DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION

Advisory Committee on 

Immunization Practices (ACIP)

 

Summary Report

June 22-23, 2011

 Atlanta, Georgia 

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Table of Contents Page

Agenda 4-5 

Acronyms 6-8 

Wednesday: June 22, 2011

Welcome and Introductions 9-13

Herpes Zoster (HZ)

 Introduction

 Merck Vaccine Supply Status and Projections

 Licensure of Zostavax® For Adults Ages 50-59

14-27

Varicella

 Update on Varicella Epidemiology Since Implementation of Routine 2-Dose Varicella Vaccine for Children

27-32 

Meningococcal Vaccine

 Introduction

 Menactra® Indication for Two-Dose Series in 9 and 12 Month Olds

 Recommendation for Infants at Increased Risk for Meningococcal Disease

 Vaccines for Children (VFC) Program Vote

 MenAfriVac® (Meningococcal A Conjugate Vaccine) Introduction in Burkina Faso

32-52

MMR Vaccine Working Group Update

 Introduction

 2011 Measles Epidemiology Update (US)

53-57

Pertussis

 Introduction

 Safety of Maternal Vaccination to Mother and Fetus

 Decision and Cost-Effectiveness Analysis: Maternal Vaccination and Cocooning

 “Cocooning”

 Timing of Maternal Vaccination: Pregnancy or Postpartum? 

 Proposed Recommendation on use of Tdap for Contacts of Newborns (Cocooning) and Special Situations

 Tdap in Pregnant and Postpartum Women through Age 18 Years

 Emergency of Pertussis in Children Aged 7 through 10 Years and Early Evaluation of DTaP Effectiveness in California

57-83 

Vaccine Supply 84

Human Papillomavirus (HPV) Vaccines 

Introduction

Background

Quadrivalent HPV Vaccine: Duration of Protection

HPV-Associated Oropharyngeal Cancer

Cost-Effectiveness Issues for Male Vaccination

Policy Considerations: HPV for Males

84-103

Public Comments Day 1 103

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Thursday: June 23, 2011

Agency Updates

 CDC 

 Center for Medicare and Medicaid Services (CMS)

 Food and Drug Administration (FDA)

 Department of Defense (DoD)

 Department of Veteran’s Affairs (DVA)

 Heath Resources and Services Administration (HRSA)

 Indian Health Services (I HS)

 National Vaccine Advisory Committee (NVAC)

 National Vaccine Program Office (NVPO)

104-107

General Recommendations: Febrile Seizures

Introduction

Clinical Aspects of Febrile Seizure

Safety Data Update

Burden of Disease Information: Next Steps

107-118 

Hepatitis B Vaccine

Introduction

Update of Hepatitis B Incidence Among Persons with Diabetes

Cost-Effectiveness of Hepatitis B Vaccination Among Persons with Diabetes

Next Steps

118-132 

13-Valent Pneumococcal Conjugate Vaccine (PCV13)

 Introduction

 Public Health and Economic Impact of PCV13 in US Adults ≥50 Years of Age

 Current Epidemiology of Pneumococcal Disease in Adults

 Considerations for PCV13 Use Among Adults: Summary of Immunogenicity and Efficacy; Cost-Effectiveness Studies

132-146

Influenza

 Introduction

 Epidemiology / Surveillance Update

 2010-2011 Seasonal Vaccine Coverage

 2010-2011 Season Vaccine Effectiveness

 Fluzone® High Dose Update

 Intradermal Influenza Vaccine

 Influenza Vaccine and Egg Allergies

146-166

Public Comment Day 2 167

Certification 167

Participant Roster 168-174

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PURPOSE PRESIDER/PRESENTER(s)

8:00 Dr. Carol Baker (ACIP Chair)

Dr. Larry Pickering (ACIP Executive Secretary; CDC)

8:30

Dr. Paul Cieslak (ACIP, WG Chair)

Dr. Eddy Bresnitz and Mr. Jim Robinson (Merck)

Dr. Rafael Harpaz (CDC/NCIRD)

Discussion

10:00

Information Dr. Stephanie Bialek (CDC/NCIRD)

10:15

10:45

Dr. Cody Meissner (ACIP, WG Chair)

Information Dr. David Johnson (Sanofi)

Discussion & 

Vote

Dr. Amanda Cohn (CDC/NCIRD)

Vote Dr. Lance Rodewald (CDC/NCIRD)

Information Dr. Thomas Clark (CDC/NCIRD)

11:40

Dr. Jon Temte (ACIP, WG Chair)

Information Dr. Huong McLean (CDC/NCIRD)

12:00

1:00

Dr. Mark Sawyer (ACIP, WG Chair)

Dr. Sonja Rasmussen (CDC/OID)

Dr. Garrett Asay (CDC/NCIRD)

Dr. Jennifer Liang (CDC/NCIRD)

Dr. Jennifer Liang (CDC/NCIRD)

Vote Dr. Jennifer Liang (CDC/NCIRD)

Vote Dr. Jennifer Liang (CDC/NCIRD)

VFC Vote Dr. Lance Rodewald (CDC/NCIRD)

Information & 

Discussion

Dr. Lara Misegades (CDC/NCIRD)

2:45 Information Dr. Lance Rodewald (CDC/NCIRD)

3:00

3:30

Dr. Janet Englund (ACIP, WG Chair)

Dr. Lauri Markowitz (CDC/NCHHSTP)

Dr. Alfred Saah (Merck)

Dr. Aimee Kreimer (NCI) 

Dr. Harrell Chesson (CDC/NCHHSTP)

Dr. Eileen Dunne (CDC/NCHHSTP)

5:00 Public Comment

5:15 Adjourn

· Introduction

· Emergence of pertussis in children aged 7 through 10 years and 

early evaluation of DTaP effectiveness in California

Break

· Introduction

Vaccine Supply

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 22-23, 2011

Herpes Zoster Vaccine

AGENDA ITEM

Welcome & Introductions

Wednesday, June 22, 2011

· Introduction

Varicella

· Discussion

· Tdap in pregnant and post-partum women through age 18 years

Break

Meningococcal Vaccine

· Introduction 

· Menactra indication for a two dose series in 9 and 12 month olds

· Recommendations for infants at increased risk for 

meningococcal disease

· Safety of maternal vaccination to mother and fetus

· Update on varicella epidemiology since implementation of 

routine 2-dose varicella vaccination for children

· MenAfriVacTM (meningococcal A conjugate vaccine) introduction 

in Burkina Faso

· "Cocooning"

· Timing of maternal vaccination: pregnancy or post-partum?

· Proposed recommendations on maternal Tdap vaccination

Information & 

Discussion

· Policy considerations - HPV vaccine for males

Information &

· Licensure of Zostavax for adults of ages 50-59

· HPV-associated oropharyngeal cancer

· Merck vaccine supply status and projections

Pertussis

Lunch

· Quadrivalent HPV vaccine: duration of protection

· Proposed recommendation on use of Tdap for contacts of 

newborns ("cocooning") and special situations

· Decision and cost-effectiveness analysis: maternal vaccination 

and cocooning

· Vaccines for Children (VFC) program vote

MMR Vaccine Work Group Update

· Introduction

· 2011 measles epidemiology update (U.S.)

Human Papillomavirus Vaccines

· Background

· Cost effectiveness issues for male vaccination 

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PURPOSE PRESIDER/PRESENTER(s)

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 22-23, 2011

AGENDA ITEM

8:00 Dr. Carol Baker (Chair, ACIP)

8:15

Information Ex officio members

8:30

Dr. Jeff Duchin (ACIP, WG Chair)

Dr. Harry Keyserling (WG Member, SHEA; Emory 

University School of Medicine)

Dr. Jerome Tokars (CDC/NCEZID)

Discussion Dr. Andrew Kroger (CDC/NCIRD)

9:45 Break

10:15

Dr. Mark Sawyer (ACIP, WG Chair)

Ms. Meredith Reilly (CDC/NCHHSTP)

Dr. Tom Hoerger (RTI International)

Dr. Trudy Murphy (CDC/NCHHSTP)

11:15

Dr. Mike Marcy (ACIP, WG Chair)

Dr. David Strutton (Pfizer)

Dr. Tamara Pilishvilli (CDC/NCIRD)

Dr. Tamara Pilishvilli (CDC/NCIRD)

12:35 Lunch

1:45 Influenza

· Introduction Dr. Wendy Keitel (ACIP, WG Chair)

Information

Dr. John Kelso (Scripps Clinic, University of 

California, San Diego); Dr. Matthew Greenhawt 

(University of Michigan Medical School, Ann Arbor); 

Dr. Matthew Fenton (NIAID, NIH)

Vote Dr. Lisa Grohskopf (CDC/NCIRD)

Information & Dr. David Johnson (sanofi pasteur)

& Discussion Dr. David Johnson (sanofi pasteur); Dr. Pedro Moro 

(CDC/NCEZID)

3:05 Public Comment

3:20 Adjourn

DTaP

NCCDPHP

NCEZID

NCHHSTP

NCI 

NCIRD

OID

RTI

SHEA

TBD

Tdap

WG Work Group

Agency Updates

National Center for Chronic Disease Prevention and Health Promotion

National Center for Emerging and Zoonotic Infectious Diseases

National Center for Immunization and Respiratory Diseases

To be determined

Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine

National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention 

Information & 

Discussion

· Public health and economic impact of PCV13 in US adults ≥50 

years of age

CDC, CMS, DoD, DVA, FDA, HRSA, IHS, NVPO, NIH

· Safety data update

· Cost effectiveness of hepatitis B vaccination among persons with 

diabetes

· Next steps

· Considerations for PCV13 use among adults; summary of 

immunogenicity and efficacy; cost-effectiveness studies

· Introduction

Hepatitis B Vaccine

General Recommendations: Febrile Seizures

· Clinical aspects of febrile seizures

Society for Healthcare Epidemiology of America

National Cancer Institute

Office of Infectious Diseases

Research Triangle International

Diphtheria, Tetanus, and Acellular Pertussis Vaccine

Acronyms

Information 

Information & 

Discussion

· Introduction 

· Current epidemiology of pneumococcal disease in adults

13-valent Pneumococcal Conjugate Vaccine (PCV13)

· Introduction

· Update of hepatitis B incidence among persons with diabetes 

· Fluzone High Dose update

· Intradermal influenza vaccine

· Influenza vaccine and egg allergies

· Proposed recommendations

· Burden of disease information; next steps

Unfinished Business

Thursday, June 23, 2011

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Acronyms

AAP American Academy of Pediatrics

ABCs Active Bacterial Core Surveillance 

ACHA American College Health Association

ACNM American College of Nurses and Midwives

ACP American College of Physicians 

ACIP Advisory Committee on Immunization Practices

ADL Activities of Daily Living 

AEs Adverse Events

AHIP America’s Health Insurance Plans 

AIM Association of Immunization Managers 

AIN Anal Intraepithelial Neoplasia 

AMA American Medical Association

ANA American Nurses Association 

ASTHO Association of State and Territorial Health Officials

BLA Biologics License Application

BRFSS Behavioral Risk Factor Surveillance System 

CAP Community Acquired Pneumonia 

CDC Centers for Disease Control and Prevention

CDPH California Department of Public Health 

CIN Cervical Intraephithelial Neoplasia

cLIA Competitive Luminex immunoassay 

CMI Cell-Mediated Immunity 

CMS Centers for Medicare and Medicaid Services

COI Conflict of Interest

CUA Cost-Utility Analysis 

DoD Department of Defense

DSMB Data Safety Monitoring Board

DTaP Diphtheria, Tetanus, and Pertussis 

DVA Department of Veterans Affairs

EBRWG Evidence-Based Recommendations Work Group 

ECMO Extracorporeal Membrane Oxygenation 

EIP Emerging Infections Program

EIS Epidemic Intelligence Service

ELISA Enzyme-Linked Immunosorbent Assay 

EMR Electronic Medical Record

FDA Food and Drug Administration

FIFO First In First Out 

GAO Government Accounting Office 

GMCs Geometric Mean Concentrations

GMTs Geometric Mean Titers

GRADE Grades of Recommendation Assessment, Development and Evaluation 

GSK GlaxoSmithKline

HCC Hepatocellular Carcinoma 

HCP Healthcare Personnel 

HCUP Healthcare Cost and Utilization Project

HICPAC Healthcare Infection Control Practices Advisory Committee 

HepA Hepatitis A

HepB Hepatitis B

HHS Department of Health and Human Services 

Hib Haemophilus influenzae B 

HPV Human Papillomavirus

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HMO Health Maintenance Organization 

HZ Herpes Zoster

HZV Herpes Zoster Vaccine 

HRSA Health Resources and Services Administration 

IARC International Agency for Research on Cancer 

ICURs Incremental Cost-Utility Ratios 

ICD-9 International Classification of Diseases, Ninth Revision

IDSA Infectious Disease Society of America

IDU Injection Drug Use

IgG Immunoglobulin G

IHS Indian Health Services

ILI Influenza-Like Illness

ILINet Influenza-Like Illness Surveillance Network

IOM Institute of Medicine

IPD Invasive Pneumococcal Disease 

ISO Immunization Safety Office

JAMA Journal of the American Medical Association 

LEEP Loop Electrosurgical Excision Procedures

LTPS Long Term Persistence Study 

MCO Managed Care Organization

MMR Measles, Mumps, Rubella

MMRV Measles, Mumps, Rubella, Varicella

MMWR Morbidity and Mortality Weekly Report

MOMs Moms on Meningitis 

MSM Men Who Have Sex With Men 

NACCHO National Association of County and City Health Officials 

NACI National Advisory Committee on Immunization 

NBP Nonbacteremic Pneumonia 

NCHHSTP National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

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

NFID National Foundation for Infectious Diseases

NHANES National Health and Nutrition Examination Survey 

NHIS National Health Interview Survey 

NIAID National Institute of Allergy and Infectious Diseases 

NIH National Institutes of Health

NIS National Immunization Survey 

NMA National Medical Association

NNDSS National Notifiable Diseases Surveillance System 

NPP Non-bacteremic Pneumococcal Pneumonia

NVAC National Vaccine Advisory Committee 

NVPO National Vaccine Program Office

OPA Opsonophagocytic

PAHO Pan American Health Organization

PBNA Pseudovirion-Based Nutralization Assay 

PCR Polymerase Chain Reaction 

PCV Pneumococcal Conjugate Vaccine

PHN Post-Herpetic Neuralgia 

PPACA Patient Protection and Affordable Care Act 

PPV23 23-Valent Polysaccharide Vaccine

QALY Quality-Adjusted Life Year 

RCA Rapid Cycle Analysis

RCT Randomized Controlled Trial

SAEs Serious Adverse Events 

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SBA-HC Bactericidal Assay Antibody Titers using Human Complement 

SME Subject Matter Expert

SPR Seroprotection Rate 

SPS Shingles Prevention Studies

STPS Short Term Persistence Study 

Tdap Tetanus and Reduced Diphtheria Toxoids 

TIV Trivalent Inactivated Influenza Vaccines 

UK United Kingdom 

US United States

USPHS US Public Health Service 

VAERS Vaccine Adverse Event Reporting System

VFC Vaccines for Children

VICP Vaccine Injury Compensation Program

VIS Vaccine Information Statement 

VSD Vaccine Safety Datalink

VZV Varicella-Zoster Virus

WG Working Group

WHO World Health Organization

ZEST Zostavax® Efficacy and Safety Trial 

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June 22, 2011

Discussion

Dr. Carol Baker

Chair, ACIP

Dr. Larry Pickering 

Executive Secretary, ACIP / CDC

Dr. Baker called the meeting to order, welcoming those present. She then introduced Dr. 

Pickering who delivered the administrative announcements.

Dr. Pickering welcomed everyone to the June 2011 Advisory Committee on Immunization 

Practices (ACIP) meeting. As with previous ACIP meetings, he indicated that the proceedings 

of this meeting would be accessible to people not in attendance via the World Wide Web, and 

he welcomed those who could not attend the meeting in person. Notably, during the February 

2011 meeting there were 27,570 sites watching.

He then recognized several others in the room who were to be present throughout the duration 

of the ACIP meeting to assist with various meeting functions: Stephanie Thomas, Committee 

Management Specialist for ACIP; Natalie Greene, Maximum Technology Corporation; and 

Tanya Lennon, Special Assistant. Those with any questions were instructed to see him, any of 

these individuals, or Dr. Baker. He indicated that boxed lunches would be provided for a charge 

during the first day of the meeting in the hallway outside of the auditorium, and that coffee and 

tea would be available in the hallway for the duration of the meeting. 

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

for others on the tables outside of the auditorium. Slides presented at this meeting will be 

posted on the ACIP website approximately one week after the meeting concludes, the live 

webcast will be posted within three weeks following the meeting, and meeting minutes will be 

available on the website within 90 days following this meeting. Members of the press interested 

in conducting interviews with various ACIP members were instructed to contact Tom Skinner, 

CDC Public Affairs Specialist, who was in attendance, for assistance in arranging the interviews.

Dr. Pickering recognized the following visitors:

From the World Health Organization’s (WHO’s) Pan American Health Organization (PAHO), and 

from Ministries of Health of PAHO member countries:

 Dr. Cara Janusz, PAHO Technical Officer, PAHO Office in Washington, DC

 Dr. Gloria Rey, Sub-director, Lab Network of the National Institute of Health in Colombia, 

liaison to the National Committee on Immunization Practices in Colombia

 Dr. Gabriel Wolf Oselka, Technical Advisory Committee on Immunizations in Brazil

 Dr. Misael Gómez, National Immunization Program in Mexico

Welcome and Introductions

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 Dr. Cristina Marino, President of Colombian Association of Pediatricians, Member of the 

National Committee on Immunization Practices

 Dr. Rafael Haeussler, Director of Integrated Primary Care Programs at the Guatemalan

Ministry of Health

From The Republic of Korea: 

 Ms. Min Jung Seo, Assistant Director, Korea Centers for Disease Control & Prevention

 Ms. Kwang Suk Park, Research Scientific Officer, Korea Centers for Disease Control & 

Prevention

 Ms. Jonghee Kim, Technical Specialist, Korea Centers for Disease Control and Prevention

Those unable to attend this ACIP meeting for either or both days included the following:

Ex Officio Members

 Dr. Richard Gorman from National Institutes of Health was unable to attend; Dr. Mirjana 

Nesin attended on his behalf.

 Dr. Norman Baylor, ex officio member representing the Food and Drug Administration (FDA) 

was unable to attend; Dr. Wellington Sun attended on his behalf.

 Dr. Bruce Gellin, Director, National Vaccine Program Office (NVPO) was unable to attend; 

Dr. Mark Grabowsky, NVPO Deputy Director, attended on his behalf.

 James Cheek, MD, MPH, liaison for Indian Health Services (IHS) was unable to attend; Amy 

Groom, MPH, Director, IHS National Immunization Program attended on his behalf. 

Liaison Representatives

 Dr. Joanne Langley has concluded her term as the chair of Canadian National Advisory 

Committee on Immunization (NACI), and Dr. Bryna Warshawsky is the new ACIP liaison 

representative for NACI.

 Dr. Mark Netoskie, liaison representative for America’s Health Insurance Plans (AHIP) was 

unable to attend; Dr. Richard Doskey, Regional Medical Officer for Humana/New Orleans, 

attended on his behalf.

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

not directly related to discussions of ACIP in the hall and to turn off all cell phones or place them 

in the vibrate mode. 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. 

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

comment. During this meeting, a time for public comment was scheduled following the 

afternoon sessions during both meeting days. In certain circumstances, a formal comment 

period may be scheduled during the deliberations of a specific agenda item rather than at the 

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end of the day in order to be considered before a vote is taken. Those who planned to make 

public comments were instructed to visit the registration desk in the rear of the room to have 

Stephanie Thomas record their name and provide information on the process. Those who 

registered to make public comments were instructed to state their name, organization if 

applicable, and any conflicts of interest (COIs) prior to making their comments.

With regard to disclosure, to summarize conflict of interest provisions applicable to 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 a member’s 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 (DSMBs) may 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 the vaccines of that company.

Detailed instructions for submission of names of potential candidates to serve as ACIP 

members may be found on the ACIP website:

E-mail: acip@cdc.gov Web homepage: www.cdc.gov/vaccines/recs/acip/ 

Nominations: http://www.cdc.gov/vaccines/recs/acip/req-nominate.htm 

Applications for ACIP membership are due no later than November 18, 2011 for the term 

beginning July 2012. Interested parties were encouraged to complete an application and submit 

it by the deadline.

The following information was shared pertaining to ACIP:

Next ACIP Meeting: Tuesday and Wednesday October 25-26, 2011

Registration Deadlines: Non-US Citizens June 3, 2011 / US Citizens Monday October 10, 

2011

Vaccine Safety: www.cdc.gov/vaccinesafety/ 

Immunization Schedules:

http://www.cdc.gov/vaccines/recs/schedules/default.htm 

Childhood Vaccine Scheduler (interactive):

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

Adult Vaccine Scheduler (interactive):

http://www.cdc.gov/vaccines/recs/Scheduler/AdultScheduler.htm 

Vaccine Toolkit:

http://www.cdc.gov/vaccines/spec-grps/hcp/conversations.htm 

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Dr. Pickering noted that at every meeting, an update is provided on the status of ACIP 

recommendations. Since the last meeting there has been one ACIP statement published in the 

Morbidity and Mortality Weekly Report (MMWR): 

 Policy Note: Japanese Encephalitis Booster Dose; Publication date: 5/26/2011; Vol 

60(20):661-663

All ACIP recommendations published since 01-01-11 are reported in the following table:

The following conflicts of interest were declared:

 Dr. Tamera Coyne-Beasley: Research support from pharmaceutical companies is made to 

her university

 Dr. Janet Englund: Research support to her university from MedImmune, Novartis, 

Adamas, and Chimerix

 Dr. Wendy Keitel: Research support is made to her institution from Novartis

 Dr. Cody Meissner: Payments are made to Tufts University Medical Center by

MedImmune, Pfizer, and Roche for participation in multi-center clinical trials 

 Ms. Sara Rosenbaum: Research support to her university

 The remainder of the ACIP members declared no conflicts

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Dr. Baker lamented that June was a sad time of year, given that there were five retiring 

members: 

 Dr. Lance Chilton, Associate Professor, University of New Mexico

 Dr. Paul Cieslak, Medical Director, Oregon Immunization Program, Oregon Public Health 

Division

 Dr. Janet Englund, Professor, Department of Pediatrics Seattle Children's Hospital

 Dr. Franklyn Judson, Professor of Medicine, University of Colorado

 Dr. Jon Temte, Professor of Family Medicine, University of Wisconsin School of Medicine 

and Public Health has been reappointed until June 30, 2015 

Dr. Baker called each retiring member forth, presented them with a certificate and an engraved 

plaque, and thanked them for their service. Retiring members offered the following comments:

Dr. Chilton said that he had very much appreciated being on this committee. He quipped that 

before he joined ACIP, he thought that ACIP decisions were handed down on an engraved 

stone to Larry Pickering on a mountain top. He now knows that is not how decisions are 

handed down. He acknowledged the great deal of work that occurs during ACIP meeting, as 

well as in the work groups, and very much appreciated the chance to be involved in both 

components of the work. 

Dr. Cieslak said that it had been a privilege to serve on this committee, and that it had been like 

drinking data from a fire hydrant. He expressed his appreciation to Drs. Pickering and Baker, as 

well as the CDC staffers who make the deliberations possible. It has been an honor to be 

associated with his colleagues on this committee. 

Dr. Judson said it had been a real pleasure to serve on ACIP, and that he thought as a 

deliberative body, ACIP serves the country well, and the broader public health community 

globally.

Dr. Janet Englund said it had been a pleasure and an honor to serve on this committee. She 

said she thought they needed to acknowledge the unsung heroes, who are the CDC staffers 

who have worked harder than ever over the past few years. 

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Discussion

Session Introduction

Paul R. Cieslak, MD

Advisory Committee on Immunization Practices

Chair, Zoster Working Group

Dr. Cieslak introduced the Herpes Zoster Vaccine session, which included presentations on the 

following topic areas:

 Overview of Zoster Work Group (WG) deliberations regarding herpes zoster vaccine in 

adults 50–59 years of age

 Merck vaccine supply status and projections 

 Licensure of zoster vaccine among adults 50–59 and detailed review of considerations of 

the WG

With regard to background, Dr. Cieslak reminded everyone that the FDA licensed Zostavax® for 

adults ≥60 in May 2006. In October 2006, ACIP recommended Zostavax® for adults ≥60. In 

2010, Merck completed the Zostavax® Efficacy & Safety Trial (“ZEST”) in persons aged 50–59. 

In March 2011, the FDA extended the indications for Zostavax® to adults aged 50–59.

The Zoster Work Group’s terms of reference were to review new data regarding use of zoster 

vaccine among persons 50–59 years of age, consider revision of ACIP recommendations and 

review zoster vaccine post-licensure data. Regarding the methods, approach, and activities, the 

Zoster WG has engaged in 14 conference calls and net-conferences since September 2010. 

They reviewed published and unpublished data pertaining to the epidemiology and natural 

history of zoster; zoster vaccine safety, immunogenicity, and efficacy data in persons 50 and 

older; programmatic issues, including financing, storage and handling; manufacturing, supply, 

and marketing information; and economic analyses.

The WG does not propose revision of existing recommendations regarding zoster vaccine. The 

rationale for this conclusion is that there is insufficient evidence regarding duration of vaccine 

protection to vaccinate well before the peak of zoster incidence. Perhaps paramount in the 

minds of many members of the WG was that it might be inappropriate to expand 

recommendations while zoster vaccine remains in short supply. If the limited supply of vaccine 

is used at ages during which zoster incidence is low, overall zoster incidence may increase. 

The decision of the WG is not intended to prejudice future deliberations.

Herpes Zoster Vaccine

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The next steps for the Zoster Working Group are to assess new data and address relevant 

issues regarding a variety of issues, including Zostavax® in persons taking corticosteroids, 

duration of immunity, Zostavax® in persons with HIV infection, inactivated OKA-VZV in marrow 

transplant recipients, and other issues that arise. The membership of the working group will be 

adjusted as appropriate, and Dr. Jeffrey Duchin will serve as the new chair of this working group 

upon Dr. Cieslak’s departure.

Introductory Remarks: Merck Vaccine Supply Status and Projections

Dr. Eddy Bresnitz

Merck & Company, Inc.

Dr. Bresnitz expressed his gratitude for the opportunity to make a few introductory comments. 

Last summer, Merck requested that CDC reconstitute the Zoster WG that was disbanded in 

2006 subsequent to making the current recommendations. He offered Merck’s appreciation for 

CDC’s willingness to consider making a recommendation in the 50 to 59 year old age group to 

help prevent herpes zoster and its complications.

As Dr. Cieslak noted, one of the reasons for the WG’s decision not to vote on a 

recommendation change at this time regarded uncertainty about whether the vaccine supply 

would meet the increased demand generated among persons 50 through 59 years of age. 

Although Dr. Bresnitz explained that Merck is confident about its ability to meet projected 

increased demand, based upon experience and market research, Merck certainly respects the 

decision of the WG and CDC to postpone a vote and to emphasize vaccination of the eligible 

population 60 and older. 

Dr. Bresnitz pointed out that while Dr. Robinson’s upcoming presentation was intended to help 

the ACIP membership understand why Merck is optimistic about its ability to meet expected 

demand of zoster vaccine, it is important to note that addressing the supply constraints is 

necessary, but not sufficient to improve herpes zoster vaccine coverage in the US among the 

eligible population. There have been great improvements in adult vaccination coverage over 

the last decade, but the vaccination uptake has plateaued in this population for a variety of 

reasons. One reason is that the culture and enterprise for adult vaccination needs 

strengthening at all levels, which was highlighted in a report that was recently voted on by the 

National Vaccine Advisory Committee (NVAC). That report reflects improved uptake of adult 

vaccines, but also reflects on the fact that there are many factors other than vaccine supply that 

impact uptake. 

Merck looks forward to working collaboratively with CDC, ACIP, and other stakeholders to 

improve uptake of herpes zoster and other vaccines. The decision by the WG to postpone the 

vote begs the question: For how long? Dr. Bresnitz noted that as they listened to the 

presentations that followed his, Merck would like ACIP and CDC to consider the establishment 

of criteria or milestones, with input from Merck that would trigger reconsideration of a vote and a 

potential recommendation for the 50 to 59 year old population at some future point. Specifying 

such criteria or milestones could create a common platform for establishing a joint move forward 

to making this important vaccine available to all eligible US people over the age of 50, as well as 

globally to people who can benefit from the vaccine as Merck builds its supplies and inventory. 

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Supply Update on Varicella Containing Vaccines

James Robinson, Vice President

Vaccines Product & Technical Operations

Merck Manufacturing Division

Mr. Robinson indicated that he is responsible for vaccine manufacturing at Merck. His specific 

responsibilities are the long-term production strategy for Merck’s vaccines, as well as technical 

support of manufacturing. He has been with Merck for 15 months, and has spent the majority of 

his time working on this particular topic in order to improve this supply issue. Prior to joining 

Merck, he had 25 years of experience in vaccine manufacturing and development in the 

industry, including running the nation’s only influenza manufacturing facility for 9 of those years. 

The Zostavax® story begins somewhat before the licensure of Zostavax® in 2006. Varivax®, 

the varicella vaccine for chicken pox, was licensed in 1995. The bulk manufacturing process to 

support that product is the same process that supports all other products in this product line. 

The 1995 licensure of Varivax® was followed by licensure of ProQuad® (MMRV) in 2005 and 

the Zostavax® (Shingles) licensure in 2006. Each product has been licensed in both a frozen 

and a refrigerated formulation. All six products are manufactured from the same vaccine bulk, 

and different products require different amounts of bulk. To put in context one of the 

challenges, the manufacturing of the refrigerated formulation of Zostavax® requires 12 

equivalent doses of Varivax®. Zostavax® frozen requires 8 equivalent doses of Varivax®. 

Obviously, a decision must be made about what to make. Merck decided to prioritize the 

Varivax® formulation. However, manufacture of Zostavax® is more challenging than 

manufacture of Varivax®, and a percentage of batches do not have the potency for Zostavax® 

vaccine. A number of efforts are underway to improve this issue, and some progress has 

already been shown with the most recent results. 

While manufacturing vaccines is always complex, Dr. Robinson has never experienced a 

vaccine manufacturing process more complex than that needed to prepare bulk for the varicella 

vaccine product line. Varicella is an intercellular virus that grows on an attached cell line. In the 

manufacturing of a single batch of bulk, there are more than 25,000 individual manufacturing 

steps. The steps are completed in customized robotic systems in Grade A space to make sure 

the product has the appropriate quality. The capital, complexity of managing and maintaining 

that system, and cycle times are extensive. Improvements being made today will not be seen 

for approximately a year with respect to products reaching the marketplace. Improvements 

observed over the last 7 months were the result of work that was done roughly 12 to 18 months 

ago. Merck is already making the 2012 supply of varicella-containing products, and the 2011 

supply is already complete in the bulk form and is in various stages of analytical testing, form fill, 

and release.

Regarding variability of potency in the process, from a virology standpoint, it is not a highly 

variable process. However, from the standpoint of how Merck’s vaccines are designed, it is a 

sometimes a challenge to make the higher potency products. If there is any sustained period of 

time that there are no high potency batches, the ability to make Zostavax® is diminished. 

However, Merck is always able to and has successfully supplied Varivax® for the pediatric 

population in recent years. Merck is committed to meeting that market first; however, they 

continue to focus on ensuring that the company can meet all demands for all markets for these 

products.

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Over the last three years, Merck has produced from 1.7 to 2 million doses of Zostavax® vaccine 

per year in addition to Varivax® and with varying amounts of ProQuad® each year. Merck 

takes orders on a first in first out (FIFO) basis, and does not have preferred buying groups. 

They have been able to supply this product consistently at that level, although not consistently 

to meet the overall demand for this product in the marketplace. Since December 2010, 

approximately 2 million doses of Zostavax® have been distributed to over 38,000 unique 

customers across all customer types, and covering all 50 states plus the District of Columbia. In 

the last 7 months, that is more than any prior 12 month period since the product was launched. 

They expect to deliver another 2 million doses in 2011, doubling any previous year’s supply of 

Zostavax® vaccine. Merck expects to continue to increase that with increases of more than 

25% in 2012. With new facilities coming online, the opportunity to increase is expected, not in 

terms of percentage, but in terms of fold increases in supply. Again, these near-term 

improvements are based on work that was done last year.

Merck is executing a comprehensive strategy for reliable and ample supply. Whereas the 

process itself and the biology is variable, there are many things that organizations can do to 

reduce other variability, such as logistics variability, managing cold chain, and the process 

overall. Merck has increased diligence in these areas and has been able to produce some 

significantly better results over the past 12 months. The comprehensive strategy focuses on 

reliability in terms of work flow optimization and standardization, potency in terms of process 

enhancements, and capacity in terms of new facilities. Merck has invested over $1 billion over 

the last few years in new infrastructure for vaccines. The lion’s share has been allocated to 

building its varicella-based product supply, including a $750 million investment in Durham, North 

Carolina focused on manufacturing new bulk as well as sterile form filled vials of live viral 

vaccines. Meeting customer and patient demand across Merck’s portfolio of varicella-containing 

vaccines is a key priority for Merck. Merck’s goal is to stay off of CDC’s supply shortage list, 

and to work together with the agency to bring more products to more people.

In summary, live virus manufacturing is inherently complex. Varivax® will continue to be 

prioritized over other varicella-containing vaccines. The 2011 performance for supply of 

Zostavax® has materially improved versus prior years, with additional improvement expected in 

2012 and beyond. A comprehensive strategy is being executed to deliver a reliable and ample 

supply of all varicella-containing vaccines. Merck is committed to meeting customer and patient 

demand across its portfolio of varicella-containing vaccines, and to working closely with ACIP 

and the working group to manage recommendations moving forward. Merck welcomes any 

opportunities to present to ACIP regarding its supply situation.

