the candidate vaccine viruses have the same antigenic profile as 

their wild type viruses. A number of fatal cases have been examined to determine whether 

there are any differences antigenically or genetically between the fatal and more severe cases 

and the milder cases. Certainly in terms of antigenicity, no difference is observed whatsoever.

In summary of genetic and antigenic analyses, the combination of gene segments of nH1N1 

viruses had not been reported previously and has still not been found in any frozen specimen 

collections. Re-assortment had occurred between Eurasian swine influenza viruses and North 

American swine lineage triple reassortant viruses. It is not clear at this time whether the 

reassortment event occurred in North America or in Asia and then was exported from Asia. No 

genetic markers for severe disease in viral genes has been detected yet. The virulence 

markers identified for the H5N1 and 1918 Spanish Flu viruses are not seen in the novel H1N1 

viruses. However, a caveat to that statement is that not all of the virulence markers for 

influenza viruses are known, and they can vary depending upon the gene constellation. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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Genetically and antigenically homogeneity suggests a single introduction in humans with 

onward spread and evolution. Homogeneity made selecting a reference vaccine virus relatively 

easy compared to seasonal influenza. However, it has been demonstrated that passage in 

eggs that limit dilution to select viruses that grow to high titers in eggs can result in antigenic 

and genetic variation in the viruses. Thus, vaccine manufacturers will have to be very careful as 

they work with these viruses.

Naturally, determining the antiviral resistance profile or antiviral susceptibility profile to 

oseltamivir, zanamivir, and the M2 blockers (e.g., amantadine and rimantadine) is important. In 

The current seasonal H1N1s are largely resistant to oseltamivir but sensitive to zanamivir, and 

mainly sensitive to the M2 blockers. On the other hand, H3N2 viruses are sensitive to 

oseltamivir and zanamivir, but resistant to the M2 blockers. Influenza B viruses are sensitive to 

oseltamivir and zanamivir. Of the novel H1N1 viruses, 216 were tested that were isolated from 

many countries globally. All of them are sensitive to oseltamivir and zanamivir, but are 

consistently resistant to the M2 blockers.

Many questions have been raised about whether seasonal influenza vaccine would afford any 

level of protection against novel H1N1 virus because the seasonal virus does contain H1N1 

components. Therefore, Jackie Katz and her group immediately began soliciting panels of 

serum that were available through a number of sources, with many collaborators providing 

serum. Pediatric subjects 6 months to 9 years of age who had seasonal influenza vaccines 

were found to have no detectable antibodies to the novel H1N1 virus following vaccination. 

They did have a detectible micro neutralization titer of 42. Micro neutralization is much more 

sensitive for picking up antibodies to novel influenza viruses than HI titers (haemagglutinationinhibition). Although following vaccination there was no increase in antibody whatsoever to the 

novel influenza virus, as expected, there was a robust response to the vaccine virus. This was 

true for all of the panels, and was true for trivalent inactivated vaccine as well as live attenuated 

vaccine. While the hope was that a more robust response would have been observed postvaccination in those children who received a live attenuated vaccine, unfortunately that was not 

the finding. There was a slightly different picture for adults 18-64 years of age in that prevaccination, there was detectible antibody. When further stratified by age to examine 

individuals over 60 years of age, higher levels of cross reactive antibody was observed in their 

serum with a slight rise in titers. Thus, there is not a very promising picture with regard to cross 

protection afforded by seasonal influenza vaccines, and the conclusion is that there would be 

minimal to no protection afforded by seasonal vaccine against novel influenza H1N1. Some 

data have been gathered in Japan and in the United States to examine vaccine effectiveness of 

seasonal vaccine against novel H1N1 virus. Although the data are not robust yet, a signal has 

not been found to indicate there is protection in either country.

Another component of public health risk assessment is to determine pathogenesis and 

transmissibility of the novel H1N1 viruses. For this assessment, a ferret model was used 

because that is the best model and best predictor to examine what will occur in humans. This 

model has been used to examine H5N1, 1918 viruses, and seasonal influenza viruses. While 

this model will not necessarily answer all questions regarding what will occur in humans, it will 

offer interesting hypotheses to consider. When seasonal H1N1 viruses were compared with two 

novel H1N1 viruses, increased morbidity was observed in the ferrets. The novel H1N1 viruses 

replicated to very high titers in lung tissue and could be recovered from the intestinal tract of 

internasaly inoculated ferrets. The results that although some labs have somewhat conflicting 

results, the results suggest that there may be higher virulence of novel H1N1 viruses compared 

to their seasonal H1N1 counterparts in this ferret model.
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The investigators also wanted to try to measure the efficiency of transmission of these viruses 

compared to seasonal influenza viruses, so they assessed transmission through direct contact 

in which an inoculated ferret was joined by a contact ferret one day post-inoculation in the same 

cage. The contact ferret was then monitored for infection. With seasonal viruses, they always 

observed that the contact ferrets are all infected and begin to shed virus early after contact. 

Cages were designed in an effort to develop a ferret model for transmissibility. The cages are 

perforated, with infected ferrets and inoculated ferrets placed in one cage and contact ferrets 

placed in an adjacent cage to be monitored for infection. What was consistently observed with 

seasonal H1N1 and H3N2 viruses was that the inoculated ferrets began to shed virus one day 

post-inoculation. All three ferrets in this experiment become infected, shed viruses to high titers, 

and then experienced titer decline to return to baseline by day seven. The contact ferrets began 

shedding virus the day after exposure and there was a similar pattern, just delayed by a couple 

of days since they were the contact ferrets. This was respiratory droplet transmission, with no 

directional airflow in these experiments. With novel H1N1 viruses, a different pattern was 

observed in that not all of the contact ferrets in the adjacent cages are infected (e.g., only 2 out 

of 3 of the ferrets were infected). There was also somewhat of a delay compared to what was 

observed in the contact ferrets for seasonal influenza viruses. The conclusion for the work 

going forward is that novel H1N1 viruses exhibit less efficient respiratory droplet transmission in 

comparison to seasonal H1N1 viruses. Given that transmission occurred in only 4 of 6 droplet 

contact pairs and that infection was delayed compared with seasonal H1N1, these data suggest 

a hypothesis that perhaps additional virus adaptation in humans may be required to reach the 

high-transmissible phenotype observed with seasonal H1N1 and H3N2 viruses. This may be 

reflected in the fairly low secondary attack rates that have been observed in households in 

California and Texas.

In conclusion, genetic and antigenic characterization of viruses, serologic assays, animal 

models, and epidemiologic assessments are all critical components for public health risk 

assessment. To date, there has been substantial consistency between laboratory and 

epidemiologic results, which suggests that novel H1N1 may not be fully adapted to humans. 

Epidemiologic and virologic surveillance are important for identification of future changes in 

antigenic characteristics, transmission characteristics, severity of disease, antiviral resistance, 

and intensity (e.g., surge) in US cases. There is a limited understanding of diversity of influenza 

viruses in pigs globally, which is a major gap in pandemic preparedness. USDA’s efforts to 

initiate surveillance should be supported and encouraged by public health, putting the “One 

Health” concept into action. Ensuring virus sharing between public health, animal health, 

academia, and industry is a key component of planning.

Key questions remaining for the 2009 H1N1 response include: What is the timing of the 

expected fall wave of 2009 H1N1 in the Northern Hemisphere? What will be the timing and 

dosing for 2009 H1N1 monovalent vaccine, if recommended, based on clinical trial data? Who 

are the target populations for 2009 H1N1 vaccine? Will reassortment occur with 0-resistant 

seasonal influenza viruses or with H5N1 viruses? It is known that a novel H1N1 is circulating in 

Egypt where there are cases of H5N1 occurring in the populations that seem to be most 

susceptible to novel H1N1viruses. How will antiviral drugs be used, assuming they are 

effective? What will be the effectiveness of non-pharmaceutical interventions? The question 

most frequently asked is: What is the difference between bird flu and swine flu? To that Dr. 

Cox quipped that that for bird flu, tweetment is needed and for swine flu oinkment is needed. 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

214

Discussion Points

An inquiry was posed regarding whether in the ferret model investigators had any data on 

viremia and / or stool shedding of the virus.

Dr. Cox responded that they continue to work on this, but have no evidence for viremia. There 

is no evidence for a virus in other organs (e.g., brain, spleen, et cetera). They have information 

only for the intestine at this point. Additional data are expected from more detailed examination 

of the tissues.

Dr. Morse requested information about the status of the development of rapid tests for novel 

H1N1 virus and their potential application for the fall seasons.

Dr. Cox responded that the rapid tests commercially available are being compared for their 

ability to detect novel H1N1 virus. It is known that many of the commercially available tests do 

detect novel influenza virus. The sensitivity is not as high as would be expected, so the realtime PCR assay will probably be an assay of choice. It is not as rapid and is not a bedside test, 

but it can be utilized by laboratories accustomed to using real-time PCR. There is, of course, a 

lot of work going on in industry and with various partners to try to develop bedside tests. 

However, so far none of them are as sensitive as the real-time PCR assay and are not nearly as 

sensitive as viral culture. CDC has been working diligently with many partners to try to develop 

a simple, inexpensive, rapid test that can be used at the bedside.

Gus Birkhead (NVAC) requested further information pertaining to the comment made earlier that 

CDC had sent out candidate vaccine strains to the company without the usual safety testing.

Dr. Cox explained that there is new safety testing done for seasonal vaccine candidate viruses; 

however, because this is a novel strain and it is unknown how it will behave, and because safety 

testing was required for the H5N1 candidate vaccine viruses, it was determined within the WHO 

network that the novel viruses should be tested using the same kinds of assays used for H5N1 

to ensure that the vaccine manufacturers could work with these candidate vaccine viruses 

safely in their facilities. The agency had to demonstrate that the reassortant viruses were less 

pathogenic in ferrets and similar to the donor of the internal genes in terms of the pathogenicity. 

They had to look for ability to replicate in eggs and not kill the embryos. Because increased 

pathogenicity has been observed in ferrets, CDC felt that this was very important. Once the 

agency was able to develop a safety dossier and submit that to WHO, and engaged in some 

consultation, it was agreed that these viruses were attenuated relative to their parent wild type 

viruses and that they could be used by vaccine manufacturers.

Dr. Temte inquired as to the current status on serological assays for this virus in patients, and 

what the plans were for conducting any serological surveys in the population.

Dr. Cox responded that CDC is first planning to examine what was occurring in Mexico in 

certain areas to try to determine the bottom part of the pyramid. It is known that fatal and 

severe cases are much more likely to be detected than milder cases. Therefore, CDC is 

conducting sero-surveys in partnership with its Mexican colleagues to try to determine the 

denominators as accurately as possible. They are having to use a micro neutralization assay, 

which is a difficult assay in that it is time- and labor-intensive. There is also the complicating 

factor with the pre-existing cross reactive antibody that exists in older populations. That is, the 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

215

older someone is, the more likely they are to have cross reactive antibody. Intensive work will 

be required to ensure that the proper cut off is used so that denominator is being measured 

well. Sero-surveys are also being conducted in populations in the US to better understand the 

denominators. CDC is examining serum that has been banked from blood donors to achieve a 

much finer analysis of exactly what the age break is for cross reactive antibody. While it is 

known to increase by age, CDC wants to go decade by decade to assess which epitopes cross 

reactive antibody might be reacting to. 

Dr. Meissner pointed out that one of the questions anticipated to arise with a novel H1N1 

vaccine strain will regard Guillain-Barré Syndrome (GBS), particularly if this strain retains its 

sensitivity to antiviral agents. He noticed that the phylogenetic tree included the 1976 New 

Jersey isolate, although he could not tell how much homology there might be between the 

hemagglutinin from the 1976 strain and the current strain that is circulating. With that in mind, 

he wondered if there were any thoughts on the degree of relatedness among the critical 

epitopes on the hemagglutinin molecule and what the risk might be of another association of 

GBS in this vaccine.

Dr. Cox replied that there was a great deal of difference genetically in the HA between the New 

Jersey virus and the new viruses. The average number of amino acid differs, and the 

neuromitidaise is totally different because it resulted from introduction of a different avian H1N1 

virus into swine in Europe, and then with subsequent evolution in pigs in Europe and Asia. 

There has been no identification of specific epitopes on the HA that were responsible for the 

association of GBS with the swine influenza viruses with the New Jersey vaccine. There have

been a variety of hypotheses, including one that has to do with a monitor of neuromitidaise 

activity and the amount of acid for that which might have been contained in the vaccines made 

in 1976. CDC is carefully assessing the neuromitidaise activity of these viruses compared to 

the swine New Jersey viruses, particularly given that there is not a solid hypothesis for why GBS 

was associated with the swine flu vaccine in 1976 and not with subsequent vaccines. 

Dr. Lett inquired as to whether shedding studies were being conducted in humans or whether 

the ferret studies might help to inform the exclusion period now used for H1N1. The 7-day 

exclusion period is causing a lot of disruption. People are asking whether CDC is going to 

consider changing the recommendations, especially since children recover faster.

Dr. Cox responded that shedding studies are on-going, though it will take some time for them to 

be completed. These are very important studies because it is critical to know how long people 

might be shedding and at what titers. If shedding occurs at very low levels, people may not be 

infectious. Thus, CDC is trying attempting to quantitative detection of virus. They hope to have 

this information by the fall.

Dr. Schuchat added that epidemiologic data carefully evaluate the period of transmissibility, 

which may be updated.

It was noted that the understanding from animal model studies appeared to be that the virus 

was not transmitted as easily under conditions of high temperature or high humidity. With that 

in mind, an inquiry was posed regarding whether there were unique physical or chemical 

characteristics of the novel virus.

Dr. Cox responded that what has been observed in the past when a novel influenza virus has 

been introduced into the human population were focal outbreaks during the summer months. In 

1957 and 1968, there was an introduction during the late spring / summer. Focal outbreaks 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

216

were observed then, but the epidemic did not really get going until the following fall. There 

appears to be a different pattern this year with this particular virus. It is believed that it is 

spreading in schools where there is a high density of highly susceptible individuals who are in 

very close contact with each other. The same is being observed in summer camps and other 

high density, close contact settings. In terms of activity in the population overall, it appears to 

be declining. However, CDC hears from its Mexican colleagues that activity has been 

increasing in the Yucatan where it is currently very warm. The Yucatan was relatively spared 

during the first wave of infections. CDC expected to see a seasonal factor and decrease of 

influenza activity earlier than they did. The weather has been somewhat cooler in the 

Northeast, which could have contributed. However, a consistent pattern has not been observed 

for this virus.

Kathleen Coelingh (MedImmune) requested further information about immunogenicity in 

humans. From MedImmune’s experience with the live attenuated reassortants, novel H1N1 is 

quite immunogenic in ferrets. However, she had not heard anything about how inherently 

immunogenic this particular hemagglutinin might be in humans. She noted that all of the 

manufacturers will be conducting immunogenicity tests on the human vaccines. She wondered 

what sort of assay would be feasible to measure the immune response following the vaccine. 

She also wondered whether there were any post-infection data from people infected in Mexico, 

California, or elsewhere.

Dr. Cox replied that what is observed in ferrets cannot be completely extrapolated to what will 

be observed humans. Therefore, the inherent immunogenicity of the antigens is unknown. 

CDC expects that because a large portion of the population will have been exposed to an H1N1 

virus previously in their life, the novel H1N1 vaccines may be a lot better than the H5N1 

vaccines were in terms of their immunogenicity. This will not be known for certain until the 

human studies are conducted. CDC hopes to be able to use haemagglutination-inhibition

assays, but has been using micro neutralization simply because they were trying to detect 

antibody with the most sensitive test possible. They hope in the CDC laboratory to be 

comparing haemagglutination-inhibition assays to micro neutralization assays even to a greater 

extent as they move forward. CDC will be working with partners to provide information that 

develops as time go on. Post-infection and post-vaccination data can be different. With the live 

attenuated, similar types of responses might be expected, but not enough sera have been 

tested yet for CDC to be able to say anything about inherent immunogenicity.

Vaccine Program Implementation Plans

Pascale Wortley, MD, MPH

Immunization Services Division, CDC

Dr. Wortley reported on key aspects of CDC’s implementation planning for H1N1 vaccination. 

The situation planned for in pandemic planning differs from what is occurring. CDC is looking 

forward to having larger amounts of vaccine than hoped for in the past. The illness does not 

appear to be as severe as it was in 1918. The disease that began in the US was really not the 

scenario that had typically been planned for. To top it off, there will be a confluence of seasonal 

and pandemic vaccination, which really complicates the process and was never discussed in 

terms of pandemic planning. 