Update: Zoster Vaccine for Adults 50-59 Years of Age 

Rafael Harpaz, MD MPH, CDC Lead, Zoster Working Group

National Center for Immunizations and Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Harpaz pointed out that Dr. Cieslak set the stage for his presentation by reporting the 

decision of the WG that it is not appropriate to consider changing the current ACIP 

recommendations for zoster vaccination of adults age 60 years and older. Given that zoster 

vaccine is now licensed and available for persons 50 to 59 years, the WG felt that it was very 

important to present their conclusions to ACIP and to be very transparent about how the WG

arrived at its conclusion. .

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In terms of the current status of herpes zoster vaccine (HZV) licensure and recommendations, 

as a reminder, the current zoster vaccine is for adults aged ≥60 years without any specified 

contraindications. This includes persons over 80, who are frail, with chronic illnesses. The 

vaccine is not intended for treating herpes zoster. It is recommended regardless of whether a 

patient reports a history of shingles. It is not necessary to screen for varicella history or to 

check varicella titers. Immunosuppression is a contraindication for HZV, and it is not 

recommended for persons who previously received varicella vaccine. The FDA initially licensed 

the vaccine for adults age 60 and older in May 2006, and extended it to adults ages 50 to 59 

years in March 2011. This was based on the demonstrated efficacy and safety in a Phase 3 

clinical trial, Zostavax® Efficacy and Safety Trial (ZEST), and related data.

In terms of the background of herpes zoster and post-herpetic neuralgia (PHN), important 

clinical manifestations of zoster are that it causes an acute, self-limited pain syndrome that can 

be disabling. It can cause acute ophthalmic involvement as well. The complications are of 

varying frequency and severity and include, most importantly, chronic pain or PHN. This pain is 

very difficult to control and can result in interference with activities of daily living; depression and 

its sequelae (e.g., isolation and occasional suicides); and many complications from the 

medications, particularly for the elderly population that is so afflicted by the disease. Chronic 

visual impairment can occur, there can be skin scarring or changes in pigmentation, secondary 

bacterial infections may occur, or there could be neurologic complications (e.g., meningitis, 

palsies, stroke syndromes).

With regard to the economic burden of herpes zoster, there are direct medical and non-medical 

costs such as outpatatient visits, emergency department visits, and / or hospitalizations; 

specialist referrals and consultations; laboratory tests and imaging / x-ray studies; and 

medications and therapeutic procedures. Indirect costs may include absenteeism and reduced 

productivity (also called presenteeism); productivity losses associated with deaths; care giving 

by family who help with activities of daily living; and / or pain and suffering. Most of the total 

herpes zoster disease burden, the predominance of which is pain and suffering, is borne by the 

individuals themselves. Pain and suffering are not usually even considered in most economic 

analyses of vaccine preventable diseases, and pain and suffering are very hard to measure.

Regarding the impact of age on burden of herpes zoster, virtually all adults are latently infected 

varicella zoster virus. Data from the National Health and Nutrition Examination Survey 

(NHANES) study published by Paul Kilgore about eight years ago show that the seroprevalence 

among the non-institutionalized population increases by age. According to these data, by age 

40, approximately 100% of the population is seropositive and thus at risk of herpes zoster 

[Kilgore, PE, et al. J Med Virol, 2003; 70:S111-118]. These results have been confirmed in 

subsequent NHANES data, and are also supported by the very few cases of varicella (e.g., 

chicken pox) reported amongst older adults in the US. 

The burden of herpes zoster increases sharply after age 50 years. Not only does the incidence 

of herpes zoster itself increase with age, but also among persons who experience zoster the 

following increase as well: the proportion of herpes zoster with non-pain complications (e.g., 

ophthalmic, neurologic, and skin complications); the proportion of persons with zoster who are 

hospitalized (with the length of stay and cost increasing as well); the proportion of herpes zoster 

associated with death, although for persons who are immunocompetent those numbers are 

quite small so they need to be validated; interference with activities of daily living (ADLs); and 

the proportion of herpes zoster with acute pain and progression to PHN. In terms of PHN, 

severity and duration of pain, inability to tolerate pain, duration / risk of prolonged pain increase 

with age as well. Even amongst persons who have PHN of a particular severity and particular 

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duration, age impacts the vulnerability, resilience, ability to access care, ability to tolerate pain 

medications. These factors are very hard to measure and have not been fully measured. Dr. 

Harpaz would argue that these are particularly important for the oldest old. The only exception 

to the relationship of increasing age to increasing burden of zoster is work loss and loss of workassociated productivity, since the portion of persons who are retired clearly increases with age. 

Data that support these assertions show that almost every aspect of the burden of zoster 

disease increases strikingly with age, more than just as a function of the risk of zoster or even 

the risk of PHN, that themselves are exponential. Data published four years ago by Barbara 

Yawn regarding zoster incidence in the general population of Olmsted County from 1996-2001 

illustrate the increase of zoster as age increases [Yawn BP, et al. Mayo Clin Proc, 2007; 

82:1341-9]. Data based on administrative claims data from the Marketscan databases show the 

impact of increasing age on the risk of zoster [Marketscan administrative claims data, Insinga et 

al., J Gen Intern Med. 2005, 20:748-53]. The percentage of zoster patients with non-pain 

complications are shown in Yawn’s Olmstead County data. These complications include skin, 

neurologic, and other ocular complications [Yawn et al., Mayo Clin Proc. 2007; 82:1341-9]. 

Data from the United Kingdom (UK) reflect the portion of persons with zoster who are 

hospitalized by age. These data show that even among a subset of persons with zoster who 

are hospitalized, the length of stay increases with age [Van Hoek et al. Vaccine 2009, 27:1454-

67]. Data from Connecticut pertaining to the rate of zoster-associated hospitalizations in the 

general population by age capture both the increase of zoster by age in the population, as well 

as the risk that those cases will progress to be hospitalized, which increases by age. These 

rates increase many fold from the age of 50 to 75, with 67% of HZ hospitalizations in persons 

>65 years of age[Lin F, Hadler JL. J Infect Dis 181(2000):1897-905].

Turning to the risk of PHN, Yawn’s data from Olmstead County show that the risk of zoster 

progressing to PHN defined as pain lasting at least 90 days increase 4-fold from patients age 50 

to 59 to patients over age 80 years. The same data expressed as an incidence of PHN in the 

general population rather than the proportion of zoster progressing to PNH illustrate that the rate 

increases many fold from the age of 50 to the age of 70 or 80 [Yawn, Mayo Clin Proc. 2007; 

82:1341-9]. Data from the UK regarding the proportion of PHN of moderate to severe pain by 

age show that even when controlling for PHN of a given duration, the severity of pain increases 

with age [Gauthier A, et al. Epidemiol Infect. 2009, 137:38-47], while data from the Shingles 

Prevention Study show how zoster impacts the activities of daily living as a function of age 

[Schmader K et al. J Am Geriatr Soc, 2010, 9:1634]. The only exception to the rule that every 

aspect of zoster grows worse with age is illustrated by data from the Bureau of Labor Statistics 

that show a decline in the portion of the total population in the workforce by age. Because of 

retirement, the impact of zoster and its complications on work loss decline with age as does the 

reduced productivity of persons who are at work with remaining zoster- or PHN- pain 

[http://www.bls.gov/cps/wlf-table1-2005.pdf]. 

To summarize, not only is the entire adult US population infected with varicella and thus at risk 

of HZ the rest of their lives, but the burden of HZ disease actually increases greatly in the latter 

half of life, decade by decade. This is a very different pattern from most other vaccine 

preventable diseases for which the peak risk period is self-limited or declines to low levels in the 

latter half of life, decade by decade. The only exceptions might be influenza, for which a 

vaccine is given each year, and perhaps pneumococcal disease. 

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With respect to the vaccine, the Shingles Prevention Study (SPS) by Oxman and others focused 

on adults ≥60 years of age and enrolled over 38,500 subjects in 22 US sites with mean follow 

up of 3.1 years. The vaccine efficacy for preventing HZ was 51.3%, while the vaccine efficacy 

for preventing PHN was 66.5%. This suggests that in addition to presenting zoster, the zoster 

that did occur among vaccines (e.g., vaccine failures) was milder than the zoster that occurred 

in the unvaccinated controls. The zoster among vacinees was also less like likely to progress to 

PHN, referred to as an incremental effect. There was also a trend for zoster among vaccinees 

to cause less interference with activities of daily living. Importantly, the incremental effect has 

been observed only in adults ≥70 years of age, at least in a convincing manner.

During the February 2011 ACIP meeting, Dr. Hung Fu Tseng presented data published in the 

Journal of the American Medical Association (JAMA) based on observations of 75,800 adults 

≥60 years of age in a large health maintenance organization (HMO) who had received vaccine 

as a part of routine clinical practice. He demonstrated that the field effectiveness of the vaccine 

was 55%, which is very similar to the SPS trial, and that the vaccine was more effective at 

preventing hospitalization associated with zoster (65%). The clinical trial and observational data 

differed, however, in an important way. The Oxman study showed that the vaccine efficacy for 

preventing zoster declined with age, but the Tseng study showed no such decline. These 

disparate results are explained on the basis of the fact that case finding between the two studies 

differed. It suggests that for persons 60 years of age and older, vaccine efficacy is stable by 

age for more severe and clinically meaningful disease picked up in a clinical setting than was 

observed in an observational study where there was aggressive case finding. In that setting, 

vaccine efficacy was more likely to decline with age for those milder cases that were seen in 

that context.

Also during the February 2011 ACIP meeting, results were presented regarding the ZEST 

clinical trial in subjects 50-59 [Schmader IDSA 2010]. The ZEST study included 22,400 

subjects in multiple US and ex-US sites, with a mean follow-up 1.3 years. The vaccine’s 

effectiveness at preventing HZ was 69.8%. Vaccine effectiveness at preventing PHN was not 

studied in the ZEST study because patients are only followed for 21 days. However, there was 

no difference in HZ severity-by-duration score by vaccine status (i.e., no evidence that HZ in 

vaccinees was milder in this age group). 

Safety of the vaccine has been assessed in SPS, ZEST, a large phase 4 trial, and two large 

observational studies, and safety has been monitored by the Vaccine Adverse Event Reporting 

System (VAERS). There is little suggestion to date of severe adverse events regardless of age. 

Conversely, local injection-site reactions appear to be very common and that risk declines with 

increasing age at vaccination.

The combined data from ZEST of persons 50 to 59 years of age and from the SPS in persons 

60 years and older show a striking decline in vaccine efficacy by age. These two studies were 

conducted in different settings with somewhat different methods, which is a very important 

caveat [ZEST (Schmader IDSA 2010) and SPS (Oxman NEJM 2005, 352:2271-84)]. These 

data stand in marked contrast with data from the observational studies in Southern California by 

Tseng et al, which shows that the vaccine performance is really quite stable by age [Tseng et al. 

JAMA 2011, 305:160-166]. As mentioned, one explanation for this is that vaccine efficacy 

against clinically meaningful disease is better retained with increasing age. Data from the SPS 

were used to evaluate vaccinated and unvaccinated persons in the study who developed zoster 

to determine whether they also developed PHN. There was an incremental effect in preventing 

PHN amongst vaccinees 70 years of age and older, although the numbers were small so the 

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confidence limits were pretty wide, No such effect was noted for persons age 60 to 69 years 

[Oxman, ACIP, Oct. 24, 2006].

In summary, the burden of zoster increases with age, and the performance of the zoster vaccine 

as a function of age is quite complex, with relative preservation of protection as a function of 

age for more severe disease and less for milder disease. In this context, if one is deciding upon 

a policy to vaccinate at the age of 50 to 59 rather than the later age, the duration of protection is 

quite important. The SPS lasted 5 years from 1999 to 2004, with a mean duration of follow-up 

of 3.1 years. The subset of subjects from that study was subsequently enrolled into an 

extension study called the Short Term Persistence Study (STPS), the purpose of which was to 

collect data on longer-term vaccine efficacy. These data clearly show that the zoster vaccine 

protects for 3 to 4 years, and the data are consistent with the possibility that it might protect for 

years longer as well. However, given the unique epidemiology of zoster with its burden of 

disease increasing over time over decades, the unanswered question is: Will the vaccine 

protect 15 years or 30 years when it really counts? The Long Term Persistence Study (LTPS) 

will extend the results of the STPS by several years, the results of which are anticipated within 

the year. The LTPS, however, uses historic controls. Most of the controls dropped out or 

became vaccinees themselves. Given that the incidence of zoster in the general population is 

changing, it requires sophisticated adjustments and it will be difficult to interpret the results. 

Immunogenicity is not especially helpful because there are no good serologic or cell-mediated 

immunity (CMI) correlates. There will be follow-up observational studies that will be important in 

time.

Data on durability of protection from the SPS combined with the STPS show that after a decline 

in vaccine efficacy during the first year, which seems to be a consistent finding in all of the 

studies, the efficacy appears to be relatively stable during the subsequent 3 years. Beyond that, 

it is really difficult to know whether vaccine efficacy is waning by year 7, much less to predict 

how well the vaccine will work years later. It is important to note the very wide confidence limits 

after year 3 or 4. Related data from the same study assess the efficacy of preventing PHN 

defined as 90 days of zoster pain or more. These PHN results are very unstable because the 

numbers are quite small, but it can certainly be said that all of the point estimates are greater 

than zero, so the vaccine is offering protection. However, it is not possible to say much about 

waning up to 7 years or beyond [Schmader, IDSA 2008]. 

According to the Social Security Administration (SSA), persons in the 50 to 59 year age group 

are expected to live 30 years [http://www.ssa.gov/oact/STATS/table4c6.html]. The 

epidemiology of zoster during those 30 years thus becomes very relevant, and we would want 

the vaccine to last that long.. 

The question with which the WG had to grapple was: Should zoster vaccine be recommended 

for person 50 to 59 years of age? Applying the Yawn data to a cohort of persons exactly 50 

years of age and following them for 7 years highlights the very limited extent to which those data 

on durability inform the issue at hand when compared to the timeframe of interest [Yawn et al. 

Mayo Clin Proc. 2007; 82:1341-9]. This emphasizes the challenge of extrapolating 7 years of 

imprecise data for decades to where most of the burden of occurs.

Even if zoster vaccine protects indefinitely with no waning at all, giving the vaccine to a person a 

long time before the burden of disease is highest is economically inefficient. It is analogous to 

taking out a mortgage on a retirement home at the age of 50 and only using it sporadically until 

age 75 years. Those dollars could be used otherwise, working in other ways. Economists call 

this concept discounting, and the conventional discount value used in the US for economic 

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studies is 3% per year. If one gave a hypothetical vaccine with lifelong protection 10 years 

before it was needed to prevent the corresponding disease, the cost of the hypothetical vaccine 

would be increased by about 30%. 

The WG heard several presentations on economic analyses of zoster vaccine in adults age 50 

to 59 years from manufacturers and CDC. The ACIP guidelines regarding economic analyses 

require that these be fully peer-reviewed by CDC economists before presentation to the ACIP. 

In light of the working group’s decisions on this vaccine, those peer reviews were not completed 

and, therefore, are not being presented during this session. However, Dr. Harpaz presented 

published data on related issues to illustrate some of the points regarding the impact of age and 

duration of protection on the cost-effectiveness of zoster vaccine.

Among adults ≥ age 60 years, the cost-effectiveness of zoster vaccine is less favorable at the 

youngest and oldest ages of that range. They form a J-shaped curve. It is less favorable at 

younger ages due to the lower burden of zoster. Protection is likely to wane by time zoster 

vaccine recipient reaches older ages when the burden of disease is high. Even assuming lifelong protection, outlay for the vaccine at an earlier age while the disease burden is low is 

economically inefficient. In terms of older ages, the cost-effectiveness is less favorable because 

of the decline in vaccine efficacy at older ages, and due to death in the elderly before the 

vaccine benefit accrues. The J-shaped curve is progressively more acute assuming shorterlived vaccine duration of protection; whereas, it is flatter if longer vaccine protection is assumed. 

Regarding the impact of age at zoster vaccination on its cost-effectiveness as compared to no 

vaccine policy at all, data from Canada were presented, assuming 15 years of waning

protection. The data show that the cost-effectiveness becomes more favorable with increasing 

age from 60 to 70 years, but then begins to become less favorable in a very steep manner due 

to the reduced initial vaccine efficacy and the issue pertaining to persons dying before the 

vaccine benefit accrues [Najafzadeh, Pharmacoeconomics 2009; 27:991-1004]. Similar data 

from the US show cost-effectiveness of the zoster vaccine at various ages 60 and greater 

compared to no recommendation. In this analysis, the investigator assumed that the vaccine 

does not wane at all through life, so there is very little curvature to the J. Just the same, there is 

a slight increase in the favorability of vaccinating at the age of 70 to 74, presumably due to 

discounting [Pellissier JM, et al. Vaccine 2007, 25:8326-37]. 

Data from the UK address the same question using various assumptions regarding vaccine 

effectiveness against PHN. Once again, the cost-effectiveness becomes more favorable if 

instead of vaccinating at age 60, vaccination is given at age 65, depending upon the 

assumptions [AJ van Hoek et al / Vaccine 27 (2009) 1454-1467]. The UK used these data to 

recommend the vaccine for persons 70 years of age, with a catch-up program for persons 70 to 

79. This is understood to be the current policy; however, the vaccine is not available at all in the 

UK at this time. In data addressing the same question for the US that assume the vaccine lasts 

only 10 years, the J-shaped curve is very prominent. The favorability of the vaccine increases 

with age to age 70 years, and then declines dramatically at older ages according to these data 

[Rothberg, et al., Clinical Infectious Diseases 2007, 44:1280]. Looking at the Rothberg data 

from the same paper in 2007 in a somewhat different way, the duration of protection is 

highlighted in terms of the way it influences the cost-effectiveness of different age 

recommendations for the reasons noted earlier. The most favorable cost-effectiveness across 

the range of duration of protection is vaccinating at age 70 years. In terms of the impact of 

duration of vaccine efficacy on cost-effectiveness, for 60-year old patients cost per QALY begins 

at around $300,000 with a very short duration of 4 years of protection, thus being extremely 

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unfavorable, and then plummets at 18 years to under $50,000 per QALY, a more favorable 

level.

In terms of programmatic considerations, zoster vaccine is the most expensive adult vaccine at 

approximately $161 per unit dose and about $151 for a 10-pack. Regardless, it is about 4 times 

the cost of pneumococcal vaccine and 10 to 20 times the cost of the various influenza vaccines. 

This leads to barriers to patients as well as to providers who have very high up-front inventory 

costs. The US formulation of Zostavax® must be stored at freezer temperature (≤5o F), a 

barrier for many providers in terms of stocking the vaccine. Medicare Part D financing is a 

barrier for many persons age ≥65 year, given that the reimbursement is very complex and 

typically involves high up-front or non-reimbursable costs. In addition, there are generic barriers 

to adult vaccination, including competing priorities for the provider in terms of chronic disease 

management and acute care needs; fragmentation of care for seniors, many of whom have 

multiple primary care doctors or specialist providers and no one knows who is accountable for 

handling the vaccines; lack of institutionalized well adult visits; and lack of a counterpart to 

school entry laws with a gatekeeping function in seniors. One bright spot is the growing role of 

pharmacies. Zoster vaccine can be administered in pharmacies in 45 states, including 35 states 

on a walk-in basis. This is remarkable in that it means pharmacies can provide a means to 

rapidly increase uptake, depending upon the level of promotion, interest, and vaccine supply.

There have been recurring supply problems for Zostavax® and other OKA-VZV containing 

vaccines such as ProQuad®. Several episodes over the past few years have been caused by a 

series of independent problems. Since licensure, there has not been a single full year during 

which Zostavax® has been unthreatened by disruptions or delays. Regarding the current status 

of the OKA-VZV vaccines, Zostavax® backorders are currently being filled, but the situation 

remains dynamic. ProQuad® is not currently available. Varivax® is prioritized, so the supply 

has never been directly affected over these years. Merck has been hopeful about future supply, 

but was reassuring during the prior disruptions and upon the initial launch of Zostavax®. A 

letter from the manufacturer dated July 2008 distributed just a few weeks after the ACIP 

recommendations for the zoster vaccine were published, stated that the reasons for shipping 

delays for Zostavax® were multi-faceted and noted that the demand for the vaccine increased 

due to increasing publicity and awareness, and that demand for varicella vaccine that relies on 

the same vaccine bulk material also increased to unprecedented levels driven by the ACIP 

recommendation for a second varicella vaccine dose. 

The potential impacts that these disruptions have on vaccine uptake are that they frustrate 

providers who must answer for lack of availability, potentially leading them to stop offering 

zoster vaccine. Patients may never return to be vaccinated, which leads to missed 

opportunities. Also, in a setting of short supply, there is not going to be much provider- or 

patient-level marketing and promotion, so providers and patients may be unfamiliar and 

uncomfortable with the vaccine. Finally, disruptions hinder public-sector activities and goal 

setting regarding zoster vaccine, including those for CDC’s own program. CDC had planned a 

number of activities to promote zoster vaccine, but cancelled them in light of the supply 

situation.

There are a number of considerations regarding expanding recommendations to adults age 50-

59 years before sustainable supplies are assured. In 2009, the most recent year for which 

National Health Interview Survey (NHIS) data are available, zoster vaccine uptake in adults ≥60 

years was just 10%. This may be somewhat higher currently. That means about 90% of adults 

≥60 years remain to be vaccinated. CDC projects that there will be approximately 93 million 

adults ≥60 years during this decade. Not all of these will be eligible for vaccine, but 40% uptake 

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by adults ≥60 years would require approximately 3.7 million doses per year throughout the 

decade. That compares to the approximately 7 million doses that were administered during the 

first 3 to 4 years based on the NHIS data. If the recommendations are expanded to adults age 

50 to 59 years, the corresponding numbers of adults ≥50 years would be about 140 million total, 

which would mean about 5.6 million doses would be needed per year to reach 40% of that 

target.

There are other implications to expanding the recommendations to adults age 50 to 59 years 

before sustainable supplies are assured. First, it can jeopardize the credibility of all of the 

players in the vaccine enterprise, public and private. Also in the setting of limited supplies, 

expanding the recommendation can lead to the diversion of vaccine to persons 50 to 59 years 

of age instead of to persons 60 years of age and older. This could occur due to differential 

promotion, differential patient interest, or differential barriers to access (e.g., Medicare Part D 

[ages 65+] vs. private insurance [ages 50-64]). This would result in a distorted policy that might 

reduce, rather than increase, disease prevention.

Assuming that 1 million doses of zoster are given to persons 50 versus 60 years of age in 2011 

and zoster outcomes are followed through 2015; and that there is no waning of initial vaccine 

effectiveness; and that there is no incremental effect at preventing PHN among vaccine failures 

for either age; the anticipated results of excess cases would be as follows:

 1,838 acute herpes zoster cases

 960 PHN cases (pain ≥90 days)

 1,107 PHN cases (pain 30-89 days) 

 321 herpes zoster cases with non-pain complications

 16,412 herpes zoster-associated outpatient visits

 323 herpes zoster -associated hospitalizations

 2,490 herpes zoster-associated hospital days 

For ACIP recommended programs, CDC is ultimately responsible for assuring that they work 

effectively and correctly. ACIP has never adopted an expansion of a vaccination program in the 

midst of a supply shortage. In fact, there were extensive discussions at CDC over the past year 

regarding whether the Zoster WG should be attempting to identify risk groups and prioritize 

allocation of the vaccine. In summary, it is hard to make the case to address an expansion in 

recommendations of the vaccine to new age groups before sustainable supplies are assured, 

especially if it might result in more, not less, disease.

Based on consideration of these issues, the Zoster WG agreed that it was not appropriate for 

ACIP to address a change in the zoster vaccine recommendations in the current context. The 

basis of this conclusion varied among the different members of the working group, but most 

members felt that the supply issues alone made for a compelling reason. Others were also 

concerned about the lack of evidence on durability of protection, although that was not quite as 

universal. 

In terms of next steps, CDC will prepare a Notice-To-Readers, which will alert public and 

providers about change in Zostavax® indication; report the results of the June 2011 ACIP 

meeting; emphasize the importance of current recommendations that persons ≥60 years of age 

be routinely offered zoster vaccine; and will point interested persons to CDC websites for more 

guidance. CDC will revise its HZ/HZV websites accordingly. The Zoster Working Group 

recognized that some providers or patients may wish to use licensed Zostavax® at ages 50 to 

59 years, and suggested that CDC provide limited technical guidance for such unThis document has been archived for historical purposes. (7/1/2011) 24

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recommended use based on the principles in current ACIP recommendations for persons age 

60 and older.

Discussion Points

Dr. Baker pointed out that one of the limitations has been the requirement for a freezer for this 

vaccine, which many providers do not have. With that in mind, she wondered whether the 

refrigerated formulation was anticipated to be available in the future.

Dr. Robinson responded that the refrigerated formulation requires 50% more bulk, so there 

would be fewer doses available if this formulation is prioritized. The frozen formulation is 

currently prioritized in order to have more doses available. As the supply expands, more doses 

of the refrigerated formulation can be made available. 

Dr. Judson thought there had been some publications to suggest that the field was getting 

closer to identifying CMI correlates.

Dr. Harpaz responded that two correlates have been used in the SPS and other studies. One is 

the fold rise of antibody levels, and the other is using various measures of CMI. Both are 

weakly correlated with protection, but they do not meet the test of being predictive.

Dr. Chilton said that as a pediatrician, he appreciated the emphasis on getting varicella vaccine 

distributed and as a senior citizen, he is glad to have his Zostavax®. His hospital requires all 

hospital employees, especially those who have contact with children, to be immunized against 

varicella unless they can prove they previously had varicella. He wondered why ACIP was not 

recommending Zostavax® for those who previously had varicella vaccine. In addition, he 

wondered whether anyone was studying the booster dose for those who had the vaccine at age 

60 years and are turning 70. 

Regarding the question about why the vaccine is not recommended for those who have 

previously had varicella vaccine, Dr. Harpaz replied that most individuals receiving the vaccine 

will not be aging to 50 years of age for decades, so it is still an academic point. To date, the 

data have shown that persons who are infected with the OKA strain, i.e., vaccinated with the 

attenuated varicella vaccine, are at much lower risk of zoster than persons who had the wildtype disease. That is very reassuring, and CDC continues to monitor the data closely. A 

conundrum would occur if we needed to consider giving an OKA based vaccine to someone to 

protect them from activation of that very same previously-administered attenuated virus. 

Regarding the question about whether a booster dose is being studied, Dr. Bresnitz responded 

that Merck has begun a booster study that was initiated a few months ago. This study is limited 

to a couple of the centers that were involved in the SPS. On average, these patients are about 

10 years older than when they were first vaccinated. This is an immunogenicity and safety 

study, the results of which will not be available for several years. 

Dr. Jenkins inquired as to whether private insurers are covering Zostavax®. 

Dr. Harpaz replied that surveys have shown that private insurance companies covering about 

90% of persons 60 years of age and older are offering the vaccine with first dollar coverage. 

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Dr. Bresnitz added that in the 65 years of age and older population, most will have Medicare 

Part D. For those 60 to 64 years of age, coverage depends upon their benefits. Over 90% of 

those privately insured or insured through Medicare Part D will have coverage under whatever 

plan they have. That coverage will depend upon their benefits, co-pays, co-insurance, dollar 

limits, et cetera. He did not believe that first dollar coverage applied to the Medicare population. 

A number of private insurance companies have already approved coverage for individuals in the 

50 to 59 years of age population. Of those who have insurance, about 35% are now covered for 

vaccination if they are between the ages of 50 to 59. 

Dr. Rosenbaum pointed out that an increasing paradox for ACIP with the implementation of the 

Patient Protection and Affordable Care Act (PPACA) is that virtually all public and private 

insurers other than Medicare will have first dollar coverage with no co-payment for all ACIP 

recommended immunizations. Under Medicare, vaccines are covered as Part D outpatient 

prescription drug benefits rather than as a Part B ancillary service. Medicare Part B will pay for 

the administration of the vaccine, but beneficiaries covered through Part D are subject to a $250 

deductible and cost sharing. Because it is not an in-office service the problem of stocking and 

supply is magnified. There is going to be an increasing situation in which routine use of some 

vaccines is particularly compelling for the elderly, those with disabilities, et cetera. However, 

these individuals will have the most difficulty getting financial access to the vaccine. This is 

recurring, disturbing, and perverse outcome of PPACA. ACIP should take this into 

consideration when tackling the larger questions of immunization policy. 

Dr. Temte pointed out that as an adult practitioner, he is forced into cost-effective services for 

his patients. He is amazed at how many of his patients over 65 years of age know about 

Zostavax®, how many want it, and how many refuse it when they understand the out-of-pocket 

costs. He is very good about providing Zostavax® for those patients ages 60 through 64 and 

364 days who still have private insurance. However, this comes to a halt once their Medicare 

goes into effect. Less than 5% of his patients on Medicare accept this vaccine. This is a case 

in which social policy does not match the science.

Dr. Bresnitz added that there is a provision under PPACA for the Government Accounting Office 

(GAO) to assess the issue of vaccine coverage in the Medicare population, although he was not 

sure whether it focused only on Zostavax®. A report should soon be published on this.

Dr. Marcy noted that an article was published by Harpaz et al in the Annals of Internal Medicine

that showed that the major barrier of adults getting zoster vaccine was financial. He thought it 

was important to note that only 2% to 7% of the eligible population has received the vaccine. It 

is too expensive, which a very simple answer to this complex situation.

Dr. Poland emphasized that supply issues make the complex cost issue even more difficult. He 

thought it was a good idea to put in place a planned mechanism to assess this situation in the 

future. He thought providing the vaccine at an age prior to the highest burden made sense. 

This is routinely done in the provision of pediatric vaccines, often decades before children are at 

risk. Among adult practitioners, increasingly more preventive measures are coalescing around 

the age of 50 when mammograms, colonoscopies, and other preventive measures are 

considered. Pediatrics established routine preventive visits and provisions of vaccines within 

that context, which drives the routine vaccine schedule, similarly and in parallel for age 50 years 

for adults. He also supported strong consideration of giving guidance of either suggested or 

recommended use in specific individuals for which the benefits might be clearer (e.g., 

immunosuppressed, chronic diseases, under age 60 years with a previous zoster episode). A 

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publication of the January 2011 proceedings of the Mayo Clinic showed a surprisingly high rate 

of recurrence—higher than what anyone was taught in formal training. 

Dr. Harpaz agreed that the study regarding recurrence was eye-opening for many people. The 

risk of recurrence reported was similar to the risk of an initial episode. In terms of consideration 

of vaccinating those under the age of 60 based on increased risk, there is no evidence that 

there is a higher risk in this age group. Immunocompromised individuals are of significant 

importance to consider, and the working group discussed this issue several years ago in terms 

of going below the recommended age group for certain subgroups. In theory, it is unknown 

whether protection against zoster would be retained if one became immunocompromised after 

vaccination. The only empirical evidence is that there was a group of individuals in the SPS 

who became immunocompromised and were followed prospectively. The zoster vaccine did not 

protect that group once they became immunocompromised. In the final analysis, more 

evidence is needed with regard to this issue. His program is very interested in this issue, and 

would like to assess it using observational data and so forth. 

Dr. Bresnitz pointed out that the vaccine cannot be used in those who are already 

immunocompromised, but Merck has launched a study using an inactivated vaccine in a 

transplant patient and is about to launch a study in tumor malignancy patients.

Dr. Harpaz noted that there is also an on-going study in people anticipating kidney transplants. 

Dr. Judson emphasized the importance of knowing whether immunosuppression degrades 

normally durable natural immunity before making a recommendation.

Discussion

Stephanie Bialek, MD MPH, Herpes Virus Team Lead

Epidemiology Branch, Division of Viral Diseases

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Bialek presented an update on the implementation and impact of the routine 2-dose varicella 

vaccination program for children. ACIP made a change from a routine 1-dose to a 2-dose 

varicella vaccination program for children in June 2006, with the first dose administered at age 

12 to 15 months and the second dose administered at age 4 to 6 years. The rationale for this 

change was that outbreaks occurring in highly vaccinated school populations placed a 

significant resource burden on state health departments. There is also incomplete protection 

after 1 dose, and improved disease control is anticipated with a 2-dose program. The second 

dose is expected to provide protection to the 15% to 20% of children who do not respond to the 

first dose. The risk of varicella is 3-fold lower in 2-dose vaccinees compared to 1-dose 

vaccinees.

There are a number of challenges to understanding the extent of implementation of a 2-dose 

varicella vaccination program among 4- to 12-year olds. There are no single national estimates 

of 2-dose coverage among 4- to 12-year old children. The National Immunization Survey (NIS) 

describes 1-dose coverage among children 19 through 35 months of age, and the NIS-Teen 

describes 2-dose coverage among 13 through 17 year olds. Dr. Bialek used a variety of 

sources to describe uptake among 4- to 12-year old children, including the number of doses 

Varicella

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distributed, adoption of school entry requirements, the Kindergarten Survey, and coverage 

estimates from varicella surveillance sites.

In terms of the number of doses of varicella vaccine distributed in the US from 2005 through 

2009, there was a dramatic 2.6-fold increase in doses distributed in 2007 compared to 2006. 

The number of doses distributed has stayed at that level or higher since [Biologics Surveillance 

Data, 2005-2009]. Data from 2000-2010 pertaining to varicella vaccine doses administered by 

age group from the Varicella Active Surveillance Project in Antelope Valley, California show a 

dramatic increase in the number of doses administered to 3- to 5-year olds, 6- to 9-year olds, 

and 10-to 12-year olds. This suggests that there was increased catch-up vaccination as well as 

well after the second dose recommendation. 