Pandemic planning always includes discussions about uncertainties. Interestingly, CDC is 

potentially 3 to 4 months away from a vaccination campaign and is still faced with many 

uncertainties. This make the task highly complex for planners. CDC is still not able to tell state 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

217

planners specifically how much vaccine they can expect to have or exactly when. There is 

expected to be vaccine available from five manufacturers, not all of which make pediatric 

formulations. Therefore, issues remain about when the vaccines will come online, for what 

populations they can be used, and how that relates to priority groups. Also not known is exactly 

what the vaccine formulations will be and whether they will be adjuvanted. CDC is waiting to 

hear more about the priority groups for vaccination. It is not known whether severity of illness 

will change or remain as observed to date. One of the complicating factors from an 

implementation point of view regards the timing of the H1N1 vaccine and the seasonal vaccine 

and how those will relate to each other. That has implications for implementation. Another 

major unknown pertains to what the demand will be for these vaccines. It is understood from 

every year of seasonal vaccine implementation, demand is very difficult to anticipate and / or 

control for. The upcoming vaccination effort could be quite large. To put it into perspective, 

depending upon who the vaccine is recommended for, there could be as many as 600 million 

doses for administration, accounting for 2 doses per person. To put that into context, about 150 

million doses of pediatric vaccines are distributed annually, including Vaccines For Children 

(VFC) vaccine and private sector vaccine. There is a maximum of 115 million doses of 

seasonal influenza vaccine. It is important to keep in mind that this would be in addition to the 

doses of novel influenza vaccine, given that shipping of the other vaccines is not expected to 

cease during this period.

Another important challenge is that the public health infrastructure at the local and state levels 

has been reduced, particularly over the last year. The National Association of County and City 

Health Officials (NACCHO) conducted a survey to determine the proportion of staff and budget 

cuts in local health departments, with 27% reporting lower budgets in 2008 compared to 2007 

and 44% (n=1,079) anticipating cuts for 2009 and similar patterns expected in terms of staff 

layoffs. Local health departments are a foundation for the response to H1N1. At the state level 

there has been a considerable amount of discussion about utilizing a delivery model that blends 

vaccination in public health run clinics, which is always the model thought of traditionally in a 

pandemic setting, with delivery through the private sector. “Private sector” is meant in the 

broadest sense of the word (e.g., provider offices, workplaces, retail settings, et cetera).

Key issues involved in preparation include identifying and engaging providers (e.g., public, 

private, community). It is probably fair to say that in the past, providers probably would not have 

anticipated that they would be engaged to deliver a pandemic vaccine. Immunization programs 

naturally think of their VFC providers because those are the ones with which they have close 

relationships. Other providers need to be brought into the fold as well, which is more difficult 

because there may not be existing relationships. To determine what the capacity might be, 

conversations are underway between immunization programs and local chapters of medical 

societies to determine willingness, feasible, et cetera. Given the number of children to be 

vaccinated, consideration must be given to what gap public health must fill. There are 

numerous issues pertaining to payment mechanisms for vaccinating. Because of the 

challenges at the state and local levels in terms of running clinics, there is a need for funds to 

augment staffing either through directly augmenting local health department staff or making 

funds available to them to establish contracts with others (e.g., community vaccinators) who can 

assist in running these clinics and provide the manpower for such an effort. In addition, if 

vaccine is going to be administered through the private sector, reimbursement for administration 

needs to be addressed. Based on preliminary conversations with America’s Health Insurance 

Plans (AHIP), it appears that this will not be problematic in the provider setting. There also will 

be issues regarding uninsured children and adults.
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There are also key issues with respect to distribution, allocation, and ordering. Distribution is a 

major issue given the amount of vaccine that will need to be delivered. Two main options are 

currently being explored. One option was the basis of pandemic planning in the past, which 

was direct distribution from manufacturers or distributors to sites that are referred to as “Ship To 

Sites” that would be designated by states. At the state level, this would entail breaking down of 

packing / packages and repackaging and distributing the supply throughout the state to a 

considerable number of end users. With five manufacturers, this could become extremely 

complex. The second option is centralized distribution, which is the process used for the VFC 

program. That process has just come online in the last couple of years and is fairly new. CDC 

is in the process of exploring whether this would be feasible. Obviously, it would be a much 

better solution from the perspective of state and local planners. In either case, the end users 

have to be identified, which remains a major component of the work to be done. This harkens 

back to 2004 to allocation and ordering of vaccine. Regardless of the distribution used, public 

health will control where vaccines go. In that respect, this differs from centralized distribution 

when providers order. While public health will not physically handle the vaccine in a centralized 

distribution system, it will control distribution of vaccine to ensure that it is allocated to providers 

designated as end users based on the amount of vaccine relative to demand. Again, this is very 

difficult to predict. There will obviously be a considerable amount of complexity in creating 

systems that will allow the allocation / distribution effort to function smoothly. 

There are also inventory capacity issues. Distribution of novel H1N1 vaccine will be occurring at 

the same time as seasonal vaccine distribution. If pediatricians are receiving pre-loaded 

syringes, there are space implications that must be considered. Ordering procedures would 

differ for novel versus seasonal vaccine, which also must be addressed. It is also imperative to 

monitor doses administered. One key aspect of this is providing a denominator to be able to 

evaluate adverse events. Therefore, it will be very important at the beginning that doses 

administered are monitored and systems must be created to do this. This is currently referred 

to as Countermeasure Response Administration (CRA). If both the public and private sectors 

are to be involved in administering vaccines, stipulations will have to be placed on reporting 

because it will be critical that the doses administered be reported according to the protocols that 

have been established. Priority groups must also be respected. It is known from 2004 that this 

can be challenging in a private sector setting. Policies will have to be established to support 

physicians in being able to respect priority groups. The issue of a second dose may also have 

to be addressed. Also not clear is whether the novel vaccine will be administered under 

Emergency Use Authorization. If so, this is likely to create further complications. 

Contingency planning also poses a major difficulty. Consideration must be given to what is 

reasonable to expect with respect to private sector delivery. The situation in the fall could be 

incompatible with private sector administration. Therefore, an approach that is not dependant 

on the private sector must also be planned for. There is a basic issue of capacity. It is already 

known from previous work related to the expansion of the pediatric influenza guidelines that 

pediatric offices cannot absorb all school-aged children, so there must be alternatives for those 

children. There could potentially be a situation in which diseases are occurring at the same time 

as vaccination. Depending upon the severity of disease, there would not only be an increase of 

sick visits, but also an increase in “worried well” visits that would really make it challenging from 

a provider perspective. Plans need to be developed in such a way that they can be dialed up or 

down with involvement of public sector and private sector depending upon the situation as it 

plays out in the fall.
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Overarching issues include coordination between programs at the state level, and between 

state, local, and federal levels. At the state level in particular, this is a joint endeavor between 

immunization programs and preparedness programs, which will play out differently in different 

locations. Coordination will be especially critical in relation to communication. Messaging is 

probably going to be the most complicated ever faced. Another issue is expectation 

management. Potentially a lot of vaccine could come available at once, so consideration must 

be given to the expectation in terms of how quickly it can be administered. Undoubtedly, there 

will be variations across states related both to differences in infrastructure and differences in 

demand.

Supplemental funding is expected for accelerated planning and early implementation, which 

CDC is hoping to be able to allocate to states very quickly. The agency has formed a Vaccine 

Implementation Steering Committee with representatives from key public health partners (e.g., 

ASTHO, NACCHO, AIM, Preparedness Directors, CSTE, and NPHIC). They are also working 

with provider organizations and others. Distribution planning is a key activity, and CDC is 

working to develop scenarios to help people think through how they will establish these 

programs. Scenario planning includes permeations of disease severity, timing of disease with 

respect to timing of vaccine, and getting people to think ahead to how they would tackle different 

population groups.

Plans to Assess the Effectiveness of Seasonal and Pandemic Influenza Vaccines 2009-10 

David Shay MD, MPH

Prevention and Modeling Team

Epidemiology and Prevention Branch

Influenza Division, NCIRD, CDC

Regarding some background and assumptions, Dr. Shay reiterated that pandemic H1N1 

vaccine would be purchased by the US government. Safety and limited immunogenicity studies 

will be conducted for currently licensed vaccines before use. The adjuvanted and other nonlicensed vaccines may require Emergency Use Authorization before use. The preliminary 

estimate is that 60 million doses of monovalent H1N1 vaccine will be available for distribution as 

early as September 2009. There are initial contracts with each of the 5 large producers, which 

are for inactivated and live vaccines and bulk adjuvants. It is expected that 2 doses of 

monovalent pandemic vaccine will be offered, and that concurrently or subsequently a seasonal 

campaign will also be conducted. 

In thinking about vaccine effectiveness, consideration has to be given to whether illness is 

prevented by the pandemic vaccines, and whether clinical vaccine effectiveness differs for 

receipt of one versus two doses of vaccine and whether that varies by age, presence of 

underlying illnesses (e.g., obesity), or by vaccine type. Also important to consider is whether 

vaccine effectiveness varies by outcome measured (e.g., symptomatic illness, medically 

attended acute respiratory illness, hospitalization). Rapid vaccine effectiveness assessment will 

be required for some outcomes, and there will be a need to evaluate absolute vaccine benefits 

versus absolute risks for adverse events, particularly for rare but important events like GBS. 

CDC plans to use lab-confirmed influenza outcomes whenever feasible to improve the validity 

and comparability of vaccine effectiveness estimates. Sensitivity and particularly specificity of 

clinical outcomes is fairly low, and specificity varies by age group and during the course of an 

outbreak. Vaccine effectiveness must be estimated for pandemic H1N1 and seasonal influenza 

(e.g., H3N2). CDC plans to leverage existing platforms developed over the past five seasons 
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using lab-confirmed outcomes for seasonal vaccine effectiveness to estimate pandemic vaccine 

effectiveness as well.

Vaccine effectiveness assessment for prevention of reverse-transcription polymerase chain 

reaction (rRT-PCR) confirmed medically attended influenza is now underway in four communitybased sites (e.g., Marshfield Clinic, University of Michigan, University of Rochester, and 

Vanderbilt University; referred to as the 4 MMRV sites). In terms of vaccine effectiveness for 

prevention of influenza hospitalizations, CDC has a system in the emerging infections program 

(EIP) in 10 EIP sites in which influenza hospitalizations as diagnosed by provider-ordered 

clinically available tests are being examined. There will also be early assessments of vaccine 

effectiveness among health care workers and perhaps others at high priority for receipt of 

vaccine who may not be well-captured in the community-based studies. Some crude vaccine 

effectiveness assessments will be conducted basically by the screening method. For example, 

there was interest early on before some of the serology data were available about the 

effectiveness of receipt of 2008-09 seasonal vaccine for the novel H1N1 strain.

Community assessments cases address patients seeking medical care for acute respiratory 

illness who consent and test positive for influenza again by PCR. The comparison group is 

basically those who seek care, but test negative for flu. Vaccination data is collected by a 

variety of means according to the sites, but it depends on either self-report, electronic medical 

record, or record review. CDC has developed a system to make interim and final vaccine 

effectiveness estimates for each season. Similar methods will be used to assess vaccine 

effectiveness for outpatient outcomes for next season. 

Referring to data for 2351 subjects enrolled at the four MMRV sites during the December to 

February time frame, Dr. Shay reported that in terms of outcome of all influenza (n=319), 

vaccine effectiveness for the early part of last season was roughly 55% with a confidence 

interval of 37%-68%. Against influenza A (n=208), effectiveness was approximately 66% with a 

confidence interval of 50% to 79%. Against influenza B (n=111), effectiveness was 21% with a 

confidence interval of -31% to 53%. Vaccine effectiveness was adjusted for study site, age 

group, presence of high-risk conditions, and 2-week enrollment interval. Through supplemental 

funding, testing for rRT-PCR for influenza (including nH1N1) continues. Rochester has enrolled 

116 cases of nH1N1 through 25 June 2009, and ascertainment of vaccine status on-going. 

These cases have been predominantly in children and young adults.

In the EIP system, cases include hospitalized patients in 10 EIP sites who test positive for 

influenza by clinical tests (most either rapid antigen or immunofluorescence tests). Controls are 

age- and community-matched persons who are not hospitalized with an acute respiratory illness 

up to the date of admission of the corresponding case. Case and control interviews and 

medical record reviews are conducted. The first study of vaccine effectiveness for labconfirmed hospitalizations among young children was conducted in the 2005-06 through 2007-

08 seasons. The first study for similar outcome among older adults started during 2008-09 

season. The large catchment area is strength of EIP system, given that it permits vaccine 

effectiveness assessments for the more severe outcomes, like hospitalization, that have driven 

expanded vaccine recommendations. Studies to address other needs are also planned, such 

as those assessing vaccine effectiveness among those who receive vaccine early. 

Assessments are also planned among civilian health care workers and others who may be 

vaccinated early. CDC is going to work closely with the Department of Defense (DoD) to 

coordinate plans and methods for vaccine effectiveness studies for pandemic and seasonal 

influenza. There are expected to be special situations that may require rapid results. For 
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example, early in the nH1N1 outbreak, there was interest in whether receipt of seasonal vaccine 

was associated with protection from infection with new virus.

Investigators have been working on a rapid case cohort analysis for vaccine effectives. Cases 

were RT-PCR positive for novel H1N1, aged 18 years and older, with a vaccination history 

available in the line listing data that were collected early on in the outbreak. These are statelevel analyses that were restricted to states that had 5 or more cases with this type of 

information (e.g., Arizona, Colorado, Connecticut, Kentucky, Pennsylvania, and Virginia). 

Vaccine status in cases was compared with Behavioral Risk Factor Surveillance System 

(BRFSS) influenza vaccine coverage estimates for 2008. Those data were only available for 

individuals aged 18 and above, so that was the age restriction. The current analysis only has 

the data for 169 cases, but more data are being accrued and are adjusted for only broadly by 

age category. The vaccine effectiveness was not positive (-26%) with a very wide confidence 

interval (-78% to 11%). Certainly, there was no indication that vaccine was associated with any 

protection. These data are consistent with those from serology studies Dr. Cox presented, 

which do not suggest cross-protection with seasonal influenza antibodies.

In summary, CDC is monitoring for pandemic H1N1 at the four community-based sites that have 

been established, with plans to continue this effort. The agency hopes to expand to include 

some additional sites west of the Mississippi River; however, it is not clear whether this will be 

feasible, certainly before the fall. Larger studies using nationally reported cases are in progress. 

Several methods will be used by CDC to provide estimates of vaccine effectiveness during the 

next season for both pandemic and seasonal vaccines. It is important to keep in mind that even 

with PCR-confirmed outcomes, the number of possible circulating strains and the potential use 

of multiple vaccines are going to present challenges, particularly for rapidly assessing vaccine 

effectiveness. As an example, an 18-month child could receive up to 4 doses of influenza 

vaccines during the course of the season, and all that would have to be coordinated with the 

timing and diagnosis of influenza in that child.

Influenza Vaccine Effectiveness: DoD Approaches and Plans

COL (Ret) Jose L. Sanchez, MD, MPH

Armed Forces Health Surveillance Center (AFHSC)

Dr. Sanchez indicated that he represented the Department of Defense (DoD) Armed Forces 

Health Surveillance Center (AFHSC). He reported on the military’s past approaches for 

determining vaccine effectiveness, and what DoD’s future plans are. Some of the data 

presented by Dr. Sanchez have been published in the peer-reviewed literature, to which he 

invited those present to refer. 

The first method to which Dr. Sanchez referred was pioneered by the Armed Forces Health 

Surveillance Center in which introspective analyses were conducted of pneumonia and 

influenza and influenza-like illness (ILI) rates as well as influenza-related hospitalizations. This 

is done routinely for active duty military personnel for the last 5 years. There has been good 

catchment in terms of diagnosis, hospitalizations, and out-patient visits for these conditions. 

Thus, it is a very complete assessment that allows the military to compare vaccine effectiveness 

for both inactivated and live attenuated vaccine. The military uses both products in different 

types of active duty populations. One drawback is that the military represents a highly 

immunized group, with many seasonal vaccines being used. Therefore, the military is primed or 

seasoned. Thus, there are low levels of susceptibility. Unfortunately, the military does not have 

good vaccination and encounter data on dependents to conduct similar analyses, given that 
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many visits and hospitalizations occur for dependents out of network (e.g., outside of the 400+ 

military treatment facilities that comprise the defensive program system). Hospitalizations and 

outpatient visits were coded as ICD-9 codes for fever, cough, and sore throat, which may be 

diagnosed by the clinician with a rapid test. However, these are not PCR or culture proven 

endpoints, which must be kept in mind.