In terms of the varicella vaccination requirements for school entry in September 2007, a year 

after the recommendation was made, 4 states required 2 doses, 41 states required 1 dose, and 

6 states had no requirements. In the most recent school year, 2010, the number of states that 

required 2 doses for school entry at some point had increased to 30 and only 2 states had no 

school entry requirements. In terms of the estimated 2-dose coverage among children in 

kindergarten for the 2009-2010 school year, coverage estimated by program grantees ranged 

from 85% to 100%. Idaho, Nevada, and Pennsylvania collect information on 2-dose coverage 

among kindergartener students, but they do not have statewide 2-dose school entry 

requirements. Coverage among these three states is somewhat lower (63%, 77%, and 79% 

respectively), although it is still substantial considering there is no school requirement [MMWR 

June 3, 2011 Vol. 60/No. 21]. It is important to note that these data are collected in a variety of 

ways at the state level, and reflect a varying number of schools that have been surveyed, as 

well as doses that have actually been validated. But, they do offer a picture of what is 

occurring, at least among kindergarten students. 

Minnesota is one of the states in which CDC is conducting active surveillance for varicella 

outbreaks in 79 schools. The highest 2-dose coverage is among kindergarteners in these 

schools and among 7th graders, the two grades for which there is a school entry requirement in 

Minnesota. There has been a fair amount of 2-dose uptake among other grade levels that are 

not directly affected by the school entry requirement. There is fairly high 2-dose coverage 

among 1st and 2nd graders. However, 2-dose coverage remains fairly low among 3rd - 6th 

graders, which highlights the role of catch-up vaccination. In the Varicella Active Surveillance 

Project in Antelope Valley, California in 2009, where there are no varicella vaccine school entry 

requirements, kindergarten 2-dose coverage was 84% among kindergarten students and 96% 

among 5 year olds enrolled in a large managed care organization. 

The National Immunization Survey among teens is one of the only sources of data available for 

monitoring varicella vaccination coverage among adolescents. From the NIS-Teen, a history of 

varicella disease is becoming less common among adolescents, reported by only 66% of 13-17 

year olds in 2007. One dose varicella vaccination coverage among teens without a history of 

varicella increased from 66% in 2006 to 76% in 2007. Two-dose coverage among teens without 

a history of varicella remains low in the first year since the ACIP recommendation, with only 

19% of teens having received a second dose [MMWR Aug 20, 2010 Vol 59 No. 32]. More work 

is needed to ensure that catch-up with a second dose is fully implemented among adolescents. 

In addition, mechanisms are needed for monitoring vaccination coverage among older 

adolescents, including college students. 

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With respect to varicella vaccine safety, post-licensure safety monitoring of varicella vaccine 

reflecting 16 years of use and over 65 million doses is reassuring. Serious adverse events 

continue to be rare. Understanding adverse events following varicella vaccination requires 

varicella zoster virus (VZV) strain identification as there is no way clinically to determine whether 

a potential vaccine-related adverse event is due to or wild-type VZV or vaccine strain VZV. 

Laboratory capacity to perform VZV strain identification remains critical to monitoring potential 

adverse events following vaccination with this live virus vaccine. 

Shortly after the 2-dose program was recommended, severe local injection site reactions were 

reported after administration of the second dose of varicella vaccine. These resolved without 

complications, and are not commonly reported. [Walter PIDJ 2009]. While this does not seem 

to be a major problem with the second dose program, it is continually being assessed through 

the Vaccine Adverse Event Reporting System (VAERS). 

The strengths of VAERS are that this system can rapidly detect signals, can detect rare adverse 

events, and generates hypotheses for further study. VAERS data are available to the public via 

the internet at http://vaers.hhs.gov/index. VAERS also has well described limitations in that it 

cannot assess causality as it lacks information on unvaccinated comparison groups, has 

reporting biases (e.g., underreporting, differential reporting, stimulated reporting) and 

inconsistent data quality and completeness. Based on crude reporting rates for all U.S. VAERS 

reports after any dose of single antigen varicella vaccine from 2005 through 2009, the total 

reporting rates for all events have been fairly stable. It appears that there has been a decline in 

the last few years of serious adverse events. In summary, the FDA has not identified any new 

safety signals through routine surveillance for varicella vaccine since 2006 when the second 

dose was recommended for all children. Adverse events most frequently reported to VAERS 

are those expected from previous experience with the use of varicella vaccine (e.g., injection 

site erythema, swelling, and warmth). An analysis of reports to VAERS since the second dose 

recommendation is currently underway.

With regard to varicella incidence and outbreaks during the routine 2-dose varicella vaccination 

program, since 2006 when the second dose was recommended, a 78% decline has been 

observed in the two varicella active surveillance project sites; these declines have been seen in 

all age groups. The declines are especially noted in the age groups for which the second dose 

was recommended: 1 to 4 year olds and 5 to 9 year olds [Varicella Active Surveillance Project 

2000-2010; 2010 data preliminary]. There has been a 98% decline in varicella incidence overall 

since the introduction of varicella vaccination in 1995. The proportion of total cases which have 

occurred in vaccinated individuals has been approximately 60%. While 2-dose cases have 

been observed, this seems to have been at a fairly stable rate. There are similar data from 

other states. Varicella incidence declined 50% from 2005 to 2008 in Connecticut, with declines 

especially noted in 1- to 14-year olds [Kattan JID 2011]. In New Hampshire, varicella incidence 

declined 60% from 2006 to 2010, with greater than 70% declines among 5- to 14-year olds 

[Daly, Abstract presented at CSTE 2011].

With respect to outbreaks, the best longitudinal data come from the Varicella Active Surveillance 

Project in Antelope Valley, California (1995-2009). In the 2006-2009 period, a total of 21 

outbreaks were reported. This was in contrast to 42 outbreaks from 1999-2001, 46 outbreaks 

from 2002-2005 prior to the second dose recommendation, and in comparison to 236 shortly 

after the vaccination program was implemented. In the two most recent periods, the median 

number of cases and outbreaks has been fairly stable as have the duration of the outbreaks.

 

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Data on varicella outbreaks are available for a number of states. Connecticut reported 42 

outbreaks from 2005-2006, with a median size of 14 cases; and 2 outbreaks from 2008-2009, 

with a median size of 5 cases [Kattan JID 2011]. Six state and local health departments are 

funded by CDC to conduct varicella outbreak surveillance in schools. The overall picture from 

these projects is that very few outbreaks are being observed in these sites. Dr. Bialek shared 

data from three of these sites. New York City conducted surveillance in 120-330 schools and 

reported 1 outbreak in a non-participating school during the 2009-10 school year. Minnesota 

conducted surveillance in 80 schools statewide and reported 15 outbreaks from nonparticipating schools. West Virginia conducted surveillance in all public schools statewide and 

reported 19 outbreaks (n=167 cases). A case-control study is being conducted in West Virginia 

to assess 2-dose vaccine efficacy. 

At the time the 2-dose policy was recommended in the United States, a single vaccine efficacy 

study had been published. Kuter et all in PIDJ in 2004 showed a 98% 2-dose vaccine 

effectiveness. The three estimates that have been published since then have ranged from 88% 

to 98%.

In summary, the routine 2-dose varicella vaccination program for children has been fairly 

extensively implemented. Thirty states have 2-dose varicella vaccination school entry 

requirements, and in those states, 2-dose coverage among children in kindergarten was 

reported as 85% or higher. Fairly robust uptake has also been observed in sites that do not 

have 2-dose coverage, though coverage in these states lags somewhat behind coverage 

reported in those states with school entry requirements. In terms of impact, varicella incidence 

has declined in all age groups coincident with implementation of routine 2-dose varicella 

vaccination program for children. The greatest declines have been observed among children 

aged 5-14 years. Outbreaks also appear to be less common than they were during the 1-dose 

vaccination program.

Regarding future directions, it is clear that there is still room to more fully implement the routine 

second dose of varicella vaccine for the recommended age groups, and there is also work to do 

with catch-up vaccination for older children and adolescents. Additional studies are anticipated 

to better define incremental effectiveness of one versus two doses of varicella vaccine. The 

scarcity of varicella outbreaks has limited opportunities to investigate vaccine effectiveness, 

which speaks to the success of the program. Continued laboratory surveillance to monitor 

varicella vaccine adverse events associated with this live virus vaccine remains important, as is 

continued surveillance to monitor the long-term impact of routine 2-dose varicella vaccination on 

the epidemiology of varicella.

Discussion Points

Dr. Baker pointed out how nice it was to hear a wonderful public health success story. One of 

her motivations for Zostavax® is that she no longer sees varicella with complications in her 

hospital.

Dr. Hahn (CSTE) mentioned that although Idaho was shown as one of the two states with no 

requirements, earlier in the year, they passed a 2-dose requirement kindergarten entry 

requirement.

Dr. Whitley-Williams (NMA) wondered whether there was a correlation between the sites where 

the outbreaks occurred and the level of coverage.

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Dr. Bialek replied that while this is an area of great interest, they do not have enough data to 

assess the correlation. The sites that were funded to conduct varicella surveillance are a fairly 

even mix of sites that have a 2-dose school entry requirement and sites that do not. While 

kindergarten coverage appears to be higher in states with a 2-dose school entry requirement, 

overall coverage in schools appears to be fairly similar across all of the sites regardless of 

school entry requirement at this point in the early phases of the program. It is not possible to 

attribute a difference in outbreak rates by coverage at this point. As noted, having so few 

outbreaks has made this difficult to evaluate.

In terms of the age distribution in the outbreaks, Dr. Schaffner (NFID) wondered whether there 

was a shift to the older age groups. 

Dr. Bialek responded that a subtle shift has been noted in the active surveillance sites in that 

there has been an increase in median age of outbreaks from 8 to 9. Outbreaks are still 

occurring in elementary and middle schools. Given the small numbers found in the surveillance 

projects, it is difficult to definitively determine whether there has been an age shift. A majority of 

the outbreaks are being seen in middle school children, although they are still common among 

elementary students. CDC recently investigated an outbreak in Texas that was exclusively 

among elementary school students. 

Dr. Marcy wondered whether anyone had followed up on outbreaks to determine whether they 

could be traced to a single medical group or single provider. There a numerous ways to handle 

this vaccine, which is very fragile. 

Dr. Bialek said her understanding was that this had been assessed in several previous 

outbreaks, but there has never been a situation identified in which there was a single provider 

who was the source of vaccination in children in whom there was breakthrough disease. 

Dr. Seward added that early on in the 1-dose program this was assessed extensively, but states 

tired of looking because they could not find anything. In response to Dr. Schaffner’s question, 

Dr. Seward reported that age of infection is increasing, especially in unvaccinated persons. 

However, the incidence by age has dramatically declined in all age groups. There has not been 

an increase in incidence in any older age groups. People get confused with proportions versus 

incidence. It is important to keep in mind that incidence has dramatically declined in all age 

groups. 

Dr. Meissner agreed that this is another example of the remarkable success of a 

recommendation and guidance from CDC in terms of controlling another infectious disease. 

There was a great deal of discussion about adoption of the initial varicella vaccine, and there 

was a lot of reluctance to accept the recommendation for a second dose of the vaccine. He 

remembered that many people felt initially that the recommendation should have begun with 2 

doses. It was the perseverance of many people at CDC, including Dr. Seward, who brought 

about this accomplishment. 

Dr. Baker offered gratitude to former ACIP members for helping with that effort.

Dr. Seward indicated that there would be presentations during future ACIP meetings regarding 

the impact of the varicella vaccination program in preventing varicella-related deaths. A 97% 

decline in varicella deaths in children is reported on in a paper by Dr. Mona Marin that will soon 

be published in Pediatrics. In addition, future presentations to ACIP could also include updates 

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on the safety and effectiveness of varicella vaccine for preventing both varicella and herpes 

virus zoster in HIV-positive children.

Ms. Stinchfield (NAPNAP) reported that Children’s Hospital in Minnesota sees about one 

chicken pox case per month. These are primarily picked up through their coding and records 

review, meaning that they were not even sick enough to be tested, and as a result these cases 

were not picked up through lab surveillance. These children were evaluated clinically, 

diagnosed, and sent home. Having an in-patient in the hospital with severe chicken pox is 

highly rare, although it used to be very common. They are also not seeing severe illness in 

outbreaks. This speaks to herd immunity.

Discussion

Introduction

H. Cody Meissner, MD

Advisory Committee on Immunization Practices

Dr. Meissner reported that in the January 18, 2011 MMWR, two new recommendations were 

published for the use of meningococcal conjugate vaccine, including guidance for routine 

vaccination of adolescents as well as a booster dose. In addition, guidance was offered for a 2-

dose primary series administered 2 months apart for persons 2 through 55 years of age at 

increased risk of infection due to persistent complement component deficiency or functional or 

anatomic asplenia. Other persons at increased risks, such as microbiologists or travelers to an 

endemic area, were recommended to receive a single primary dose. An MMWR statement is 

being prepared that discusses the FDA approval in January 2011 of Menveo® (MenACWYCRM) in children 2 through 10 years of age. This statement also provides guidance regarding 

the interchangeability of the two MCV4 vaccines. This statement will note that either of the two 

MCV4 vaccines may be used in people 2 through 55 years of age and are preferred to 

quadrivalent meningococcal polysaccharide vaccine. Routine use of MCV4 in children 2 

through 10 years of age is not recommended.

The last MMRW report on prevention and control of meningococcal disease was published in 

May 2005. An updated supplement is being prepared and will include all recommendations for 

the use of the meningococcal vaccines. In April 2010, the FDA approved the use of MCV4-D 

Menactra® in children as young as 9 months of age. Prior to this, no meningococcal vaccine 

was licensed in children less than 24 months of age. Approval for this age group was based on 

the results from trials that evaluated the safety and immunogenicity of the vaccine in children 

who received a 2-dose series with a 3-month interval beginning at 9 months of age. During this 

session, the working group proposed expanding the age range for vaccination of certain 

children at increased risk from 2 through 10 years to 9 months through 10 years. It is 

anticipated that the number of children 9 through 23 months who will qualify for this indication 

will be small. Routine use of the vaccine in children 9 months through 23 months will not be 

recommended. Within the next year, FDA approval for two infant quadrivalent meningococcal 

conjugate vaccines is anticipated. These two vaccines would be administered in a 4-dose 

series at 2, 4, 6, 12 through 15 months of age. The working group is continuing to consider the 

issues surrounding routine infant and toddler vaccination. A discussion of the role of infant 

meningococcal vaccine is anticipated during the next ACIP meeting in October 2011.

Meningococcal Vaccine

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During this session, presentations were offered regarding immunogenicity and safety of 

Menactra® in children aged 9 through 23 months; recommendations for children aged 9 through 

23 months at increased risk for meningococcal disease; and an update on MenA conjugate 

vaccination campaign in Burkina Faso, Mali, Niger—three contiguous countries in West Africa.

Menactra® Indication for a Two-Dose Series in 9- and 12-Month Olds

David R. Johnson, MD, MPH

Senior Director, Global Medical Affairs

Sanofi Pasteur

Dr. Johnson reported that there is enormous variation throughout the world in terms of the 

serogroups that cause invasive meningococcal disease, and residents of the US have global 

contacts. A current example is a cluster of W135 cases in Southeast Florida from Argentina

and Brazil presumably. In the US, serogroups vary over time. Serogroup A was predominant in 

the first half of the 20th Century. There is no clear explanation regarding why serogroup A 

seemed to disappear, and there probably will not be a good explanation for its return if indeed it 

does return. From 1990-2008, seriogroup C decreased and then increased. Serogroup B 

decreased and Y increased. W135 remained more or less constant. Clearly, it is important to 

focus on all of these serogroups. In terms of the number of deaths due to vaccine-preventable 

invasive pneumococcal disease from 1998-2007, deaths in children at age 1 year, 2 through 4 

years of age, and 5 through 9 years of age are similar to deaths in children less than 1 year of 

age. Case fatality rates during this time period for all age groups were 16.3% for serogroup W135, 14.7% for serogroup C, and 12.0% for serogroup Y [Cohn AC, et al. Clin Infect Dis.

2010;50(1):184-191].

A number of years ago, the US Public Health Service (USPHS) asked vaccine manufacturers to 

develop quadrivalent vaccines. Indeed, these quadrivalent vaccines have become the standard 

of care since the 1980s. Menactra® is used worldwide and nearly 40 million doses have been 

distributed in the last 6 years since its first licensure. sanofi pasteur sought to extend the age 

indication for Menactra® down to 9 months of age to addresses an unmet medical need in this 

age group; provide the broad protection of a quadrivalent vaccine; provide clinical benefits 

similar to those of a 2-4-6 + booster schedule but with half the doses; and avoid issues 

associated with the increasingly crowded vaccination schedule at 2, 4, and 6 months of age.

The clinical development program included one Phase II study and three Phase III studies to 

support license extension of Menactra® down to 9 months of age. These included the following:

 Phase II: MTA26 (vaccination schedule), safety and immunogenicity of 1 and 2 dose 

schedules of Menactra®

 Phase III: 1) MTA44 (safety and immunogenicity), safety and immune response to a 9+12 

schedule of Menactra® given alone or concomitantly with either MMRV or PCV7 at 12 

months; 2) MTA37 (safety and immunogenicity), safety and immune response to MMRV or 

PCV7 when given with or without Menactra® at 12 months; and 3) MTA48 (safety), safety of 

Menactra® given concomitantly with MMRV + PCV7 + HepA compared to MMRV + PCV7 + 

HepA administered without Menactra® 

In the Phase II study, three groups were given 2 doses of Menactra® at 9 and 12 months of 

age, 9 and 15 months of age, or 12 months and 15 months of age. The three control groups in 

this study received either a single dose of Menactra® at age 15 months or 18 moths, or the 

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polysaccharide quadrivalent vaccine Menomune® at age 3 to 5 years. Blood samples were 

taken after each dose to assess the immune responses. Serum bactericidal assay antibody 

titers using human complement (SBA-HC) ≥1:4 are considered by many to be protective. In the 

study, the more conservative threshold of ≥1:8 was utilized. After a single dose of Menactra®, 

responses for A and C serogroups were consistent across the age range of 9 months to 18 

months. There were increases across this increasing age range for serogroups Y and W135. 

After 2 doses of Menactra® given to groups 1, 2, and 3 in this study, the antibody responses 

were high and comparable across all of the 2-dose schedules. About 3 years later, 60 of the 

children who had received 2 doses of Menactra® in MTA26 were given a booster dose of 

Menactra®, and their responses were compared to those from age-matched children receiving 

their first dose. Pre-vaccination seroprotection rates were higher in children who were 

previously primed with Menactra® and the post-vaccination titers were substantially higher, 

showing a very strong booster response in those who were previously primed. Comparing 

these data from Menactra® with those from several studies in the UK that have assessed 

persistence and boosting in children who received varying numbers of doses of meningococcal 

conjugate serogroup C vaccine, the antibody persistence following infant doses of MCC 

vaccines was similar to the persistence following infant / toddler doses of Menactra®. After a 

booster dose given in the second year of life, two years later these titers return to their prebooster baseline. This suggests that Menactra® gives comparable responses in this age group 

to the MCC vaccines that are used in Europe, and that regardless of the infant schedule, 

preschool boosting is necessary if on-going protection is desired.

In the Phase III studies, participants received Menactra® alone, Menactra® with concomitant 

vaccines, or concomitant vaccines alone. Sanofi Pasteur has safety data from over 3200 

participants in these three studies, and immunogenicity data from about half of them. In 

MTA44, participants received Menactra® at 9 and 12 months of age without or with MMRV or 

PCV7. A high proportion of the participants in this study achieved SBA titers ≥1:8 against each 

serogroup, and this seemed to be unaffected by co-administration of MMRV or PCV7. MTA37 

had a very similar design, but with a control group who received MMRV and PCV7 alone at 12 

months of age. Seroprotection rates in this study were consistently high after the second dose. 

The measles, mumps, rubella, and varicella seroprotection rates seem to be unaffected by coadministration with Menactra® compared to co-administration of MMRV and PCV7. The 

geometric mean antibody concentrations to some of the pneumococcal serotypes were 

decreased with co-administration of PCV7 and Menactra® compared with PCV7 and MMRV. 

Opsonophagocytic assays (OPA) were conducted, and the results were quite consistent with 

the geometric mean titer (GMT) results with the enzyme-linked immunosorbent assay (ELISA) 

geometric mean concentrations (GMCs). However, the proportion of participants who had OPA 

titers ≥1:8, which is the conservative estimate of pneumococcal protection, was essentially 

100% for all 7 serogroups. The reverse cumulative distribution curves emphasize that the OPA 

titers were substantially greater than 1:8 and that these were much greater than 1:4, which is 

often used as a threshold for pneumococcal protection.

In summary of the immunogenicity data, Menactra® induced protective levels of meningococcal 

responses in infants and induced protective levels of meningococcal responses when coadministered with MMRV or PCV7. Protective levels of MMRV responses were achieved when 

given with Menactra®, as were protective levels of PCV7 responses achieved when given with 

Menactra®.

With respect to safety, the objectives were to describe safety profile of Menactra® given at 9 

and 12 months of age, and to assess the safety profile of Menactra® given with or without other 

recommended vaccines at 12 months of age. The Phase III safety study assessed Menactra® 

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given alone at 9 and 12 months, Menactra® given concomitantly, and concomitant vaccines 

given with each other. From this study, there are data from over 3200 subjects. In terms of 

immediately adverse events, no difference was observed by treatment group. Solicited injection 

site reactions were collected for 7 days. In terms of tenderness, injection site reactions were 

slightly higher when Menactra® given with MMRV or PCV7, but no higher than when the 

concomitant vaccines are given with each other. The same was true with erythema at the 

injection site. Rates of injection site swelling across the different study groups were consistently 

quite low. Systemic reactions were collected for days 0 through 7 after vaccination. When 

Menactra® is given alone, fever is quite infrequent. When given concomitantly with other 

vaccines, fever is no more frequent than when other vaccines are given by themselves. 

Unsolicited adverse events were similar if Menactra® was administered alone or with 

concomitant vaccines. Medically significant adverse events were followed from Day 30 to 6 

months following vaccination, with 2% to 4% medically significant adverse events reported 

across all of the treatment groups. There was no difference between the groups. The same 

can be said for serious adverse events at 2% to 3% and no difference from group to group.

In summary of the safety data, Menactra® was safe when administered alone to infants as 

young as 9 months of age, and when administered concomitantly with MMRV, PCV7, or HepA 

at 12 months of age. Safety profiles of MMRV, PCV7, and HepA vaccines were comparable 

when administered with or without Menactra® at 12 months of age. The overall conclusions 

from these clinical studies are that Menactra® induced immune responses predictive of 

protection when 2 doses were administered 3 months apart to infants as young as 9 months of 

age. Menactra® was safe when administered to infants as young as 9 months of age, whether 

given alone or with concomitant vaccines. 

In terms of indication and usage, Menactra® vaccine is currently indicated for active 

immunization to prevent invasive meningococcal disease caused by N meningitidis serogroups 

A, C, Y and W-135. Menactra® is approved for use in individuals 9 months through 55 years of 

age. With respect to the infant indication, for the primary schedule Menactra® is given as a 2-

dose series at 9 and 12 months of age. For the catch-up schedule, in children up to 23 months 

of age, Menactra® is given as a 2-dose series 3 months apart. Nearly 40 million doses of 

Menactra® have been distributed worldwide. This quadrivalent vaccine is indicated for 

individuals 9 months through 55 years of age. The 2-dose infant schedule is designed to 

prevent meningococcal disease with half the number of doses that would be required if started 

at 2 months of age, and it avoids the already crowded immunization schedule. 

Sanofi Pasteur recognizes that the current epidemiology of meningococcal disease in the US 

does not support a universal infant recommendation. However, if and when that epidemiology 

changes, they strongly believe that Menactra® vaccine’s 2-dose infant indication is the best 

approach for infant immunization in the US because it provides the broad protection of a 

quadrivalent vaccine early in life; it is expected to provide substantial reductions in morbidity and 

mortality; it requires only half the number of doses of a 2-4-6 plus booster schedule; and it 

avoids disruptions of, or interference with, the infant 2-4-6 schedule. 

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Recommendation for Infants at Increased Risk for Meningococcal Disease

Amanda Cohn, MD

CDR, US Public Health Service

Advisory Committee on Immunization Practices 

Dr. Cohn discussed ACIP’s recommendations for MCV4-D, Menactra®, as a two-dose primary 

series for children aged 9 through 23 months of age at increased risk for meningococcal. As 

noted, MCV4-D as a two-dose primary series for children aged 9 through 23 months of age was 

approved by FDA in April 2011. This is the first meningococcal vaccine licensed for children 

aged less than 24 months. However, two infant vaccines with 2-, 4-, 6-, and 12-month 

schedules are likely to be licensed within a year. The working group is currently weighing the 

pros and cons of routine infant immunization, including MCV4-D. This information will be 

presented to ACIP during the October 2011 meeting.

The goal of this session was to extend the high-risk recommendations for 2 through 10 years 

and 19 through 55 years down to age 9 months of life. There are no prior ACIP 

recommendations for vaccinating high risk infants aged less than 24 months. The ACIP working 

group recognizes that all infants aged less than 1 year have higher rates of disease compared 

to other age groups; however, the focus of this session’s recommendation was to focus on 

specific groups with medical conditions or exposure risks that put them at elevated risk above 

the general population. These recommendations would mirror the 2- through 10-year old 

recommendations for children at increased risk for meningococcal disease. There are likely 

less than 5000 persons in this age group who would fall into these high-risk groups annually.

In terms of defining high-risk children ages 9 through 23 months, there are four groups of infants 

considered to be at increased risk. The first group is children with complement component 

deficiencies. Complement component deficiencies generally present later in life and are not 

recognized by 2 years of life; however, a child may have a family history or some other reason 

of known history of complement component deficiency that would indicated for vaccination. The 

second group of children is comprised of children with functional or anatomic asplenia, including 

infants with sickle cell disease. Approximately 1500 infants are born each year in the US who 

have sickle cell disease who would be included. Infants who are in a defined risk group for a 

community or institutional outbreak would also be included. These are very rare in the US and 

occur infrequently, but should be included in the new recommendations. Also included are 

infants traveling to an area where meningococcal disease is epidemic or highly endemic, such 

as those infants who are traveling with their families to the Hajj or who are living in the 

Meningitis Belt in Sub-Saharan Africa.

In terms of immunogenicity of MCV4-D in persons aged 9 through 23 months, MCV4-D has 

demonstrated immune response after second dose of Menactra® at 9 and 12 months. Dose 1 

is modestly immunogenic for serogroups A and C, but not very immunogenic for serogroups Y 

and W-135, although it was highly immunogenic for all groups following the second dose. Most

children do not have protective antibody levels 3 years after the second dose. For serogroups 

C and Y, less than 20% of infants have protective antibody levels. However, there was a strong 

response after the booster dose as demonstrated previously.

Regarding the data that showed co-administration with PCV7, pneumococcal IgG GMCs lower 

when co-administered with MCV4-D at 12 months. Serotypes 4, 6b, and 18c did not meet 

statistical criteria for non-inferiority, but the absolute values were lower for all serotypes. While 

detectable functional antibody was present for 99% to 100% of persons who had an OPA 

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activity of ≥1:8, the OPA geometric mean titers support the conclusions of the IgG ELISA data 

showing reduced overall absolute values of titers. No data are available on co-administration 

with PCV13, which is the vaccine that would currently be co-administered in children receiving 

meningococcal vaccine in this age group. The clinical significance of lower titers is not yet 

understood. 

With respect to the safety of MCV4-D in children ages 9 through 23 months of age, prelicensure safety data met non-inferiority criteria at 9 and 12 months. The safety profile is 

comparable to other vaccines given at 12 months. However, post-licensure safety surveillance 

will be continued for children through age 23 months since all of these data were generated 

among children vaccinated at ages 9 and 12 months.

There are some issues that are important to point out in terms of extending the high risk 

recommendations down to 9 months of age. First, there would be inconsistency in the interval 

for infants compared to older children who are recommended for a 2-dose primary series. 

Therefore, infants aged 9 through 23 months would be recommended for a 2-dose primary 

series 3 months apart, or as persons older than 2 years are currently recommended for a 2-

dose primary series spaced 2 months apart. ACIP is considering ways to simplify this 

recommendation in the full ACIP statement. For this session, it was proposed that the licensed 

indication be kept for 2 doses 2 months apart in 9 through 23 month old infants. In terms of the 

timing of booster dose after a 2-dose primary series for persons who remain at increased risk 

for meningococcal disease, while it is preferable to have the same booster dose interval for 

younger and older children, the available data indicate that the booster is needed 3 years after 

vaccination for young children remaining at increased risk. Therefore, a 3-year interval after the 

2-dose primary series for young children and a 5-year interval for older children who are 

vaccinated were proposed.

Pertaining to co-administration with PCV13, the interference demonstrated with PCV7 may be 

clinically relevant for children with asplenia or sickle cell disease. The reason for the greater 

concern for these children is because they are at increased risk for pneumococcal disease in 

general. They may also have reduced response to the vaccination. Multiple visits for vaccines 

in this special population may be feasible because they may have more medical visits anyway, 

so it may be easier to separate the doses for this specific group of children as opposed to the 

general population. While there is not a great understanding of the clinical significance of lower 

absolute GMT titers, it is believed that an abundance of caution should be taken for children 

with asplenia or sickle cell disease with respect to co-administration. It is really the serotypes 

that are in PCV13 but not in PCV7 that children with asplenia or sickle cell disease are at 

increased risk for at this time, because transmission of the serotypes in PCV7 are very low. 

This recommendation is really based on an inference from PCV7 to PCV13. The options for 

policy would be to recommend that PCV13 and MCV4 be administered at least 30 days apart 

for children with asplenia or sickle cell disease. The recommendation could continue to be 

made to vaccinate children with asplenia at age 2 years and not extend down to age 9 months 

for this group to avoid the issue of co-administration; however, that would reduce flexibility for 

providers. It would be preferable to allow providers to start giving meningococcal conjugate 

vaccine at age 9 months for this group when there would not be a co-administered vaccine, and 

then to allow one vaccine to be given at 12 months. Or, there could be no recommendation to 

administer these vaccines separately.

In terms of the proposed language for the vote, the background section would include 

information about immunogenicity, duration of protection, and co-administration. In the section 

outlining high-risk groups for persons aged 2 through 10 years and 19 through 55 years, 

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language would be included for children aged 9 through 23 months at increased risk for 

meningococcal disease to receive a 2-dose series of MCV4-D, 3 months apart. Additional 

recommendations underneath these would address special considerations. The first would be 

that children requiring protection prior to travel may receive Dose 2 as early as 2 months after

Dose 1 to ensure that they receive 2 doses prior to travel. The second point would be that in 

children with functional or anatomic asplenia, MCV4-D and PCV13 should be administered at 

least 30 days apart when feasible. The third point is that a 2-dose series is required for any 

child whose first dose was received prior to their second birthday. This is really a clarification 

point. If a child receives MCV4-D at 18 months but does not return to the office until after 2 

years of age, they would still need the second dose. The fourth point is that those who remain 

at increased risk for meningococcal disease should receive a booster dose 3 years after the 

primary series.

Points for discussion and vote were recapped as follows:

 Children aged 9 through 23 months at increased risk for meningococcal disease should 

receive a 2 dose series of MCV4-D, 3 months apart. 

 Children requiring protection prior to travel may receive Dose 2 as early as 2 months after 

Dose 1.

 In children with functional or anatomic asplenia, MCV4-D and PCV13 should be 

administered at least 30 days apart when feasible.

 A two-dose series is required for any child whose first dose was received prior to their 

second birthday.

 Those who remain at increased risk for meningococcal disease should receive a booster 

dose 3 years after the primary series.

Discussion Points

Regarding co-administration with other vaccines, Dr. Sawyer pointed out that many providers 

give diphtheria, tetanus, and pertussis (DTaP) vaccine as young as 12 months of age. Since 

MCV4-D and PCV are conjugated to diphtheria, he wondered whether any information was 

available on co-administration with DTaP regarding the immunogenicity of both vaccines and 

safety as the diphtheria protein is added up. 

Dr. Coyne-Beasley noticed that immunogenicity and safety data were available for hepatitis A, 

and was interested in knowing whether there were immunogenicity and safety data for hepatitis 

B or for varicella, which can also be given at 12 months of age.

Dr. Johnson responded that studies have not been completed with concomitant administration 

of Menactra® and DTaP vaccines. No studies have been conducted with hepatitis B vaccine, 

nor are any anticipated. 

Dr. Keitel inquired as to whether there were any data showing GMCs of antibodies against the 

meningococcal serogroups and the effects of co-administration. Threshold titers were shown 

rather than absolute titers. While threshold titers may be high across the board at a certain 

point after vaccination, a year later, if the GMC was much lower, it could fall to a low threshold 

faster. 

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Dr. Johnson responded that they do not measure GMC. They may measure GMT of the SBA 

antibodies. He thought they had shared those data with the working group.

Dr. Cohn added that the working group had seen GMC data for the functional antibodies, but 

not co-administered with other vaccines. The GMCs have not been directly compared when coadministered versus not co-administered, but they were very high after the second dose when 

not co-administered. 

Dr. Baker inquired as to whether post-immunization was defined as 28 days.

Dr. Johnson responded that it was in that range.

Dr. Judson inquired as to whether the proposed immunologic mechanism of interference was 

related to the conjugate. 

Dr. Cohn did not believe that the mechanism of interference was known, but there will be data 

from other meningococcal conjugate vaccines and their co-administration with PCV7 as well, 

which will help to understand whether it is the conjugate or type of vaccine versus a 

meningococcal polysaccharide issue. 

Dr. Keitel wondered whether, if levels continue to decline to pre-immunization levels 3 years 

after vaccine, there was a proposal to administer boosters every 2 to 3 years.

Dr. Cohn indicated that currently the recommendations for older children who remain at 

increased risk for meningococcal disease are to vaccinate every 5 years with meningococcal 

conjugate vaccine. The way the recommendations would be stated is if a child’s last vaccine 

was received prior to age 6 years it would be 3 years, and if was received after age 7 years or 

older it would be 5 years after the previous dose.

Dr. Baker asked whether Dr. Johnson had data in this age group for sickle cell disease 

specifically and if not, whether any would be forthcoming.