Recently published in the Journal of the American Medical Association (JAMA), DoD examined 

the period of 2004-2007. Investigators were able to demonstrate very consistently the morbidity 

reduction for trivalent and activated vaccines. That level of reduction is more aggressive for live 

attenuated influenza vaccine (LAIV) in active duty populations among non-recruits or seasoned 

individuals. When the split of the active duty population was examined between recruits (18-21 

years of age) versus non-recruits, a clear pattern was observed in which LAIV appears to be 

more effective than trivalent inactivated influenza vaccine (TIV) in recruits. Conversely, among 

non-recruits, TIV appears to be somewhat better than LAIV. Again, the caveat is that these are 

highly immunized populations and this resource may not be generalizable to the larger US 

population.

Another approach utilized by the military in the past has been screening methods to monitor 

field effectiveness in which vaccination coverage in the cases is compared to the vaccination 

coverage in the target population at large. The Air Force system is known as the Air Force 

Complete Immunization Tracking Application (AFCITA). This system has been in place for the 

last 12 years. There are a number of assumptions that have to be taken into consideration. 

The analyses that have been conducted do not include efficacy or effectiveness against novel 

H1N1 since this occurred after the April 2009 time frame after the bulk of the vaccination 

program had taken place. Another caveat is that “vaccination” is arbitrarily defined as being 

protected 14 days or more after vaccination and not protected within the first 14 days. Another 

drawback of this system is that the analysis is limited to the period of high vaccination coverage. 

Normally in the military, depending upon the branch of service, 80%-90% vaccination rates are 

not achieved in active duty until late December. Thus, to determine the effects of vaccination 

reliably, examination must be made of what occurs after December. The estimates of vaccine 

effectiveness vary considerable when a lesser proportion of the population is being immunized. 

Effectiveness by subtype can also be assessed. For the Air Force, there is confirmation by 

culture or RT-PCR and cultures, so it is possible to determine effectiveness against Influenza A 

and against which subtype.

A third approach utilized by the military for the last 6 years, which was pioneered by the Navy 

Health Research Centers, is the conduct of a program at 8 training centers throughout the US. 

This is prospective population-based fever or respiratory illness surveillance in which there is 

laboratory confirmation of cases, screening by RT-PCR and confirmation by culture. Thus, it 

permits subtype-specific vaccine effectiveness estimates. Again, this is a highly immunized 

group. Recruits are required to receive influenza vaccine upon arrival, which usually occurs 

between the periods of October through the end of the expiration date of the vaccine, which is 

usually June or July. An assumption is made that for the first 14 days of being in camp, a recruit 

is assumed to be susceptible. It is assumed that there will be enough cases of novel H1N1 to 

go into the full winter timeframe, since recruits will be vaccinated with the new vaccine as soon 

as it becomes available in about September. The data in this system can be examined by 

effectiveness against the different subtypes, and by any area of the country. Of the 8 training

centers, there are good data for 7. The 8th did not have enough data at the time of this 

presentation. 
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With regard to the future, the military intends to continue to perform population-based 

assessments of seasonal vaccine effectiveness using hospitalization data. They may be able to 

include vaccination effectiveness estimates against H1N1 vaccine if it is used next season. The 

military is also planning cost-effectiveness analyses comparing LAIV versus TIV and a new 

study among DoD beneficiaries to assess vaccine effectiveness against both seasonal and 

novel H1N1. Colleagues will continue to measure seasonal vaccine effectiveness on military 

basic trainees and could estimate what the impact is of the seasonal vaccine against novel 

H1N1 among basic trainees. The military would like to establish a multi-site tri-service 

cooperative effort to measure effectiveness and efficacy over multiple years in active duty 

children, spouse, family members, and retirees. 

There have been predictable outbreaks in clusters in both recruits and non-recruits of the novel 

H1N1. The military intends to follow study protocols on a standardized CDC approach so that 

they can compare results. The emphasis will be on young (18-30 year old) vaccinees and 

recruit to recruit in Advanced Individual Training (AIT) posts where there have also been 

outbreaks. Immunogenicity and safety can be examined for the first 8-12 weeks. Dr. Sanchez 

showed a series of 10 maps to illustrate the military clusters of novel influenza. There have 

been at least 7 shipboard outbreaks to date. There have also been outbreaks among trainees 

at Lackland Air Force Base in San Antonio, at the Naval Recruit Training Center in Great Lakes, 

and in some of the other installations in the Southeastern part of the United States. Cases have 

also been reported from Kuwait among troops deployed to Southwest Asia. The onset of those 

cases or the actual seeding of those cases occurred from two locations in the Southern US at 

Fort Bliss in Texas. There were also cases from Fort Wiley, Kansas who were deployed 

eventually to Kuwait. Apparently, many of them have started over-incubating at these two 

transition sites, which soldiers pass through before deploying to the Southwest Asia theater.

The joint DoD / CDC collaboration to supplement the new and on-going vaccine evaluation 

being performed by others mentioned earlier will include a retrospective influenza diagnosisbased case-controlled study to examine effectiveness of the MMRV approach as well as the 

consideration of prospective randomized control trial (RCT)-based trials among specific groups 

at risk such as recruits, shipboard populations, and other special groups. The military 

population is at risk, with young military personnel who have acquired this novel strain and will 

probably predictably have the same type of problems in the fall and winter. The DoD has good 

data collection and laboratory-based systems and offers a unique opportunity to conduct realtime evaluation of both seasonal and novel vaccines.

Monitoring the Safety of a Pandemic H1N1 Influenza Vaccine

Cindy Weinbaum MD, MPH

Acting Director, Immunization Safety Office

CDC, National Center for Infectious Diseases

Dr. Weinbaum reported on monitoring the safety of the pandemic H1N1 influenza vaccine, 

noting that as with the distribution methods, there are also many uncertainties about safety 

monitoring. Decisions are still pending about the full production and use of a pandemic H1N1 

flu vaccine. If the vaccine is recommended, vaccine safety monitoring will be an important 

aspect of the program. Thus, planning has already begun and in fact, began when the first case 

was identified, to implement safety monitoring if vaccination is undertaken. There is a great 

deal of uncertainty about the program, which makes planning for safety monitoring really 

challenging. There is also uncertainty about when the vaccine will become available, who the 

target groups will be for the initial use of the vaccine, and in which settings the vaccine will be 
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administered. If it is administered through the settings that are used for routine influenza 

vaccination, it will be very difficult to have adequate lot and manufacturer information for every 

vaccinated individual.

Other planning challenges for safety monitoring include the probability of concurrent use with 

seasonal influenza vaccine, so if there is any safety signal, knowing whether it is associated 

with the new seasonal flu vaccine or with the new novel flu vaccine will be difficult. There will be 

five manufacturers, so tracking which person received which manufacturer’s vaccine will be 

difficult. There will be 8 or 9 total vaccine products, including the possibility of using an 

adjuvanted vaccine, that might be used under an Emergency Use Authorization. This will 

further limit the pre-utilization data. There is the distinct possibility of limited pre-utilization data 

and particularly of limited data for some sub-populations of particular interest, which might 

include children and pregnant women. Moreover, there is an anticipated need for two doses for 

at least some individuals. That would mean that safety monitoring would have to be done not 

only after a first dose, but also after a second dose in case there is a two-dose effect, which 

would delay the ability to make any conclusive statements about the safety of this vaccine until 

the 21-day period between doses passed. One the other hand, the need for two doses also will 

provide an opportunity for a provider to see an individual who already received a dose of 

vaccine again and inquire about any adverse events that might have occurred in the interim. In 

addition to those adverse events that are being prepared for, which are adverse event that have 

been observed previously with other seasonal flu vaccines as well as the swine flu vaccine, 

there is the possibility of unanticipated adverse events that will have to be monitored for. 

There will be vaccination of a large number of people in a short time period. In a seasonal flu 

vaccination campaign, 80% to 90% of individuals who are going to be vaccinated in a given 

season are vaccinated within the first about 4 weeks after vaccination is initiated. Therefore, 

safety monitoring will have to be done very quickly and might be challenging. As noted, the 

historical experience with the 1976 swine flu vaccine makes everyone extra cautious about 

utilizing this vaccine. GBS, an acute inflammatory demyelinating polyneuropathy of unknown 

origin, was observed after vaccination was initiated in 1976 with swine flu vaccine. GBS may be 

triggered by antecedent infections and about 30% or 40% is associated with infection with 

Campylobacter jejuni, but is also seen after respiratory infections. Some recent studies have 

illustrated an association of GBS with influenza-like illness (ILI) or confirmed flu, which again will 

make monitoring for GBS even more challenging in the context of people getting the flu and 

receiving vaccine. The background incidence rate in adults is about 1 per 100,000 personyears, and is much higher in people over the age of 50. 

The 1976 vaccination program against swine flu was initiated in October of 1976 and was 

suspended in December of 1976, once preliminary data suggested an increased risk of GBS 

among vaccinees and the threat of the pandemic had passed. The current situation is 

somewhat different because, in fact, infection is on-going. Subsequent analyses of these GBS 

cases suggested an attributable risk of vaccine-related GBS among adults on the order of about 

1 case per 100,000 vaccinees. There were a total of about 500 vaccine-related GBS cases out 

of the 40 million doses that were distributed. This risk was not associated with any one of the 4 

manufacturers, and studies have been conducted to examine remaining vaccine from the 1976 

vaccine to look for the presence of Campylobacter antigens, which was one of the theories of 

this association. Campylobacter antigens were not found in the vaccine. Ganglioside 

antibodies were found to develop after vaccination with the 1976 vaccine in mice, but 

subsequent seasonal flu vaccines also induced these antibodies in mice. The answer to the 

question of why this occurred after that vaccine is still not settled, which makes it important to 

continue to monitor that. Continued monitoring has been done to look for GBS after seasonal 
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influenza vaccines. Consistent association has not been found, although with the 1992-1993 

and 1993-1994 seasons, a slight increased risk in GBS after vaccination was noted. However, 

was on the order of about 1 case per million persons vaccinated, or a much less frequent 

association.

Safety is an element every step of the way. Because the vaccine will be used in such large 

numbers, post-marketing safety monitoring is where the rare adverse events will be found. The 

objectives for post marketing safety monitoring include timely identification of clinically 

significant adverse events following vaccination, rapid assessment of the significance of these 

adverse events that are identified, and the evaluation of the risk of vaccine-associated GBS. 

Timely identification should be able to be done with enhanced surveillance through the Vaccine 

Adverse Event Reporting System (VAERS); using the active surveillance with sequential 

analytic methods through Vaccine Safety Datalink (VSD) sites; and the Defense Medical 

Surveillance System (DMSS)), as the military will be an early user of vaccine. Also, special 

studies are being planned to examine hospital admission and discharge data and surveys of 

neurologist and others.

VAERS is a volunteer reporting system that is national in scope; that is flexible in that it can 

receive reports by internet, phone, fax, and mail and can assimilate all of those reports in real 

time; and is scalable. CDC is currently working to increase the staffing of nurses, coders, and 

analysts at VAERS to meet possible need. VAERS is also designed to accept reports not only 

from providers through electronic medical records or from manufacturers, but also directly from 

vaccinees or families. VAERS is going to require some enhancements to better quickly identify 

adverse events, although VAERS has been very useful in identifying adverse events associated 

with vaccines in the past. The enhancements that are under way or that are needed include 

communications efforts to support reporting, which will have to include providing information at 

the time of vaccination. CDC is also working to figure out ways by which to facilitate reporting of 

manufacturer and lot number, and this might be by providing written record to the patient and / 

or by bar coding vials so that information can be scanned directly into a patient record.

Another way to identify possible signals for adverse events is through active surveillance using 

managed care organization as sequential analytic methods, which allows rapid assessment of 

pre-specified adverse events. CDC will be able to perform a simultaneous analysis with 

appropriate comparison groups through these methods, and chart confirmation is feasible. This 

will allow quick identification of events that are highest priority for further investigation; however, 

this will require that accurate information on vaccination be available in managed care 

databases and also that sufficient numbers of individuals are vaccinated in managed care 

systems, so that there will be sufficient numbers necessary to identify rare adverse events. 

Active surveillance also includes a number of possible collaborations inside and outside the 

federal government, some of which are established and some of which are very new for CDC. 

After these signals are identified, it will be necessary to assess the significance of adverse 

events. Certain pre-specified adverse events can be assessed through a sequential analytic 

approach. A list has already been developed based on experience with prior flu vaccines, the 

1976 vaccine, and biological plausibility of adverse events that CDC would like to monitor. 

Background rates are currently being collected so that CDC will know as quickly as possible 

whether the rates being observed exceed background rates. As noted, CDC also anticipates 

that there will be other adverse events that have not been pre-specified. These will need rapid 

study utilizing linked immunization and outcome records. The agency expects to do a 

comparison of observed cases with expected cases based on known incidence rates and is 
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prepared to conduct field investigation in collaboration with state health departments if 

necessary.

The third prong in CDC’s strategy involves evaluating the risk of GBS associated with the 

pandemic flu vaccine. Of course, there is no particular reason to think that this should be 

associated. They are not very homologous, but CDC is planning to engage in active case 

finding of incident GBS cases in multiple areas. Ascertainment of vaccination status and other 

risk factors for GBS will be done when a case found. This is expected to be done using the 

assistance of the Emerging Infections Programs and state and local health departments. CDC 

is trying to enlist the assistance of the American Academy of Neurology (AAN) to created a 

listed surveillance with neurologists for GBS.

There remain unresolved issues regarding safety monitoring. The role of the VSD sites in 

vaccine administration under state and local plans is important, given that only if sufficient 

numbers of people under surveillance are vaccinated will a definitive association or lack thereof 

with possible adverse events be permitted. CDC is also still working on how to facilitate 

collection of accurate information on manufacturer and lot number after vaccination.

In summary, the established surveillance systems (e.g., VAERS, VSD, military) are going to be 

utilized and enhancements are planned for all of these systems. There are new collaborations 

being developed and that need to be developed so that CDC can extend the number of 

individuals under surveillance for adverse events. There is a need to consider vaccine safety 

monitoring when planning vaccine distribution in terms of tracking, manufacturer dose, and who 

is vaccinated. Vaccine-related risks will eventually need to be assessed in light of the severity 

of the pandemic. If the pandemic is wide spread and severe, the threshold for accepting mild 

vaccine associated risks will be much higher than if the pandemic is not as bad as predicted and 

the risks associated with vaccine are significant. 

Discussion 

With 5 manufacturers producing vaccine, Dr. Morse inquired as to whether consideration had 

been given to trying to stratify allocations geographically by region, state, and manufacturer to 

make it easier to track administration, monitor adverse effects, minimize changes in product 

between first and second dose, optimize data from the VSD system, et cetera.

Dr. Wortley responded that the thinking in the past has always been the opposite of that for risk 

management to distribute every manufacturer’s vaccine across the country. The thinking was 

that if certain states were assigned to certain manufacturers and there was a glitch, there would 

be a major problem. However, she thought Dr. Morse’s suggestions should be considered in 

terms of pros and cons.

Regarding the infrastructure of the plan to deliver vaccine, Dr. Sawyer indicated that his local 

health department, as had many others, experienced significant cuts in the last year. With that 

in mind, he requested further details pertaining to the magnitude of supplemental funding CDC 

was trying to obtain to build back up the infrastructure not only to deliver novel H1N1 vaccine, 

but also to assist in all other efforts including monitoring for safety. He also requested further 

information about potential provider administration fees, particularly for providers not actively 

engaged in government sponsored health care. 
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Dr. Wortley deferred the first question to Dr. Schuchat, given that there were some issues still in 

flux. With respect to the second question, CDC envisions that vaccine that would be delivered 

in a provider’s office and the provider would actually bill either Medicaid or private insurers just 

as if it were a regular vaccination. Preliminary conversations with America’s Health Insurance 

Plans (AHIP) have indicated that insurers will likely cover this vaccine. Interestingly, even under 

Emergency Use Authorization, CDC initially thought this might be a problem. What may be 

trickier, just as it is for seasonal vaccine, is being vaccinated at a local pharmacy or other venue 

outside the practitioner’s office. There are issues regarding contracts that exist between those 

entities and the health plans. In the doctor’s office, one thing that will vary just like it would for 

any other vaccine is the state-to-state variation in Medicaid rates.