Dr. Johnson responded that they do not have these data, or specific plans to study this in 

children with sickle cell disease. However, there are on-going studies in children with HIV 

infection.

Dr. Cieslak requested clarification regarding whether there were immunogenicity data on the 

specific group of children to whom the proposed recommendation would apply, and incidence in 

children in this age group with these specific diseases. 

Dr. Cohn replied that she could not provide the incidence of disease among children in this age 

group because it is so rare. The incidence of meningococcal disease is so low that even if a 

child’s risk is 10 times greater, it is still highly unlikely that a case of meningococcal disease will 

be observed in a child with sickle cell disease in a year. To put this into perspective, assessing 

10 years of Active Bacterial Core Surveillance (ABCs), in 10% of the US population there were 

only 2 cases of meningococcal disease in persons with sickle cell disease in any age group. 

Many children have penicillin prophylaxis, so it is difficult to compare whether those rates would 

be different pre- or post-penicillin prophylaxis. The risk was determined a while ago, but the 

actually number of cases and incidence is very low. Even if risk among children with sickle cell 

disease is high, the incidence would still be very low considering the low population numbers. 

Unlike children with complement component deficiency who have a risk of thousands greater 

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than the general population, this risk is greater but not significant enough to see an increase in 

cases.

Dr. Judson asked whether there were data for the booster dose at 3 years, and if so, whether it 

was what would be predicted or if there were any homologous interference with subsequent 

doses.

Dr. Johnson responded that these data showed that children who had been primed with two 

doses in the MTA26 study had very good responses. Essentially, 100% of them had SBA titers 

greater than or equal to 1:8.

Dr. Duchin asked whether there was anything about the specific pneumococcal serotypes that 

achieved lower titers with co-administration that would allow one to predict what serotypes, if 

any, would also have interference with PCV13. He wondered if the additional serotypes were 

causing a greater proportion of disease, whether there was a biological reason to expect that, 

what the plans were to monitor and detect this, and if the manufacturers planned any studies 

using PCV13.

Dr. Cohn responded that this would be hard to predict. While it is inferred given that it is the 

same type of vaccine, there are no data to demonstrate whether this is the case. It is the 

additional six serotypes. In terms of plans to monitor, because the numbers of very small 

(n=~2000 children per year), there is no consensus that this is going to be a population level 

problem. The rationale for separating the vaccine from others is because there are plenty of 

indications of adverse events, especially in children with asplenia or sickle cell disease.

 

Dr. Johnson added that at this point, there are no plans to conduct studies using PCV13. 

Dr. Meissner emphasized that a major concern in children 9 months through 23 months of age 

who are asplenic or have sickle cell disease is pneumococcal disease. The risk for 

meningococcal disease is so low that it is difficult to quantify. Since there are no data for 

MCV4-D and the 13-valent pneumococcal vaccine, it is not clear whether the recommendation 

is arbitrary since it is not based on solid information. The real issue to keep in mind is not to 

jeopardize protection against pneumococcal disease in these high risk children.

Dr. Baker pointed out that what also is not known is the biologic meaning of the blunting.

Dr. Coyne-Beasley noted that they had not heard a lot of information about the cost or costeffectiveness of this strategy, and wondered whether there were additional data about this.

Dr. Cohn responded that cost-effectiveness data would be presented for different options for 

routine immunization, but analyses have not been done for these select high risk groups 

because these recommendations for these groups have been longstanding. This is not so 

much a public health recommendation as it is a patient-specific one.

Dr. Baker stressed that with 2,000 subjects out of a cohort of over 4 million, this type of study 

could never be done accurately.

As a specialist caring for these children, Dr. Englund sees 50 a year in her regional tertiary care 

clinic that covers children for 2000 miles. Even without recommendations, they struggle with 

how to protect children who have complement deficiency that is usually proven by a first time 

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episode of pneumococcal vaccine. Although the numbers are small, she strongly urged her 

colleagues to consider a recommendation for this limited population.

Dr. Temte wondered how many of the approximately 2000 children receive most of their care in 

a specialty setting where a relatively complex recommendation is more easily implemented. Of 

concern is that children with sickle cell disease may not have the benefit of receiving care in a 

specialty center and may have these recommendations applied to them in a chaotic primary 

care setting instead.

Dr. Englund responded that the subspecialty geographic settings in which she has worked (e.g., 

Midwest, South, and West Coast) have clinics where these children are seen about once per 

year for routine check-ups, even though their primary care is delivered by their primary care 

physicians. Many of these children are vaccinated according to routine schedules. 

Approximately 70% of the asplenic children in her state have already received their Prevnar® by 

the age of 6 months, so she is less concerned about the concomitant Prevnar® issues. 

Dr. Baker pointed out that the degree of complexity could be reduced through communication 

between the primary care physician and the specialist. 

Dr. Judson said he was comfortable with the extrapolation to PCV-13, given that the two 

vaccines are made by the same manufacturer using the same method, and PCV-13 has all 7 

components of the PCV-7. However, he thought that the interval of 30 days was arbitrary. The 

last time he reviewed the data 20 years ago or so the IgG half-life was 28 or 30 days. The only 

other information that bears on this is for maternal antibody and life virus vaccines. Measles 

vaccines were first delayed by 6 months, then 9 months, and finally by 12 or 15 months. Even if 

there is passive antibody titer every 30 days, there is likely to be an interference problem well 

beyond 30 days. 

Dr. Baker noted that the half-life for total IgG is three weeks, but vaccine-induced antibodies 

vary such that the half-life for antibody to pertussis toxin is 36 days, but may be longer for one of 

the other pertussis antigens. Three weeks is a best guess, but the biologic meaning remains 

unknown.

Dr. Keitel emphasized that while this is a nice discussion, the mechanism of interference is 

unknown and may have nothing to do with anything.

Ms. Rosenbaum pointed out that she had noticed that there are times when ACIP makes a 

routine recommendation because there is evidence of risk, and sometimes they make a 

recommendation tied essentially to discretionary exercise of clinical judgment. She requested 

an explanation of the significance of the difference, and expressed great concern about payers 

over-riding health evidence.

Dr. Baker responded that routine recommendations are influenced heavily by burden of disease

and the epidemiology change and the amount of vaccine coverage. Even with a quadrivalent 

meningococcal vaccine, serogroup Group B disease is not being addressed for this particular 

bacteria. In terms of cost-effectiveness, with tiny populations like this where epidemiologically 

there is increased risk, there has to be a lot of discretion. For example, in 2005 when the 

adolescent meningococcal quadrivalent recommendation was made, in addition to those with 

asplenia or sickle cell, at its discretion, because there was no data for HIV-infected people, 

ACIP recommended that HIV-infected adolescents receive this vaccine because of the potential 

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perceived risk. ACIP is not just a rubber stamp for FDA licensing requirements where 

immunogenicity and safety are documented. This is very complicated. 

Dr. Cohn added that the cost of the vaccine for this small number of children is minimal in terms 

of the overall cost of their care. For children who are traveling, the cost is part of the parents’ 

choice to travel and part of travel expenses. 

Ms. Rosenbaum said she was hearing that the real difference between a discretionary and a 

routine recommendation for certain risks has to do with the amount of economic analysis that 

can be done, in addition to the clinical analysis, so ACIP is fairly confident that within an 

economic framework a routine recommendation can be made. 

Dr. Cohn indicated that the number of children at risk is substantially smaller than for 

pneumococcal vaccine and asthma. There are hundreds of children with complement 

component deficiencies. With a prevalence of a risk of 5% or 10%, it is more of a routine 

recommendation for high risk groups as opposed to these types of targeted recommendations.

Dr. Pickering pointed out that it is not only burden of disease, but also severity of disease. 

Children with these underlying immune deficiencies do not do very well, and they do not do very 

well rapidly. Pneumococcal disease clearly is the major disease see in children with asplenia 

and gamma globulin anemia. If this vaccine is given, does it really interfere with the 

pneumococcal response enough to cause concern? That overrides the cost-effectiveness 

issue.

Ms. Rosenbaum clarified that the reason she was pressing in this case had nothing to do with 

the recommendation per se as much as it had been a challenge for her in the context of zoster 

vaccine. That is, if it is known that there are certain health risks in the under 60 years of age 

population, why is ACIP not recommending routine vaccination when certain health risks are 

present. She has reviewed ACIP’s patterns around this question and finds that often she 

cannot assess a pattern. That is why she wanted to know why they sometimes recommend 

discretionary and sometime routine with certain health risks. Routine with health risks sends a 

much more powerful message to payers than a discretionary message.

Dr. Baker clarified that this is a routine recommendation in a high risk population. She then 

requested that Dr. Brady summarize the AAP’s Committee on Infectious Disease’s opinion 

about this issue.

Dr. Brady (AAP) supported the fact that they do not want to do anything that would potentially 

impact the burden of pneumococcal disease, particularly the asplenic and sickle cell patients. 

The issue with meningococcal disease, given the low burden of disease, has been discussed in 

all of their conversations. He suggested that if ACIP voted on the proposed recommendation, 

that they make sure to recommend that the pneumococcal conjugate vaccine is given prior to 

meningococcal and not make that a choice if they are going to be separated by 30 days to avoid 

the potential impact on the pneumococcal vaccine. Since the mechanism of immunological 

interference is unknown, it is unclear whether it lingers for some period of time. If it did, it would 

be very disappointing to find out if the booster dose of meningococcal vaccine was adversely 

affected by a 9-month dose of meningococcal vaccine. He wondered whether it would be 

reasonable to either postpone this vote until there was information regarding whether a dose of 

PCV13 given after the meningococcal vaccine has any impact on the pneumococcal vaccine. 

Those with complement component deficiency are easier because in those patients Neisseria 

meningitidis disease represents the risk. In the sickle cell and asplenic patients, it is 

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pneumococcal disease that is the larger risk. The other option would be to consider removing 

sickle cell and asplenia from this recommendation and include the ones where the advantage of 

giving meningococcal is seen. The numbers are small, but the population of complement 

deficient patients is rarely diagnosed at less than 2 years of age. It is important not to impact 

pneumococcal disease in the sickle cell patients. 

Dr. Foster (APhA) said he remembered years ago there was a discussion of 28 days versus one 

month versus 30 days, and everything was decided at that point to be 28 days. It might be 

easier and less confusing to make it 28 days,

Dr. Baker noted that in terms of 2- and 3-month intervals, multiples of 28 becomes somewhat 

difficult.

Dr. Duchin requested clarification regarding whether they could assume that children vaccinated 

at age 12 months who received both vaccines and experienced interference were all receiving a 

fourth dose of PCV7.

Dr. Cohn replied that this would have been their fourth dose of PCV7. While the response may 

be lower, they are likely protected. This is more likely to be a long-term protection issue for 

these children as opposed to immediate protection in terms of interference.

Dr. Baker pointed out that postponing the vote would probably cause a delay of a year, and no 

studies are planned.

Dr. Brewer (ANA) inquired as to whether these recommendations would need to be revisited as 

new vaccines come on-line that have different schedules and numbers of doses.

Dr. Cohn responded that they would be revisiting these recommendations in the context of 

routine recommendations. 

Regarding the distinction between this and the zoster discussion, Dr. Schaffner (NFID) pointed 

out that in this circumstance, everyone was convinced that both pneumococcal and 

meningococcal vaccine will provide protection to these children. The question regards how to 

do it. In contrast, the two populations raised earlier in the morning in terms of zoster included 

those who have previously had zoster but were younger than age 60 and those individuals 

about to undergo immunosuppression. It is entirely unknown whether the vaccine will provide 

protection. 

Dr. Whitley-Williams (AMA) shared the same concerns expressed by Dr. Brady, and expressed 

her hope that through interagency efforts there would be a push to monitor the children being 

immunized with hemaglobinopathies. This opportunity will be lost once they are immunized with 

the MCV4-D. CDC and the manufacturer should make sure that study is done. She also noted 

that she received several calls from local pediatricians when the licensure was extended for 

administering the meningococcal conjugate vaccine as early as 9 months of age. The feedback 

from the calls was concern that this would be a routine recommendation. She felt the news 

media had caused confusion, as well as concern among pediatricians that they would have to 

administer meningococcal conjugate vaccine routinely as early as 9 months of age. She 

emphasized the importance of focusing on at risk children. 

Dr. Baker agreed that it is a very important communication issue, depending upon the results of 

the vote.

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Dr. Halsey (Johns Hopkins) commented on the most likely biological mechanism for the 

interference. This was well-documented when tetanus was used as the conjugate protein for 

Haemophilus influenzae b (Hib) and pneumococcal conjugate vaccines and given 

simultaneously with DTP. If that is true, it was dose-related. Ron Dagan and Juhani Eskola 

clearly described this, and other studies confirmed it. If this is true, it is likely to be exacerbated 

by giving the PCV13 and simultaneously with DTaP. Ron Dagan has told Dr. Halsey that he 

had suggestive data for possible carrier suppression with the CRM protein carrier. He urged the 

committee to contact Dr. Dagan for this information, although it may not be conclusive. 

Certainly, the studies need to be done to determine whether that is the mechanism. It is doable 

and there may be some data available from existing studies. 

To address Dr. Whitley-Williams question and concern, Philip Hosbach (sanofi pasteur) 

indicated that there is a 2- to 10-year old recommendation for high risk children that doctors 

have previously followed. The vaccine is not overused, nor does the company promote outside 

that recommendation. He suspected the same would be true for this recommendation as long 

as it is clearly communicated.

Dr. Baker called for public comment. 

Echo Bennett (National Meningitis Association): Hello. My name is Echo Bennett and I am 

here today because my son, Gavin, contracted meningococcal disease as a baby. I will never 

forget the day this disease changed our lives forever. Gavin woke up that morning with a slight 

fever and refused to eat. I called the local health clinic, and they assured me he probably had 

the flu. But, it wasn’t the flu. It was much, much worse. Only 18 hours after his symptoms 

began, my healthy, happy, 6-month old son was placed in an induced coma and put on life 

support. I was told he was diagnosed with meningococcemia, yet I was unaware of what the 

even was. Gavin was so small and so sick, and there was nothing I could do for him. He was 

given a 10% chance of survival, but despite the odds, Gavin survived, but not without a price. 

The Neisseria group C bacteria severely damaged his little arms, legs, and face, and he showed 

signs of heart and lung disease. He had to undergo a dozen surgeries in his 9 weeks of 

hospitalization, including muscle flapping, skin grafting with donor sites, a tracheotomy, 

colostomy, and major facial reconstruction. Doctors were able to save his limbs from 

amputation, but the scars covering his body are a constant reminder of his battle with 

meningococcal disease. This was a little over two years ago, but we are still feeling the effects 

today. Gavin has since undergone 6 more surgeries, and has countless ahead of him. His 

health is constantly a concern for his doctors to prevent any further effects throughout his 

lifetime. When Gavin became ill, he was transferred to three different hospitals before receiving 

the treatment that would ultimately safe his life. This is not an easy disease to diagnose or 

treat, yet it’s simple to prevent. There are many other families who have been affected terrible 

by this disease, whose children suffered as infants and now have lifelong debilitating effects or 

those whose children who, tragically, did not survive. I am here to speak for all of them, for Lisa 

Nailman and her daughter Sara, for Molly Dejordan and her son Kenton, for Chrissie Bickham 

and her daughter Jaily, for Everchris Davis and her son Terrance. These are just a few of the 

Moms on Meningitis (MOMs) who could not be here today. If you were to ask any of us, we 

would tell you to do whatever you can to keep your children safe, healthy, and happy. Educate 

yourselves and vaccinate your kids. We would have done anything to help our kids at this point 

in time. So, I’m here to tell you that we strongly support the recommendation for meningococcal 

vaccination for infants, with the recommendation having a 30-day time period between receiving 

pneumococcal vaccination and starting meningococcal vaccinations. On behalf of the National

Meningitis Association Moms on Meningitis, thank you for your consideration and time today.

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Frankie Millie (Meningitis Angels): I’m Frankie Millie, the Founder and National Director of 

Meningitis Angels. Today is the 13th anniversary of my only child’s death, so I stand here in his 

memory and in honor of all of the Meningitis Angels across the country. I want to thank this 

committee for their dedication to this issue. I am totally confused at this point, and there have 

been some great valid concerns raised here today with this recommendation. So, what I’m 

going to say to this committee today is probably going to kind of freak you all out, but I think that 

this committee, being who you are, need to make the best recommendation on this particular 

issue that you know to make, and I would ask you that if you decide to recommend this vaccine, 

or even do a permissive, that you vote “Yes” for VFC coverage as well, because if you’re going 

to make a recommendation, then you need to make it available to these kids. At lot of these 

children who are high risk already are probably VFC kids, so I’m going to sit back here and just 

pray for you guys to make the right decision. Thanks. 

Dr. Cohn recapped that she thought the decision regarded whether to include asplenia and 

sickle cell children in this recommendation, and take Dr. Brady’s advice and recommend that 

the booster dose of PCV13 be given at least 30 days prior, or even 90 days prior, to the second 

dose of MCV4. That would be Option 1 versus removing the sickle cell and asplenia children 

from this group and not protecting them against meningococcal disease until they are age 2 

years of life to ensure that they are receiving adequate pneumococcal protection. Children with 

HIV are included in the VFC resolution. It is a permissive recommendation for older age groups, 

so the resolution for these children would be extended down to 9 months of age. 

Motion 

Dr. Sawyer made a motion to accept the recommendation as stated, with the exclusion of the 

anatomic asplenia and sickle cell groups who would be dealt with subsequently, and that the 

other high risk groups be maintained (e.g., travelers to endemic areas, families moving to 

endemic areas, and those with complement component deficiencies). Dr. Meissner seconded 

the motion. The motion carried with 13 affirmative votes, 1 negative vote, and 1 abstention. 

Dr. Cohn indicated that the second issue would be that two proposals could be made. ACIP 

could vote to recommend the vaccine down to 9 months for children with sickle cell disease and/ 

or asplenia, with the caveat that they receive the 4-dose pneumococcal booster dose (PCV13) 

prior to the second dose of meningococcal conjugate vaccine (Menactra®). Or, a 

recommendation could be made not to include children with functional or anatomical asplenia in 

this recommendation.

Dr. Coyne-Beasley wondered whether this should be done before the first dose of Menactra® 

given at 9 months. While they were saying second dose, even one dose could cause 

interference.

Dr. Cohn responded that that technically would be 3 months prior. 

To clarify, Dr. Baker reminded everyone that there is no routine vaccination recommended at 9 

months of age, so this would move to 12 months. Practitioners would need to know if they were 

doing catch-up because something was delayed to make sure that they administer four doses of 

PCV13. 

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Dr. Englund expressed concern with simultaneous administration, which she thought should be 

included. Some children might have two doses to catch up.

Dr. Cohn noted that the original language stated that they should be administered at least 30 

days apart, which suggests that they should not be co-administered. 

Dr. Englund believes that it is interference, although there are no data. Two huge populations 

that are perhaps underappreciated are cardiac patients and heterotaxia patients. 

Ms. Ehresmann requested clarification regarding whether only non-simultaneous and at least 30 

days was to be included, or if the recommendation was to complete the series with at least 30 

days and not simultaneously. 

Dr. Baker clarified that non-concomitant is the important issue, because that is where there is 

data for on interference. 

Dr. Cohn added that the language could state “do not co-administer” and then determine 

whether it should be 30 days or 90 days, and the guidance or background section could explain 

that pneumococcal vaccination should take priority over meningococcal vaccination for children 

with asplenia. 

Dr. Keitel noted that based on the data ACIP was provided, there is evidence that 

pneumococcal conjugate vaccine given with PCV results in more antibody titers, but she 

wondered what happened when pneumococcal vaccine alone was compared to pneumococcal 

vaccine with MMR.

Dr. Cohn responded that there are no data about this.

Dr. Sawyer made a motion to recommend the meningococcal conjugate vaccine as stated on 

the screen for patients with functional or anatomic asplenia, and that specific language should 

be included that the vaccine not be co-administered with pneumococcal conjugate vaccine. The 

priority should be to complete the primary pneumococcal conjugate vaccine series or booster at 

least 30 days before administering the meningococcal conjugate vaccine. Dr. Meissner 

seconded the motion, at which time further discussion ensued.

Dr. Judson remained concerned that the key science behind these recommendations. If the 

mechanism is antibody against the conjugate that somehow renders the vaccine less 

immunogenic or less able to be process, the greatest problem would not be with coadministration. It would be the related issue of administering live viruses at the same time or at 

some longer interval afterwards. He does not feel confident that co-administration is the 

problem. If this is antibody mediated, it may be far more complicated.

Dr. Keitel agreed. In the circumstances in which carrier suppression has been documented, it 

had nothing to do with simultaneous administration of vaccines. It had to do with antibody 

present in the serum at the time. Therefore, there is no basis for concluding that a 30-day 

interval would be adequate. 

Dr. Baker noted that the data show that there is not a problem with MMR, so she thought that in 

terms of live virus vaccines they could be assured that there was no problem with coadministration.

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Dr. Judson clarified that he was saying that by analogy, the interference between live virus 

vaccines probably was an antibody, and that it was better to give them together than to separate 

them by the weak or month where there might be interferon interference.

Dr. Duchin was not sure that people would be able to interpret what was intended by the 

sentence “priority should be given to PCV13.” It was not clear whether the intent was to 

complete the series or that the series should be initiated before the MCV series. He suggested 

making the language more specific.

Dr. Sawyer thought this could be clarified by stating that if a pneumococcal conjugate vaccine 

was due it should be given first, with the 30-day interval.

Dr. Meissner reminded everyone that the burden of disease for Neisseria meninngitidis in this 

population is miniscule; whereas, the benefit of protection from invasive pneumococcal disease 

in these children is without question.

Dr. Plotkin emphasized that there is extensive literature on epitopic carrier suppression and 

enhancement. This phenomenon is not unusual at all. The control interval has been usually 

been a month or so in studies identifying epitopic suppression. 

Dr. Baker requested that Dr. Cohn work on the language, and that they return after lunch to vote 

on the revised language.

Upon the meeting reconvening following the lunch break, Dr. Sawyer indicated that after 

speaking with his colleagues and realizing how recently the pneumococcal suppression data 

became available, he preferred to withdraw his motion to allow the working group more time to 

carefully evaluate the potential impact of meningococcal vaccine suppression in children, 

especially those with asplenia. Dr. Meissner withdrew his second of the motion as well.

Dr. Baker concluded that this issue would appear on a future ACIP agenda when more 

information is available to present. 

Vaccines for Children (VFC) Program Vote

Lance E. Rodewald, MD

Director, Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Rodewald reminded everyone that ACIP is the sole authority for the VFC formulary, and if 

there is a change in the indicated age, group, or number of doses, there must be a VFC 

resolution such that the VFC program is consistent with ACIP recommendations. The purpose 

of this resolution was to update the eligible groups for meningococcal vaccination to include 

children 9 through 23 months of age at increased risk of meningococcal disease and to update 

the intervals for booster doses, and Dr. Rodewald noted that the language would be edited to 

match the vote.

The original wording for eligible groups was as follows:

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 Children aged 2 through 10 years who are at increased risk for meningococcal disease, 

including

– children who have complement deficiencies (C3, properidin, factor D, and late 

component deficiencies); 

– children who have anatomic or functional asplenia; 

– children with HIV infection; 

– travelers to or residents of countries in which meningococcal disease is 

hyperendemic or epidemic;

– children who are who are part of an outbreak of a vaccine-preventable 

serogroup.

 All children aged 11 through 18 years

The revised wording will read as follows:

 Children aged 9 months through 10 years who are at increased risk for meningococcal 

disease, including

– children who have complement deficiencies (C3, properidin, factor D, and late 

component deficiencies); 

– children with HIV infection; 

– travelers to or residents of countries in which meningococcal disease is 

hyperendemic or epidemic;

– children who are who are part of an outbreak of a vaccine-preventable 

serogroup.

 All children aged 11 through 18 years

This is the new table, with the proviso that it must be revised to match the recommendation and 

break this down into two different age groups:

 

Age Subgroup Primary 

Vaccination

Booster Dose

9 

through 

23 

months 

of age

Children with 

complement 

deficiencies; 

functional or 

anatomic asplenia; 

Two doses of MCV4, 

three months apart 

If first dose received at age 

9months through 6 years 

and remain at increased risk 

for meningococcal disease,

should receive an additional 

dose of MCV4 three years after 

primary vaccination. Boosters 

should be repeated every five 

years thereafter.

Children with HIV, 

if another 

indication for 

vaccination exists

Two doses of MCV4, three 

months apart 

All others in this 

age group 

recommended for 

vaccination 

(travelers to the 

Meningitis Belt, 

etc)

Two doses of MCV4 , 

three months apart 

(infants receiving the 

vaccine prior to travel can 

receive the doses as early 

as two months apart)

The recommended schedule intervals for 9 through 23 months of age are reflected in the 

following table, which again will be revised to match the recommendation:

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Age Subgroup Primary 

Vaccination

Booster Dose

2 through 

18 years 

of age, 

with high 

risk 

conditions 

(2)

Children with complement 

deficiencies; functional or 

anatomic asplenia

Two doses of 

MCV4 , two 

months apart 

If first dose received at age 9 

months through 6 years and 

remain at increased risk for 

meningococcal disease, should 

receive an additional dose of 

MCV4 three years after primary 

vaccination. Boosters should be 

repeated every five years 

thereafter.

 

If first dose received at age 7 

years or older and remain at 

increased risk for 

meningococcal disease, should 

receive an additional dose of 

MCV4 five years after primary 

vaccination. Boosters should be 

repeated every five years 

thereafter.

Children with HIV, if 

another indication for 

vaccination exists

Two doses of 

MCV4 , two 

months apart 

All others in this age 

group recommended for 

vaccination (travelers to 

the Meningitis Belt, etc)

Single dose of 

MCV4 

The recommended schedule intervals for all other children 11 through 18 years of age will 

remain the same:

Age Primary 

Vaccination

Booster Dose

All other 

children 

11-18 

years of 

age

Routine vaccination 

with MCV4 at ages 

11 through 12 

years 

If vaccinated at age 11 through 12 

years, should receive a one-time booster 

dose at age 16 years

 

If vaccinated at age 13 through 15 

years, should receive a one-time booster 

dose at age 16 through 18 years

The following table notes were revised to correct the omission of the polysaccharide vaccine. 

This just needed to be included and was not something that ACIP voted on as a committee.

Table Notes

(1) At the time of this resolution, there are currently two licensed MCV4 products. One 

product, Menactra ®, is manufactured by sanofi pasteur and is licensed for use in 

persons aged 9 months through 55 years of age. The second product, Menveo ®, is 

manufactured by Novartis Vaccines and Diagnostics, Inc. and is licensed for use in 

persons aged 2 through 55 years of age. A meningococcal polysaccharide vaccine is 

also available. This product is licensed for use in persons 2 years of age and older and 

may be used when meningococcal conjugate vaccine is unavailable or contraindicated.

(2) Includes children who have complement deficiencies (C3, properidin, factor D, and late 

component deficiencies), anatomic or functional asplenia, and children with HIV 

infection; travelers to or residents of countries in which meningococcal disease is 

hyperendemic or epidemic; and children who are who are part of a community outbreak 

of a vaccine-preventable serogroup.

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There are no changes to the recommended dosage and contraindications / precautions, which 

read as follows:

Recommended dosage 

– Refer to product package inserts. 

Contraindications and Precautions

– Contraindications and Precautions can be found in the package inserts available 

at 

http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM09

3833 

The statement regarding the update based on published documents will be included, and will be 

modified to parallel the recommendation: 

[If an ACIP recommendation 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.]

Motion 

Dr. Chilton made a motion to accept the VFC resolution as amended. Dr. Cieslak seconded the 

motion. The motion carried with 15 affirmative votes, 0 negative vote, and 0 abstentions. 

MenAfriVacTM (Meningococcal A Conjugate Vaccine) Introduction in Burkina Faso

Thomas Clark, MD, MPH

Epidemiology Team Lead, Meningitis and Vaccine Preventable Diseases

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Clark presented information to help frame CDC’s work in vaccine preventable diseases in a 

global context, and to share some early good news pertaining to the implementation of 

MenAfriVacTM in Sub-Saharan Africa. The “Meningitis Belt” of Sub-Saharan Africa extends from 

Senegal in the West to Ethiopia in the East. It is a region that is at extremely high risk for 

epidemic meningitis, with predominantly serogroup A meningococcal disease. Across the 

“Meningitis Belt” there are some 430 million people at risk. Roughly 25 countries are 

susceptible to outbreaks, but 7 countries are classically described in the “Meningitis Belt,” 

including Mali, Burkina Faso, Niger, Nigeria, Chad, Sudan, and Ethiopia.

Meningitis epidemics are linked to climate. The climate of this region is characterized by two 

seasons, the monsoons and high humidity in what would be the US’s summer and prevailing 

winds from the Sahara in what would be the US’s winter, bringing with them dust and dry air. 

These coincide with meningitis epidemics. Outbreaks of meningitis disease within the region 

are really local, so within given districts and villages, attack rates can be as high as 1000 per 

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100,000 or more, so 1% of the population can be affect. Across the belt, there are thousands or 

tens of thousands of cases each year, as has been the case for 100 years. Intermittently, in 8- 

to 12-year cycles, there are explosive epidemics across the region. The most recent occurred 

in 1996 with 200,000 reported cases [WHO/AFR, October 2006]. Somewhat different from 

pneumococcal and Haemophilus influenzae type b disease, the incidence of meningococcal 

disease in the region extends well into the third decade of life, so there is a larger population at 

risk and the prevention strategy, therefore, is different [Campagne et al. Bull World Health 

Organ 1999;77(6):499-508],

It was clear after the 1996 outbreak that reactive vaccination with polysaccharide vaccines was 

an unacceptable strategy, and not a good preventive strategy for epidemic meningitis. So there 

was an appeal by the Ministers of Health in the region to develop a conjugate vaccine, a better 

vaccine, for the region. In 2001, the Meningitis Vaccine Project was founded through a grant 

from the Gates Foundation. This project was a collaboration between PATH and WHO resulting

in a consortium of manufacturers manufacturing a serogroup A conjugate vaccine. SynCo 

BioPartners in Amsterdam made the polysaccharide (NmA PS), Statens Serum Institute in 

Denmark made the tetanus toxoid (TT) carrier protein, an FDA-developed conjugation method 

was utilized, and the Serum Institute of India manufactured the vaccine. The contracted price 

that was agreed upon for this vaccine is $0.40 per dose.

The pre-licensure trials were quite dramatic, with substantially higher titers among older children 

and adults in Africa than the polysaccharide comparison vaccine. There were equally 

impressive responses, 20-fold higher titers, among 12- to 23-month old children in Africa than 

the polysaccharide comparison vaccines. Most importantly, there was evidence of a booster 

response in 12- to 23-month old children, so behaving like a conjugate vaccine.

The vaccine was licensed late in 2009 and prequalified through WHO in June 2010. That set 

the “wheels in motion” for a sub-national implementation for adverse events surveillance 

beginning in September 2010 in Mali, Burkina Faso, and Niger. The implementation strategy for 

the vaccine was 3-fold. It is rapidly inducing herd immunity by large scale mass vaccination 

campaigns targeting people 1 to 29 years of age in the affected countries (> 90% vaccine 

coverage achieved), and then protecting new birth cohorts with intermittent catch-up campaigns 

or incorporation into the EPI schedule. The EPI dosing and schedule have yet to be worked out 

and licensed. An important part of this is the overlap. There are other serogroups that can 

cause disease and outbreaks in the region, so on-going surveillance and epidemic response are 

important in the event of a W125 outbreak, for example.

This is the first time that a vaccine like this has been developed in this way for Africa, and the 

first time this sort of strategy has been applied to a regional problem. Therefore, the approach 

to evaluation is comprehensive for the impact of this vaccine, including monitoring of adverse 

events, coverage surveys, operational research, impact on epidemics (surveillance), impact on 

carriage (herd immunity), vaccine effectiveness, immunology of vaccine failures, molecular 

epidemiology, and duration of protection. There is a 5-year plan to understand the duration of 

protection of this vaccine, which is the important question.

In Burkina Faso, Mali, and Niger, 20 million doses were given last year. The entire country of 

Burkina Faso was vaccinated in 10 days, with 12 million doses given and administrative 

coverage of over 100%. Among the adverse events, there were very low rates of expected 

typical reactions. There were also very few severe adverse events, none of which were 

determined to be unusually causally related to the vaccine [WHO, SRWG meeting, 3/5/11].

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In terms of attack rates by district in Burkina Faso in the heart of the “Meningitis Belt,” each year 

numerous districts cross the epidemic threshold of 15 cases per 100,000 over a 2-week period. 

2009 is acknowledged to be a quiet year, but 3 districts still cross the epidemic threshold and 

numerous districts cross the alert threshold. In contrast, only 2 districts reached the epidemic 

threshold in Burkina Faso. These are thresholds to mount vaccination campaigns. Usually the 

epidemic threshold is 100 cases per 100,000 and no districts met that threshold this year. In 

2011, the trajectory of reported cases of meningitis by clinical definition is much lower than any 

year recently [Meningitis Weekly Bulletin, Week 19, 2011. WHO Inter-Country Support Team]. 

Among 2665 suspect cases to date, 1437 have been tested by culture +/- PCR, and there have 

been 4 confirmed serogroup A cases in the country. This is an unprecedented occurrence of 

disease. Usually about 20% of cases have laboratory confirmation; however, this year 80% of 

cases have confirmation. In terms of occurrence related to case confirmation, unlike most years 

with an appreciable serogroup A burden of disease, predominantly pneumococcal with very little 

meningococcal serogroup A disease are being observed this year [Meningitis Weekly Bulletin, 

2004-10. WHO Inter-Country Support Team; Reunion du Comite National de Gestion des 

Epidemies, 2011 (weeks 1-22), DLM Burkina Faso]. 

This is compelling and very good news from the first country in the region to implement this 

vaccine. Mali and Niger are on track to vaccinate the rest of the country this year, and Nigeria, 

Chad, and Cameroon will begin vaccinating later this year. Within the next couple of years, the 

other couple of high risk countries will be finished. The hope is that within 10 years the goal of 

ending epidemic meningitis in Sub-Saharan Africa will be achieved. This translates to 

prevention of 123,000 deaths; prevention of permanent disability in 287,000 children and adults; 

savings of approximately $99.7 million in direct medical costs; and elimination of epidemic 

meningitis as a public health concern in Africa.

CDC’s Division of Bacterial Diseases, Immunization Safety, and Global Immunization had a role 

in technical support for the development and implementation of the vaccine and now the 

evaluation, but are clearly just players in a much larger collaboration.

Discussion Points 

Dr. Schaffner (NFID) called attention to and recognized Dr. Mark LaForce, who is an Epidemic 

Intelligence Service (EIS) alumnus and is the individual who orchestrated this extraordinary 

public health achievement.

Dr. Meissner inquired as to whether there were plans to use this vaccine in Asia where there is 

a lot of serogroup A disease.

Dr. Clark responded that there is a contracted supply for the “Meningitis Belt” of tens of millions 

of doses per year. The implementation strategy matches the supply. In the future, they will be 

able to sell the vaccine to anyplace which wishes to purchase it, and there is a development 

plan for a 5-valent conjugate vaccine with the same technology so there is CWY and also 

serogroup X, which has been a recently described cause of epidemics in Africa.

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Discussion

Introduction

Jonathan Temte, MD, PhD, 

University of Wisconsin

Chair, ACIP MMR Work Group

Dr. Temte introduced the Measles, Mumps, Rubella (MMR) Vaccine Working Group, ACIP’s 

newest working group. ACIP recommendations for the use of MMR vaccine are >10 years old, 

and there have been several changes since 1998. ACIP shortened its recommendations for 

avoiding pregnancy after vaccination from 3 months to 28 days in 2001. In 2006, ACIP updated 

recommendations for mumps vaccination. ACIP also updated recommendations for healthcare

personnel. Monovalent vaccines are no longer available, although MMRV is available. Measles 

and rubella were declared eliminated in the US; however, mumps outbreaks have occasionally 

occurred among highly vaccinated populations.

The MMR Vaccine WG’s terms of reference are to review the epidemiology of measles, mumps, 

rubella, and CRS; review existing statements pertaining to MMR vaccine; review new data on 

the MMR vaccine; consider safety and immunogenicity among persons with HIV; consider a 

third dose for mumps outbreak control; and revise / update existing recommendations into a 

single document. The WG has engaged in two teleconference thus far. The MMR Vaccine 

WG’s proposed schedule of activities is as follows:

Dates Topic

June – August 2011 Measles vaccination policy

September – November 2011 Mumps vaccination policy

December 2011 – January 

2012

Rubella vaccination policy

February – April 2012 Policy related to all 3 diseases

May – June 2012 Draft updated MMR vaccine 

recommendations

Dr. Temte shared the list of WG members, indicating that Huong McLean is serving as the CDC 

lead. He also shared a copy of the minutes from the first ACIP meeting May 25-26, 1964. A 

statement was included reading, “From the status of studies reported recently at a meeting on 

rubella at the Division of Biologics Standards, it would appear that the development of 

practicable rubella vaccines may not be anticipated for some years.” In fact, 40 years after that 

statement, rubella was declared eliminated.

MMR Vaccine Working Group Update

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2011 US Measles Epidemiology Update

Huong McLean, PhD, MPH

Division of Viral Diseases

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. McLean reported that since measles was declared eliminated in 2000, approximately 50 to 

60 cases are observed annually. As of June 17, 2011, there have been 156 measles cases 

reported in the US since January 2011. This is the most cases reported in the US since 1996 

when there were 508 cases. From 1997 to 2001, the cumulative number of cases by month of 

rash onset has increased each month. For 2002 to 2010, excluding 2008, the curve leveled off 

in June and July and there are very few cases in the second half of the year. The year 2008

was very similar to the post-elimination years, except at a higher magnitude. Record numbers 

were reached in 2011, and it is unclear whether this will level off or if cases will continue. 

Of the 156 cases reported as of June 17, 2011, 89% were in US residents. There were 12 

outbreaks, defined as a chain of transmission of three or more cases. The median outbreak 

size was 4, with a range from 3 to 21 cases. Most outbreaks have been contained early, with 

the exception of Minnesota which had 21 cases. The outbreaks were limited in part because of 

the timely and resource-intensive response of local health departments. The median age was 

16 years, with a range of 3 months to 84 years. Of those, 85% were unvaccinated or had 

unknown status, 70% were unvaccinated, 30% had an unknown or undocumented vaccination 

status, 34% required hospitalization, and 87% were import-associated. 

Of the cases, 17% were under 12 months of age, which is normally too young for vaccination, 

and 4% were 12 to 15 months of age. Of note, 46% (n=12) of those 6 to 15 months acquired 

measles while traveling abroad or on an international flight and should have been vaccinated 

before travel. Most of the cases in adults 20 to 39 years of age had either unvaccinated or 

undocumented status. Most in the younger age groups were unvaccinated. Almost half of the 

adults 20 years of age and older had unknown vaccine status. Among US residents who were 

known to be unvaccinated, 32 (70%) of children / adolescents had religious or personal 

exemption to vaccination. There were 11 (24%) missed opportunities of those who were eligible 

but were not vaccinated. Among adults, 7 (44%) had a philosophical objection to vaccinations 

and were born before 1957. 

Among the 53 hospitalizations, 52 (98%) were unvaccinated or had unknown vaccination status 

and 1 (2%) had received 1 dose. The individual who had received 1 dose was hospitalized for 

observation only. Complications included 9 (17%) cases of pneumonia. There was no 

encephalitis or deaths. Overall hospitalization was 34%, with the highest rate among those 

under 5 years of age: 44% <12 months, 48% 1 through 4 years, 16% 5 through 19 years, and 

32% ≥20 years. 

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There have been importations from all regions. Known sources of importation are reflected in 

the following table:

WHO Region

Total 

no. of 

cases Countries

Genotype 

identified

African 2 Kenya (1), Nigeria (1) B3 (2)

Eastern 

Mediterranean

2 Pakistan (1), Jordan (1) D4 (1)

European 25 France (12), Italy (4), Poland (1), Romania 

(1), Spain (1), United Kingdom (4), 

France/United Kingdom*(1), 

France/Italy/Spain/Germany *(1)

D4 (11), 

G3 (1)

Americas 1 Dominican Republic†(1) D4 (1)

South-East 

Asia

16 India (15), Indonesia (1) D8 (5), 

D4 (1)

Western 

Pacific

7 China (2), Philippines (4), 

Philippines/Vietnam/Singapore/Malaysia*(1)

H1 (1), 

D9 (2)

As noted, 70% of US importations are among US residents traveling abroad. To put this into 

perspective, Dr. McLean reviewed measles cases in Europe from January through May 2011. 

As of May 12, there have been greater than 10,000 cases from 18 countries. Outbreaks are ongoing in France, Spain, and Belgium. In France, there have been 12 encephalitis cases and 6 

measles-related deaths 

[http://www.invs.sante.fr/surveillance/rougeole/Point_rougeole_200511.pdf].

To summarize, there has been an increased number of cases. This is the highest number of 

cases since 1996 (n=156). This is in large part due to a number of importations, particularly 

countries visited by US travelers. Despite these outbreaks and importations, spread has been 

limited due to the high 2-dose vaccination coverage and rapid control efforts in the US. Of the 

importations, 70% have been among US residents traveling abroad. It is important to increase 

awareness of measles and vaccination among travelers.

CDC response efforts have included a collaborative effort of the CDC laboratory, which has 

been assisting in testing and retesting as needed through the Division of Viral Diseases with 

epidemiology and laboratory services. This division has consulted with health departments on 

response measures as needed. Communication activities include MMWR updates, interviews 

with the media, and other efforts (e.g., websites, provider education, travel education).

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Discussion Points

Dr. Schaffner (NFID) pointed out that their neighbors in this hemisphere were responsible for 

almost no importations, because they have done such a good job eliminating measles through 

immunization. It is now time to ask Europe why they do not immunize their children. 

Dr. Cieslak said he was impressed by the lack of cases from Japan, which used to be a major 

exporter of measles to the US. He requested comments on the measles picture in Japan.

Hajime Kamiiya (National Institute of Infectious Diseases, Tokyo) replied that Japan is in the 

fourth year of a catch-up campaign. The number of cases is currently down to about 300 per 

year, which is about 3 per 100,000.

Dr. Plotkin indicated that the problem in Europe is that they do not mandate vaccination against 

measles, rubella, or mumps. He thought the US government could complain to the European 

Union about this situation. His French friends in medicine and vaccines are frustrated and 

unhappy, but the French government is doing little about it. 

Dr. Baker indicated that the case of measles they saw in February was an imported case in a 

child who left the country at 11 or 12 months of age who had not been vaccinated. She said 

she was astonished by the very high rate of hospitalization, but that she suspected that a lot of 

those children are being admitted with a diagnosis of Kawasaki Disease. Measles is difficult to 

differentiate, especially for those who have never seen a case. She wondered whether they 

had or would have any information on admitting diagnosis. Her patient had bacterial pneumonia 

as a complication of measles, which was completely missed for two days. They were fortunate 

that the child was in a private room and was sick enough that he did not go outside of the room, 

resulting in pretty good infection control. She believes that one problem with spread is not 

knowing the diagnosis.

Dr. McLean responded that they do not typically collect admitting diagnoses unless states 

provide it. There were a couple of cases that were misdiagnosed.

Ms. Stinchfield (NAPNAP) reported that Children’s Hospital of Minnesota saw 12 of the 14 

children who were hospitalized there. Very seasoned infectious disease physicians thought 

they were dealing with Kawasaki Disease until the sibling presented and looked similar. Other 

children presented in March with otitis media, fever and a lot of gastrointestinal symptoms and 

still no rash. In retrospect, it is easy to judge, but when in the middle of it and the first case 

presents, it does look like similar illnesses. The message for everyone, seasoned clinicians or 

people who have never seen measles, think measles if there are characteristic diagnostic 

criteria and international travel.

A participant indicated that 20 years ago, he was at the St. Paul, Minnesota Health Department 

when there was a small outbreak of measles at a small college. Students from there had 

traveled to Disney World in Orlando. As the state epidemiologist, he had to quarantine those 

children and other primary contacts. He was curious about college students coming to the US 

from the UK, Asia, et cetera who do not have current immunizations. He thought immunizations 

should be up to date when freshman are admitted to college. 

Dr. Baker pointed out that US college students need to be up to date as well before traveling 

outside the US. 

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Dr. Turner (ACHA) reported that there is variability among states in terms of college preentrance requirements. Where he is in Virginia, students entering college are required to have 

a cadre of immunizations proven with a clinician’s signature in order to be admitted. There were 

four cases of measles in Charlottesville this spring. He checked their records and found that 

they had virtually 100% compliance among their 24,000 students. Conversely, California only 

requires evidence of a hepatitis B vaccine upon college entry. They assume that since they 

have good primary and secondary school entry requirements, all college students are 

appropriately vaccinated. They do not take into account that 20% to 25% of students are 

international, nor do they consider importation associated with international travel.

Dr. Greg Wallace (CDC) pointed out that sometimes exchange students are younger than 

college age. He emphasized that 70% of the US’s direct importations are actually the result of 

unvaccinated US residents traveling abroad. This is an area in which a direct impact can be 

made.

Dr. Moore (AIM) reported that a lesson learned in Tennessee is that there are those who were 

born in the late 1960s and early 1970s who missed out on the 2-dose MMR recommendation. 

She was born in the early 1970s and received her second dose before she went to Vanderbilt 

Universityas an undergraduate in 1999. Two of Tennessee’s cases were in their 40s who may 

have received inactivated vaccine and thought themselves to be vaccinated. They had no idea 

that they were unprotected until they returned from Europe with the disease. Tennessee has 

been focusing efforts on vaccination this group as well.

Discussion

Introduction

Dr. Mark Sawyer

Chair, ACIP Pertussis Vaccine Working Group

Dr. Sawyer reported that the Pertussis Vaccine Working Group was given the not so small task 

of reviewing existing statements on infants and young children (1997), adolescent (2006), adults 

(2006), and pregnant and postpartum women and their infants (2008) and consolidating these 

into a single statement. They were also charged with reviewing new data on Tdap, including 

effectiveness of ACIP recommendations, the interval between Td booster and Tdap, the use of 

Tdap in adults ages 65 years and older, vaccination of health-care personnel and need for 

post-exposure prophylaxis, pregnant and breastfeeding women in terms of Tdap use and 

cocooning strategies, and revaccination. In addition, this WG will review the updated 

epidemiology of tetanus and diphtheria.

Current ACIP recommendations for use of Tdap vaccine during pregnancy are as follows:

 During pregnancy

 ACIP recommends administration of Td for booster protection against tetanus and 

diphtheria in pregnant women. However, health-care providers may choose to 

administer Tdap instead of Td during pregnancy to add protection against pertussis 

in special situations.

Pertussis

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 Postpartum

 Tdap is recommended as soon as feasible in the immediate postpartum period to 

protect the women from pertussis and reduce the risk for exposing their infants to 

pertussis.

 Cocooning

 Adults who have or who anticipate having close contact with an infant age <12 

months (e.g., parents, grandparents, child-care providers, and HCP) should receive 

a single dose of Tdap.

Some data were presented to ACIP during the February 2011 meeting. The reason the WG

continues to pursue this issue is because they feel that the existing language is inadequate and 

is not sufficiently protecting infants from pertussis. Additional information requested by ACIP in 

February included safety of Tdap in mother and fetus, the effect of maternal vaccination on 

infant immune response to primary DTaP, and cost of a maternal Tdap vaccination program. 

This session addressed the following topics:

 Safety of Tdap in pregnant women and infants

 Decision and cost effectiveness analysis

 Pertussis maternal immunization study (interim data)

 Cocooning

 Timing of maternal vaccination (pregnancy or postpartum)

 ACIP recommendations for vote

 Emergence of pertussis in children aged 7 through 10 years and early evaluation of DTaP 

effectiveness

Based on reported pertussis incidence by age group from 1990 to 2009, infants have 

substantially higher rates of disease and the largest burden of death compared to other age 

groups. Many cannot be vaccinated and require other strategies for prevention of pertussis. 

The WG members felt that current strategies to prevent infant deaths are insufficient

[CDC, National Notifiable Diseases Surveillance System and Supplemental Pertussis 

Surveillance System]. A breakdown by age groups of reported pertussis-related deaths over 

the past 30 years shows that the great majority of deaths occur in infants 0 through 1 month of 

age, before they are eligible to receive the first dose of DTaP. This does not include the 2010 

California outbreak during which 10 deaths occurred in infants less than 2 months of age [Vitek 

CR, et al. Pediatr Infect Dis J 2003; 22(7): 628-34; and National Notifiable Diseases 

Surveillance System, CDC, 2009]. Several studies have provided evidence that of known 

sources of transmission, household members were primarily responsible for transmission of 

pertussis to infants. More specifically, parents were the most commonly identified source of 

pertussis [Wendelboe AM, et al. Transmission of Bordetella pertussis to Young Infants. Pediatr 

Infect Dis J 2007;26: 293–299; Bisgard KM, et al. Infant pertussis: who was the source? Pediatr 

Infect Dis J 2004; 23(11):985-989].

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The WG has been meeting on this topic for 6 to 8 months, and has gone through an evolution of 

thinking about the process. Almost everyone on the working group believes that the scale 

needs to be changed, which currently favors immunization postpartum versus during pregnancy. 

The majority opinion of the working group is that the scale needs to be balanced to have 

immunization during pregnancy at least on an equal footing with postpartum immunization. 

There is a significant minority opinion on the WG that immunization during pregnancy should be 

favored based on current knowledge about the safety and efficacy of such an approach. Next 

steps include revision of the pertussis vaccines statement and consolidation of all of the 

recommendations, continued review of the use of Tdap vaccine in persons age 65 years and 

older, and the need for a Tdap revaccination.

Safety of Maternal Vaccination for Mother and Infant

Sonja A Rasmussen, MD, MS

Centers for Disease Control and Prevention

With regard to background, Dr. Rasmussen pointed out that pregnant women are traditionally 

excluded from pre-marketing clinical trials for ethical reasons. Pre-marketing animal studies are 

performed, but do not always predict the experience of humans. Thus, there is little information 

available to guide use during pregnancy at the time a new medication or vaccine is marketed. 

Most available information about the effects of medication and vaccine use in human pregnancy 

comes from observation of exposures post-marketing. The goal is to determine whether 

benefits of the medication or vaccine exceed the potential risks of teratogenicity.

A teratogen is an agent that acts during pregnancy to irreversibly alter growth, structure, or 

function of the developing embryo or fetus. Recognized teratogens include infections, 

medications, nutritional factors, lifestyle factors, environmental exposures, and maternal

conditions. Potential adverse outcomes following exposures during pregnancy include 

spontaneous abortion, fetal death, preterm birth, small for gestational age (SGA) / intrauterine 

growth restriction (IUGR), birth defects, developmental disabilities (e.g., vision or hearing 

impairment, intellectual disability, autism), and cancer in offspring.

The teratogenicity of an agent depends upon the nature of the agent, dose, route of 

administration, gestational timing, other concurrent exposures, and the genetic susceptibility of 

the mother and embryo or fetus. Time periods of teratogenesis are shown in the following table:

Time Period Gestational 

Weeks

Examples of Teratogenic 

Effects

Preimplantation 

(fertilization to 

implantation)

0–2 weeks Spontaneous abortion or 

recovery (“all or nothing”)

Embryonic 2–9 weeks Structural birth defects 

Fetal 9 weeks–

delivery

Intrauterine growth restriction

Intellectual disability

Fetal death

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Typically, inactivated viral vaccines, bacterial vaccines, and toxoids are considered safe during 

pregnancy. Live and / or live-attenuated virus vaccines are contraindicated during pregnancy 

because of theoretical risk of transmission of the virus to fetus. However, no evidence has 

demonstrated an increased risk to mother or fetus from any currently available live vaccines 

(e.g., mumps, measles, rubella, varicella) [Reviewed in Gruslin et al., J Obstet Gynaecol Can 

30:1149-54, 2008].

Vaccines currently recommended during pregnancy include influenza vaccine, which protects 

pregnant women and infants <6 months of age. ACIP recommends trivalent inactivated vaccine 

for all women who are or will be pregnant during the influenza season. Tetanus toxoid vaccine 

protects infants born to women in developing countries from neonatal tetanus from neonatal 

tetanus where primary immunization has not occurred. WHO recommends 2 doses in first and 

1 in each subsequent pregnancy. There is no evidence to demonstrate an increased risk to 

mother or fetus.

VAERS is the spontaneous reporting system co-administered by FDA and CDC. The strengths 

of this passive surveillance system include rapid signal detection, ability to detect rare adverse 

events, generation of hypotheses, encouragement of reports from healthcare providers and 

acceptance of reports from patients and others, and availability of data to the public. The 

limitations of the system are reporting bias (e.g., underreporting, stimulated reporting), 

inconsistent data quality and completeness, it is not designed to assess whether a vaccine 

caused an adverse event (AE), and it lacks an unvaccinated comparison group.

VAERS data from January 1, 2005 – June 30, 2010 showed that 129 (1.2%) of 10,350 US 

reports to VAERS after Tdap vaccines involved pregnant women. Of the 129 reports, 4.7% (6) 

were classified as “serious.” There were no maternal deaths [CDC/ISO unpublished data]. The 

most commonly reported pregnancy-specific AEs include 21 (16.3%) spontaneous abortions; 5 

(3.9%) gestational diabetes; 2 (1.6%) each of stillbirths, oligohydramnios, ectopic pregnancy, 

threatened abortion, and sub-chorionic hemorrhage; and 1 (0.8%) each of gestational toxemia, 

preterm delivery, chorioamnionitis, prolonged labor, and congenital anomaly (gastroschisis). 

The most commonly reported non-pregnancy-specific AEs include 7 (5.4%) injection site 

reactions. No unexpected patterns or unusual events have been observed.

Pregnancy registries have been established by sanofi pasteur for Adacel® (Tdap) and 

GlaxoSmithKline (GSK) for Boostrix®. There were 49 Tdap exposures from the Phase IV 

clinical trials, and one baby with a birth defect. Of the 49, 34 (69%) had no AEs, 10 (20%) had 

serious AEs (gestational diabetes, threatened labor, spontaneous abortion, preeclampsia, 

syncope/hypotension/bradycardia, pregnancy-induced hypertension, tuberculin test positive), 

and 3 (6.1%) had non-serious AEs. There were 47 (96%) with known pregnancy outcomes, 

including 44 live births with 1 unrelated congenital anomaly (hydronephrosis diagnosed 

prenatally pre-vaccination), 2 spontaneous abortions, and 1 elective abortion. The registry 

cases are divided into prospectively and retrospectively reported cases. For the retrospective 

cases, there is information about infant outcome at the time of the report. For the prospective 

cases, there are no data about the outcome. Of 480 prospective spontaneous reports, 263 

(55%) had no AEs, 27 (6%) had serious AEs (spontaneous abortion, gestational diabetes, 

preterm labor, tubal rupture, preeclampsia, syncope/headache, ovarian cancer, labor 

complication NOS), and 31 had non-serious AEs. There were 119 (25%) with known pregnancy 

outcomes, including 101 live births (no congenital anomalies), 2 elective abortions, and 16 

spontaneous abortions. Of 10 retrospective spontaneous reports, 7 (70%) had no AEs, 2 (20%) 

had serious AEs (2 spontaneous abortions), and 1 had non-serious AEs. For all 10 there was a 

known pregnancy outcome, including 8 live births (1 with patent foramen ovale and peripheral 

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pulmonic stenosis), and 2 spontaneous abortions. Peripheral pulmonic stenosis is commonly 

seen in newborns and is not considered a major birth defect. Data are not yet available from 

GSK’s Boostrix® pregnancy registry.

Other issues that may be of potential concern are thimerosal, fever, and hyperthermia. No 

scientific evidence exists that thimerosal-containing vaccines are a cause of adverse events 

among children born to women who received vaccine during pregnancy. Neither Adacel® nor 

Boostrix® contain thimerosal or mercury. Fever appears to occur infrequently in less than 5%. 

Fever does have the possibility of adverse outcomes during pregnancy, but most of those 

adverse outcomes are in the first trimester. Hyperthermia from fever or hot tub use during the 

first trimester has been associated with certain birth defects, most commonly neural tube 

defects. A meta-analysis by Moretti et al (2005) suggests a 2-fold risk of neural tube defects 

with maternal fever during first trimester. Antipyretics appear to attenuate the association. 

Maternal infection, inflammation, and fever noted at admission for delivery have been 

associated with an increased risk of cerebral palsy, but it is unclear whether this is related to 

fever or to underlying infection.

In conclusion, killed vaccines are believed to be safe during pregnancy; however, it is difficult if 

not impossible to prove the safety of medication or vaccine use during pregnancy. A very large 

sample size is required to detect rare adverse events, and most studies are too small to rule out 

a small to moderate increased risk. In addition, exposures during pregnancy can cause a wide 

range of effects, including problems with development and risk for cancer. It is necessary to 

weigh the benefits with potential risks. Current data suggest that potential risks, if any, are likely 

to be small.

Tdap Vaccination to Prevent Pertussis in Infants: 

A Decision and Cost-Effectiveness Analysis 

Garrett R. Beeler Asay, PhD, MA

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Asay reminded everyone that the impetus for this study was that during the February 2011 

ACIP meeting, interest was expressed in understanding the cost-effectiveness of vaccination 

during pregnancy with Tdap as compared to cocooning and postpartum vaccination. The 

objectives of the study were to analyze the cost-effectiveness of alternative Tdap interventions 

in preventing infant pertussis and to assess the pregnancy dose, postpartum dose, postpartum

+ Tdap administered to the father, and postpartum + Tdap administered to the father + Tdap 

administered to grandparents.

In terms of pertussis incidence among infants less than 12 months of age based on data from 

2001-2009, the highest rates of disease occurs during the first 2 months of life. As DTaP doses 

are added, incidence declines. With regard to hospitalizations and deaths as a percentage of 

total cases, the highest percentage of hospitalizations and deaths occurred in the first two 

months of life [CDC, National Pertussis Surveillance System and Supplemental Pertussis 

Surveillance System (2010)].

The current ACIP recommendation to protect infants with Tdap is through cocooning by 

administering a Tdap booster for unvaccinated household members and caregivers of newborn 

infants1

. This was found to be cost-effective in one study from Netherlands2; however, there are 

no studies on cost-effectiveness in the US [1 Bisgard et al. 2004; Murphy et al. 2008; Van Rie 

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and Hethcote 2004; Wendelboe et al. 2007; 2 Westra et al. 2010]. An alternative strategy would 

be to move the postpartum dose to earlier during pregnancy, preferably in the third trimester. 

This would have two potential benefits. The first would be to protect the infant against 

transmission from the mother similar to postpartum, and the second would be a likely benefit of 

direct immunity to the infant through maternal antibodies [ Healy et al 2004; Van Savage et al 

1990; Gall et. Al. 2011; Leuridan, et al. 2008; Shakib et al 2010]. Both of these strategies 

would have the same program cost because only one dose would be administered.

A potential cost is that transplacental antibody may interfere with active antibody production 

following primary DTaP dose, which is known as “blunting.” There is mixed evidence for 

blunting from acellular vaccine [Belloni (2003); Englund et al (1995); Halasa (2008); Van 

Savage (1990); Wood (2010)]. Because this is an issue, an increase in risk of disease during 

the second and third month of the infant’s life is included rather than modeling the change in 

efficacy. While a benefit may be achieved by potentially lowering disease in the first few 

months, people seem to be concerned about what may occur later with additional doses. 

In terms of the methods of analyses, it was assumed that mothers were vaccinated in the third 

trimester of pregnancy and that there would be full efficacy of the vaccine when the baby is 

born. Then the increase in risk of disease during the second and third month would be included 

to model “blunting.” For the postpartum dose, a 2-week delay in booster immune response in 

the mother was assumed. For additional cocooning doses, a best-case scenario was assumed 

for the doses given prior to the birth of the infant so that they are fully protected. All vaccine 

cost were assumed to be the same for all Tdap doses at $37.55 per dose1 + a $20 

administrative cost2 [1 CDC 2011a; 2 Caro 2005]. A simulated birth cohort model was used with 

about 4,131,019 (2009 birth cohort size) infants followed for one year1

. Monthly incidence, 

hospitalization, and death rate were included. The societal costs perspective was included for 

infants only. The reason the benefits to adults from receipt of this vaccine were not modeled is 

because this strategy is primarily used to prevent infant disease. The analytic horizon was 

comprised of direct disease costs totaled over the first year of life. For life years lost, the 2009 

average life expectancy of 77.9 years2 was used [1. Hamilton 2010; 2 US Census Bureau 2011].

In terms of the model structure, the base case is DTaP alone. Each of the strategies will be 

compared to DTaP alone. Then there are the pregnancy dose, postpartum dose, and 

postpartum plus cocooning doses. The outcomes include outpatient disease, severe respiratory 

disease, neurologic disease, and death. The model tree is repeated each month of the cohort, 

for a total of 12 months (incidence varies by age), and outcomes are repeated for cocooning 

and base case.

Regarding general model inputs, 72% coverage was assumed for all doses because the 

investigators wanted to model the effect of a fully implemented program. Tdap efficacy of 85% 

was assumed. For incidences, hospitalizations, and deaths, the mean 2000-2007 incidence 

was used from national surveillance data. This is a period of time for which cocooning was not 

fully implemented or recommended. A 15% under-reporting rate and a 3% discount rate were 

assumed. For intervention model inputs, it was assumed that maternal antibodies were 60% 

efficacious and that they would last for two months. A 10% increase in the risk of disease was 

assumed in months 2 and 3 due to blunting. Based on the literature, transmission from the 

mother was assumed to be 35%, from the father 15%, and the grandparent 6%. Medical and 

non-medical costs were included for each outcome. The medical costs included outpatient visit 

($110), inpatient respiratory illness ($7,323), inpatient neurologic illness ($7,032), and death 

($15,808). The non-medical costs included outpatient visit ($47), inpatient respiratory illness 

($487), inpatient neurologic illness ($745), and death ($735). The QALYs were 0.85 for 

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outpatient visits, 0.58 for inpatient respiratory illnesses, 0.51 for inpatient neurologic illness, and 

0 for deaths [Lee et al. 2007 and Lee et al. 2005]. The public health response cost used was 

$2,162 (minimum $1,081; maximum $3,243).

In terms of the results, when the postpartum dose is added to the base case (DTaP), the graph 

shifts down over several months. The shift is not even. In the first month it is somewhat smaller 

because the mother is not fully protected when the baby is born. By the second month, the 

mother has the full booster response to the vaccine. Further out in months, incidence 

decreases and the benefit to vaccination decreases as well. Regarding the pregnancy dose 

compared to the postpartum dose, impact is lower in the first two months because the dose was 

given earlier so the mother has more protection when the baby is born, and also due to the 

transplacentally transferred antibodies. In the second month, the line is somewhat above the 

pregnancy dose due to the increase in risk of disease from blunting. However, it is still below 

the base case because by vaccinating the mother, the risk of disease was lowered for all age 

groups. That overrides the blunting effect for these assumptions. The addition of cocooning 

doses shifts the line down again, as it does when the grandparent is added. The shifts become 

smaller with each addition because the mother is the greatest identified source of transmission, 

so the greatest benefit comes from vaccinating the mother. The pregnancy dose has lower 

cases in the first few months when infants have the highest rates of deaths and hospitalizations. 

 

Regarding the mean percentage of reductions from the base case for all interventions, 

pregnancy is predicted to have a 33% reduction in cases, which is higher than the other 

interventions. This is similar with hospitalizations (38%), and more so with deaths (49%). The 

program costs are the same for pregnancy and postpartum ($171 million) because only the 

timing was changed—no doses were added. As doses are added for fathers and grandparents, 

the program costs increase to $342 million and $513 million, respectively. 

Based on this model, the program cost per QALY to save one year of perfect life for an infant 

with the pregnancy scenario is $415,442. With the postpartum scenario it is $1,174,143. By 

adding the father, the cost per QALY rises to $2,154,170 and by adding the grandparent the 

cost rises to $5,418,427. Therefore, according to the model, vaccination during pregnancy is 

the most cost-effective method.

Many sensitivity analyses were done, although Dr. Asay shared only one during this session. 

Assuming a worst case scenario of a 50% increase in risk of disease in months 2 and 3 and 

20% efficacy of maternal antibodies, compared to the base case the second and third months 

are above the base case, but in the first two months there are lower rates of disease. 

Compared to the postpartum dose, vaccine administration during pregnancy has a greater

reduction in deaths; however, hospitalizations and cases have a greater reduction when vaccine 

is administered postpartum. In terms of overall cost per QALY saved, vaccine administration 

during pregnancy is more cost-effective than postpartum administration.

In conclusion, two factors drive pregnancy cost-effectiveness. The first is when the mother is 

fully protected at birth for a given vaccine efficacy because the dose was given earlier, and 

second there is maternal antibody transfer to infant, giving the infant some form of direct 

protection in the first few months. In the worst-case scenario with 50% risk of disease in months 

2 and 3, the pregnancy dose was still found to be more cost-effective. Additional cocooning 

doses are predicted to be less cost-effective because they are preventing less disease. 

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The limitations of the model are that only infant disease was measured. The benefits to adult 

from being vaccinated were not assessed. The model also did not measure the vaccine 

recipient’s time away from work or transportation cost. This is a static model. If a fully dynamic 

model had been utilized, the cost-effectiveness results would be somewhat better, but the 

ranking among interventions would not change. Finally, there is no clinical trial to evaluate 

efficacy maternal antibodies in infants or blunting.

Pertussis Maternal Immunization Study

Dr. Jennifer L. Liang

ACIP Pertussis Vaccine Working Group

Dr. Liang reported that during the previous week’s WG call, interim data were presented from 

Stage 1 of the Pertussis Maternal Immunization Study, and Dr. Scott Halpern was kind enough 

to permit her to present these data on his behalf during this session. The study is sponsored by 

Dalhousie University. It is a double-blinded randomized clinical trial using Td or Tdap. The Tdap 

product used is Adacel®. This is a large trial that plans to enroll 440 pregnant women in two 

stages. Enrollment for Stage 1 is complete. The final infant visit and interim analyses on safety 

and immunogenicity were completed and presented to the Data Safety Monitoring Board the 

previous week. Stage 2 enrollment will commence in August or September 2011 and trail 

completion should occur in December 2012. 

The analysis of the two groups was blinded and included 48 infants whose mothers received 

either Td or Tdap during their late third trimester. For one group, there was evidence of lower 

geometric mean antibody levels one month after third DTaP dose. Therefore, antibody levels 

were analyzed at 0, 2, 4, 6 months. At birth and 2 months, elevated antibody titers were 

observed in the same group that had lower levels at the third DTaP. For both groups, there was 

an increase in antibody from 6 to 7 months indicating a response to the third DTaP dose. For 

both groups, antibody levels were comparable at 4 to 6 months. The Data Safety Monitoring 

Board recommended continuation of the study with Stage 2. The working group reviewed the 

interim data and concluded that the data are reassuring, and are consistent with published 

literature and assumptions made in the decision analysis presented by Dr. Asay.

Does “Cocooning” Work to Prevent Pertussis in Infants?

Dr. Jennifer L. Liang

ACIP Pertussis Vaccine Working Group

Dr. Liang reminded everyone that since 2005, ACIP has recommended cocooning as a strategy 

to protect infants from pertussis. Dr. Asay presented results from a model comparing the 

effectiveness of Tdap given either during pregnancy or during postpartum and cocooning to 

prevent infant pertussis. But in the real world, does cocooning work to prevent pertussis in 

infants? The WG group has heard about two examples of successful cocooning programs, one 

at the local level at Ben Taub General Hospital in Houston, Texas and another at the state level 

in 18 birthing hospitals in Nevada. In Nevada, either all birthing hospitals are either actively 

cocooning or beginning a cocooning program. Important success factors for these programs 

are having a champion for the cause, having donated healthcare provider time, and providing 

free Tdap to mothers and their families. 