Dr. Schuchat added that CDC, the administration, and Congress are well aware of the fiscal 

challenges that states have in terms of the public health infrastructure. Congress passed a 

supplemental war bill and a contingency bill that would include additional funds. The 

administration is in discussions with Office of Management and Budget (OMB). The lack of 

ability to engage in this kind of vaccination program without additional support is wellrecognized, and the magnitude of support is likely going to vary depending on the size of the 

program.

Dr. Neuzil stressed that it is certainly one goal of this program to get vaccine out and lessen 

morbidity and mortality from the pandemic virus. It is also important for this program to be 

strengthened such that it will not undermine the seasonal vaccination program in general. She 

agreed that safety surveillance is really critically important, noting that there are a number of 

lessons other than GBS from the 1976 swine flu having to do with temporally but not causally 

related events (e.g., the cluster of deaths that occurred in Pittsburgh during the 1976 influenza 

campaign). At some point, ACIP would like to hear about the detailed communication plans that 

will go along with risk management. Speaking to Dr. Sanchez, she said she was really quite 

impressed with the system that has been built and expressed her hope that they could capitalize 

on that for innovative safety assessments.

Dr. Marcy agreed that the 1976 GBS vaccine relationship was a cautionary tale about how real 

or perceived adverse events can affect an entire immunization program. It seemed to him that 

notably absent was the role of the Clinical Immunization Safety Assessment (CISA) network. It 

seems very important to specify and accurately delineate an adverse event and prevent what 

could be a mining of VAERS by the media. The media is just waiting to find something that is 

going to appear. If “it bleeds, it leads” and when it leads, it leads all over the country in the 

news. 

Dr. Weinbaum responded that CDC anticipates CISA’s involvement in reviewing adverse events 

reported to VAERS. There will be a major need to assure that any signal that comes up in 

VAERS is validated by record of use of that individual and on a population basis through the 

VSD managed care organization data. In terms of the question about communicating, the 

media, and damage control, CDC will do its best to make sure that they are aware of all signals 

and that they follow them up appropriately.

Dr. Schuchat elaborated that hopefully people are aware of how high a priority CDC gives to 

communication and to the H1N1 response to date. It has been among the agency’s highest 

priorities to support state and local health departments, as well as the media, to get good 

information to people quickly. During this panel, several components of vaccination planning 

were presented, although the Communication Team did not present. This team includes a 
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number of experts in this area. The agency views communications as critical, both for 

vaccination planning and the entire response in terms of what the country will continue to go 

through over the summer and in the fall. They will be happy to share communications plans the 

committee in the future. These plans are much more extensive than just vaccine safety risk 

management. There are also issues of supply, demand, flow, early deaths, et cetera. Focus 

groups have been initiated, and extensive plan are in place to get good information to people, 

when they need it, where they need it, and in as open and transparent a manner as possible.

Dr. Temte stressed that the potential safety issues could not be over-emphasized. There is a 

potential perfect storm of very rapid development and deployment of a new vaccine, over an 

incredibly wide target, in a medical care system that is terribly broken and very disparate. He 

had an experience with a gentleman who received travel vaccines from a travel clinic, who was 

later seen by a neurologist. Two months later, it was Dr. Temte who finally decided look into 

this and file a VAERS report because nobody else thought it was their duty. He was concerned 

that if they looked at only one group (e.g., neurologists), signals may be overlooked if they are 

not neurological. There must be a wider approach and the VAERS system needs to be more 

user-friendly. No one has the 45 minutes it takes to enter information into this system. 

With respect to improvements, Dr. Weinbaum indicated that a new web interface for VAERS is 

due to be rolled out in September, which is intended to facilitate web-based reporting for 

VAERS. Some of the communications campaigns planned pertain to soliciting and increasing 

reporting to VAERS. Hopefully, through a combination of publicizing VAERS and making it 

easier to utilize for reporting, the amount of reporting that actually occurs will be enhanced.

Dr. Ehresmann noted that Minnesota uses a system that was developed in Wisconsin as do a 

number of other states. She wondered if there was a key constellation of information that CDC 

wanted to collect to have real time data on vaccine adverse events.

Dr. Weinbaum responded that using those information systems has not been a core part of the 

Immunization Safety Office’s (ISO) planning. The VSDs have 9.2 million people in managed 

care, and they have a vaccine registry that is linked with their electronic health record data. 

CDC is definitely planning to use those. Based on the discussions during this meeting with 

respect to the possibility of using other immunization information systems, ISO needs to pursue 

and flesh that out. Others in the Immunization Services Division may have worked on this more 

than ISO has.

Dr. Schuchat added that the primary way in which immunization information systems have been 

considered in terms of denominator information was with the thought that adverse events would 

be presented elsewhere. However, if there are places in which electronic health records have 

been linked with severe adverse event registries, this would be worth exploring.

Dr. Chilton noted that several weeks ago, Secretary Sebelius and Education Secretary Duncan 

sent a letter to school superintendents about schools’ involvement in an effort this fall. He did 

not hear anything in the presentations about the place of school immunization.

Dr. Wortley replied that if school aged children were at the front of the line for vaccine, schools 

will have to be considered as potential vaccination venues. There are various ways of doing 

that, either according to the model for seasonal flu in which vaccination occurs during school 

hours, or through clinics held at schools. Schools are familiar locations and using them would 

alleviate some of the complexities pertaining to collecting consent in advance, which is a 
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challenging issue with regard to school-based vaccination. CDC is in the process of working 

with the Department of Education, with CDC staff planning to attend a joint meeting organized 

by the Department of Adolescent and School Health (DASH) and NACCHO. Many partners 

were also expected to attend from educational-related organizations. This meeting was 

expected to offer a good chance to hear about concerns, which CDC could think about as they 

prepared guidance for vaccinations related to school-aged children.

Regarding the recruitment of private providers to administer vaccine, Dr. Birkhead (NVAC) 

requested further information about the comment that there have been discussions with AHIP 

which suggested that reimbursement should not be a problem. NVAC’s Finance Working Group 

issued a report last September illustrating problems with such reimbursement. New York has 

tried to explore how managed care reimbursement occurs for vaccine administration, finding 

that this is a “black box.” New York negotiated provider-by-provider in terms of how payment 

would occur. Reimbursement for administration of vaccines ranged from $2 to $20. In some 

practices, there was not a specific reimbursement amount, given that it was basically included in 

the per capita payments that were made to the provider for those patients. If they really were 

trying to encourage providers to take on the role of vaccinating, telling them that two additional 

vaccines would be required in their existing rate would do little toward convincing providers to 

sign on. The complicating factor is that providers typically have arrangements with multiple 

plans, so they do not know exactly what reimbursement they are going to get. There seems to 

be a role for CDC and AHIP to communicate affirmatively with plans in the US about this 

problem. There needs to be transparency in how the reimbursement is going occur if providers 

are actually going to sign on. CDC and CMS need to drive home the issue that providers are 

simply not going to volunteer their time for no payment. There have been many reports of 

Tamiflu not being covered by plans, which highlights the issue that as many plans as there are, 

there are that many different arrangements for how payment occurs. There is not unified and 

does not instill confidence that there will be widespread recruitment of the private sector. 

Dr. Wortley agreed, clarifying that what she intended to convey was that in preliminary 

conversations, CDC has been told that the insurance industry intends to support this. However, 

it is not a uniform industry and it is incredibly complicated to work within, particularly given that 

there are many insurance plans and products. CDC intends to tackle these issues and is 

forming a group to focus just on this issue.

Steve Foster (APhA) said he thought they were underestimating the ability / willingness of 

patients to pay for their own medication. Many times patients present at pharmacies whose 

plans will not cover what they take, yet many of them are willing to pay themselves. During the 

vaccine shortage a few years ago, people were walking in and they did not care that they had to 

pay themselves as long as they could obtain their vaccine. Other potential groups / venues to 

consider for distribution include colleges of pharmacy, colleges of medicine, and the vast 

number of students who are willing to help. Perhaps this could be coordinated through health 

departments. 

Sandra Fryhofer (ACP) said she was convinced that there would be a vaccine for H1N1 virus in 

the fall, and that she was impressed with the plans to evaluate vaccine safety and effectiveness. 

However, she remained concerned about distribution even though McKesson is a large 

company that is used to distribution. She also remained concerned about getting people 

vaccinated. While ideally it would be prudent to administer seasonal influenza vaccine as soon 

as possible, the reality is that this does not always occur. She stressed the importance of 

making both seasonal and novel vaccine available to patients, who already have limited time to 
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obtain their vaccines (e.g., time off from work, et cetera). Also of concern is that during these 

economic times, patients may not be as willing or able to pay for vaccines themselves. It is 

highly likely that an increasing number of patients will not have health plans; therefore, 

consideration should be given to how these vaccines might be acquired at cheaper prices.

Dr. Santoli indicated that she works in the branch within the National Center for Immunization 

and Respiratory Diseases (NCIRD) that supports the current contract with McKesson for 

distribution, under which half of the childhood vaccine in the US is distributed, including 

seasonal vaccine. On the public side, that is a relatively small amount of seasonal influenza 

vaccine. Given that after three years, this system for distribution can meet the needs of many 

providers, it seemed to be a good place to start. One of the thoughts when the system was 

created was to determine whether this might be a way to assist in response to emergencies. 

Clearly, the magnitude of novel influenza vaccine to be distributed and the time frame absolutely 

dwarf what occurs every year. CDC approached McKesson because they are a much larger 

distributor than the group CDC works with, and because CDC has a system that they know can 

work. McKesson has been given all of the assumptions and is aware of the very uncomfortable 

uncertainty of going from 0 doses to 600 million. With this information, they have been asked to 

consider what they can leverage within their own company and what they might leverage 

through partnerships with other distributors. She expects McKesson to develop a plan that will 

work. 

Sandra Fryhofer (ACP) encouraged the agency to have a Plan B in place. “Putting all eggs in 

one basket” could result in a scenario similar to what occurred a couple of years ago when there 

was only one company producing influenza vaccine.

Harry Keyseling suggested reviewing the oral polio community campaigns as a model for 

community campaigns, stressing that they should not underestimate the opportunity to ask 

healthcare professionals to volunteer. 

William Schaffner (NFID) pointed out that a major stumbling block in 1976 was liability 

coverage, which he had not heard mentioned.

Geoffrey Evans (HRSA) responded that legislation was passed in 2005 known as the Public 

Readiness and Emergency Preparedness (PREP) Act, which sets up liability protection for 

makers of covered countermeasures as declared by the Secretary of Health and Human 

Services (HHS). The pandemic H1N1 vaccine and Relenza and Tamiflu have been declared 

covered under this authority. Funding has recently been authorized to put into effect the 

compensation elements of this act, which would be an administrative program modeled after the 

Smallpox Vaccine Injury Compensation Program. The Health Resources and Services 

Administration (HRSA) has the responsibility for administering and putting that into effect. This 

is all very embryonic at this point.

William Schaffner (NFID) thought there needed to be some discussion about seasonal influenza 

administration and its timing. He wondered whether the manufacturers were going to have an 

opportunity to indicate how much seasonal vaccine they have and when they plan to begin 

shipping.

Geoffrey Evans (HRSA) suggested that if possible, it would be beneficial to have a separation of 

the seasonal program from the H1N1 supply and distribution to clarify safety.
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With respect to nomenclature, Patsy Stinchfield (NAPNAP) pointed out that numerous terms 

were being utilized to describe novel influenza (e.g., swine flu, H1N1 influenza, novel influenza, 

pandemic H1N1, pandemic virus) and soon that would be overlaid that with “seasonal H1” and 

pick your “N1 combination.” With that in mind, she thought it was time to move to something 

broader, such as “2009 pandemic influenza” perhaps shortened to “pan flu.” This is going to 

affect public communication and media messages. The media is already stumbling over H1N1 

and what that really means. It is going to be very difficult to separate the various vaccines, 

particularly if people are presenting four times in one season. Even the manufacturers’ labeling 

of those vaccines for medication errors and safety issues will be affected by nomenclature. 

Dr. Schuchat agreed with the priority of clear communications. There is mixed information 

currently about what people understand and what messages will be the clearest. 

As the co-chair for the National Influenza Vaccine Summit, Litjen Tan (AMA) reported that 

CDC’s Communications Team would be presenting during the Summit’s H1N1 session. The 

goal of the Summit is unification of messages pertaining to influenza. The Summit is seeking 

guidance from everybody in terms of messages (e.g., community immunizers, distributors, 

manufacturers, et cetera). 

Kelly Moore (Tennessee Immunization Program urged the committee and others to reflect on 

the debacle of 2004. Many of the suggestions currently being discussed were attempted then, 

with many challenging logistical issues that resulted ultimately with only 60 million doses being 

distributed and millions of doses unused despite best efforts to get it to the right people. Her 

department is much less capable of administering vaccine now than it was then because of 

personnel cuts. Therefore, she stressed that they could not permit distribution and trying to 

manage the product too carefully get in the way of actually administering the vaccine. States 

must get out of the way. When her state dictated where vaccine was to be distributed, vaccine 

shipments were delayed dramatically. Nursing homes were waiting a month after they placed 

their orders through the state. 

Dr. Santoli responded that there was centralized distribution in 2004-2005 that was drastically 

different from the current system, in that there were 12-15 distributors. The effort was to 

attempt to share equitably among planners to distribute flu vaccine. There was no coordination 

among them, and there was not a good method for getting information back from them. That 

quasi-centralized distribution was invented during the shortage. There is, indeed, a lot to learn 

from that experience. The discussion about centralized distribution is drastically different from 

what occurred in 2004-2005.

Regarding the cross strain effectiveness of A/BRISBANE/59/07, Robert Malone (Focus 

Diagnostics) said he assumed that with respect to the aggregated analysis across all vaccines, 

the database is not large enough to support a break out of TIV versus live attenuated in terms of 

the T-cell component to potential protection.

Dr. Shay responded that most of the vaccine that is still distributed in the US is TIV. In the 

analysis done so far, conclusions can probably only be drawn about TIV. That will probably be 

true for the data received from community-based sites as well. 

Robert Malone (Focus Diagnostics) thought it would be very useful to actively capture data 

relating to potential effectiveness of the live attenuated vaccine.
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Dr. Lett agreed that states needed to be taken out of the way to a certain extent to allow the 

vaccine to get to the private sector. In her state alone there are probably 20,000 private 

providers who are not enrolled in a VFC program. She thought every state was probably in a 

similar situation. While states may need to have some control over public clinics and 

emergency dispensing sites, it is imperative to widely disseminate this vaccine. With that in 

mind, perhaps CDC needs to think about other contracts with other distributors such that 

shipping can occur directly from the manufacturers to the private sector.

Dr. Wortley replied that potentially the system could evolve into this; however, the unknown at 

this point is that it is not entirely clear how much vaccine there will be in the beginning. Because 

vaccine must be allocated across the country, the system must be flexible.

Dr. Santoli added that the discussions so far have pertained to states controlling what occurs in 

the beginning, using a centralized distributor. Consideration must be given to how to 

subsequently transition from state control to non-state control. That has yet to be mapped out, 

but should probably be taken under advisement with the group of states CDC converse with on 

a regular basis regarding planning.

Summary of Issues / Next Steps

Anthony Fiore, MD, MPH

Influenza Division, NCIRD, CDC

Dr. Fiore summarized that in terms of the epidemiology and virology, circulation of novel H1N1 

continues in the US, although it appears to be declining. Morbidity has largely been among 

younger adults and children. It is believed that a large proportion, and perhaps virtually all of 

the younger population, is susceptible and co-circulation of both seasonal and pandemic viruses 

is expected. Therefore, plans need to be in place for co-circulation. Vaccine development 

appears to be proceeding as planned. The timelines for availability and the supply are not 

certain and depend upon yet unknown production constraints and formulations that are 

ultimately chosen. However, the initial vaccines are likely to be similar to seasonal vaccine 

formulations and not adjuvanted, depending upon immunogenicity studies. In terms of 

implementation goes, planning has been done for near simultaneous seasonal and H1N1 

vaccine programs. Communication is expected to be a major challenge, and perhaps a new 

session will be needed on that during the next ACIP meeting. The uncertainties about 

availability, formulation, program scale, and demand continue to make planning challenging. 

Assessment plans are in place, including vaccine effectiveness and safety plans.