 

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A number of challenges continue to impact the implementation of cocooning programs. Even 

after 5 years, cocooning is still a relatively new immunization platform with little infrastructure to 

ensure effective implementation. In addition, pertussis awareness varies. Two populations 

require vaccinations, including postpartum women and their families. Postpartum vaccination is 

not typically administered in the setting of new immunization providers. There are also 

reimbursement issues [Healy CM, et al. Pertussis immunization in a high-risk postpartum 

population. Vaccine. 2009 Sep 18;27(41):5599-602]. 

Thus, 5 years later, cocooning is not working at a national level. Most cocooning programs 

achieve moderate postpartum coverage among mothers, and have very limited success in 

vaccinating fathers or other family members. There is poor uptake of Tdap even when made 

available at no cost to birthing hospitals. At this time, there are no demonstrations of program 

sustainability or scaling-up of cocooning programs. Examples of not fully successful examples 

include Jefferson County, New York. During the increase in pertussis incidence, the state made 

Tdap available to birthing hospitals in Jefferson County, but uptake was poor. In California, 

during the 2010 epidemic, free Tdap was made available to birthing hospitals for a limited time. 

Not all birthing hospitals accepted the free vaccine to implement a cocooning program because 

of the work it would require, and not having the ability to sustain the program once free vaccine 

was no longer available. California is currently surveying the birthing hospitals that did 

implement a cocooning program to determine how many of them have been able to sustain their 

programs through alternative funding for Tdap.

Limited data are available regarding the effectiveness of cocooning, and have assessed only 

the maternal postpartum dose. One ecological study found no impact of only maternal 

postpartum Tdap on infant disease.1

 In one state, pertussis incidence in infants born at 

hospitals with a postpartum Tdap policy was lower compared to hospitals without a postpartum 

Tdap policy, suggesting that vaccinating new mothers may reduce transmission of pertussis 

from mothers to infants. 2 [

1 Castagnini L, et al. Impact of maternal postpartum Tdap 

vaccination on pertussis illness in young infants. IDSA , Vancouver Canada. Presented on 

October 23, 2010; 2 Winter K, et al. Effectiveness of postpartum Tdap vaccination in California 

hospitals. CSTE, Portland Oregon. Presented June 2010].

The WG unanimously concluded that while they would recommend cocooning all contacts of 

infants who are not current on Tdap, cocooning is an insufficient national strategy to prevent 

pertussis morbidity and mortality in newborn infants. This led the WG to ask the question: to 

prevent neonatal pertussis, should the timing of the mother’s Tdap vaccination change from 

postpartum to during pregnancy?

Discussion Points

Dr. Baker indicated that the data that was presented as an abstract form was in press at Clinical 

Infectious Disease. This was a comparison of a cocooning hospital that is a public hospital 

where patients are primarily Hispanic. The highest number of deaths occur in Hispanic infants. 

The vaccine, 7-day a week nursing, and faculty time are free. Families are being immunized, 

not just the mother. Dr. Castagnini’s data pertained just to women, and in a 17-month period of 

time there was no impact on prevention of pertussis disease as defined clinically and by positive 

PCR plus clinical manifestations. This has been extended to the families in the hospital before 

the mother is discharged. The nurses educate the mother and find out how many family 

contacts, and 50% of fathers and 96% of women are given Tdap at a cost of at least $1 million 

per year. When the program ends in December, the hospital will end the program because 

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there no reimbursement for them for this program. Cocooning everybody is very difficult to 

implement. 

Dr. Judson asked whether “cocooning” as term every caught on so that patients and their 

families understood what it meant.

Dr. Baker replied that this is a medically uninsured, under-served population. English is usually 

a second language, so the nurses are bilingual. The patients and their families had no clue. 

Part of this was education in an appropriate language, but these were obviously accepting 

parents who wanted their families protected. One thing that made the program very difficult was 

the pandemic, because the hospital would not let any family member visit the mother, including 

the father. The father was permitted in during delivery, but was not allowed back in until he 

returned to pick up the baby.

Dr. Coyne-Beasley expressed her appreciation for the presentations, especially Dr. Asay’s very 

clear description of the cost-effectiveness analyses.

Dr. Cieslak noted that they usually think in terms of incremental costs, and it struck him that the 

$171 million might be tallying the cost of vaccinating these women. However, there is already a 

recommendation to vaccinate these women. The only difference regards when to vaccinate 

versus adding any vaccine costs. 

Dr. Asay responded that this was correct, but in abiding by the standards used for costeffectiveness, the cost of the dose has to be included because this is a program that would 

hopefully be fully implemented. It is true that the current recommendation is that these women 

should be vaccinated at some time point. Just moving the postpartum dose back could have no 

change in program costs.

Dr. Baker pointed out that in their program, women know whether they received a shot or not at 

some time. They have no clue what the shot was. For those that can be determined, it was 

usually influenza vaccine.

Ms. Rosenbaum pointed out that ironically, because of the way many public and private insurers 

pay for maternity care, this could actually cut the cost because what could happen is that it will 

be treated as part of the global fee and no incremental payment will be made; whereas, before 

there may have been some cases in which providers were paid extra postpartum, although even 

that is unreliable. This is the problem with anything that is pregnancy-related. The tendency on 

the part of insurers of all kinds to pay for specific procedures that fall within their general 

concept of pregnancy-related is pretty low. However, if something is not called “pregnancyrelated” it will not be recognized as a standard of care and there will not be an argument for 

building it into the global fee. She underscored the notion that at worst, this is a wash in terms 

of the cost.

Dr. Marcy inquired as to whether blunting pertained only to pertussis or if it also included 

tetanus and diphtheria antibody levels. He also requested clarification about what they meant 

by “blunting” and what level is no longer offering clinical efficacy. Although he was unclear what 

was even meant by “blunting,” it seemed to be the variable upon which this discussion was 

based.

Dr. Liang replied that the concerns about blunting were raised with regard to whether maternal 

antibodies would interfere with the infant’s primary immune response for primary DTaP doses. 

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The correlates of protection are not well-understood. The clinical implications of lower response 

to primary DTaP series are unknown. Because it was a concern in 2005 when the original 

recommendation was made, they were trying to address this with the current data available and 

within the model, what the impact would be. 

Dr. Asay added that diphtheria and tetanus were not modeled. Regarding blunting, by 

vaccinating the mother, a dose is being added to the schedule. This will lower the overall risk of 

disease for every age group. If efficacy is falling, at the same time the risk of disease is also 

falling. 

Dr. Judson requested confirmation that blunting is a concept, there is no definition, and there 

are no true correlates to reduce efficacy. 

Dr. Liang confirmed that this was correct.

Dr. Clark pointed out that most of the literature pertains to diminished response to the primary 

series for pertussis antigens. Analogous is that there are some data on a birth dose of acellular 

pertussis vaccine. There has some diminished response to diphtheria antibody, but all children 

reach protective titers, so there is a correlate of protection. The blunting question really regards 

diminished response to the primary series, because of the presence of maternal antibodies. 

The data from Scott Halpern’s study were reassuring that there is a response in all children. 

However, the correlate of protection does not exist so the clinical efficacy is not known. This is 

why a modest hypothetical increase in disease occurrence was built in, assuming that this 

would be the only impact.

Dr. Marcy indicated that Joe St. John was administering neonatal whole cell pertussis 

immunization in the late 1960s. He wondered whether neonatal birth immunization as is done 

with Hepatitis B might be the ultimate answer if there was great concern about blunting. 

Dr. Baker noted that the study Dr. Clark quoted pertained to acellular pertussis vaccine alone 

that was conducted in Switzerland. When Kathy Edwards’s group in Nashville assessed 

currently available vaccine in neonates, it did not work. There would have to be some sort of 

acellular pertussis vaccine alone product if they were going to back up to the neonate.

Regarding sustainability of cocooning, Dr. Temte indicated that anecdotally in his experience 

family practice does a terrible job of cocooning. Technology has made this worse, because with 

the electronic medical record (EMR) everything he does requires a lot of excess time. For him 

to immunize his patient in the room is pretty simple. To immunize his patient and her husband, 

who is also a patient, requires him to open another window, log this in, and go through an 

incredible series of steps to order a vaccine. He wondered whether Dr. Campos-Outcalt heard 

similar issues, and how many pregnant patients’ other family members obstetricians would be 

able to provide vaccines for. Hospitals will not do this because they cannot afford the 

administration costs. 

Dr. Campos-Outcalt (AAFP) agreed that cocooning is very hard to sustain because there are a 

number of administrative issues. When his daughter-in-law was pregnant, he sent his wife to 

her internist, not a family physician, for a vaccine. She received her influenza vaccine, but when 

she returned he asked about Tdap and she said it was not even discussed. This is a frequently 

overlooked vaccine for adults regardless.

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Dr. Gall (ACOG) responded that an obstetrician will see a pregnant woman 8 to 15 times during 

her pregnancy. It takes a lot of time to talk about vaccines like influenza, Hepatitis A, and Tdap 

to get her up to speed. Tdap has been given during pregnancy and have published data about 

this. However, it is unknown who is with the patient (e.g., husband, boyfriend, or someone 

else). The grandparents rarely attend a visit with the mother. It is unknown who else is in the 

household constellation who needs the vaccine, and there is no way to finance those other 

people. 

Dr. Baker stressed that the key is finding out who is in the household and who will be around the 

baby during the first year or even first 6 months of life. This is potentially a huge number of 

contacts. They have on-going funding from private foundations, et cetera. She thinks that even 

with 50% of the fathers and 96% of the mothers, they may not observe an effect from 

cocooning. Again, this hospital has 4000 to 5000 deliveries per year, and the cost of the 

program is more than $1 million per year. In many states, it is a law that someone has to be a 

patient for a hospital nurse to administer a vaccine. They have to have two nurses, hired by the 

children’s hospital, to do this work. To say it is complicated and expensive is an 

understatement. This is all because pregnant women are orphans in terms of medications and 

vaccines. 

Dr. Englund said that cocooning has never been proven to work. A prospective, multi-site, 

international study in 2007, up to one-third of all cases were outside the home. Although it is 

known that the mother and father are responsible for well over half or even up to two-thirds of 

the cases and that the other one-third are casual contacts. Cocooning is doomed to fail, and it 

is not scientifically proven. Maternal immunization offers the opportunity to protect against the 

most important risk factor and the baby with one cheap vaccination. 

Dr. Baker pointed out that hospitals pay for MMR postpartum immunization with no problem. It 

is a matter of convincing Medicaid to include this tiny cost. 

Dr. Duchin agreed with all of the observations that were made about the difficulty of cocooning, 

but he sees that as typical of risk-based vaccination recommendations, which have traditionally 

been very difficult and have not been very successful. With Hepatitis A and B, there were very 

low coverage rates before moving to a broader recommendation. Pneumococcal vaccine was 

challenging as well. Trying to single out certain risk groups within a larger population has 

always been difficult, and cocooning is especially difficult, but it is not that unique to this 

population. 

Dr. Baker reminded everyone that they have already recommended that all adolescents and 

adults be given Tdap vaccination, but adults are not given this vaccine. The amount of medical 

capture time for a pregnant woman makes the implementation of that recommendation 

potentially doable. 

Dr. Chilton noted that 2 of New Mexico’s 38 birthing hospitals are using a cocooning strategy, 

and they are seeing only about two-thirds of mothers immunized and far less than this in the 

one other contact allowed in these hospitals. They have fewer resources than Dr. Baker 

described in her hospital. With no dedicated resources, it may be difficult to sustain any efforts.

According to the data presented, Dr. Cieslak pointed out that there has been an average of 

about 18 infant deaths per year from pertussis over the past decade. Given that there are about 

4 million births per year, this is less than 1 in 200,000 infants. One could make the argument 

that they should be considering whether vaccinating pregnant women not likely to cause more 

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than 1 in 200,000 miscarriages or spontaneous abortions. What concerns him even more is 

that when this many pregnant women are vaccinated, a certain number of them are going to 

have miscarriages, stillbirths, preeclampsia, et cetera and they are going to blame the vaccine 

for it. Consideration needs to be given to the potential impact on vaccine programs from a 

recommendation like this.

Dr. Baker indicated that there would be presentation regarding timing in pregnancy. Most 

serious adverse events associated with pregnancy occur early. If women are being vaccinated 

during the third trimester, there will not be a congenital anomaly. The baby is just growing. She 

deferred this comment to the next discussion.

Dr. Gall (ACOG) pointed out that everyone in the US has at least one or two early ultrasounds. 

There is an anatomy scan at 18 to 20 weeks, and there may be an early scan for diagnosis at 8 

to 14 weeks. If the vaccine is positioned at 18 to 20 weeks or after ultrasound, it would be 

known whether the baby had pre-existing issues. 

Dr. Baker noted that vaccine and administration costs are much less than ultrasound, not that 

she is against ultrasound.

Timing of Maternal Tdap Vaccination:

During Pregnancy or Postpartum?

Dr. Jennifer L. Liang

ACIP Pertussis Vaccine Working Group

Dr. Liang indicated that in the end, the WG decided that given that Tdap coverage among adults 

is very low and that most pregnant women would be eligible for Tdap, the real issue to discuss 

would be the timing of when an unvaccinated pregnant woman should be vaccinated (e.g., 

during pregnancy or postpartum). Over the course of 8 months, the WG weighed the facts and 

experiences of others to reach a number of conclusions. Dr. Liang explained how each 

conclusion was reached. 

First, the WG concluded that postpartum vaccination is a suboptimal national strategy to prevent 

infant pertussis morbidity and mortality. Five years after ACIP’s recommendation for cocooning, 

there is no widespread implementation. It is difficult for all close contacts of newborns to be 

vaccinated. There is poor uptake of Tdap when made available to birthing hospitals, and no 

demonstration of program sustainability. 

Second, the WG concluded that vaccinating pregnant women during the late second or third 

trimester is acceptably safe for both mother and fetus. As Dr. Rasmussen presented, Td and 

TT have been used extensively in pregnant women. No evidence indicates administering either 

vaccine during pregnancy are teratogenic. Data and expert opinion support that Tdap is 

acceptably safe to both a pregnant woman and the unborn fetus. And finally, the WG

recommends Tdap during the third or late second trimester to minimize concerns about adverse 

fetal effects associated with Tdap vaccine.

Third, the programmatic cost of vaccinating with Tdap during pregnancy or postpartum is the 

same. There is already a recommendation in place for postpartum Tdap vaccination. The 

model presented by Dr. Asay shows that by changing the timing of maternal Tdap vaccination 

from postpartum to during pregnancy, the programmatic costs and the number of Tdap doses 

would be the same. But, administering Tdap during pregnancy would prevent more infant 

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cases, hospitalizations, and deaths. Based on the model, for every scenario, the impact of 

vaccinating during pregnancy is favorable. 

Fourth, the WG concluded that there are not sufficient concerns about blunting of an infant’s 

immune response to primary DTaP series to not recommend maternal vaccination during 

pregnancy. Transplacental antibodies may interfere with infant’s active antibody production

following primary DTaP. The degree of interference to infant’s immune response is not yet 

known, but is short-lived. The clinical importance is not clear. The benefits of protection 

outweigh risk of less protection later in infancy. Current on-going studies will not answer clinical 

significance. 

Fifth, the WG concluded that late second or third trimester maternal vaccination may prevent 

infant pertussis during the same pregnancy. Vaccinating a pregnant woman with Tdap will 

provide protection against pertussis to the mother herself. For the infant, transplacental transfer 

of maternal antibodies may provide protection against pertussis in early life. Again, the 

effectiveness of preventing infant pertussis is not yet known.

Dr. Liang reminded everyone that in his opening remarks, Dr. Sawyer conveyed the WG

conclusions on the timing of Tdap vaccination. After 8 months of discussion, the WG does not 

believe that postpartum Tdap as part of the cocooning program should be the preferred national 

strategy to prevent pertussis in neonates. The majority of WG members supported language 

which put Tdap during pregnancy or Tdap postpartum on equal footing. A minority of WG

members supported language which gave preference to Tdap during pregnancy. Both of these 

options were presented to ACIP for consideration and vote as follows:

General Recommendation Proposed Language for Maternal Tdap Vaccination: 

Option 1

Women’s healthcare providers should implement a maternal Tdap vaccination program for 

women who have not previously received Tdap. Healthcare providers should either administer 

Tdap during the third or late second trimester* or immediately postpartum.

*After 20 weeks gestation

Option 2

Women’s healthcare providers should implement a maternal Tdap vaccination program for 

women who have not previously received Tdap. Healthcare providers should administer Tdap 

preferably during the third or late second trimester*. Alternatively, they would administer Tdap 

immediately postpartum.

*After 20 weeks gestation

Discussion Points

Regarding the small number of deaths, Dr. Baker pointed out that the babies do not just die 

within 24 to 48 hours after hospitalization. They have one to three weeks of extracorporeal 

membrane oxygenation (ECMO). To be placed on ECMO in her hospital, on day one it’s nearly 

a half a million dollars. She does not think that they should be measuring costs of a baby’s 

death, but it is not just a quick death. A tremendous amount of medical resources are required 

for those infants.

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Dr. Clark (SME) agreed, and pointed out that there are numerous reasons pertussis is missed 

as a diagnosis. Especially in infants, pertussis is under-recognized and under-reported. The 

absence of cough is a major reason, but the lack of apnea as a presentation in the case 

definition misses cases and deaths that occur before two weeks of cough. Several cases in 

California were confirmed as pertussis, but they were not reported because of the case 

definition. 

Dr. Judson pointed out that pregnancy is a state of mild immunosuppression. He wondered if 

anything practical was done in terms of outcome, efficacy, antibody titers, et cetera.

Dr. Liang responded that at this time, there are no data.

Dr. Baker emphasized that when clinical trials are not permitted in pregnant women it is very 

difficult to answer this question. Dr. Halpern’s study will assess pre- and post-immunization 

during pregnancy. His window begins at 26 weeks. There will be maternal and infant sera 

information. The NIH trial will also have this information. There will not be a large number of 

subjects. The immune suppression that Dr. Baker has observed relates to tolerance to the fetus 

rather than immune suppression to vaccine response.

Dr. Judson stressed that not only is acellular pertussis being administered, but also diphtheria 

and tetanus are being administered. The schedules for immunization should not be identical 

based on duration of protection and antibody. He wondered whether there was any concern 

about this. When he began working in medicine, tetanus and diphtheria were administered 

anytime anyone was cut and / or presented in an emergency department for anything. Ten 

years after that, papers were being published on the dangers of over-immunization with tetanus, 

and that optimal spacing was 10 years in most cases. Now there seemed to be a concept that 

there is no danger in over-immunizing. He wondered whether this had been shown adequately. 

Dr. Baker replied that there are data on Td from Dr. Halpern in children that show that a 2-year 

interval is no problem, and shorter than a 2-year interval was based on risk / benefit balancing. 

She has occasionally inadvertently immunized adults with Tdap in as short as 6 weeks with no 

problems. 

Dr. Clark (SME) added that this did not involve very much additional antigen. Effectively, 

transmission of toxigenic Corynebacterium diphtheriae has been eliminated, so there is really 

very little exposure anymore. There is minimum occurrence of tetanus disease, and the current 

schedule and strategy are responsible for that. Thus, he did not believe they were talking about 

dramatic changes that would cause concern one way or the other.

Dr. Gall (ACOG) indicated that in his study that was recently published, Tdap was used so there 

were data on response to tetanus and diphtheria antigens. They responded nicely, so there 

was no blunting between the pertussis antigen and the tetanus and diphtheria. The responses 

were not astronomical, but they were very reasonable. 

Dr. Marcy thought the toxicity studies were from a famous destroyer study, where those in the 

Navy were receiving tetanus shots annually. Administering an annual vaccine has gone out of 

practice. He wondered what the interval should be for women who have not previously received 

Tdap. It is known that pertussis antibody levels, whatever that means, fall off after about 5 

years. If antibodies are given cross-placentally to the fetus, they are already being diluted to 

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some extent, so he thought it was important to include the interval. Women who have not 

received Tdap within a certain period of time should receive it again. 

Dr. Baker responded that the problem is that they don’t have this information, although they will 

be hearing about it in future meetings. 

Dr. Marcy said that if they were going to base everything they were going to vote on upon 

information, they would not be voting.

Dr. Baker said that what is different for those who are not young babies is that pertussis 

immunization provides cell-mediated as well as humoral immunity. However, babies do not 

have cell-mediated immunity. They have only maternal antibody or their own antibody that they 

make after their primary series.

Dr. Liang clarified that the phrase of “not previously received Tdap” is also to address the fact 

that Tdap is currently licensed and recommended for only one time use. The recommendation 

is geared toward women who have never received Tdap.

Dr. Coyne-Beasley pointed out that the statement was made during the presentations that the 

programmatic costs of Tdap vaccine during pregnancy or postpartum are equal; however, if 

administered during pregnancy the vaccine prevents more infant cases, hospitalizations, and 

deaths. The presentation also indicated that in every scenario, vaccination during pregnancy is 

favorable. She was trying to understand the context of that comment within a recommendation 

that did not favor immunization during pregnancy versus postpartum. 

Dr. Baker responded that a significant minority of the WG thought that should be favored, but a 

significant majority believed otherwise.

Dr. Sawyer reported that the feeling of those on the WG who held the majority opinion was that 

there is a lack of data on blunting, and that some data specifically addressing that issue will be 

forthcoming in the next one to two years. Therefore, they believed that it was premature to 

make a recommendation strongly in favor of immunization during pregnancy. 

Given that it could affect the VFC vote, Ms. Rosenbaum requested clarification regarding 

whether they were saying that vaccinating the mother is important not only because protects the 

baby from her transmitting illness, but also because it stimulates the creation of antibodies 

within the infant. That is, when the baby is born it would have antibodies in its system that it 

would not have otherwise.

Dr. Baker clarified that an adolescent or adult pregnant woman will benefit because she will 

make antibodies to protect her against pertussis herself. The side benefit is to hopefully transfer 

protective antibodies to the baby. The influenza model is a good example. This is a very bad 

disease in a pregnant woman, so she is immunized. The benefit for the baby is substantial in 

terms of febrile respiratory disease.

Dr. Duchin was impressed by the presentation making a strong argument for vaccination during 

the latter stages of pregnancy, and the WG not favoring that opinion versus weighing them 

equally. He requested further information about the data that would be forthcoming that might 

make it less desirable to recommend vaccination during pregnancy at this time. It was not clear 

to him exactly how to weigh that in consideration of the two options proposed.

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Regarding the working group discussions about Option 1 versus Option 2, Dr. Liang clarified 

that Option 1 gives equal weight to Tdap immunization during pregnancy or postpartum. Those 

who supported this language did not feel that there was sufficient evidence to justify preference 

of one versus the other. Cocooning has yet to be proven effective, and it is known that infants 

are born with maternal antibodies. However, the effectiveness of those antibodies has also not 

yet been proven. Due to those concerns and the concerns about blunting, many of the WG

members felt that there was insufficient data to justify the preference of during pregnancy 

versus postpartum immunization.

Dr. Duchin inquired as to whether any studies were underway that would offer additional data 

about the effectiveness of maternal antibody transfer to the infant.

Dr. Liang replied that she did not know of any studies underway to address this issue. It would 

likely take a large number of pregnant women to be vaccinated and infants to be followed up in 

order to understand the significance of maternal antibody transfer. This information may never 

be available.

Dr. Baker reminded everyone that Tdap is a booster vaccination. It was licensed and 

subsequently recommended by ACIP on the basis of serologic bridging, not on the basis of an 

efficacy trial. Although there is no protective correlate, it was licensed because the antibody 

concentrations in Tdap-immunized adolescents and adults were similar to the efficacy studies 

performed in young infants. Thus, there is some information.

Dr. Sawyer added that the information the WG is looking forward to is specific data from two 

small studies that will illuminate the exact degree of blunting. The preliminary data the working 

group heard the previous week was encouraging that although there may be some blunting, it is 

a relatively mild effect. Those are the only additional data that will be forthcoming.

Dr. Baker clarified that the preliminary data pertained only to first versus third dose, so the 

additional data will address a lot more points to understand the degree of blunting after the first 

and second doses. It is known that the first dose primes, but does not protect. 

Dr. Duchin noted that the modeling addressed that to some degree by still favoring prevention of 

disease in the first month or two regardless of what occurs with blunting.

Dr. Keitel pointed out that efficacy of acellular pertussis vaccine in adults for prevention of 

pertussis has been demonstrated. Joel Ward was the senior author.

Dr. Temte stressed that potential adverse birth outcomes is an important issue. There are very 

limited data to evaluate that effect. He wondered whether the WG discussed prospective 

planning to monitor for potential adverse fetal outcomes. 

Dr. Liang replied that the WG did not have specific discussions on follow-up, but she would 

assume CDC would do so.

Dr. Baker added that there are two pregnancy registries that have been active all along. Most 

people in the registries were immunized during the first trimester.

Dr. Jenkins pointed out that a natural number of spontaneous abortions would occur, and that it 

would be important to assess the outcomes to determine the context.

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Dr. Hahn (CSTE) noted that prenatal vaccination falls to the obstetric provider for the most part, 

while postpartum falls into the hospital setting. This means two different groups need to be 

aware of this, and balancing them equally is a reminder that this is a shared responsibility. 

Hospitals need to be put on notice that they need to check whether women received Tdap 

during pregnancy.

Dr. Chilton did not believe that in general those who care for pregnant women have done very 

well at immunizing pregnant women, and that if there was an additional reason for them to do 

so, it might also strengthen the recommendation to administer influenza vaccination during 

pregnancy as well.

Dr. Baker noted that obstetrical care providers did a really great job last season with influenza 

vaccinations compared to previous seasons.

Dr. Moore (AIM) pointed out that from a program management perspective, she would not agree 

that this is a programmatically equivalent process. Programs consider lines of defense to 

protect the neonate. The first line of defense is pre-conception immunization, the second is the 

three months during the third trimester when they are in the clinic a lot, and the last line of 

defense is postpartum immunization. The last line of defense provides the least amount of 

protection for the infant, as shown in the presentations, so they do not consider these lines of 

defense to be equivalent. There’s a major difference in having 3 months versus 3 days to 

vaccinate a woman. Programmatically, a better job can be done with a preference on 

vaccinating unvaccinated women during the third trimester. If two groups are responsible, each 

will assume the other handled it. It is necessary for people to take ownership at each point in 

the process up to the time the baby is delivered.

Dr. Gall (ACOG) felt that if Option 1 was selected, nothing would be done. This is basically the 

same inertia that will keep people doing what they are already doing. There will be no driving 

force. Option 2 says that it is preferable to vaccinate during pregnancy, but cocooning is also 

an option for those who do not wish to vaccinate. He thought cocooning should be removed as 

it is not working, and it was unclear to him why they kept “beating a dead horse.”

Dr. Campos-Outcalt (AAFP) noted that while they were all reassured about the safety of the 

vaccine, many of their patients will not be. Even though it is given in the second or third 

trimester, which is unlikely to lead to any adverse events, the number of potential claims from 

people who think the vaccine has harmed their baby during that time is unknown and could be 

significant. He thought because the vaccine is given to children, these claims would be 

submitted to the Vaccine Compensation Program, which should help with that problem. 

Dr. Duchin wondered what was known about the acceptability of the strategy of vaccinating 

mothers during pregnancy, and how likely it is that this recommendation would be adopted. 

Dr. Baker replied that it is not the mothers who won’t accept vaccination, it is the doctors. If 

recommended by an obstetrician, acceptance rates are over 90%. Her program has nursing 

providing education, and there are postpartum orders from the doctors. Her population is a 

highly vaccine accepting women of Hispanic ethnicity. She believes a medical platform will be 

easier from a programmatic point of view.

Regarding insurance coverage of obstetrical care and deliveries, Dr. Doskey (AHIP) noted that 

a number of individual policies are still sold in the US that do not include obstetrical coverage. 

Everything associated with those admissions are denied, including vaccination.

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Dr. Baker replied that fortunately, that represents a relatively small number of people in the 

population base. However, undocumented immigrants receive paid hospital care immediately 

upon delivery and their Medicaid eligibility is taken care of for the mother and baby. This is a 

reverse situation where the poor and disadvantaged have an advantage.

Dr. Doskey (AHIP) stressed that the portion of the population with individual policies is expected 

to grow as the exchanges come into play over time.

Ms. Rosenbaum added that coverage for maternity care is a mandatory essential benefit, and 

hopefully all women in the individual market eventually will be covered. 

Dr. Baker pointed out that issues that will occur years from now were not ACIP’s concern during 

this meeting. 

Dr. Brewer (ANA) indicated that ANA has an affiliate relationship with the American College of 

Nurse Midwives, and they speak in favor of Option 2.

Dr. Temte asked ACOG and AAFP representatives to comment on whether their organizations 

would endorse a recommendation for immunization of pregnant women if ACIP were to vote for 

this.

Dr. Gall (ACOG) felt that ACOG would endorse such a recommendation. He tried to get ACOG 

to include pregnancy in 2009 in their recommendations; however, ACOG insisted on following 

ACIP’s decision at that time.

Dr. Campos-Outcalt (AAFP) responded that AAFP places a high value on harmonization of 

vaccine records, and would probably endorse such a recommendation.

Dr. Baker indicated that in 2008, AAP recommended vaccination of pregnant women before the 

document was published.

Phil Hosbach (sanofi pasteur) suggested being careful about the wording in the 

recommendation so as not to denigrate the cocooning strategy. While it is a difficult strategy, 

many moms have been successful in getting their husbands immunized. It is better to cocoon, 

so they do not want women to give up on getting those around her immunized. Wanting to 

protect the baby will motive more people to get immunized.

Dr. Baker responded that the WG is committed to cocooning. She reminded everyone that at 

least 10% to 11% of babies are born pre-term in this country, and it is unknown what level of 

maternal antibody would be protective in those babies. She thought cocooning was very much 

should be a continued recommendation regardless of the option selected.

Dr. Sawyer confirmed that this was correct.

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Motion: General Recommendation for Maternal Tdap Vaccination 

Ms. Ehresmann made a motion to accept Option 2. Dr. Coyne-Beasley seconded the motion. 

The motion carried with 14 affirmative votes, 1 negative vote, and 0 abstentions. 

Dr. Liang indicated that to address ACIP’s concerns about cocooning, the proposed 

recommendation for cocooning does not differ from what has previously been accepted by 

ACIP, and mirror the language that ACIP accepted with regard to the use of Tdap. The 

proposed language is more of a harmonization to combine the adolescent and adult 

recommendations. The proposed language for cocooning and for special situations read as 

follows: 

Cocooning 

Adolescents and adults who have or anticipate having close contact with an infant aged less 

than 12 months (e.g., parents, siblings, grandparents, child-care providers and healthcare 

providers) should receive a single dose of Tdap to protect against pertussis if they have not 

previously received Tdap. Ideally, these adolescents and adults should receive Tdap at least 2 

weeks before beginning close contact with the infant.

Special Situation Proposed Language: Pregnant Women Due for Tetanus Booster

If a tetanus and diphtheria booster vaccination is indicated during pregnancy for a woman who 

has previously not received Tdap (i.e., wound management, more than 10 years since previous 

Td), then healthcare providers should administer Tdap preferably during the third or late second 

trimester*. 

*After 20 weeks gestation

Special Situation Proposed Language: Unknown or Incomplete Tetanus Vaccination

 To ensure protection against maternal and neonatal tetanus, pregnant women who never 

have been vaccinated against tetanus should receive three vaccinations containing tetanus 

and reduced diphtheria toxoids during pregnancy. 

 The recommended schedule is 0, 4 weeks, and 6-12 months. Tdap should replace 1 dose of 

Td, preferably during the third or late second trimester* of pregnancy.

*After 20 weeks gestation

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Discussion Points

Dr. Chilton pointed out that pediatricians do see pregnant women when they present at 13, 14, 

15, et cetera. He wondered whether a woman who has a wound in the first trimester should 

receive a tetanus-containing vaccine at that time. He was not sure this was clear.

Dr. Liang replied that the working group presented the specific language to vaccinate during the 

third or late second trimester to remove some of the concern about safety. Based on the safety 

data available, there has not been any indication of negative infant outcomes for women 

vaccinated in the first trimester. 

Dr. Gall (ACOG) indicated that he would give Tdap to a woman who was injured in the first 

trimester. The study for which data are becoming available includes women who were given 

Tdap at various times during pregnancy. There will be data on the antibody levels at the time of 

delivery for the mothers and babies, so they will know whether there is any difference in their 

responses.

Dr. Baker emphasized that anything done during the first trimester is dangerous in terms of 

coincidental adverse events, and it is very difficult to assign cause. Her greater concern in 

terms of pertussis is that there is enough antibody to protect the baby. The half-life for pertussis 

and tetanus-specific antibodies is slightly longer than 30 days. The first reason for 

administration during the third or late second trimester is to avoid safety concerns pertaining to 

spontaneous abortion, congenital anomalies, et cetera. The second reason is that there are not 

enough data on the amount of antibody going to the baby. Since hospitals typically do not have 

Tdap, she suggested modifying the language to say that “If a woman is not in the late second or 

third trimester and sustains a tetanus-prone wound, she should receive TD and Tdap should be 

given after that.” 

Dr. Englund pointed out that whatever they do will drive policy, and it would be inappropriate to 

require a pregnancy test before administering Tdap. Tdap is given widely in the healthcare 

system for exposures. 

Dr. Baker agreed, pointing out that if there is a tetanus-prone wound handled by a pediatrician, 

they will do whatever they will do. However, it is handled by an emergency department, Tdap 

often is not stockpiled there other than perhaps in children’s hospitals.