In terms of early use of seasonal vaccine, current ACIP guidelines indicate that use can begin 

when vaccine is available and that this will provide protection even when there is early 

circulation of influenza viruses. There is no evidence for clinically important waning immunity 

among those vaccinated in late summer and early fall. Early vaccination will reduce overlap 

between pandemic and seasonal vaccine campaigns. Manufacturers estimate that there will be 

approximately 120 million doses for the upcoming season. There might be as many as 15 

million doses available by mid-August, 40 million by September 1, and over 90% of doses 

shipped by November 1. This offers a great opportunity to plan on early vaccination using 

seasonal vaccine, perhaps earlier than the usual planning that occurs in October and 

November. Early availability of vaccines includes both preservative-free vaccines and infant 

and toddler doses, which will be important especially since a lot of those have to be given twice 

in a season. 
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ACIP’s role in the next few months includes the usual role of epidemiologic data review; review 

of vaccine studies; and review of program plans. It appears that ACIP has a major role in 

developing and reviewing the plans for vaccination targeting, and will be working to re-assess 

the vaccine prioritization plans that were made as part of pandemic planning over the past 

couple of years. Certainly, ACIP suggestions are welcome about ways to reduce impact on 

seasonal vaccination program. The current ACIP guidance is a start toward that. ACIP and the 

vaccine workgroup will begin development of guidance for pandemic influenza vaccine use as 

more is known about what that vaccine will look like. It is likely that there will be a need for an 

off-cycle meeting prior to the standing October meeting, perhaps in July or August.

Pneumococcal Vaccine Work Group

S. Michael Marcy, MD

Clinical Professor of Pediatrics

UCLA Center for Vaccine Research

Harbor-UCLA Medical Center

Dr. Marcy reported that in 1919, Abrahams, Hallows, and French described a condition which 

began with relatively mild flu-like illness, but rapidly progressed to a purulent bronchitis and then 

what they called influenza pneumonic septicaemia [Abrahams A, Hallows N, French H. A further 

investigation into influenza pneumococcal and influenza-streptococcal septicaemia: epidemic 

influenzal “pneumonia” of highly fatal type and its relation to “purulent bronchitis.” Lancet 1919; 

1: 1–11]. They drew three faces (red, white, and blue), the first of which they described as “An 

early case in which the facial colour is frankly red, and the patient might not appear ill were it not 

for the drooping of the upper eye-lids and a half-closed appearance to the eyes.” They 

explained that this could progress to “Cyanosis in which the colour of the lips and ears arrests 

attention in contrast to the relative pallor of the face. The patient may yet live for twelve hours 

or more.” This was followed by “The heliotrope cyanosis. The patient is not in physical 

distress, but the prognosis is almost hopeless.” This was their recognition of the fact that 

secondary bacterial infection is a common problem with influenza respiratory disease, 

particularly lower respiratory disease. 

The pathophysiology of influenza with secondary bacterial infection is better understood today 

as Brundage has illustrated and as Morens indicated in his paper in 2008. Secondary bacterial 

infection, particularly with pneumococcus, is an important aspect of the morbidity and mortality 

of influenza illness. It is understood that influenza infection alone may cause serious, indeed 

fatal, pulmonary illness and that pneumococcal illness alone can do so as well, but the two 

together create “a perfect storm.” Indeed, when the two come together, the influenza 

predisposes patients to pneumococcal infection by destroying / damaging physical barriers, 

increasing adherence (NA medicated), decreasing mucociliary activity, immune cell dysfunction, 

immune system disregulation, and upregulated gene expression (toxins) [Brundage J F: 

Interactions between influenza and bacterial respiratory pathogens. Implications for pandemic 

preparedness. Lancet Infect Dis 2006; 6: 303-12; Morens D M, et al: Predominant role of 

bacterial pneumonia as a cause of death in pandemic influenza. Implications for pandemic 

influenza preparedness. J Infect Dis 2008; 198: 962-970].

Pneumococcal Vaccines
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With that background in mind, the pneumococcal vaccine working group approached the 

problem of how pneumococcal vaccine should be integrated into the program of novel H1N1 

vaccine. The group recognized that influenza plus pneumococcus yields pneumonia in many 

cases, but it also results in a fairly significant fatality rate when the two are present in large 

numbers. The working group discussed the epidemiology of novel H1N1; evidence of 

secondary bacterial infections; vaccine safety, effectiveness, and cost-effectiveness; vaccine 

supply and allocation; distribution and control; and implementation of new recommendations. 

Taking somewhat of a turn, the group also discussed the role of immunization; antivirals; 

antimicrobials; and the supply of antivirals and antimicrobials. Dr. Marcy reminded everyone 

how Cipro disappeared off of every pharmacist’s shelf during the anthrax scare and became 

virtually impossible to obtain. Thus, there is a potential for antimicrobials and antibacterial 

agents to be a problem that will have to be dealt with during the upcoming possible pandemic. 

The group also deliberated the 13-valent pneumococcal conjugate vaccine (PCV13), which may 

be available sometime in September to October in time for inclusion in the program for the 

H1N1 vaccine program, in terms of serotype specific pneumococcal disease, potential 

expanded prevention that this vaccine may offer, and options for catch up immunization. The 

group also discussed the status of the investigational 13-valent pneumococcal conjugate 

vaccine and the public health and economic impact of PCV13 (e.g., direct and indirect benefits; 

routine immunization in children ages 1 through 5 years; and catch-up program for children <5 

years old). 

Planning for Use of 23-Valent Pneumococcal Polysaccharide Vaccine (PPV23) to 

Prevent Pandemic Influenza A (H1N1)-Associated Pneumococcal Pneumonia

Matthew R. Moore, MD, MPH

Commander, USPHS

Dr. Moore first offered a recap of the February 2009 ACIP meeting with respect to policy options 

considered by the ACIP Pneumococcal Vaccines Working Group. He stressed that they were in 

a very different place in terms of thinking about pandemic influenza preparedness then. At that 

time, three potential policy options were discussed: 

• Assuming that a pandemic will occur in the near future, expand current 

recommendations for use of PPV23 as soon as possible

– Unclear target groups, unclear benefit

– Programmatic challenges to expanding target groups

– Concerns about re-vaccination and hyporesponsiveness

• Encourage implementation of current recommendations 

(http://www.pandemicflu.gov/vaccine/pneumococcal.html)

• Administer PPV23 to critical infrastructure personnel targeted for pre-pandemic influenza 

vaccine when a pandemic is declared

– Relatively young, healthy population likely to respond to PPV23

– Programmatic efficiency with pre-pandemic influenza vaccine

– Fulfills planning objective of maintaining critical response functions

Option 1 is no longer an option, Option 2 is still very much an option, and Option 3 needs to be 

modified because currently consideration would be given to administering PPV 23 to critical 

infrastructure personnel very soon and would need to think about whether there is a way to do 

that without disrupting distribution and administration of seasonal and pandemic influenza 
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vaccine. In choosing from among the options, the working group considered the epidemiology 

of pandemic H1N1 infection, including bacterial complications; safety, effectiveness, and costeffectiveness of PPV23 in persons with pandemic H1N1 infection; supply of PPV23 and 

prioritization among potential new groups targeted for vaccination; and implementation of any 

new recommendations. 

In terms of the evidence of bacterial infections among hospitalized cases of H1N1, a Morbidity 

and Mortality Weekly Report (MMWR) was published several weeks ago from California in 

which they described their first 30 cases of confirmed or probable novel H1N1 individuals who 

were hospitalized for at least 24 hours between late April and mid-May. These data are very 

consistent with Dr. Finelli described the previous day in her presentation of data on hospitalized 

cases. Most notable is that of the 30 cases, none had any evidence of bacterial infection. 

However, since the publication of that MMWR, CDC became aware of a 45 year old male who 

was found dead in his home. He was obese and had cardiovascular disease and sleep apnea. 

At autopsy, his lungs showed heavy consolidation consistent with bacterial pneumonia. The 

tissue specimens from his lungs were positive for novel H1N1, S. pneumoniae, and group C 

streptococcus. Soon after this initial publication came out, California became aware of a fatal 

case associated with secondary bacterial infection [MMWR 2009; 58(19):536-541; Personal 

communication, Dr. J. Louie, California Dept. of Public Health].

In terms of the epidemiology of the pandemic H1N1-associated hospitalizations, 142 (71%) of 

201 hospitalized cases of confirmed novel H1N1 infection had >1 risk factor for influenza-related 

complications (e.g., chronic lung / cardiovascular disease, diabetes, immunocompromised, 

smoking, chronic renal disease). Conversely, among the 59 patients with no underlying 

conditions, 20 were healthy children <5 years old. This is a group who would not normally be 

thought of in terms of administering PPV23, but is currently receiving the 7-valent 

pneumococcal conjugate vaccine (PCV7), and if and when it becomes available would receive 

the 13-valent conjugate vaccine (PCV13). Among the same cohort of hospitalized cases, about 

1/3 had abnormal chest x-ray findings consistent with pneumonia, about 2/3 of those had bilateral infiltrates and 2/3 had at least one underlying medical condition. The median age was 

about 24 years. At least from this cohort, it appears as though most patients who are admitted 

to the hospital had existing indications for PPV23 vaccine, and among those who are diagnosed 

with pneumonia upon admission, most also had indications for PPV23 vaccine. 

From this same cohort, there was evidence of bacterial infections among the non-fatal 

hospitalized cases in two instances (n=184). Within this group, a 23 month old male with 

empyema had a pleural biopsy performed and group A streptococcus was identified by 

immunohistochemistry (IHC) and by molecular assays. Also included in this group was a 58 

year old female who was previously healthy, had chest x-ray confirmed pneumonia and 

streptococcus pneumonia grown from culture collected at the time of a bronchoalveolar lavage

(BAL). When CDC first began hearing about these kinds of cases, it occurred to them that 

these are fairly invasive procedures and are not the most common way to diagnose 

pneumococcal pneumonia or even bacterial pneumonia. The situation is evolving very rapidly. 

The age range of these cases is broad. These are fatal cases with evidence of bacterial 

infections, and they range from a couple of months old to about 57 years of age. The duration 

of illness is on the order of between 1 day and about 9 days. A large proportion of these 

patients had underlying conditions, but not all of them. Roughly 1/3 of them had no known 

underlying condition as far as is known; however, this information is evolving and could change. 

The autopsy cases were diagnosed largely by IHC. 
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The working group also discussed the safety, effectiveness, and cost-effectiveness of 

polysaccharide vaccine in persons with pandemic H1N1 infection. From a safety standpoint, it 

is known that polysaccharide vaccine is safe when it is co-administered with seasonal influenza 

vaccine; therefore, it is assumed that it would be safe when administered with pandemic H1N1 

vaccine. Obviously, this will remain unknown for certain until the vaccine is available. 

Effectiveness, as discussed at length during the February 2009 ACIP meeting, depends upon 

the age of the person receiving the vaccine and whether they have any co-morbidities. From 

the standpoint of cost-effectiveness, also discussed at length in February, there was some 

agreement that most scenarios suggested that polysaccharide vaccine would be cost-effective 

under a wide range of assumptions. A key driver of the cost-effectiveness was the 

effectiveness of pre-pandemic H1N1 vaccine, which may be important moving forward in the 

discussions about polysaccharide vaccine.

In terms of vaccine supply issues, one way to think about supply is in terms of how many people 

in the country are currently unvaccinated but who have existing ACIP indications to receive the 

vaccine: 30 million individuals who smoke in the US, 21.6 million individuals who are between 

the ages of 2 and 64 years who have underlying illnesses that increase the risk of 

pneumococcal disease, 14.7 million individuals who are 65 years of age and over, and 3.4 

million individuals who have asthma. That is, it is currently estimated that there are about 70 

million people in the US who have indications for polysaccharide vaccine but have not been 

vaccinated.

If the recommendations were expanded to include additional groups outside of those listed, 

consideration must be given to who those groups might be and how many individuals this would 

include. One way to look at this is to consider the “Draft Strategy and Guidance for PrePandemic Influenza Vaccination,” which is related to but different from the prioritization scheme 

discussed the previous day. Approximately 8.1 million persons are included in “Tier 1” of the 

“Draft Strategy and Guidance for Pre-Pandemic Influenza Vaccination.” Of these, 3.2 million 

are front-line hospital-based healthcare providers (HCP) and 2.3 million are front-line outpatient 

HCP. The working group considered whether HCP should receive PPV23 to minimize time off 

from work. It would be a good idea to keep healthcare workers on the job as much as possible 

and perhaps, the administration of polysaccharide vaccine would be a good way to approach 

that.

Then the obvious next question regards whether there is evidence of bacterial complications of 

pandemic H1N1 infection among healthcare personnel. The following is the first paragraph of a 

recently published MMWR on novel influenza infections among healthcare personnel in the US:

 
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237

 MMWR 2009;58(23):641-645

The bottom line for the purposes of this discussion was that at this point, there is no evidence of 

increased risk of pandemic H1N1 infection among healthcare personnel. That is not to say that 

there have not been any infections. There clearly have been. It is just not clear that healthcare 

workers are at increased risk compared to the general population. There is also no evidence of 

increased risk of bacterial complications among healthcare personnel who have pandemic 

H1N1 infection. 

Returning to the policy options and thinking about the advantages and disadvantages, Policy 

Option 1 was simply to encourage the implementation of the existing ACIP recommendations. 

The advantages of that option are that these are groups are already known to be at increased 

risk of pneumococcal disease; administering vaccine now may provide additional benefit to 

those individuals in the context of the pandemic; and it is an opportunity to increase coverage in 

a group that has relatively low coverage at this time. The disadvantages are that historically it 

has been very difficult to increase coverage among that group, which will be even more difficult 

in time when resources are stretched; and there is inconsistent evidence of effectiveness 

against pneumococcal pneumonia among persons with co-morbidities.

Policy Option 2 regards administering polysaccharide vaccine to critical infrastructure personnel 

(e.g., healthcare personnel). This has several advantages including the potential to keep 

healthcare personnel on the job during a fall wave or perhaps even during the summer if the 

epidemiology continues; these are largely healthy individuals who would be expected to 

respond well to the vaccine; and there is some evidence of cost-effectiveness, especially in the 

absence of other interventions. Relatively speaking, implementation in healthcare workers may 

be somewhat easier than implementation in other groups. The disadvantages are that there is 

currently no evidence of increased risk of pandemic H1N1 or associated complications among 

healthcare personnel; there is the issue of hypo-responsiveness; despite this group being 

relatively easier to reach than other groups, it would still be challenging to administer 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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polysaccharide vaccine to this group given the likely need for 2 doses of pandemic H1N1 

vaccine and 1 dose of seasonal influenza vaccine; and this could divert the supply from other 

individuals who they have been trying to reach for many years.

The conclusions of the working group were that the current epidemiology does not suggest a 

need for expansion of polysaccharide vaccine recommendations to include these additional 

target groups; healthcare personnel may be a logical group for expanded recommendations if 

the epidemiology of pandemic H1N1 suggests an increased risk of pneumococcal pneumonia; 

existing recommendations should be reiterated for use of the vaccine among persons known to 

be at increased risk of pneumococcal disease; monitoring of the epidemiology of the pandemic 

(including bacterial complications) should be continued moving forward through summer and 

into the fall. The issues should be revisited as additional information becomes available.

Acting on the advice of the working group, interim guidance was posted on CDC’s website for 

the use of PPV23 during the novel influenza A outbreak. Essentially, this guidance reiterates 

the existing ACIP indications, but the working group wanted to give it a prominent place so that 

people could keep this in mind going forward. The group also discussed possible triggers for 

expansion of polysaccharide vaccine recommendations. Development of antiviral resistance 

among pandemic H1N1 strains might make administration of polysaccharide vaccine more 

attractive. There is not an available or effective pandemic H1N1 vaccine. Obviously, if elevated 

secondary pneumococcal pneumonia attack rates are observed, perhaps from the Southern 

Hemisphere going forward into the fall, this would be a trigger. Other triggers would be 

increased risk of pneumococcal pneumonia among specific populations with pandemic infection 

(e.g., healthcare personnel); or increasing severity of disease, including mortality.

In conclusion, the following questions were posed to ACIP: 

• Does the ACIP have additional comments on the policy options discussed by the 

Working Group?

• What additional information or “triggers” should push the ACIP to consider expanding 

current recommendations for PPV23 to minimize pneumococcal pneumonia as a 

complication of pandemic H1N1 influenza?

Discussion

Dr. Baker thanked the group for their nice review and congratulated them in coming to what she 

thought were very reasonable conclusions, with the flexibility to make changes as necessary 

depending upon evolving epidemiologically.

Alexis Elward (HICPAC) indicated that this information was presented to HICPAC during its 

June 2009 meeting, at which time HICPAC agreed with the pneumococcal working group’s 

conclusions that expansion of recommendations was not indicated at this time. The primary 

drivers behind that included the lack of severity of novel H1N1, and the lack of evidence of 

increased risk among healthcare workers. HICPAC also agree the conclusions should be 

revisited if the data change.