It was Dr. Keitel’s understanding was that the cocooning language was focused on addressing 

immunization of potential older contacts, predominantly after the baby is born. She wondered if 

they could build into the statement that a strategy should be implemented as soon as it is known 

that a woman is pregnant. That would give more time to ensure that other family members are 

immunized and protected before the baby is born. That reinforces the concept that a pregnant 

woman should be given Tdap. 

Dr. Baker said she thought the WG wanted to emphasize that it should be at least two weeks 

before the beginning of close contact.

Dr. Marcy reminded everyone that the closest correlative study pertained to pertussis toxin 

titers, which fall off quickly. He thought they were kidding themselves to think that a woman 

who received Tdap in 2006 would still be giving protection to the infant. However, there is no 

recommendation for a booster.

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Dr. Baker reminded them that hopefully they would have an answer to that question in October. 

She clarified that they were not voting on a new dose because they did not have the data on 

duration of protection. They were voting on people who have not received Tdap.

Dr. Duchin wondered whether they should include language advising healthcare providers on 

what to do when the pregnant woman has an unknown vaccine status. The option on which 

they voted was to vaccinate women who had not previously received Tdap, and he thought it 

would help to include a sentence about how to handle women of unknown vaccine status.

Dr. Baker responded that it could be similar to what is done for infants of unknown vaccine 

status, which is to immunize them if unsure. 

Dr. Liang clarified that the general recommendation stated that any adult with an unknown Tdap 

status should receive Tdap. 

Dr. Duchin thought this should be included in the pertussis part of the discussion, not just the 

diphtheria and tetanus discussion.

Dr. Keitel wondered what the implication of the cocooning strategy recommendation would be 

for the VFC.

Dr. Rodewald replied that VFC coverage stops with the 19th birthday, and it covers only the 

direct vaccinee. Passive vaccination is not part of the VFC program. It specifically excludes 

passive immunization for RSV immunoprophylaxis because it is not a vaccine—it is a passive 

immunization. 

Regarding the question of claims, Geoffrey Evans (HRSA) reported that to date there have been 

very few claims that alleged injury in a fetus. The best answer so far is that the law is mixed. It 

is not yet known whether a claim can go through successfully on that allegation. It has gotten to 

the point where the medical merits have received a decision in terms of whether the vaccine 

recipient can be viewed in terms of the fetus versus the individual who receives the vaccine. 

Currently, the answer is not clear. 

Dr. Pickering inquired as to whether this program covers all ages through adults.

Geoffrey Evans (HRSA) responded that it does as long as the vaccine is recommended for 

routine use in children. Any recipient, no matter what age, can file a claim or have a claim filed 

on their behalf.

Dr. Judson said that for healthy pregnancies, the only time women are seen for sure in the third 

trimester will be just before delivery.

Dr. Baker said that this was no longer common. 

Dr. Gall (ACOG) clarified that the third trimester begins at 28 weeks, so 28 to 40 weeks 

constitutes the third trimester, 13 to 28 the second trimester, and 1 to 13 weeks the first 

trimester. Women are seen every 4 weeks until about 28 weeks, at which time they are seen in 

3 weeks, followed by every 2 weeks, and in the last month every week, so there are 8 to 13 

visits. 

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Dr. Judson requested clarification about whether the vaccine would be given right around 

delivery, even though that would be considered the third trimester.

Dr. Baker said she thought there were very good data on the percent of number of obstetrical 

visits in the US. Women certainly present in the third trimester. Even in her extremely 

disadvantaged population, no women have presented at delivery having had no prenatal care. 

They have immunized 18,000 people. At least two weeks would be required for sufficient 

maternal antibody levels to be available for transport to the fetus.

Dr. Judson wondered whether they would immunize at the delivery visit if a woman slipped 

through.

Dr. Baker responded that this would be postpartum. 

Dr. Cieslak emphasized that wound management is typically a “do it now” situation, but the 

language indicates a preference for the late second or third trimester. He thought this could 

cause someone to wait another three months before giving a booster.

Dr. Baker noted that this language could be improved for clarity.

Dr. Clark (SME) said that wound management was a separate issue and the recommendation 

would be to administer Tdap.

Motion: Cocooning and Special Situation Language

Ms. Ehresmann made a motion to accept the Cocooning and Special Situation Language that 

aligns with Option 2. Dr. Temte seconded the motion. The motion carried with 15 affirmative 

votes, 0 negative votes, and 0 abstentions. 

VFC Resolution Update:

Vaccines to Prevent Diptheria, Tetanus, and Pertussis

Lance E. Rodewald, MD

Director, Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevent

Dr. Rodewald reminded everyone that and ACIP vote is required if there are changes to the 

ages, groups, or doses of a vaccine. The purpose of this resolution was to revise the previous 

resolution to incorporate new recommendations regarding the vaccination of pregnant 

adolescents. Eligible groups continue to be children and adolescents aged 6 weeks through 18 

years. There were no changes in the recommended schedule or intervals. Only Table Note #7 

was changed to mirror the vote for Option 2:

(7) Option #2 Adolescents who are pregnant and have not previously received Tdap 

should receive Tdap preferably during the third or late second trimester (after 20 weeks 

gestation). Alternatively, Tdap can be administered immediately postpartum.

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Discussion Points

It seemed to Ms. Rosenbaum that there was a plausible argument in terms of immunization of a 

pregnant woman, whether it is this vaccine or influenza, regardless of her age if it is the 

immunization of a Medicaid-eligible child. It is Medicaid-eligible children who are covered under 

the VFC program. Under the Medicaid statute, an infant who is born to a woman who is 

enrolled in Medicaid is automatically enrolled in Medicaid. There is no separate application 

process because the only feasible way to immunize the infant effectively is to do so in utero. 

This is a rare instance in which it would be within the confines of the statute to define an infant 

prior to birth as a Medicaid-eligible child. Children up to age 21 are entitled to all ageappropriate immunizations. Pregnant women would be entitled to all appropriate immunizations 

regardless because they are entitled to pregnancy-related care. The significance of the VFC 

issue in this context is the provisions of free vaccine to obstetrical practices, which would 

immeasurably increase the likelihood of an immunization being provided, as well as reaching 

certain un-insured or under-insured children. Ms. Rosenbaum proposed that CDC enter into a 

formal discussion with CMS about the feasibility in the case of infectious diseases, for infants 

who are born enrolled in the program, to be treated as Medicaid-eligible children for purposes of 

VFC. She thought this would have an extraordinary effect of being able to do much more to 

actively engage obstetrical practices in what ACIP recommends as the standard of practice.

Dr. Pickering thought that with this suggestion, they should engage in a discussion with the 

university attorney regarding this issue.

Dr. Rodewald agreed that it would be beneficial to have a discussion with CMS, and that in this 

case there is passive rather than active immunization of the child. 

Ms. Rosenbaum added that from a clinical point of view, the issue of active versus passive has 

a meaning. From a legal point of view, it may have very limited meaning. That is, the most 

efficient way to immunize the child is to do so in utero, and that makes the child a Medicaideligible child.

Dr. Wharton acknowledged that this discussion would be initiated internally.

Motion: VFC Resolution 

Dr. Chilton made a motion to accept the VFC Resolution. Dr. Coyne-Beasley seconded the 

motion. The motion carried with 15 affirmative votes, 0 negative votes, and 0 abstentions. 

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Emergence of Pertussis in Children Aged 7 through 

10 Years and Early Evaluation of DTaP Effectiveness

Lara Misegades, PhD, MS, EIS Officer

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Misegades discussed the emergence of pertussis in 7- to 10-year olds and presented 

interim results from two evaluations of DTaP effectiveness. Based on data from 1922 to 2010, 

since the introduction of whole cell pertussis vaccine in the late 1940s, the number of reported 

pertussis cases has fallen dramatically. However, pertussis continues to be endemic. The last 

large increase in reported cases occurred in 2004 and 2005. The data for 2010 is not yet 

finalized, but the number of cases are expected to surpass the number of cases in 2005 [CDC, 

National Notifiable Diseases Surveillance System and Supplemental Pertussis Surveillance 

System and 1922-1949, passive reports to the Public Health Service]. 

Based on data regarding reported pertussis incidence by age group from 1990 through 2010, 

infants still have substantially higher rates of disease compared to other age groups. However, 

disease rates among 7- to 10-year olds have been increasing since 2005 [CDC, National 

Notifiable Diseases Surveillance System and Supplemental Pertussis Surveillance System

*2010 data are provisional]. Beginning in 2005, an increase was observed among 7-year olds. 

This group is the first birth cohort who have largely received acellular vaccine for all 5 pertussis 

doses. With each successive year, a stare step picture of disease has essentially emerged 

among this birth cohort, although the case count scale differs by year. In 2009, the case count 

dropped at age 11, which is consistent with the recommendation for Tdap. This trend also holds 

for the later birth cohorts. Given these data, it was important to more closely asses DTaP 

effectiveness and duration of protection.

Previous clinical trial estimates of DTaP efficacy vary widely depending upon the case definition, 

the vaccine type, the schedule, and the trial design. Estimates from trials using the WHO case 

definition vary from 59% to 93%, and one previous study assessing the US 5-dose schedule 

estimated short-term effectiveness at greater than 95% for 4 to 5 doses up to 59 months of age, 

or just shy of 5 years of age. CDC is currently conducting two evaluations of DTaP 

effectiveness and duration of protection. The first is a case-control estimate using provider 

verified immunization and conducted in collaboration with the California Department of Public 

Health (CDPH). The second is a multi-state registry-based assessment. Dr. Misegades briefly 

described the methods and interim results from these two assessments. California reported an 

increase in the number of pertussis cases as early as February 2010. The state declared an 

epidemic on June 18, 2010 and by the end of 2010, more than 8000 cases had been reported. 

As of September 2010, there was a high burden of disease in California in the 7- to 10-year old 

age group despite high vaccine coverage. This is reflective of the national data and provided an 

opportunity to evaluate the pertussis vaccine program [California Department of Public Health, 

Immunization Branch].

The primary objectives of the CDPH / CDC Pertussis VE Assessment were to estimate the 

overall effectiveness of DTaP following the complete childhood series, and determine the 

duration of protection by assessing vaccine effectiveness at specific time points postvaccination. Counties with either a high incidence or high case counts were invited to 

participate. Health Officers from the following 15 counties agreed to participate in the 

assessment: Alameda, Del Norte, El Dorado, Fresno, Madera, Marin, Merced, Orange, 

Riverside, San Diego, San Luis Obispo, Santa Cruz, Santa Clara, Sonoma, and Stanislaus. 

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The study included cases and controls who were 4- to 10-years of age at illness onset or 

enrollment from the 15 participating counties. Three unmatched controls per case were 

selected from the same providers reporting the cases. All vaccine history information for both 

cases and controls was collected through in-person visits to provider offices. Logistic 

regression was used to calculate vaccine effectiveness, accounting for clustering by county and 

provider. 

All confirmed, probable, and suspect cases were included in the analysis aged 4 to 10 years, 

based on the CDPH case definition. This is a modified CDPH definition, which includes a 

suspect case category for PCR-confirmed cases with a cough of any duration and Epi-Link 

cases with a cough of any duration plus one other symptom. Last December, data collection 

teams had completed approximately 3800 abstraction forms and data on an additional 500 

people have recently been received. Information on both cases and controls is being linked to 

pertussis surveillance and immunization registry and manufacturer lot data in order to exclude 

children who were pertussis cases in previous years, and also to help verify and assess the 

completeness of the vaccine date and brand information. Dr. Misegades presented interim 

results from this study that did not yet include the recently received data. 

The range of recommended ages for the fifth DTaP dose is 4 to 6 years. To get a sense of 

when cases and controls were receiving the fifth dose, the distribution of age at fifth dose was 

assessed. In this assessment, both cases and controls in California received the fifth dose 

earlier in the range, with 65% of cases and 68% of controls receiving it at 4 years of age. With 

regard to interim vaccine effectiveness results, the vaccine effectiveness estimate for 5 doses 

compared to no doses across all ages was 85.9% with a 95% confidence interval of 75.6% to 

91.9%. The recommended childhood vaccination schedule for pertussis allows for a fourth dose 

only schedule if the fourth dose is received after the fourth birthday. The preliminary vaccine 

effectiveness estimate for the fourth dose received after age 4 compared to zero doses across 

all ages is 80.4%. Regarding the time since fifth dose analysis estimate using unvaccinated as 

the reference category, the estimated vaccine effectiveness is 94.5% among children who are 

less than one year out from their fifth DTaP dose. There is a modest decrease in effectiveness 

for each year after this. For example, two years after the fifth dose, vaccine effectiveness is 

estimated to be 90.8% and by the time children are 5 or more years out from their last DTaP 

dose, the estimated vaccine effectiveness is 69.1%.

The next steps for the California assessment are to link the data with both registry and 

manufacturer data, and assess the completeness of the vaccine data and brand information. 

Additional analyses will also be done to assess the potential impact of case definition, vaccine 

product, and incomplete vaccination records on the vaccine effectiveness estimates.

CDC is also assessing waning of immunity in the 5 years post-DTaP dose through a registrybased evaluation of incidence rates and risk of pertussis. EIS Officer, Sara Tartof, is leading 

this evaluation. Although this is a multi-state assessment, the results presented during this 

session were based on data from Minnesota. DTaP information from Minnesota’s immunization 

registry was linked to pertussis surveillance information for the 1998-2003 Minnesota birth 

cohorts. Only children who received all 5 DTaP doses, with their fifth dose between the ages of 

4 and 6 years of age, were included in the analysis. The total linked cohort size is 

approximately 200,000 with 353 confirmed and probable pertussis cases. Cumulative incidence 

and rate ratios were calculated for each year following the fifth DTaP dose up to five years out. 

Individuals aged out of the analysis at age 10, and rate ratios were calculated using the one 

year post-vaccination group as the reference. Adjustments were made for repeated measures 

correlation structures. Both incidence proportion and risk increased with increasing time since 

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the fifth DTaP dose. At 5 years out, the risk of disease is about 4 times higher than the risk in 

the year immediately following the fifth dose. 

To summarize, preliminary California results suggest that short-term vaccine effectiveness 

estimates are consistent with pre-licensure estimates, and there continues to be additional 

evidence that the vaccine protects well against a range of clinical presentations captured by the 

pertussis case definition. It was not possible to estimate vaccine effectiveness through the 

Minnesota assessment due to the lack of a clearly defined unvaccinated group in the 

immunization registry, but the increased risk with increasing time since fifth dose support the 

California findings. These results suggest that waning of immunity is occurring prior to the 

adolescent Tdap booster. Moving forward with these analyses, consideration will be given to 

whether this is the primary factor driving the current disease burden and trends among 7- to 10-

year olds and whether any interventions or policy changes might be needed.

Discussion Points

Dr. Judson noted that the epidemiology of pertussis has always been problematic. When 

assessing a relatively small group in a specific age group, often the answer pertains to 

diagnostic bias. Over the decades, Colorado has almost always had one of the highest rates of 

pertussis. There are many pertussis pediatric infectious disease experts, a large children’s 

hospital in central Denver, and a state laboratory with high capacity for pertussis tests in 

Colorado. Therefore, whenever few patients are reported in the newspaper or through MMWR,

index suspicious increases and anyone with a cough in the suspect group will receive a 

diagnostic test and many people are pulled in who are not really clinically pertussis. 

Dr. Misegades responded that the various case definitions will be assessed to determine how 

those may impact estimates. A preliminary assessment restricted to confirmed only, all children 

who meet the clinical case definition, does not appreciably change the vaccine effectiveness 

estimate.

Dr. Baker requested clarification regarding whether the investigators were using “cough for two 

weeks” for the definition in this age group.

Dr. Misegades confirmed that they are using “cough for two weeks.”

Dr. Plotkin (Vaccine Consultant) mentioned that based on the Swedish data from the acellular 

pertussis trial conducted in the 1990s, it appears that efficacy is waning following acelluar 

pertussis. Interestingly, the data suggest that immunity is holding up better in the whole cell 

group. That is something for ACIP to think about in the future.

Dr. Baker concluded that ACIP is every interested in the duration of protection of DTaP and 

Tdap.

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Discussion

Dr. Lance Rodewald

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Rodewald reported Merck is not currently distributing its adult hepatitis B vaccine. The 

dialysis formulation is available, and the adult formulation is anticipated to be available in the 

third or fourth quarter of 2011. Production and supply of GSK's adult hepatitis B vaccine and 

hepatitis A/hepatitis B combination vaccine currently are sufficient to meet demand for routine 

adult usage of adult Hepatitis B vaccine. Merck anticipates availability of its adult hepatitis A 

vaccine some time in 2012. Production and supply of GSK's adult hepatitis A vaccine and 

hepatitis A/hepatitis B combination vaccine currently are sufficient to meet demand for routine 

adult use of adult Hepatitis A vaccine. 

DTaP-IPV (Kinrix ®) is currently unavailable in both syringe and vial presentations. Re-supply is 

expected in July 2011. MMRV (ProQuad®) will not beavailable for the remainder of 2011. 

Merck is committed to returning ProQuad to the market. Details regarding timing and availability 

will be provided at a later date. Merck has adequate supplies of M-M-R II® and VARIVAX® to 

meet current demand. Since December, Merck has released zoster vaccine doses in all months 

except February. Customer wait times for orders are approximately 2 to 3 months. Merck 

expects to continue to release doses of ZOSTAVAX® regularly for the balance of 2011, but as 

inventory is building and demand remains strong, backorders may persist. 

With regard to supply constraints Cervarix vials will be discontinued as of September 2011. 

Pre-filled syringes will continue to be available. 

CDC’s vaccine supply / shortage webpage is available at: http://www.cdc.gov/vaccines/vacgen/shortages/default.htm. 

 

Discussion Points

Introduction

Dr. Janet Englund

Chair, ACIP HPV Working Group

Dr. Englund reminded everyone that in October 2009, FDA licensed the quadrivalent HPV 

vaccine for males 9 through 26 years of age for prevention of genital warts. ACIP stated that 

HPV vaccine may be given to males 9 through 26 years of age for prevention of genital warts, 

but did not include the vaccine in the routine immunization schedule for males. ACIP voted to 

include HPV vaccine for eligible males in the Vaccine For Children program. In December 

2010, the FDA included the indication for prevention of anal cancer in females and males. 

Subsequent to this, the HPV Working Group (WG) has discussed what additional 

recommendations may need to be made for HPV vaccine.

Vaccine Supply Update

Human Papillomavirus Vaccines

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Dr. Englund reviewed the presentations to be given during this session related to HPV vaccine 

for males and investigations of the long-term effectiveness of the quadrivalent HPV vaccine. 

While this session was designed to prepare ACIP for an upcoming vote, there were no votes on 

this topic during the June 2011 ACIP meeting.

Background

Lauri Markowitz, MD

National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

Centers for Disease Control and Prevention

Dr. Markowitz reminded the committee that there are two HPV vaccines licensed for use in the 

US. The quadrivalent vaccine was licensed in June 2006 for females and ACIP recommended 

routine use in females 11 or 12 years of age and catch-up through 26 years of age. In 2009, the 

bivalent vaccine was licensed for use in females and ACIP revised recommendations to state 

that either vaccine would be used for routine vaccination of females. In 2009, the quadrivalent 

vaccine was licensed for use in males based on data showing efficacy against genital warts and 

ACIP provided guidance that the vaccine may be used in the licensed age range. Both 

vaccines are included in VFC for females and the quadrivalent vaccine for males. As mentioned 

earlier, as of December 2010, quadrivalent vaccine has an indication for prevention of anal 

cancers.

Since February 2010, ACIP has continued to review data related to HPV vaccine for males. In 

October 2010, ACIP reviewed quadrivalent vaccine safety and heard data presented from the 

VSD rapid cycle analysis for females, and reviewed vaccine efficacy data in males, HPV 

vaccination program and coverage in females, provider acceptability, and cost-effectiveness. In 

February 2011, ACIP reviewed the epidemiology of HPV-associated cancers in the US, and 

heard a presentation on anal infection and anal cancer. Additional cost-effectiveness analyses 

were also presented. 

As reported during the February 2011 meeting, there are about 7000 HPV 16/18 associated 

cancers in males diagnosed annually in the U.S, including about 1400 HVP 16/18 associated 

anal cancers. During the last ACIP meeting, information was reviewed about the epidemiology 

and natural history of anal infection and cancers. Of note, among the cancers in males, the 

majority of HPV-associated cancers are cancers of the oropharynx. Because of this and 

because of requests from members of the committee, Dr. Markowitz indicated that oropharynx 

cancers were to be discussed during this session. There is no FDA licensed indication for 

prevention of oropharynx cancers for the quadrivalent HPV vaccine. ACIP needs to consider 

how they will handle outcomes for which there is no indication. This will be discussed again in 

future GRADE presentations.

With regard to vaccine efficacy in males, there are data for prevention of HPV vaccine-type 

related genital warts and AIN2/3. The genital wart efficacy data comes from a study in 

heterosexual males and men who have sex with men (MSM). A smaller study in MSM provided 

data on efficacy against anal pre-cancer lesions. In females, several larger efficacy studies 

were conducted, including two Phase 3 trials called Future I and Future II as well as a Phase 2 

study. These have been combined in several analyses to assess efficacy for major endpoints. 

These studies have found high efficacy for prevention of cervical pre-cancers, vulvar and 

vaginal pre-cancers, and genital warts in females. 

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Based on data from these studies, quadrivalent HPV vaccine has an indication for prevention of 

the following diseases caused by HPV types 6, 11, 16, and 18: cervical cancer, vulvar cancer, 

vaginal cancer, anal cancer in males and females, genital warts in males and females, cervical 

adenocarcinoma in situ (AIS), cervical intraepithelial neoplasia (CIN) grades 1 – 3, vulvar 

intraepithelial neoplasia (VIN) grades 2 and 3, and vaginal intraepithelial neoplasia (VaIN) 

grades 2 and 3. There are no data on efficacy against oropharyngeal cancer, penile cancer, or 

RRP, nor are any studies in progress. From the quadrivalent vaccine studies in females, there 

has been no evidence of waning protection, although some vaccinees have lost detectable 

antibody. 

Follow-up data available are through 5 years from the Phase 2 study. Dr. Markowitz indicated 

that during this session, some data would be shared from the post licensure studies being 

conducted by the manufacturer. There are multiple monitoring efforts on-going in the US, 

including those to assess cervical and other cancers through cancer registries, HPV typing has 

been initiated in several sites, CIN monitoring with HPV typing of lesions in sentinel projects, 

genital warts through network of STD clinics, and type-specific HPV prevalence in NHANES and 

looking at types in routine Pap specimens.

As has been presented in the past to ACIP, coverage is increasing in females, but is still low. In 

2009, 44% of females age 13-17 years had initiated vaccine nationally; 27% had received all 

three doses. This summer, National Immunization Survey (NIS)-Teen data will be available 

from 2010 and will include coverage in males and females as well as data on bivalent vaccine 

uptake. Although there are no NIS-Teen data on uptake in males yet, there are data from other 

sources. The Immunization Information Sentinel Sites are funded to enhance and analyze data 

routinely collected in the sentinel areas. In males ages 13 to 17 years, vaccination increased 

throughout 2010 (year after quadrivalent vaccine licensed for use in males) , but coverage was 

just over 4% in the highest site [Courtesy of K Cullen, CDC]. Dr. Markowitz also showed data 

from the 8 managed care organizations (MCOs) that participate in the Vaccine Safety 

Datalink;since the beginning of 2010 through May 2011 the number of doses administered 

increased from 0 to over 700 doses per week for males. By comparison, females doses in the 

MCOs were about 7 times higher per week in May 2011 [Vaccine Safety Datalink Courtesy of E 

Weintraub, CDC].

The WG is continuing to review new data related to HPV vaccines, epidemiology, HPVassociated cancers, and vaccination program issues. The working WG is focusing on 

considerations for recommendations for males; there is increasing support for routine use of 

vaccine in males.

Quadrivalent HPV Vaccine: Evidence for Durability of Protection

Alfred J. Saah, MD, MPH

Merck Research Laboratories

Dr. Saah presented results of two long-term follow-up studies, as well as serological data on a 

new assay that Merck developed to address the issue of apparent HPV type 18 seronegativity, 

which is really an assay-specific phenomenon more than having any basis in reality.

The current data on duration of protection results from a Phase II study P007, which has 5-year 

data, as well as a Phase II study in which the monovalent vaccine was assessed during the 

initial proof of concept. There are 9 years of follow-up data from monovalent HPV 16 vaccine. 

Also with P007, Merck was able to demonstrate that a challenge dose of vaccine demonstrated 

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immune memory. For the longer-term studies, Merck has assessed young women 16 to 26 

years of age in the Nordic Long-Term Follow-Up Study. This study is being conducted in four 

Nordic countries (Denmark, Iceland, Norway and Sweden), and will follow approximately 5400 

women for 10 years after the end of the study—14 years for women who were vaccinated in the 

base study. There also will be effectiveness data from a long-term extension study of Gardasil® 

in adolescents vaccinated from the ages of 9 to 15.

During this session, Dr. Saah presented information from the 6-year report from the Nordic 

Long-term follow-up study. The 8-year report will be available the second or third quarter of 

2012 and will include a good deal more follow-up data. The data presented during this session 

represented a mean of 6 years from the beginning of the study, known as Future II or Protocol 

015. The benefit of this population is that it acts as a sentinel cohort. The population was 

vaccinated approximately 3 to 4 years before the vaccine was licensed, so if there are 

breakthrough episodes of disease, they can be identified early.

Cohort 1 is the cohort that was vaccinated at baseline that is comprised of approximately 2700 

women who will contribute approximately 14 years of follow-up after vaccination by the end-ofstudy. Cohort 2 is a group of 2100 women who were vaccinated at the end of the study who 

received placebo. Another group of approximately 600 women who elected not to be 

vaccinated at the end of the base study. They self-selected and are being followed, but no data 

are available on this population to date. The primary endpoint is HPV 16/18-related CIN 2 or 

worse. This endpoint was selected because such lesions are routinely biopsied. This is a 

registry-based surveillance system, so the investigators are able to obtain the biopsies by 

identifying women who have had Pap tests and subsequent biopsies or loop electrosurgical 

excision procedures (LEEP). These biopsy blocks are retrieved and submitted to the laboratory 

that has done all of the HPV PCR work throughout the base study. There is no placebo control 

group. The statistical methodology being used in this study is a controlled chart method, which 

is a method borrowed from manufacturing to set the parameters and determine whether the 

numbers of cases observed exceed the parameters set. It was estimated that efficacy would be 

maintained above 90%, and there are a certain number of cases that would be expected if 

vaccine efficacy fell below that level. The secondary endpoints include CIN 2 or worse related 

to HPV 31, 33, 35, 39, 45, 51, 52, 56, 58 or 59 and CIN (any grade), AIS, cervical cancer, vulvar 

cancer or vaginal cancer related to HPV 6, 11, 16 or 18. This is an interesting group because 

vulvar and vaginal lesions are not routinely biopsied unless surgery is considered. The safety 

endpoints include deaths, cancers, hospitalizations and other safety outcomes that the 

investigators are able to assess in various patient registries. 

With regard to the primary endpoint analysis for the per protocol population, individuals received 

three doses of vaccine and had baseline seronegativity and were PCR negative at the end of 

the vaccination series. Of the 1000 women who had subsequent follow-up during the first two 

years of follow-up after the end of the base study, there were no cases of HPV 16/18-related 

CIN 2/3. If this population were not vaccinated, over the course of the 6 years from the base of 

the study, 23 cases of HPV 16/18-related CIN 2/3 would have been expected. In just this period 

alone of two years, 6 cases would have been expected. In any event, because the N is 

relatively low, these are women who just left a study of 4 years duration for cervical cancer and 

other lesions, there is not statistical significance to say that women are actually protected 

through 6 years. However, those data will be available in the next analysis. The number of 

person-years needs to be in the neighborhood of 2500 to 2800 for the statistical power and 

capability to be able to say with confidence that efficacy exists through a certain period. 

Certainly, trend data indicate that there are no breakthrough disease endpoints. 

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Assessment of the lesions due to the other vaccine types was determined to try to address the 

question of cross-protection or replacement. The particular population is the one that is naïve to 

the relevant type by PCR at baseline. For the 4 HPV types in the quadrivalent vaccine, this 

requires serological negativity at baseline in addition to being negative by PCR to the relevant 

type. There were 3 cases of HPV 31/33/35/39/45/51/52/56/58/59-related CIN 2/3 or worse in 

this population. Of these, 1 was HPV 31-related, 1 was HPV 33-related, and 2 were HPV 52-

related. This is more or less what would be expected over this period of two years following the 

end of Future II. Postulating that 16/18 account for about half the cases, approximately 6 cases 

of CIN 2/3 would be expected due to HPV 31/33/35/39/45/51/52/56/58/59. 

In terms of safety, Cohorts 1 and 2 were both assessed. There were two deaths, one of which 

was associated with "crashing a motor vehicle with undetermined intent", and the other of which 

was "intentional self-harm by jumping from a high place." Pregnancy was the most common 

new medical event. New medical events occurred in approximately one-fourth of the study 

subjects. Approximately 75% of the subjects had no new medical events during the first two 

years following the end of the study. There were 11 musculoskeletal disorders, including 

systemic lupus erythematosus and arthropathy. Other musculoskeletal disorders tended to 

include back aches, pubic symphysis instability, or other issues that may have been associated 

with pregnancy or regular arthritis. There was also one incident of anaphylactic shock. Dr. 

Saah clarified that he offered information about Cohorts 1 and 2 not for purposes of comparison, 

but rather for the purpose of completeness. 

In summary of the Nordic Long-Term Follow-up Study, basically a trend of continued protection 

has been show in women who were vaccinated a mean of 6 years previously. This 

demonstrates that the vaccine is generally safe and is well-tolerated for a mean of 6 years 

following vaccination.

Protocol 018 was conducted to assess safety and immune response in adolescents. This study 

included 1781 boys and girls who were randomized 2:1 to vaccine or saline placebo. The 

primary group being followed from the base study had to achieve month 42. At this point, the 

investigators are able to follow the individuals who have agreed to the study out to month 72, at 

which time they receive either a Pap test or swabs if they either reach the age of 16 and/or are 

sexually active. The same is being done with boys in terms of sampling, looking more for 

persistent infection. The catch-up group is also being studied. Interestingly, the serology 

results from month 7 to month 72, the percent positive for types 6/11/16 are all high. Type 18 

goes to 74%, which is higher than the proportions typically observed in the older populations of 

women because these were individuals vaccinated in the neighborhood of 9 to 15 years of age. 

Nevertheless, it is substantially lower than the others. This is what Dr. Saah meant earlier when 

he mentioned that it was an assay-dependent issue. Similar results were found in both sexes.

Another interesting finding was how quickly young adolescents become infected. Comparing 

the mean ages of the 12 to 15 year olds, when the catch-up group of nearly 500 were eligible for 

vaccination at the end of the study, they achieved a rather impressive rate of seropositivity to 

some of the HPV types. For HPV 6, they went from 7/1000 to 9%. For HPV 16, they went from 

7/1000 to 11%. For HPV 18, they went from 3/1000 to 6%. This is over the course of a mean of 

three years. The age range for the early vaccination was 9 to 16 years, which moved to 11 to 

18. The message here is clearly toward vaccinating youngsters before they become sexually 

active.

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The primary effectiveness endpoint for females was a combined incidence of vaccine type 

persistent infection and disease, including CIN and AIS, VIN and VaIN, genital warts, or 

cervical/vaginal/vulvar cancer. Dr. Saah shared data for all subjects who received at least one 

dose of vaccine and had at least one follow-up visit for effectiveness regardless of baseline 

sexual history, PCR status, or serostatus. These were adolescents who were largely not 

sexually active at the time that they were vaccinated. There were 157 individuals who were 

assessed for persistent infection and Pap testing. There are approximately 50 more young 

women who had only external genital exams for genital warts and did not have swabs or a Pap 

specimen taken. There was no CIN of any grade or genital warts related to any of the vaccine 

types observed in the follow-ups. 

In summary, the vaccination of adolescents prior to sexual debut provides durable protection 

from persistent HPV 6/11/16/18 infection and disease through 6 years post-vaccination. AntiHPV 6/11/16/18 antibody responses to the quadrivalent vaccine among preadolescents and 

adolescents generally persist for 6 years post-vaccination. No breakthrough cases of persistent 

infection or disease related to vaccine HPV types 6/11/16/18 were observed. Safety is similar to 

that observed in clinical program. The quadrivalent is generally well-tolerated over the longterm. These data underscore the importance of early vaccination.

Regarding assay concordance, questions were raised regarding the durability of protection 

given the “seronegativity” seen in the cLIA, particularly for HPV type 18. Data from clinical trials 

show continued efficacy for HPV 18 endpoints regardless of cLIA serostatus. Clinical long-term 

follow-up data shown here demonstrate durable protection, and there are no efficacy differences 

seen across a wide range of GMT levels, including those with the lowest GMTs. There clearly 

was an issue, which was the selection of a monoclonal antibody for the cLIA. The cLIA is a 

competitive Luminex immunoassay (cLIA). For types 6/11/16/18, a monoclonal antibody was 

identified against a single neutralizing type. For type 16, the early investigators were fortunate 

because it was both an immunodominant type as well as a highly specific epitope that was a 

major neutralizing site. For type 18, an antibody was selected that identified type 18 for its 

specificity. It was, unfortunately, less immunodominant. There were neutralizing antibodies 

present, but because this was a competitive assay, the only antibody being measured was the 

one that could compete off the monoclonal antibody. Therefore, Merck assessed the cLIA and 

a new assay, a total IgG Luminex immunoassay (IgG) that measures all of the antibodies 

against a particular virus-like particle, as well as the pseudovirion-based neutralization assay 

(PBNA). The PBNA tends to be the gold standard against which either the cLIA, ELISA, or total 

IgG assay are measured in order to identify correlation so that the easier assay can be used in 

the future. A secondary goal of the study was to potentially broaden the number of serological 

assays with high correlation to neutralizing antibody available for HPV type-specific antibody 

detection in human sera. Comparisons among assays were restricted to HPV types 16 and 18.