James Turner (ACHA) recalled that the pneumococcal recommendation had been changed to 

include smokers and asthmatics 19 years of age and older. He also inquired as to whether the 

pie chart showing 70 million included new cohorts of 19 years olds who smoke and have 
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asthma. He pointed out that link (http://www.pandemicflu.gov/vaccine/pneumococcal.html) provided 

to the current recommendations for pneumococcal vaccine needed to be updated. 

Dr. Moore responded that the pie chart showing 70 million includes new cohorts of 19 years 

olds who smoke and have asthma, and that the correct link for the website would be provided. 

Noting that there seemed to be a lot of recent data on deaths, Dr. Morse wondered whether this 

meant that the potential for new information was increasing and the same monitoring was taking 

place in the Southern Hemisphere.

Dr. Schuchat responded that international monitoring efforts are diverse. There are virologic 

surveillance systems that track influenza strains, but there are also many places where severe 

acute respiratory infection is being monitored, which would include invasive pneumococcal 

infection. There are sites such as those in South Africa where CDC has been collaborating for 

many years to conduct intensive surveillance for influenza and severe illness, but they have also 

had a national system for invasive pneumococcal infections. That is a very special population at 

very high risk for pneumococcal infections due to the HIV epidemic. Australia also has good 

pneumococcal tracking, so more information is likely to be forthcoming.

Dr. Pickering noted that obesity seemed to be a major underlying risk factor, and requested that 

Dr. Moore comment further on this issue.

Dr. Moore responded that obesity was indicated as an underlying condition in some of these 

cases. One individual had asthma as a co-morbidity with obesity, while another had 

cardiovascular disease as a co-morbidity along with obesity. However, there were individuals 

who appeared to have obesity without other underlying conditions. It is just too early to tell 

whether obesity is a risk factor for pneumococcal disease complicating H1N1 infection.

Dr. Schuchat added that some additional comparisons have been done of obesity in the 

general population and obesity in hospitalized patients. It is really morbid obesity that is overrepresented rather than just general obesity. It is fairly universal that people who are morbidly 

obese have respiratory compromise, restrictive respiratory problems, et cetera. While there are 

patients in the general H1N1 surveillance who have obesity as their only apparent medical 

problem, this is being considered as a subset of the chronic respiratory illness that is already an 

indication for both influenza vaccine and pneumococcal polysaccharide vaccine.

Cindy Whitney (CDC) commented that it was interesting as this outbreak was unfolding that 

secondary bacterial infections were not being observed in the places they were being looked 

for. That is surprising, given the older data that suggest that when examining an autopsy series 

it is always there. It is being found in the severely ill or dead when there are good specimens.
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13-Valent Pneumococcal Conjugate Vaccine (PCV13):

Disease Burden Estimates & Options for Catch-Up Immunization 

Pekka Nuorti, MD, DSc 

Respiratory Diseases Branch

Centers for Disease Control and Prevention

Dr. Nuorti began by reviewing the ACIP recommendations for use of pneumococcal conjugate 

vaccine. In 2000, the 7-valent pneumococcal conjugate vaccine (PCV 7) was introduced. It 

was initially recommended for all children <2 years of age, and children 2-4 years of age with 

certain underlying medical conditions and immunocompromising conditions. At that time, there 

was also a recommendation to consider the vaccine for children 2-4 years of age, with priority 

for those 24 to 35 months of age in the Alaska Native, American Indian, and African American 

populations, as well as those attending day care based on higher rates of disease in those 

groups. 

In 2007, the recommendation was revised to include all children less than 5 years of age. 

Today’s discussion is about the recommendation for the 13-valent vaccine (PCV13) that will 

replace PCV7 in the future. PCV13 contains 6 additional serotypes, including 19A. It is 

currently under FDA licensure review for a pediatric indication against invasive disease and 

otitis media in children less than 5 years of age. It is expected to be licensed during the 4th

quarter of 2009. Timing might allow use of this vaccine during the upcoming influenza season.

During this presentation, Dr. Nuorti provided an overview of the estimated potentially vaccinepreventable burden of invasive pneumococcal disease (IPD) caused by serotypes included in 

the new vaccine in the vaccine target group of children under 5 years of age as well as in adults 

due to the potential for indirect effects. In addition, Dr. Nuorti discussed the options that the 

workgroup has considered regarding a PCV13 catch-up immunization program for older children 

who have received all of their PCV7 doses.

With respect to the baseline rates of IPD after 8 years of routine PCV7 use, Dr. Nuorti reported 

on data from the Active Bacterial Core Surveillance (ABCs), which is an active population-based 

and laboratory-based surveillance system for IPD in a population of about 18.5 million people. 

During 1998-1999, before PCV7 was introduced, the rate in children less than 5 years of age 

was about 100 per 100,000. At that time, about 80% of disease was caused by the serotypes 

that are included in PCV7. After PCV7 was introduced, rate of PCV7 type disease decreased 

rapidly and these types are currently practically eliminated with a rate of less than 1 per 

100,000. However, soon after the vaccine was introduced, non-PCV7 type disease began 

increasing and resulted in the overall incidence of IPD, leveling at 22 to 25 cases per 100,000 

[CDC, Active Bacterial Core surveillance, unpublished].

Taking a closer look at the absolute rate differences, stratified by age and comparing the rate in 

1998 to the rate in 2007, the rate difference from 1998 to 2007 especially in children less than 2 

years of age was quite dramatic at about 120 and about 170 per 1000,000. The current rates 

are much lower than they were before PCV7 introduction. After 2 years of age, the rates 

decreased fairly rapidly. Currently, the rates in children under 2 years of age are actually lower 

than the rates in 2 year olds were in 1998, before the PCV7 was introduced and these children 

were not originally recommended to receive PCV7. 
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The 6 new serotypes included in the conjugate vaccine are 1, 3, 5, 6A, 7F and 19A. Looking at 

the rate difference in incidence by 1 year age strata, by vaccine serotype group, the same 

pattern is seen with decreasing rates by age. In addition, PCV6 type diseases constitute fairly 

similar proportion of the total rate in all of the age groups. However, the expected absolute rate 

reductions are going to be much less than they were with PCV7 given the current rates of 

disease [CDC, Active Bacterial Core surveillance, unpublished].

In terms of the proportion of remaining IPD cases by conjugate vaccine serotype in children less 

than 5, in 2007 there were approximately 5,000 estimated cases in the United States (US). Of 

the serotypes causing disease, PCV7 types are now less than 2% of the cases. The majority of 

remaining disease is caused by serotype 19A (42%), followed by 7F (14%), and serotype 3 

(5%). There are very few cases of serotype 1 and 5 disease in the US, although these types 

are important in other parts of the world and could also be important for other pneumococcal 

syndromes. For example, serotype 1 has been identified in empyema complicating pneumonia. 

There is also very little serotype 6A in invasive disease in children. Overall, the PCV13 types 

account for approximately 64% of the remaining cases or about 3,200 annual cases in the US. 

It is important to note that the three most common serotypes (19A, 7F, and 3) actually account 

for 98% of the new 6 serotypes.

With regard to overall incidence of IPD by race, the pattern is similar as in overall disease 

shown before, but there remains about a 2-fold higher risk of disease among black children 

compared with white children, although the baseline rates are much lower than they were before 

PCV7 introduction. Another important group to consider, particularly for catch-up vaccination, 

are older children who have chronic illnesses or are immunocompromising conditions (e.g., 

sickle cell disease; HIV). In 2000, PCV7 was recommended for older children 24-59 months of 

age with these conditions [MMWR 2000;49(RR-9)]. In terms of the proportion of serotypes 

causing disease among children who have underlying medical conditions compared to healthy 

children, differences were observed. Based on a combination of two years of data and 30 

identified cases with underlying medical conditions (about 10% of all cases in this age group), 

there were differences in serotypes causing disease. One of the more important differences was 

that the PCV13 types accounted for 43% of the isolates among children with chronic illnesses 

compared with about 70% among healthy children, despite small numbers this was a 

statistically significant difference. In addition, since these children are currently recommended 

to receive 23-valent polysaccharide vaccine after their conjugate vaccine series at age 2, the 11 

additional serotypes included in the polysaccharide vaccine in addition to the PCV13 types 

accounted for 13% of the disease. Many other serotypes that are not in any vaccine were also 

causing disease in this group of children who are at very high risk of disease.

Invasive disease in adults is going to be very important because of the potential indirect effects. 

Adult disease has become even more important due to the changes in the epidemiology that 

have been brought about by PCV7. Children under 5 years of age account for about 5,000 IPD 

cases per year or about 12% of the remaining disease burden. However, of the estimated 

42,000 annual cases of invasive disease in the US, in 2007, 85% occurred in adults. The trends 

in PCV7 type disease in adults are similar to those in children; PCV7 type disease has declined 

dramatically and demonstrated the indirect vaccine effects in unvaccinated groups. Decreases 

in vaccine type disease have resulted in reductions in overall rates of IPD among adults by 

about 23% to 49%, depending on the age group. With regard to the proportion of cases that 

were caused by serotypes in different vaccine formulations, there is still some PCV7 type 

disease left in adult age groups. PCV13 types caused approximately 43% to 51% of the 

disease in adults in 2007. It appears that there is a slightly decreasing trend in serotype 

coverage with increasing age. Adults 65 and older represent the highest risk groups and have 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

242

the highest rates of disease. The proportion of remaining invasive cases by PCV serotype and 

the serotype distribution in adults is quite different from children. About 7% are due to PCV7 

type disease, 14% 19A, 8% 7F, 10% serotype 3, very few serotype 1 and 5 disease, and some 

serotype 6A disease. These are the same serotypes that are causing disease in children, but 

PCV 13 type disease accounts now for about 43% of the remaining cases, while the 4 serotypes 

19A, 7F, 3, and 6A account for 99% of the new serotype disease [CDC, Active Bacterial Core 

surveillance, unpublished].

In summary, the serotypes included in PCV13 cause almost two thirds of the remaining IPD in 

children less than 5 years of age; however, it is important to note that the baseline rates are now 

much lower than before PCV7 introduction and therefore, the expected absolute rate reductions 

are smaller. Three serotypes account for 98% of the new serotype type disease and although 

the rates are lower, racial differences continue. Children 24-59 months with chronic conditions 

are a small but important group because they are likely to remain at increased risk of disease 

although the data are limited. The data are limited to numerator data, given that there is not 

good denominator information from which to calculate rates in most of these groups. The IPD 

serotype distribution in adults is different from children.

Regarding the possible PCV13 catch-up immunization strategies, typically catch-up refers to 

catching up children who have missed doses. When PCV7 was introduced, this pertained to 

unvaccinated children who were recommended for catch-up vaccinations. For PCV13, catch-up 

refers to one additional PCV13 dose for children who have been fully vaccinated with PCV7. 

The goals of this strategy would be to provide direct protection against the 6 new serotypes for 

the children who will receive the catch-up dose, as well as potentially accelerating the indirect 

effects in unvaccinated groups. The rationale for indirect effects is that children aged >12 

months may be important for transmission of S. pneumoniae, and reduction in nasopharyngeal 

carriage of certain PCV6 types.

The topics that the working group has considered for a universal catch-up program include 

safety information for the 5th conjugate vaccine dose, immunogenicity of one dose for the 6 new 

serotypes in older children, and the incremental public health impact and cost-effectiveness 

compared with routine immunization of birth cohorts. In terms of programmatic issues, realizing 

that there is going to be a considerable amount of vaccination underway in the fall, this means 

yet another vaccine to add to the crowded schedule. With that in mind, some possible options 

for a PCV13 catch-up program for older children include the following:

1. All children aged 16-59 months 

 

 OR

2. All children aged 16-35 months AND children 36-59 months with high risk conditions

 

 OR

3. All children aged 16-23 months AND children 24-59 months with high risk conditions

 OR

4. Children aged 16-59 months with high risk conditions only
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These are not in the order of preference, but instead represent the order of decreasing size of 

the target group. PCV13 can be substituted for PCV7 at any point in the schedule. One dose of 

PCV13 in children 12 months and older induces a response that is non-inferior to the 3-dose 

primary infant series, as well as functional antibody response. The safety profile of 1-2 doses of 

PCV13 after 4 PCV7 doses is comparable to a 4 dose series. Currently, no data are available 

on reduction in carriage of PCV6 serotypes after single PCV13 dose in older children (serotypes 

1,5 and 7F are rarely carried). There is no information on the duration of protection of a single 

PCV13 dose. Data are needed with regard to whether one PCV13 dose will also be sufficient 

for children 24-59 months with underlying medical conditions.

In conclusion, transition from routine infant PCV7 vaccination to PCV13 has the potential to 

substantially reduce remaining IPD. A PCV13 catch-up program would provide direct protection 

for children receiving the vaccine and might enhance the indirect effects in unvaccinated 

groups. Rapid PCV13 introduction, including a catch-up program during the 4th quarter of 2009 

might have the potential benefit of reducing pneumococcal infections complicating influenza. 

Dr. Nuorti requested that the committee consider the following questions: 

 Which groups of children should be targeted for PCV13 catch-up immunization?

– universal for all children up to certain age

– children with underlying medical conditions

– racial/ethnic populations with increased rates

 If universal PCV13 catch-up program is recommended, what age groups should be 

included?

Discussion

Dr. Meissner requested further information regarding the duration of protection among children 

who received 4 doses of PCV7 with respect to the fact that these children are now 8 to 9 years 

of age and may have a decline in antibodies.

Dr. Paradiso responded that Wyeth has data from a follow-up study conducted in South Africa. 

These data are from an efficacy trial 5 years out comparing children who had vaccination and 

those who had no vaccination. Everybody waned over that time. There was a higher antibody 

level in the children who had been vaccinated. Importantly, when these children were revaccinated after 5 years, they boosted the response better than the group that had not been 

vaccinated. These are the best data currently available. Wyeth is planning to start a study in 

Northern California to assess the original population who are now 10 to 12 years out to 

determine their antibodies and what the priming state is.

Dr. Schuchat added that antibodies can be interesting, but there is really no disease occurring in 

the 5- to 17-year age group. This was a very low risk group pre-immunization introduction, and 

it is not a group that has experienced an increase. This was not included in the information Dr. 

Nuorti presented because the scale would have to be changed so much to include them.

Amy Groom (I HS) Although the data are limited and sample sizes are fairly small for the 

American Indian / Alaskan Native populations, Dr Kate O’Brien presented information during the 

February ACIP meeting regarding the serotypes causing disease in the American Indian / 

Alaskan Native populations that are contained in PCV13. She wondered whether there was a 

similar breakdown for this population as there was for black and white populations. She thought 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

244

such data would be helpful in forming a discussion regarding recommendations and whether the 

groups wished to consider something for racial / ethnic groups.

Dr. Nuorti replied that while a discussion on this topic was not prepared for this meeting, it is on 

the list of data the group intends to review and present. It is known that the distribution of 

serotypes for Alaska Natives and American Indians differs somewhat from the general 

population. Alaska has already introduced the 13-valent vaccine as an investigational study in 

some areas because of their problem with replacement disease. The data on these populations 

will have to be examined to determine the serotype coverage in these groups. 

Patricia Whitley-Williams (NMA) wondered whether children with hemoglobinopathies were 

included in the incidence by race of IPD.

Dr. Nuorti responded that children are included. The number of children with underlying 

conditions, such as sickle cell disease, was very low in the surveillance data.

Investigational 13-Valent Pneumococcal Conjugate Vaccine (PCV13)

Peter R. Paradiso, MD 

Wyeth-Lederle Vaccines and Pediatrics

Dr. Paradiso pointed out that the data just presented was unique in the world. Wyeth has 

introduced this vaccine in national programs in 35 countries, and no country has an ABCs 

surveillance system or a group that can examine the data like this. Therefore, it is important to 

continue to support these programs at the CDC, because it helps in evaluating the impact of

vaccines. He also reminded everyone that in the 2000 ACIP recommendations, to deal in part 

with the racial disparities and to some extent economic disparities in the population, even 

though the recommendation in 2-5 year olds was permissive, the VFC covered children up to 5 

years of age. Those children who were at highest risk, either because or race of economic 

condition, had the vaccine available to them. 

During this presentation, Dr. Paradiso discussed the transition from PCV7 to PCV13, shared 

some safety and immunogenicity data on that transition, and discussed the new serotype catchup program. He reminded everyone that the serotypes common to both PCV7 to PCV13 

include 4, 6B, 9V, 14, 18C, 19F, and 23F. PCV13 contains the additional serotypes 1, 3, 5, 6A, 

7F, and 19A. In the transition from PCV7 to PCV13, the following represent the possible 

combinations of where children are expected to be at the time 13-valent vaccine is introduced:
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

245

3

Transition from PCV7 to PCV13

Infant

2 mo 4 mo 6mo

> 12 months

7v 13v 13v 13v --

7v 7v 13v 13v --

7v 7v 7v 13v --

7v 7v 7v 7v 13v

Because 7 of the serotypes, the chemistry, and the quantity are common in both products, the 

label will indicate that transition to the 13-valent product can be substituted at any point in the 

immunization schedule regardless of whether a child has received 1, 2, 3, or 4 doses of the 7-

valent vaccine. 

Referring to a French transition study, “Mix and Match at Toddler Dose 7v/13v vs 13v/13v,” Dr. 

Paradiso explained that in the second year of life, the antibody response was examined 

specifically with regard to the 6 new serotypes. In this study, children received either 3 doses of 

Prevnar® in the first year of life (in the French immunization program, that is at 2, 3, and 4 

months of age) with a booster dose in the second year of either the same vaccine or the 13-

valent vaccine. A second group received all 4 doses of 7-valent vaccine. At the 12-month age 

period for the 7 common serotypes, the response is non-inferior between the groups. That is 

the evidence that using the 13-valent for the 7 types results in the same response as the 7-

valent.

Assessment of the immune response of 1 dose of the 13-valent for the 6 new serotypes has 

been done in two ways. The first was to compare it after 3 doses in infants, which is the 

criterion used for catch-up programs with Prevnar®. Another is to examine functional antibody 

with 1 dose in toddlers compared to 4 doses in the regimen. With respect to the IgG antibody 

response to the 6 new serotypes post dose 3 in infants versus post dose 1 in toddlers, antibody 

responses following a toddler dose of PCV13 are non-inferior to that achieved after infant series 

with 13vPnC. That is, one dose in toddlers for all of the 6 serotypes induces a response that is 

as good or better by geometric mean concentration (GMCs) of antibody than 3 doses in infants. 

In the original 7 types, several of the serotypes were less with one dose in 12 month olds, with 

6B and 23F being the two most important of those. That was the reason for 2 doses in 12-24 

months. It appears that the 6 new serotypes fit into a category of good response in the toddler 

age group. In terms of the OPA antibody response to the 6 new serotypes in a 4-dose series 

versus 1 dose in toddlers used to show functionality of antibody, there was a nice functional 

response in toddlers following one dose that matches the total antibody response. Thus, these 

data are encouraging with respect to the immunogenicity of the vaccine in the over 12 month 

age group and form the basis for Wyeth’s application and Transition Request with the FDA. 

Wyeth is currently engaged in discussions with FDA regarding dosing regimens based on these 

data.
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246

There are limited safety data from an on-going study that is examining safety in children who 

have received 3 or 4 doses of PCV7 vaccine and a subsequent 1 or 2 doses of 13-valent 

vaccine. Although this is a safety and immunogenicity study, only safety data were available at 

this point. I’ll show you 2 groups that are in this study. Of the children 15 months to 2 years of 

age (n=123), 37 received 3 doses of 7-valent vaccine, 86 had 4 doses of the 7-valent vaccine, 

and all subsequently received a dose of 13-valent vaccine. The second group included 2 to 5 

year olds (n=180) who received either 3 or 4 prior doses of Prevnar®, and then received a dose 

of 13-valent vaccine. 

Prompted symptoms were examined within 1 to 7 days following vaccination for local and 

systemic adverse events, as well as adverse event reporting to include:

 Local injection site reactions (redness, swelling, tenderness)

 Temperature nightly and when fever is suspected; report highest daily 

temperature

 Decreased appetite, irritability, increased sleep, decreased sleep, and hives 

 Antipyretic use for treatment or prevention of symptoms

 Data collected via electronic diary

Nothing remarkable was observed from a safety prospective when comparing these data to the 

safety data following doses 1 through 4 in the infant population. That is, the 13-valent vaccine 

given as a 5th dose of conjugate vaccine in these children did not raise any safety concerns.

The most surprising impact of Prevnar® since the introduction in the vaccine regards the herd 

effect. While essentially identical for all age groups, Dr. Paradiso reported on those 65 years of 

age and older. The data from 2007 reflect a 100% herd effect, with the herd effect growing over 

time since the introduction of the vaccine. In fact, herd immunity continued to increase after a 

point in time when the vast majority of children, infants, were receiving Prevnar® and a high 

percentage of those children received this product as infants. It is believed that this is the result 

of the carriage in the 2 to 5 year old age group being reduced. While 2 to 5 year olds carry 

approximately half as much pneumococcus in their noses as the youngest children, there were 

more of them. The importance of the 2 to 5 year old age cohort and reduction of carriage in that 

group probably is important in inducing the herd effect. The rapidity with which children are 

vaccinated probably impacts the rapidity with which herd impact is achieved. Wyeth has 

attempted to model a catch-up program in the context of direct and indirect effects, with the idea 

that the curve can be sped up somewhat by vaccinating a larger cohort of children [% herd 

effect based on CDC’s ABC Surveillance: M. Moore, personal communication].

Wyeth has attempted to model the herd effect that is likely to be observed with the 6 new 

serotypes based upon what occurred with the 7 types of PCV7, taking a conservative approach. 

Projected indirect effects are based on the carriage potential and the immune response to the 6 

new serotypes, assuming the following [Wyeth data on file]:
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 No herd protection against serotypes 1 and 5 [these types are not typically 

carried]

 Serotypes 3 and 19A will have similar effect as 19F—a reasonable assumption 

based on their characteristics and the antibody response

 Serotype 6A will have similar effect as 6B—while their herd effect may not be as 

impressive as the rest, there was certainly a significant herd effect, which is 

intermediate between the very good herd effect of 6B and the not so good herd 

effect of 19F

 7F is a low colonizer but induces a good immune response and will have 

intermediate effect (midpoint of 6B and 19F) (this is a conservative approach)

As reflected in the data presented by Dr. Nuorti, there has been a dramatic reduction in all 

serotypes, so it is important with this assessment not to make assumptions that will be as 

dramatic as that, but that reflect that a significant herd effect is anticipated.

Also important to think about in terms of direct and indirect effects of this vaccine is that in 

interpandemic periods, approximately 50% of influenza hospitalizations are complicated by 

bacterial pneumonia. On average, 25% of influenza deaths are due to secondary bacterial

pneumonia. During the 1957 and 1968 pandemics, 70% of patients with fatal or life-threatening 

pneumonia had a bacterial etiology. The synergism of influenza and S. pneumoniae accounts 

for significant excess mortality [Scadding JG. Quart J Med 1937;6:425-65; Stuart-Harris CH. J 

Hyg 1949;47:434-8; Tyrell DAJ Quart J Med 1952;21:291-306; Simonsen L. Vaccine

1999;17:S3-10; Hers JFP. Lancet 1958;2:1141-3; Linsey M. JAMA 1970;214:1825-32].

In summary, the 13-valent vaccine provides coverage for 6 new serotypes. There is a 

significant burden in children 1 to 5 years of age and some increase in certain racial groups. 

There is significant potential for indirect effects against the 6 new serotypes that can perhaps be 

accelerated with a catch-up program. 

Public Health and Economic Impact of the 13-Valent 

Pneumococcal Conjugate Vaccine (PCV13)

David Strutton, PhD, MPH

Wyeth Research, Collegeville, PA

Adjunct Assistant Professor, Johns Hopkins School of Public Health, Baltimore, MD

Dr. Strutton explained that the goals of the research upon which he was reporting were to 

evaluate the potential public health and economic impact of PCV13 versus current vaccination 

with PCV7, and versus no vaccination in the US (results of the no vaccination comparison were 

not discussed in detail during this presentation); and assess the impact of the PCV13 new 

serotype catch-up program. These analyses were examined from three perspectives: 1) payer 

perspective (medical costs only); 2) societal perspective (as defined by USPHS Panel on CostEffectiveness in Health and Medicine); and 3) societal + productivity perspective (includes 

productivity losses). The vast majority of data shared by Dr. Strutton during this presentation 

pertained to the societal perspective.

The primary vaccination strategy examined was for PCV13’s standard administration schedule, 

which is the same that has been used with PCV7 over the past 9 years (e.g., doses at 2, 4, and 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

248

6 months, followed by a booster between 12 and 15 months). Three comparative strategies 

were examined:

Primary Vaccination Strategy: PCV13

 Vaccinate infants with PCV13 at age 2, 4, 6, and age

12-15 months

Comparators:

 PCV7 vaccination (status quo for the past 9 years)

• Vaccinate infants with PCV7 

 at age 2, 4, 6, and 12-15 months

 PCV13 with new serotype catch-up program

• 1 dose of PCV13 for all children aged 1- to <5 who have completed their 

PCV7 vaccination series at the time of PCV13 introduction

 No vaccination (to give some estimates that would be comparable to what has been 

done with Prevnar® in the past; results not discussed during this presentation)

The costs and benefits were assessed over a 10-year time horizon to allow sufficient time for 

the full indirect benefits of the PCV13 vaccination program to be realized, and the long-term 

consequences of events occurring during the 10-year study period are projected to a lifetime 

horizon. A 3% discounted rate was used. A decision-analytic Markov (state-transition) model 

was used to evaluate the following: cases avoided, deaths averted, costs (savings) and cost 

per child vaccinated, cost per quality adjusted life-year (QALY) gained, and cost per life-year 

(LY) saved.

In terms of the methods used, for PCV13 versus PCV7 and PCV13 with new serotype catch-up 

versus PCV13, the incremental economic impact of vaccinating children against 6 additional 

serotypes of S. pneumonia was assessed. The assumption was made that the 2007 serotype 

distribution of S. pneumoniae for IPD was also representative of the serotype distribution of 

pneumonia and AOM [Supported by data on serotype distribution of AOM and parapneumonic 

empyema; Bender et al., 2009; Casey et al., presented at ICAAC 2008; Byington et al., 2006]. 

Also assumed were that the benefits of PCV7 persist at the 2007 level. For the PCV13 with 

new serotype catch-up versus PCV13, the assumption was made that if there was a full catchup program of children 15 to 59 months of age with one additional dose of PCV13, there would 

be a 1-year acceleration in the accumulation of herd effects that was observed with PCV7.

The model inputs for incidence were taken from the published literature in addition to 

unpublished ABC data, including the following:

 IPD incidence based on unpublished ABC data and published literature [2007 unpublished 

ABC data, provided by Matt Moore, MD; Hsu et al, 2009]

 Mortality and long-term sequelae from published literature [Lieu et al, 2000; Shepard et al, 

2007; Tsai et al, 2008; National vital statistics reports, 2004] 

 Hospitalized and non-hospitalized pneumonia incidence estimated from NAMCS and 

NHAMCS and published literature [National ambulatory medical care survey (NAMCS) and 

National hospital ambulatory medical care survey (NHAMCS). Grijalva et al, 2007; Grijalva 

et al, 2009]

 AOM incidence based on published literature [Ray et al 2006].
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

249

Assumptions about accumulation of indirect effects were indirect effects estimated at 7 years 

post introduction, assuming 100% of indirect effects evident at year 7. A base-case, catch-up 

program is assumed to accelerate herd effects by 1 year. The percent of full indirect protection 

realized each year after launch, based on PCV7 data, is as follows:

Year Base 

case**

Catch-up

1 12% 33%

2 33% 58%

3 58% 72%

4 72% 85%

5 85% 92%

6 92% 100%

7 + 100% 100%

The center column shows accumulation of indirect effects observed in older folks in the US 

during the pre / post time period since the introduction of Prevnar® over the 7 year period to 

2007. The last column shows what the ramp up would look like if there was a 1-year 

acceleration in that accumulation of indirect effects.

The model inputs for estimated effectiveness of PCV13 included the following:

 Direct Effectiveness in Children <5 years

 IPD, pneumonia, and AOM based on clinical trial data for PCV7, adjusted to reflect 

serotype coverage of PCV13 [2007 unpublished ABC data, provided by Matt Moore, 

MD; Hansen et al, 2006; Black SB et al 2000, and Black SB et al, 2002]

 Direct vaccine protection assumed to last for 2 years and waning efficacy (91% of full 

efficacy) for the following 3 years [Madhi et al., 2009; Madhi et al., 2007; Black et al., 

2007].

 Indirect Effects:

 IPD reductions estimated from ABC data, as previously discussed [2007 unpublished 

ABC data, provided by Matt Moore, MD; Hansen et al, 2006; Black SB et al 2000, 

and Black SB et al, 2002].

 In < 5 yr olds, pneumonia and AOM adapted from ecologic and clinical trial data on 

PCV7, adjusted to reflect differences in serotype coverage for PCV7 and PCV13 

[Black et al., 2002 and Zhou et al, 2007; NAMCS and NHAMCS; Black et al, 2000 

and Zhou et al, 2008; Grijalva et al, 2007; unpublished analysis by Klugman et al, 

2009].

 In > 5 yr olds, pneumonia adapted from ecologic data on PCV7, adjusted to reflect 

differences in serotype coverage for PCV7 and PCV13 [Madhi et al., 2009; Madhi et 

al., 2007; Black et al., 2007].
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

250

Economic inputs included the following, with all dollars shown being 2008 figures:

 Costs of clinical events from published sources [Ray et al, 2006; Ray et al, in preparation; 

Mag Mutual, 2007].

 Base-case price of PCV13 was assumed to be $100 (range from $73.05 to $110)

 Price of PCV7 is $73.05 [Personal Communication, Wyeth Research].

 QALY decrements estimated from Melegaro and Edmunds [Melegaro and Edmunds, 2004]. 

With regard to the base case results estimated over a 10-year period, estimating the 

incremental public health impact that is expected to be observed to PCV13 versus PCV7, 

PCV13 would prevent an additional 110,358 cases of invasive disease; 913,836 cases of 

hospitalized pneumonia; 1.95 million cases of non-hospitalized pneumonia; and about 20 

millions of AOM. The impact of the new serotype catch up program from 15 to 59 months over 

the 10-year period compared to the PCV13 program without a catch up program is estimated to 

eliminate an additional 12,975 cases of invasive disease; 118,534 cases of hospitalized 

pneumonia; 302,287 cases of non-hospitalized pneumonia; and about 2.9 million cases of AOM 

[New serotype catch-up program includes vaccination of all children previously vaccinated with 

PCV7 in the first year after introduction of PCV13 with one dose of PCV13; assumes a one-year 

acceleration in the indirect effects]. The model predicts that PCV13 would save $8.4 billion in 

medical costs and $12.6 billion from the societal perspective over a 10-year period. This would 

translate into a cost savings of approximately $320 per child vaccinated from a societal 

perspective. From a parental perspective, the estimate is about $213 per child vaccinated in 

medial cost savings. The results of the sensitivity analyses conducted on the base case 

analyses of PCV13 versus PCV7 suggest that there would be a cost-effectiveness estimate of 

$23,461 per QALY gained and $71,569 per QL saved. This is a cost savings scenario, so there 

is a greater return of investment from the cases of disease avoided than the investment in the 

vaccination program. Indirect protection for invasive disease would still result in a cost saving 

scenario. Indirect protection against invasive disease and pneumonia would have a greater 

cost savings, as would indirect protection in children less than 5 years of age.

Pertaining to the direct benefits of a catch-up program over a 10-year period in terms of 

additional cases avoided: 2,451 cases of IPD; 29,061 cases of hospitalized pneumonia; 

115,828 cases of non-hospitalized pneumonia; and 1.8 million cases of AOM would be avoided 

in children 15 to 59 months of age. For 15 to 35 month old children 1,249 cases of IPD; 9,300 

cases of hospitalized pneumonia; 40,115 cases of non-hospitalized pneumonia; and 674,754 

cases of AOM would be avoided. For 15 to 23 month old children, 487 cases of IPD; 3,890

cases of hospitalized pneumonia; 11,570 cases of non-hospitalized pneumonia; and 237,601 

cases of AOM would be avoided. Obviously, fewer children would be vaccinated in each of 

these scenarios, so there would be fewer direct benefits to them. In terms of PCV13 + Catch-up 

versus PCV13 and the base case costs for over 10 years, the model predicts that the new 

serotype catch-up program would save $255 million in medical costs and $949 million from the 

societal perspective. From a parental perspective, a new serotype catch-up program would 

save about $19 per child vaccinated.

Regarding the sensitivity analyses on the various catch-up scenarios examined, for children 15 

to 59 months of age, an estimation of a 1-year acceleration in the herd effect was assumed for 

the base case. The same sensitivity analyses range was estimated for the other 2 catch-up 

scenarios, but since fewer children would be vaccinated and less carriage overall would be 

reduced or eliminated, less acceleration in the herd effect would be anticipated. With the 12-

month acceleration scenario, the data suggested that there would be cost savings of about $72 

per child vaccinated. Assuming that all children through 59 months of age had no effect on the 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

251

acceleration of the indirect effects for the rest of the population, the cost-effectiveness estimate 

would be about $39,000 per QALY. Thus, it would still be considered-cost effective if only 

incorporating the direct benefits of vaccination for those children participating in the catch-up 

program, in that this program would become cost saving somewhere between 0 and 6 months 

of an acceleration in the indirect effect. If the carriage is reduced in all of the birth cohorts 

through 59 months, and if the herd effect is accelerated somewhere between 0 and 6 months, it 

would become a cost saving scenario. 

In the catch-up scenario for children 15 to 35 months of age, assuming a 12-month acceleration 

in the indirect effects, there would still be cost saving. What is not known is whether realistically 

there would still be a 12-month acceleration. It is likely that there would be somewhat less 

acceleration since there would be fewer children vaccinated and less elimination of carriage. 

The price estimate of $140 per dose for PVC13 was intended to provide the cost implication of 2 

doses for 12 to 23 month old children. In children 15 to 35 months of age, if there was a catchup program and zero acceleration of herd effect, the cost for quality adjusted life year is 

estimated at $3,000. Therefore, this scenario is still highly cost-effective, approaching cost 

savings even with no catch-up program. In terms of a catch-up program for 15 to 23 month 

olds, even with zero acceleration of indirect effects, this would be a cost saving scenario 

because there is less of an investment in that catch-up program.

Wyeth conducted a number of other sensitivity analyses. In terms of vaccine price under the 

base case effectiveness assumptions, PCV13 would be cost saving at all prices over the range 

examined. Threshold analyses were also done. Under the base case assumptions, the 

threshold analysis showed that about $200 per dose is the price at which PCV13 would become 

cost neutral, or where there would no longer be cost saving. However, it would still be right at 

the threshold between highly cost effective and cost saving. From a payer prospective, the 

threshold at which PCV13 would become cost neutral would be about $166 per dose.

There are a number of limitations with respect to these studies. As these analyses are 

conducted, they are synthesized from a variety of sources. There is uncertainty around the 

potential indirect effects of PCV13. All estimates for the impact of PCV13 were estimated from 

the PCV7 experience. The impact of emerging serotype disease with PCV13 was not 

specifically estimated. This was, to some degree, inherently included in some of the estimates 

used because the indirect effects on invasive disease estimated were from PCV7, which 

included some replacement disease and all of the ecologic data used. The impact of the 23-

valent polysaccharide vaccine (PPV23) was not considered in the model. Wyeth attempted to 

address the limitations in the model in the various sensitivity analyses conducted. 

In summary, Wyeth estimated that over a 10-year period, PCV13 would avoid about 110,000 

cases of invasive disease; about 900,000 cases of hospitalized pneumonia; and about 2 million 

cases of non-hospitalized pneumonia compared to PCV7 over that same time period. A new 

serotype catch-up program from 15 to 59 months would avoid an additional 12,000 cases of 

invasive disease; 420,000 cases of pneumonia; and about 3 million cases of AOM, assuming 

the 1-year acceleration in the herd effect. The model predicts that PCV13 would save about 

$12.6 billion compared to PCV7, and an additional $950 million with implementation of the new 

serotype catch-up program. PCV13 would remain cost saving versus PCV7 at any price of 

PCV13 up to $200 dollars per dose from a societal perspective, or $166 per dose from a payer 

prospective. A serotype catch-up program will be cost-saving if there is acceleration in the 

indirect effect characteristics observed for PCV7 of at least 6 months. It is really somewhere 

between 0 and 6 months where the cost savings are realized. It appears that indirect effects 
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

252

would play an integral role in the impact of PCV13. Even when these effects are reduced or 

eliminated, PCV13 is still a favorable intervention from an economic standpoint.

Discussion

Dr. Pickering noted that CDC instituted the review of all economic analyses presentations 

recently, which Wyeth’s underwent. He wondered whether there were any major changes or 

issues that Wyeth had to address as a result of that review.

Dr. Strutton replied that the review was an asset to the evaluation and Wyeth received very 

good feedback. A major suggestion was to evaluate the other catch-up scenarios. Wyeth was 

assessing a base case of 15 to 59 months of age initially. In addition, the CDC health 

economist offered good insight on some of the utility adjustments Wyeth was using for the cost 

per QALY. 

Dr. Marcy inquired as to whether there would be any data on the durability of immunity from a 

single booster dose against the 6 serotypes.

Dr. Paradiso responded that there would not be from these studies. There will be response and 

comparative response to what was observed with Prevnar®. In the current package, there are 

not any data on durability of that response.

Assuming that Wyeth would ramp down the production of PCV7 once PCV13 is licensed and 

available, Dr. Sawyer requested an estimated timeframe during which both products would still 

be available.

Dr. Paradiso responded that Wyeth initiated production of 13-valent vaccine in the second half 

of 2008 and is now manufacturing and accumulating vaccine. The goal is to transition rapidly 

from 7-valent to 13-valent. Based on discussions with the CDC over the last several months, 

the data presented during this meeting, and preparedness efforts, Wyeth was inspired to 

accelerate its thinking about introduction from a normal transition and for the catch-up 

immunization. Supply planning must be done globally, so feedback about direction would be 

beneficial. 

Patricia Whitley-Williams (NMA) requested insight regarding potential financial challenges and 

supply that may be faced by individual practices.

Dr. Paradiso responded that through the VFC program, which fortunately can actually be 

implemented quickly, there was no lag in reimbursement with Prevnar®. In the private sector, 

they must ensure that the same occurs. There are discussions underway to ensure that the 

transition in reimbursement from the 7-valent to 13-valent occurs as quickly as possible to avoid 

supply and economic issues in private practices.

Dr. Englund said that as a pediatrician, it occurred to her that these analyses did not include the 

pain and suffering of hospitalized children. She also stressed the importance of ACIP seriously 

considering cost-effective analyses. 

Dr. Morse inquired as to whether any studies were planned to examine colonization effect or 

carriage.
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

253 

Dr. Paradiso responded that there is an on-going study to assess carriage for the new serotypes 

of the 13-valent vaccine. Unfortunately, the data from those studies will not be available by the 

end of the year as they are long-term studies. 

An inquiry was posed regarding whether it would be beneficial to think about the impact of an 

accelerated immunization schedule on the secondary effects of influenza this winter. Perhaps it 

would help to understand how quickly the target population and the possible catch-up target 

population could be immunized if the vaccine is approved.

Cindy Whitney (Respiratory Disease Branch) said she had hoped Dr. Paradiso would discuss 

doses.

Dr. Paradiso responded that over the past few months, they have been trying to accelerate as 

many doses of 13-valent vaccine scheduled in the pipeline into 2009 and earlier in 2010. Wyeth 

is currently trying to anticipate how many doses would be required, what the date would likely 

be, and how many doses would be needed such that they do not face a situation in which a 

shortage is created for routine immunization. That would be the worst case scenario. There is 

a cohort of approximately 12 to 15 million children in that group. All of those children could not 

be immunized in three months anyway, but Wyeth is trying to estimate whether they can safely 

say there will be no issues. He did not have an answer with regard to the number of doses at 

this point, but they are working hard to have a better idea as the summer progresses. 

Dr. Morse requested that Dr. Nuorti display the list of questions for ACIP members to consider 

while the analyses were fresh. 

Dr. Nuorti responded that they would be happy to receive input via email or other means of 

communication pertaining to the universal catch-up scenarios, particularly with respect to the 

upper age limit that seems appropriate to the committee. 

No public comments were offered during the third day of the meeting.

I hereby certify that to the best of my 

knowledge, the foregoing Minutes of the 

June 24-26, 2009 ACIP Meeting are 

accurate and complete. 

_____________________ 

 Date ________________________________ Dale Morse, M.D., M.S. Chair, 

 Advisory Committee on 

Immunization Practices (ACIP)

Public Comments Day 3

Certification
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

254 

International 

Abu-Elyazeed Remon Egypt

Ali Hassan Ahmed Egypt

Baker Alexandra United Kingdom

Bonadonna Lisa Italy

Dhankhar Praveen India

Dubischar-Kastner Katrin Luise Germany

Ebihara Keiko Japan

Espinal Carlos Colombia

Florez Jorge Colombia

Furuya Yoshikata Japan

Gowler Jeremy Canada

Hajime Kamiya Japan

Jiang Wu China

Keiko Ebihara Japan

Kenji Okada Japan

Khromava Alena Canada

Langley Joanne Canada

LeBlanc Julia Canada

Ma Rui China

Major Maria Canada

Mascarenas Cesar Mexico

MONTEYNE Philippe Belgium

Neame Dion Canada

Okabe Nobuhiko Japan

Okada Kenji Japan

Omer Saad Pakistan

ORIOL VALERIE France

Payne Debra Canada

Sabourin Michèle Canada

Saddier Patricia France

Salisbury David United Kingdom

Sandhu Hardeep India

senouci kamel France

Shaikh Tarteel Saudi Arabia

Shindman Judith Canada

Skowronski Danuta Canada

SOREEFAN BIBI AISHA Mauritius

Tahir huda Sudan

Tan Litjen (L.J) Singapore

Tran Trung Vietnam

York Laura Canada

List of Attendees
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

255 

United States

Abraham Katalin United States

ADLER JOAN United States

Ahuja Ajay United States

Ambrose Karita United States

Ambrose Christopher United States

Ault Kevin United States

Baker Carol J United States

Bandell Allyn United States

Batra Udit United States

Baxter Marguerite United States

Beck Robert L. United States

Bernstein Jessica United States

Birkhead Guthrie United States

Biscardi Karen United States

Blalack Gary United States

Blazek Nicole United States

Bocchini Joseph United States

Boyce Donna United States

Bozof Lynn United States

Bresnitz Eddy United States

Brown Wendy United States

BRUMLOW DEWAYNE United States

Burkholder Brenton United States

Burton Janet United States

Bush Kim United States

Campos-Outcalt Doug United States

Cannon Patricia United States

Caporizzo John United States

Carey Chris United States

Carpentier Sallie United States

Cary Donna United States

Chaney Mike United States

Chapman Louisa United States

Chilton Lance United States

Cieslak Paul United States

Cieslak Ted United States

Claxton Isabelle United States

Clover Richard United States

Coelingh Kathleen United States

Colwell Chris United States

Combs Kevin United States

Conner Penny United States

Cullison Mark United States

Curlin George United States

Dalrymple Donald "Dack" United States

D''Ambrosio Cynthia United States

Daniels Janina United States

Davis Carolyn United States
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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de Caprariis Pascal United States

Dinovitz Richard United States

Donnelly John United States

Donnelly Colleen United States

Dougherty Kelley United States

Dubin Gary United States

Duchin Jeffrey United States

Dueno Berrios Carlos United States

Duffy Colleen United States

Dull Peter United States

Dzubin Shannon United States

Ehresmann Kristen United States

Elward Alexis United States

Englund Janet United States

Etkind Paul United States

Evans Jim United States

Farnon Eileen United States

Farzan Nima United States

Feinberg Mark United States

Ferraro Louis United States

Fikry Christopher United States

Fischer Marc United States

Foster Stephan United States

Friedland Leonard United States

fryhofer sandra United States

fryhofer george United States

Fye Jessica United States

Gaffoglio Diane United States

Gall Stanley A United States

Gargano Lisa United States

Garrett Hudson United States

Gaskins Diana United States

Geddes Cathy United States

Gellin Bruce United States

Gershman Mark United States

Gershon Barry United States

Gibbs Tom United States

Gill Christopher United States

Goldenthal Karen United States

Gordon-Evans Jill United States

Greenberg David United States

Greenleaf Peter United States

Grogg Stanley United States

Gurunathan Sanjay United States

Hackman Jeff United States

Hage Raymond United States

Hahn Christine United States

Halsey Neal United States

Halstrom Erik United States

Hannan Claire United States
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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Haupt Richard United States

Heaton Penny United States

Hering David United States

Hight Leta United States

Hight Brandi United States

Hilton Betsy United States

Hinman Alan United States

Hosbach Philip United States

Howe Barbara United States

Humphrey Franklin Donelle United States

JaapK-NL JaapK-NL United States

Jackson Melonie United States

James Chuntiel United States

James James United States

Johann-Liang Rosemary United States

Johnson David United States

Jones James F. United States

Judson Frank United States

Kahn Clare United States

katz samuel United States

Keyserling Harry United States

Kimberlin David United States

Klein Nicola United States

Knouse Mark United States

Kramer Jason United States

Kroft Charlotte United States

Krull Andrea United States

Kuter Barbara United States

Laird Susan United States

Landry Sarah United States

Lease Christian United States

Lee Lucia United States

Lee Grace United States

Lee Choe Jane United States

Leger Marie-Michele United States

Lett Susan United States

Lewin Clement United States

Lewis Tamara United States

Lichtner Jennifer United States

Lievano Fabio United States

Lima Peter United States

Lorick Suchita United States

Lukus Lori United States

Lyons Russette United States

Malone Robert United States

Mansoura Monique United States

Marcy S(tephan) Michael United States

Martin Tyler United States

Martinez Lolita United States

Martone William United States
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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Mason Dean United States

Mazur Marie United States

McCubbins John (Tom) United States

McGarry Lisa United States

McGlynn Margaret United States

Mclaughlin Jeffrey United States

McLeod-Sordjan Renee United States

McLoughlin Sean United States

Meissner Cody United States

MelissaMB MelissaMB United States

Middleman Amy United States

Miller Claudia United States

Miller Michael United States

Milligan Mark United States

Mina Vivian United States

Moore Kelly United States

MOREL HEATHER United States

Morse Dale United States

Muhammad Riyadh United States

Mulach Barbara United States

murphy linda United States

Murphy Ann Terri United States

Myers Martin United States

Neloms Stacey United States

Newton Sharon United States

Nicholsosn Ouzama United States

Nott Billie United States

Obara Timothy United States

Offit Paul United States

O''Neill Kevin United States

Pahud Barbara United States

Paradiso Peter United States

Penrod Deborah United States

pernicka steve United States

Peters Martin United States

Peterson Diane United States

Pinckney Lennisha United States

Plotkin Stanley United States

Pugh Pearl United States

Quinn Jane United States

Randall Lisa United States

Ray Jill United States

Reeves-Hoche Mary Kathryn United States

Rennels Margaret United States

Richards Steve United States

Richardson Vesta United States

Robert Malone United States

Robinson Robin United States

Ross David J. United States

Rousculp Matthew United States
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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Rubin Jaime United States

Sadr-Azodi Nahad United States

Saslow Debbie United States

Sawyer Mark United States

Sawyer Leigh United States

Schaffner William United States

Schechter David United States

Schmader Kenneth United States

Schott Chris United States

Seifert Harry United States

SHAW BETTY United States

Shiff Jeffrey United States

Shivaprakash Sathyanarayana United States

SIEVERT ALAN United States

Silsbee Jeffrey United States

Silverstein Leonard United States

Skjeveland Eric United States

Smalley Hannah United States

Sobczyk Elizabeth United States

Staples J Erin United States

Stein Gary United States

Stinchfield Patricia United States

Stobbe Michael United States

Stoddard Jeffrey United States

Strikas Raymond United States

Strutton David United States

Stuerke Stacy United States

Subbarao Italo United States

Sun Wellington United States

Sutton Jacqueline United States

Sylvester Gregg United States

Temte Jonathan United States

Temte Emily United States

Thomas Lonnie United States

Thomas Michael United States

Tsai Theodore United States

Turner James C. United States

Vakil Varsha United States

Van De Velde Steve United States

Vaughn David United States

Vaupel Christine United States

Vitale Steven United States

Vogt Kitty United States

Wallace Amy United States

Walpert Kirsten United States

Walters Jean United States

Wassil James United States

Wenick Barry United States

Wexler Deborah United States

Whitley-Williams Patricia United States
Advisory Committee on Immunization Practices (ACIP) Summary Report June 24-26, 2009

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Wible Sharon United States

Wick Kathy United States

Wighton Timothy United States

Willis English United States

Wilson Paul United States

Woldemariam Mahlet United States

Wyand Fred United States

Yamada Eileen United States

Yamauchi Terry United States

Zacharyczuk Colleen United States

Zacholski Donna United States