In terms of study design, for each HPV type, samples were selected to provide comparable 

representation from different populations, bleed intervals, and range of responses in the cLIA 

with 648 samples selected for HPV 16, 623 samples selected for HPV 18, and samples selected 

from 3 clinical studies of the vaccine (e.g., P011, P019, and P020). These samples were 

specifically selected at baseline, month 7, and month 24 in all three of these studies to 

deliberately stress the system. Some were selected at or near the cutoff in baseline, and others 

were selected based on the high and low systems. These are not population data or what 

would be expected to be observed in a large group of individuals who were vaccinated 4 to 5 

years ago. Such studies are being conducted, but this was done for purposes of validating the 

assay.

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There was a very high degree of correlation between the various assays. For both HPV 16 and 

HPV 18, over all samples tested, the cLIA and IgG assays were strongly associated with each 

other and the PBNA. The correlation coefficient for all samples combined ranged between 0.92 

and 0.95 across the 3 assays and 2 HPV types. The strong agreement among the 3 assays 

was consistent across protocols and PD3 bleed intervals. The majority of correlations fell 

between 0.85 and 0.95. The association among assays was weaker for baseline samples than 

for post-dose 3 (PD3) samples, which was attributed to baseline sample proximity to the LLOQ 

of the assays. The difference in positivity rate between the cLIA and IgG assays for HPV 16 

and HPV 18 was investigated. Serostatus outcomes were compared for IgG and PBNA (based 

on cLIA serostatus outcome). Approximately 80% of the PD3 samples seronegative in the cLIA 

for HPV 16 or HPV 18 had neutralizing antibodies at or above the level of serostatus cutoff in 

the IgG assay: 22/28 for HPV 16 and 97/122 for HPV 18. Regarding the comparison between 

PBNA and IgG for cLIA-positive samples (HPV 16/18), for HPV 16, 478/478 (100%) of the PD3 

cLIA-positive samples also tested positive in the IgG and PBNA assays. For HPV 18, 402/407

(99%) of the PD3 cLIA-positive samples also tested positive in the IgG and PBNA assays.

Regarding the conclusions and clinical implications, the cLIA and the IgG assays correlate well 

with the PBNA. IgG seropositivity correlates with neutralizing antibodies in the PBNA. PD3 

cLIA-negative sera show positivity in IgG assay and PBNA. Such findings corroborate the high 

clinical efficacy against disease in cLIA-seronegative subjects. The IgG assay measures a wide 

array of antibodies against HPV and will be important in long-term serological evaluation of 

clinical vaccination programs. Evidence of durability continues to accumulate, with 5 years of 

data from Phase II, and 6 years from Phase III LTFU in 16-26 year-old women and 9-15 yearold adolescents. A high proportion of post-dose 3 cLIA-negative sera show concurrent positivity 

in IgG assay and PBNA.

HPV-Associated Oropharyngeal Cancer

Aimée R. Kreimer, PhD

Investigator

Infections & Immunoepidemiology Branch 

Division of Cancer Epidemiology and Genetics NCI, NIH

Dr. Kreimer reminded everyone that more than 120 HPV types have been identified, with about 

40 of which infect the mucosal surfaces of the genital track. These are grouped as either noncarcinogenic as they are unable to induce neoplastic transformation or about 15 carcinogenic 

types. The most important type is HPV16 as it is the most prevalent and carcinogenic. She 

also briefly reviewed the anatomy of the head neck, which is grouped into three sub-sites when 

thinking of head and neck cancer etiology, the oral cavity, oropharynx, and larynx. It is 

specifically the oropharynx that is the HPV-related sub-site of the head and neck. The 

oropharynx includes the base of tongue, tonsils, posterior pharyngeal wall, soft palate, and 

uvula; therefore, she referred to these terms interchangeably and most often as tonsillar cancer 

or oropharyngeal cancer. It is interesting to note that the oropharynx shares a common feature 

with the cervix in that it has this cancer-susceptible transformation zone, which is a junction 

where two epithelial cell-types meet. This provides a biologic rationale why HPV infection may 

cause some cancers at this site. 

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In 2005 and 2009, experts met at the International Agency for Research on Cancer (IARC) to 

review the carcinogenicity of HPV infection. They concluded that HPV type 16 has sufficient 

evidence in humans that it causes cancers of the cervix, vulva, vagina, penis, anus, oral cavity, 

and oropharynx. They then went on to say that there is limited evidence in humans that it 

causes cancers of the larynx [Lancet Oncology 2009; 10: 321]. The importance of this topic is 

highlighted by the fact that the incidence of oropharyngeal cancer is actually increasing. It has 

been documented from cancer registries that over the past 20 years, oropharyngeal cancers 

overall have been increasing [Presented at 2011 ASCO Annual Meeting, Chaturvedi AK et al]. 

In fact, this trend has been reported in developed countries around the world, including British 

Columbia1

, the Netherlands2, Sweden3, the United Kingdom4, and Australia5. Note that in 

developing countries, this phenomenon of increasing oropharyngeal cancer has not been 

documented [1 Auluck A. Cancer 2010; 116:2635, 2 Braakhuis BJ. Oral Oncol 2009;45:e85, 3 

Hammarstedt L. Acta Otolaryng 2007; 127:988, 4 Conway DI. Oral Oncol 2006; 42:586, 5 Hong 

AM. Vaccine 2010;28:3269].

Since it is known that in many developed countries use of tobacco and alcohol, which are the 

main risk factors for head and neck cancer, overall have been on the decline, it raises the 

question: What explains these increasing trends in oropharyngeal cancer? In recently 

presented data at the ASCO annual meeting in 2011, Dr. Chaturvedi and colleagues presented 

data from their testing of oropharyngeal tumor specimens from the cancer registries of Hawaii, 

Iowa, and Los Angeles from this time period. This was done with multiple assays. HPV DNA 

positivity was quite low at 16% being HPV DNA-positive in the earlier time periods. However, 

this increased such that approximately 75% of tumors occurring over the most recent decade 

are HPV DNA positive. As a note, to account for possible degradation of tumors over time, 

cervical tumors were tested as well, for which it is know that HPV is a necessary cause, and the 

HPV positivity for the oropharyngeal tumors were adjusted accordingly. This confirmed that, in 

fact, tumor degradation was not present with regard to HPV positivity. Now that it is understood 

that it is really the HPV positivity that is explaining the rising incidence of oropharyngeal cancer, 

investigators went on in the cancer registries to assess the rates of incidence for the HPV 

positive oropharyngeal cancers compared to HPV negative. Remembering that oropharyngeal 

cancer overall is increasing over calendar time, when the investigators stratified this by HPV 

positive versus HPV negative oropharyngeal tumors, the HPV positive have more than doubled 

over the past 16 years; whereas, incidence for the HPV negative tumors has declined by about 

half. Because of this important finding, the authors went on to project what the incidence rates 

of these tumors will look like over the next several decades. They contrasted this to the 

observed and projected trends for cervical cancers. Observed data were available through 

2008, and from 2008 on rates were projected based on current trends. These data reflect a 

continued decline of cervical cancer; however, at an important timepoint in 2010 (a projection 

because data are not yet available) there will actually be the same incidence of cervical cancer 

and oropharyngeal cancer in men. Projecting out to about 2020, the rates of cervical cancer will 

cross the rates of oropharyngeal cancer overall [Presented at 2011 ASCO Annual Meeting, 

Chaturvedi AK et al].

Only one prospective study to date has evaluated the question of HPV and head and neck 

cancers. The reason a prospective study is so important is because it addresses one of the key 

criteria of causality, that exposure precedes disease. In a Nordic cancer study that links to a 

serum biobank, investigators studied the association between HPV and head and neck cancer. 

In terms of all head and neck cancer combined, when the odds of seropositive patients were 

compared to the odds of seronegative patients, HPV 16 (a marker for exposure) seropostive 

patients had a 2-fold increased risk of head and neck cancer overall. These serum samples 

were collected on average about 9.5 years before cancer diagnosis, showing that exposure to 

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HPV infection preceded disease. The authors went on to stratify by different anatomic sites in 

the head and neck. Anatomic sites typically considered not to be associated with HPV infection 

such as the oral cavity had weak associations that did not attain statistical significance. For 

laryngeal cancer, there was a border line statistically significant finding with a modest odds ratio. 

However, for cancers of the oropharynx, despite having few numbers of cases, a 14-fold 

increased risk was observed of oropharyngeal cancer associated with HPV 16 L1 seropositivity 

[Mork et al. N Engl J Med 2001; 344:1125].

An important case-control study evaluated 100 oropharyngeal case patients and 200 age and 

gender matched controls was conducted in Baltimore, Maryland. The investigators assessed 

several aspects of the association of HPV infection and oropharyngeal cancer. The association 

between HPV biomarkers and oropharyngeal cancer was assessed. HPV 16 L1 serologic 

status (a marker of exposure) increased the odds of oropharyngeal cancers significantly. In the 

assessment of oral HPV 16 infection measured in oral rinse samples, again very high odds 

ratios were observed, which suggested that if someone had an oral HPV 16 infection, they were 

at increased risk of oropharyngeal cancer. An assessment of HPV 16 E6 or E7 serologic status, 

a different type of serologic marker considered to be a marker of an HPV-associated cancer, 

also found a very high odds for increased oropharyngeal cancer. Sexual behaviors were also 

assessed, and it was noted that sexual behaviors that would typically put a woman at risk for 

cervical cancer (e.g., lifetime number of vaginal sexual partners, a young age at first 

intercourse) increased the odds of having either an oropharyngeal cancer and an HPV16 

positive oropharyngeal cancer. Also observed was that having a high number of lifetime oral 

sexual partners increased the odds of oropharyngeal cancer. These data combined are taken 

to mean that sexual behavior is a risk factor for oropharyngeal cancer, which is probably 

marking transmission of HPV infection to the oral region. Also evaluated were the effects of 

whether tobacco and alcohol in conjunction with HPV infection further increased the odds of 

oropharyngeal cancer. Tobacco use alone, alcohol use alone, and tobacco and alcohol use 

combined were assessed. This was stratified by the HPV 16 L1 seronegative individuals, so 

this was a case-control comparison, and then by HPV 16 L1 seropositives. Amongst 

seronegative individuals, the interaction of alcohol and tobacco use combined was as expected. 

However, among HPV seropositives, there was no evidence of interaction. The investigators 

interpreted this to mean that there are really two pathways to getting to an oropharyngeal 

cancer, one induced by tobacco and alcohol and one by HPV infection [D’Souza et al NEJM 

2008; 356:1944].

It is now starting to be understood that HPV positive head and neck cancers actually have a 

distinct risk factor profile to those of the HPV negative. A study by Gillison et al evaluated 

tobacco, alcohol, dentition, oral sex, and marijuana use in a dose response relationship. 

Tobacco was assessed by number of pack years, alcohol by number of drink years, dentition by 

number of teeth lost, oral sex by lifetime number of oral sex partners, and marijuana by number 

of joint years. Comparing HPV positive head and neck cancers to controls, there was no 

observed association with tobacco use, alcohol consumption, or dentition. However, there was 

a dose response trend in terms of oral sex: increasing numbers of oral sex partners increased 

the odds of HPV-associated head and neck cancer. For the HPV negative cancers, the classic 

risk factors for head and neck cancer were observed (e.g., increasing tobacco use, increasing 

alcohol, and teeth loss) [Gillison ML et al. J. Natl. Cancer Inst. 2008 100:407-420].

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In terms of building the evidence that HPV-positive oropharyngeal cancers have distinct 

pathologic, molecular, and clinical features, from a pathologic perspective, they have a basaloid 

histopathology and are typically poorly differentiated. From a molecular perspective, viral 

integration and expression of the viral oncogenes E6 and E7 inactivate p53 and pRb, which is 

responsible for tumorigenesis. Fewer TP53 mutations were observed. From a clinical 

perspective, HPV positive head and neck cancers are typically diagnosed at a later stage and 

commonly have nodal metastases. Despite these cancers presenting at an advanced stage, it 

has been observed that HPV positive head and neck cancers actually have a survival 

advantage. In a randomized controlled trial assessing different modes of radiotherapy, tumors 

were tested for HPV DNA at the time of randomization. At three years, about 86% of those with 

HPV positive tumors were still alive compared to those with HPV negative tumors at 57% [Ang 

KK et al New Eng J Med 2010; 363:24]. At this point, it is believed that HPV tumor status is a 

prognostic factor for survival. This is a key point in understanding that throughout the 

continuum of disease, HPV-positive oropharyngeal cancers are a distinct disease entity 

compared to the HPV negative tumors.

Certain individuals are at a clear increased risk of oropharyngeal cancer. This includes persons 

with AIDS1 whose standardized incidence rate compared to that for the general population is 1.6 

(95%CI = 1.2 to 2.1). Husbands of women with cervical cancer2 have a 3-fold increased risk of 

tonsillar cancer. In fact, in the literature, a few cases of concurrent HPV-positive tonsillar 

carcinomas in couples (n=3)3 have been observed. Also at increased risk are individuals who 

had anogenital squamous cell carcinoma (cervical, vulvar/vaginal, or anal)4 have about a 5-fold 

increased risk for tonsillar cancer [1

Chaturvedi A JNCI 2010; 2Hemminki K Eur J Cancer 

Prevention 2001; 3

Andrews E J Iinfect Dis 2009; 4 Frisch M Lancet 1999].

With respect to oral HPV infection in people without cancer, a systematic review of the literature 

pooled all studies published to date to assess oral HPV infection and categorized the data as 

either positive for oral HPV16, carcinogenic oral HPV or overall oral HPV infection. For HPV 16, 

it was found that 1.3% of the individuals had an oral HPV 16 infection. HPV16 infection at 

anogenital sites is usually much higher than this (although genital HPV infection is closely linked 

to age at sexual initiation) Oral HPV infection of any type was observed in 4.5% of individuals; 

at anogenital sites, overall HPV prevalence is often much higher (i.e.: an order magnitude--

~45%--for cervical, penile, or anal infection) [Kreimer AR et al. Sex Transm Dis 2010; 37:386].

Because HPV prevalence is so low, it complicates looking forward in time at HPV infection. 

However, a few small studies have assessed oral HPV incidence. In a study in Finland of 

healthy men and women in an obstetrics clinic1

, there was a very low incidence of 3%. To 

contrast the 3% with what is typically observed at the cervix among women of childbearing age, 

there would be an incidence of closer to 20%, again showing that oral infection is a much more 

rare event compared to cervical infection3

 In another study, oral HPV incidence rate was lower 

among HIV negative (10%) women compared to HIV positive women (30%) in the US2

. 

[

1

Rintala M et al. J Clin Virol 2006; 35:89; 2D’Souza A et al. Int J Cancer 2007; 121:143; 3Winer 

RL et al. Am J Epidemiol 2003; 157:218].

Only two studies have focused on oral HPV persistence measured at 6 months (e.g., a typespecific oral HPV infection being at one point in time and when looked for 6 months later having 

the same time present in the oral specimen). One study assessed over 1600 men1 with an 

outcome of any HPV type. There were 56 baseline infections to follow prospectively. At 6 

months, 61% persisted. The Finland study assessed carcinogenic HPV for persistence in 460 

women, among whom there were 59 baseline infections. Of those, 100% persisted. This broad 

range conveys the paucity of data on this topic. Cervical HPV persistence, which has been 

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better characterized, is typically around 70% after a 6-month time period3

 [

1

Kreimer AR. 2010 

International IPV Meeting, July 2010; 2

Rintala M et al. J Clin Virol 2006; 35:89; 3Winer RL 

Cancer Epidemiol Biomarkers Prev 2011; 20:699]. 

 

Regarding age-specific oral HPV prevalence, a study in 3 countries of over 1500 men assessed 

increasing age categories and oral HPV prevalence. A non-significant increase was observed 

in oral HPV prevalence across age categories. This is starkly different from what is observed at 

the cervix where there is a very high prevalence soon after sexual debut that decreases as a 

woman ages. Thus, very different patterns are being observed in terms of the natural history of 

the HPV infections at the two anatomic sites (the oral region vs the anogenital region) [Kreimer 

AR, Cancer Epidemiol Biomarkers Prev 2011; 20:172]. 

As expected, the risk factors for oral HPV infection include lifetime and recent numbers of 

sexual partners, oral sexual behaviors, deep mouth kissing, current tobacco use, and 

immunosuppression induced by HIV infection. 

Important research questions remain and include the following:

 Is persistent oral HPV infection a risk factor for oropharyngeal cancer and, if so, what is the 

time between persistent oral HPV infection and oropharyngeal cancer?

 Does a precancerous state exist for oropharyngeal cancer?

 Does HPV cause cancers in the head and neck beyond the oropharynx?

 Will prophylactic HPV vaccines protect against HPV in the oral region, and thereby protect 

against a subset of these cancers?

In summary, HPV 16 causes a subset of head and neck cancers, predominantly in the 

oropharynx. Molecular, epidemiological, and clinical evidence suggest these tumors are distinct 

from HPV-negative head and neck cancers. Oral HPV 16 is rare in healthy people, although the 

natural history of the infection is not well-studied. Oropharyngeal cancer is increasing in the US 

and other countries due to HPV infection. Direct evidence showing the HPV vaccine protects 

against oral HPV infection is lacking.

HPV Vaccine Cost-effectiveness Updates and Review

Harrell Chesson, PhD

National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

Centers for Disease Control and Prevention

During this session, Dr. Chesson addressed the use of QALYs to assess vaccine costeffectiveness; HPV vaccine cost-effectiveness; and responses to ACIP queries from the 

February ACIP meeting pertaining to catch-up of males through age 26 years, details of QALYs 

gained by male vaccination, and the impact of duration of protection assumptions. 

Dr. Chesson explained that cost-effectiveness of vaccines is often assessed in terms of cost per 

QALY gained by vaccination. QALYs are useful in evaluating vaccines because they take into 

account gains in quality and length of life. Health outcomes included in recent costeffectiveness models of HPV vaccination include genital warts, CIN, cervical cancer, vaginal 

and vulvar cancer, anal cancer, oropharyngeal cancer, penile cancer, and RRP. The potential 

vaccine impact on these outcomes is assessed in terms of QALYs. There is evidence of 

vaccine efficacy for genital warts, CIN, cervical cancer, vaginal and vulvar cancer, and anal 

cancer. These are often referred to as the indicated outcomes; however, in the model 

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sometimes all of the outcomes are included—even those without evidence of efficacy to 

determine how the cost-effectiveness estimates change depending on the outcomes included.

Regarding cost-effectiveness thresholds in the US, there is no consensus on the appropriate 

cost-per-QALY threshold for determining cost-effectiveness of public health interventions. 

Likewise, there is no ACIP-established threshold for determining vaccine cost-effectiveness. A 

threshold of $50,000 to $100,000 or even $150,000 is often cited; however, this has often been 

described as arbitrary and lacking empirical or theoretical justification [See Grosse (2008), 

Weinstein (2008), and Weinstein et al. (2010)]. Another way to think about cost-per-QALY 

thresholds is to look at cost per-QALY estimates for existing vaccines in the US. The following 

table on the left shows the cost per-QALY gained by childhood vaccines in the US. The first 5 

vaccines listed have been found to be cost-saving; that is, they pay for themselves. The final 

two vaccines, while not cost-saving, still have attractive cost per-QALY estimates of about 

$10,000. The table on the right shows the cost per-QALY gained by adolescent vaccines in the 

US. HPV vaccine ranks favorably among other vaccines. As shown in the bottom rows, some 

adolescent vaccines have cost per-QALY estimates of over $100,000:

 

With regard to some of the key points presented at previous ACIP meetings, it is known that 

routine vaccination of 12 year old girls is a cost-effective use of public health resources in the 

US. These findings are consistent across a wide range of models, conditioned only that the 

vaccine provides sufficient duration of protection. However, there is more uncertainty in costeffectiveness estimates for vaccination of adult women and vaccination of males. 

The cost-effectiveness of male vaccination depends on vaccine coverage of females, at least in 

the models that take into account herd immunity (or indirect effects) of vaccination. The most 

favorable scenario for male vaccination is when coverage of females is low. Many models 

suggest that male vaccination is not likely to be cost-effective when female coverage is high. 

With higher female coverage, there is less impact of male vaccination on disease in females. 

More males are protected indirectly through female vaccination. 

The cost-effectiveness of HPV vaccination depends on the health outcomes included in the 

analyses. The most favorable scenario for vaccination is when all potential health outcomes are 

included. Vaccine costs are also an important factor in affordability and cost-effectiveness of 

male vaccination. With lower vaccine costs, male vaccinations are more likely to be costeffective over a wide range of scenarios (e.g., higher female coverage).

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HPV vaccination of MSM appears cost-effective, at least in the first and only study to address 

this issue. In that study in 2010, Dr. Kim found cost per QALY estimates of less than $50,000 

for MSM over a range of assumptions about age at vaccination and prior exposure to HPV. 

Additional data are needed to assess this in more detail, such as type-specific HPV acquisition 

by age among MSM [Kim JJ. Lancet Infect Dis. 2010;10:845-52. MSM: Men who have sex with 

men. QALY: quality-adjusted life year].

Accounting for recent trends in cancer incidence does not have major impact on male 

vaccination cost-effectiveness, because the impact of accounting for decreasing trends in some 

cancers (e.g., cervical) is offset by the impact of accounting for increasing trends in other 

cancers (e.g., oropharyngeal, anal). Possible exceptions are if recent trends are assumed to 

continue for 50 to 100 years before leveling off, or if future annual changes in cancer incidence 

are assumed to be greater than in recent years.

Routine vaccination of males in the US could be cost-effective, particularly if coverage of 

females is low (≤ 50%), and the two most recent studies that have addressed this issue found 

cost per-QALY estimates of $24,000 to $62,000. [$24,000 per QALY is from Merck model 

(Elbasha & Dasbach, 2010) with effective coverage (all 3 doses) by age 18 of ≈40% and ≈25% 

for females and males, respectively. $62,000 per QALY is from Kim et al. (2009) with 50% 3-

dose coverage of girls and boys by age 12].

However, routine male HPV vaccination might not be cost-effective, even if coverage of females 

is low. This is true in certain scenarios when key assumptions are varied, when male 

vaccination is compared to a strategy of increased female coverage, and if males vaccinated 

have mostly vaccinated partners. 

To summarize the available cost per-QALY estimates for male vaccination, the studies were 

grouped according to the outcomes that were included in the analysis. For any given study, the 

cost per-QALY gained by vaccination increases as female coverage increases. However, the 

degree to which this increase occurs differs across the studies. For the higher coverage 

scenarios, there is less agreement across the studies; whereas, in lower coverage scenarios, 

the models tend to be in more agreement. How the cost per-QALY gained changes depending 

upon what health outcomes are included in the analyses is shown in the following table of the 

Chesson study:

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As shown, the cost per-QALY gained changes depending upon what health outcomes are 

included in the analysis. Two coverage scenarios were included, a lower 3-dose coverage 

scenario in which there was 30% coverage of girls by 12 years of age and 50% coverage by 

age 26, and a higher 3-dose coverage of 50% by age 12 and 70% by age 26. Including only 

cervical outcomes, the cost per-QALY gained by male vaccination is over $100,000 per-QALY. 

As increasingly more potential health outcomes are included in the analysis, the cost per-QALY 

gained by male vaccination decreases until it reaches approximately $40,000 in the lower 

coverage scenario and approximately $80,000 in the higher coverage scenario when including 

all health outcomes. The first four outcomes listed are those for which there is evidence of 

vaccine efficacy. When limiting the analysis to those indicated outcomes only, the cost perQALY gained is about $70,000 in the lower coverage scenario and about $130,000 in the higher 

coverage scenario.

The published studies typically report cost-effectiveness of adding male vaccination to femaleonly vaccination, but another strategy to reduce HPV burden in both sexes is to increase 

vaccine coverage of females. An important public policy question to ask is: What is the costeffectiveness of male vaccination compared to a strategy of increased vaccine coverage of 

females? Chesson et al assessed this in their model and found that the incremental cost perQALY of male vaccination when including all outcomes was over $100,000 when compared to a 

strategy of increased female coverage. In contrast, when the usual approach was used of 

comparing male vaccination to the status quo female coverage, the cost per-QALY gained by 

male vaccination was in the $25,000 range. In this example, the strategy of increased vaccine 

coverage of females could incur costs of over $350 per additional woman vaccinated, above 

and beyond the cost of vaccination, and still be as cost effective as male vaccination.

Dr. Chesson presented new information in response to the questions raised during the February 

2011 meeting. The first request was for additional information regarding the cost-effectiveness 

of male catch-up vaccination. The following table shows the lower coverage and higher 

coverage scenarios used in the previous example. The top row shows the cost per-QALY 

gained by female only vaccination, the next row shows the cost per-QALY gained by adding 12-

year old boys to a vaccination program, and the bottom three rows show what happens when 

male vaccination is expanded to include 18-year olds, 21-year olds, and 26-year olds. The cost 

per-QALY gained really increases when moving beyond age 21 in the model at over $400,000 

in the lower coverage scenario when including only the indicated outcomes, and well above 

$150,000 when including all outcomes:

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While Dr. Chesson did not show the Merck model results, he pointed out that there are two key 

differences in their results and the Chesson model. First, the Merck model found that 

vaccination of males up to the age of 18 was more cost-effective than vaccinating 12-year old 

boys only. They also found that the cost per-QALY did not increase as much when gong to age 

26. It was about $50,000 when including all outcomes and about $100,000 when including the 

indicated outcomes only.

During the previous ACIP meeting, the members also requested more information about what 

diseases account for the gains in QALYs. It is known that additional health benefits accrue 

when females are vaccinated and when males are added to the female-only vaccination 

program. The models assess these health gains in terms of QALYs. The members requested 

information regarding what health outcomes account for most of the QALY’s gained. The 

following table shows the percent of QALY benefit attributable to HPV disease prevented. For 

both female only vaccination and the incremental benefit of male vaccination, cervical outcomes 

and oropharyngeal cancer accounted for over 70% of the QALYs gained. However, for male 

vaccination, oropharyngeal cancer accounted for practically the same amount of QALYs as 

cervical cancer:

Another way to look at this is to limit this analysis just to the outcomes for which there is 

evidence of vaccine efficacy. When doing so, cervical cancer is still the greatest contributor to 

the number of QALYs gained for both female only vaccination (73%) and male vaccination 

(59%). However, anal cancer (13% female; 19% male) and genital warts (9% female; 18% 

male) have a much greater impact on the QALYs gained for male vaccination than for female 

only vaccination. 

Another question posed during the last meeting pertained to the impact of duration of vaccine 

protection assumptions. With reasonable certainty, it can be said that assuming a shorter 

duration of vaccine protection would make female-only vaccination less cost-effective. 

However, a shorter duration of vaccine protection could make male vaccination less costeffective because of the reduced impact on vaccinated males [Kim BMJ (2009)]. It also could 

have the counterintuitive results of making male vaccination appear more cost-effective, given 

that the reduced impact on vaccinated females could leave a greater HPV burden to be averted 

by male vaccination even with a shorter duration of protection [Jit BMJ (2008)].

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In conclusion, male vaccination in the US is potentially not cost-effective, particularly at high 

female coverage levels. Even at current female coverage levels, male vaccination may not be 

cost-effective, particularly when compared to a strategy of increased female coverage or if 

males vaccinated have mostly vaccinated partners. However, male vaccination is potentially 

cost-effective, particularly at current female coverage levels. All available models suggest that 

there are potentially favorable cost-per-QALY estimates when female coverage is ≤ 50%. Also, 

with a lower vaccine cost, male vaccination is much more likely to be cost-effective across a 

wide range of scenarios.

Policy Considerations: HPV Vaccine for Males

Eileen F. Dunne MD, MPH

National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

Centers for Disease Control and Prevention

Dr. Dunne reviewed policy considerations for HPV vaccine for males. Quadrivalent HPV 

vaccine is licensed for males 9-26 years. In October 2009, ACIP provided guidance that the 

vaccine may be used in males 9-26 years for prevention of genital warts. Since that time, a 

variety of data has been presented, as highlighted at the beginning of this session. The 

quadrivalent HPV vaccine has been demonstrated to prevent genital warts and anal cancers in 

males, and had an indication for prevention of these two outcomes. 

In terms of estimated HPV and HPV 16/18 associated cancers for men and women, as noted, 

there are about 7000 HPV 16/18 cancers in men. The majority of these cancers are cancers of 

the oropharynx. There are no clinical trial data demonstrating efficacy for prevention of 

oropharynx cancers, or for prevention of penile cancers [National Program of Cancer Registries 

and SEER, covering 83% coverage of US population; Gillison ML, et al. Cancer 2008].

Over the last few years, the ACIP HPV WG has been deliberating on HPV vaccine for males, 

and an important consideration has been cost-effectiveness. As shown by Dr. Chesson, the 

cost-effectiveness of male vaccination appears favorable in the scenario of lower vaccine 

coverage. As vaccine coverage in females increases, cost-effectiveness of male vaccination 

becomes less favorable.

The male HPV vaccine recommendation options that have been discussed and brought before 

the committee, include retaining existing guidance for males 9-26 years (or permissive 

recommendations), or recommending routine use of 11- or 12-year old boys. In addition, the 

ACIP HPV WG has considered vaccine options for men who have sex with men. There is a 

greater burden of HPV-associated outcomes including genital warts, anal pre-cancers and 

cancers in MSM. The Kim model, as highlighted in Dr. Chesson’s, presentation demonstrated a 

favorable cost per-QALY of vaccinating MSM through age 26 years [Kim JJ. Lancet ID 

2010;845-52]. Most ACIP HPV Working Group members favor a strategy of routine vaccination 

of all males at an age at which they are likely to have the greatest benefit (e.g., 11 or 12 years) 

rather than an approach targeting MSM. The benefits of HPV vaccine to MSM would be 

emphasized and included in any male vaccine recommendation.

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If vaccine was recommended for routine use, catch-up vaccination needs to be considered. The 

WG has discussed different vaccination options. As presented by Dr. Chesson, costeffectiveness models demonstrate less favorable cost per-QALY with increasing age. For all 

scenarios, the cost per-QALY gained by male vaccination increases with age at vaccination. 

For this and other reasons, the ACIP HPV Working Group has focused on two options for catchup: catch-up through age 21 and catch-up through age 26 years.

There are different advantages of catch-up vaccination through age 26 years, or through age 21 

years. Licensure of the vaccine is to age 26, so a catch-up recommendation through age 26 

years may create less confusion about implementation. Also, this recommendation would be 

harmonized with the female vaccine recommendations. Finally, a recommendation through age 

26 years would broadly capture all men through age 26 years, including MSM seeking care. 

The advantages of catch-up vaccination through age 21 years, are that this would focus the 

program on the younger age group. This recommendation may be a better use of health care 

resources, given that the cost-effectiveness data demonstrate a higher cost per-QALY with 

increasing age. Finally, a recommendation through age 21 years would focus limited resources 

on those with the greatest benefit, but would still capture youth from high school and through 

college who may benefit from vaccination. 

For either of these considerations, it is important to note that male vaccine implementation in the 

22-26 year olds would likely be less than in the younger group, similar to what has been 

observed for females. Given limited doses delivered in that age group, the overall costs of the 

program, regardless of the recommendations for catch-up, may be minimal. Another point to 

consider regarding catch-up vaccination is harmonization with the female recommendations. If 

male catch-up vaccination was through age 21 years, it may be advantageous to harmonize 

female catch-up to age 21 years as well, which would be a change in the recommendations. An 

advantage of this is that programs would focus on the age groups in which there would be the 

greatest benefit.

The Kim / Goldie model demonstrates the cost-effectiveness of vaccination of females through 

age 26 years. For males, the cost per-QALY of female vaccination increases with increasing 

age, and the highest cost per-QALY occurs in the oldest age group [Kim JJ, Goldie SJ. N Engl J 

Med 2008;359:821-832].

As has been presented, most WG members support routine vaccination of males, particularly 

with a lower HPV vaccine cost. Opinions about catch-up recommendations vary. A few WG 

members support no catch-up, or catch-up through age 18 years. Some WG members support 

catch-up through age 21 years, and some WG support catch-up through age 26 years. Over 

the ensuing months, additional discussions of these options will take place. It is important to 

note that most WG members support harmonization of female and male recommendations 

regardless of the catch-up considerations. The next steps of the ACIP HPV Working Group are 

to discuss recommendation options, and present to ACIP an update on HPV vaccine safety, 

2010 vaccine coverage estimates from NIS, Grades of Recommendation Assessment, 

Development and Evaluation (GRADE) evidence for HPV vaccine in males, and HPV vaccine 

recommendation options.

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In conclusion, Dr. Dunne posed the following questions regarding HPV vaccine 

recommendations for males:

 What are the opinions of the committee on vaccine recommendations for males? 

 What are the opinions of the committee on vaccine catch-up options? 

 What additional information is needed for these considerations, if any? 

Discussion Points

In terms of what additional information may be needed, Dr. Temte commented on the properties 

of cost-effective analysis for a program that comes from compartmentalizing the whole program. 

A recommendation was made for the “low hanging fruit,” which was the girls and now there is a 

much “higher fruit,” which is the boys. Anytime those are assessed independently, the result will 

be very negative in terms of cost-effectiveness. He wondered what would occur if an 

assessment was made of a male and female harmonized schedule in comparison with a base 

case of doing nothing in terms of the cost-effectiveness of an HPV program for adolescents. 

Dr. Chesson replied that this could be done for the next ACIP meeting. Some of these analyses 

have been done already. However, anytime some of the options are ignored (such as femaleonly vaccination), the cost-effectiveness of the end result (such as male and female vaccination) 

will be overestimated. 

Dr. Sawyer requested clarification on the conditions that are or are not included in the costeffectiveness models. He understood the rationale for eliminating the conditions for which there 

is no evidence that HPV causes the cancer, but it was not clear why they were focusing on 

cervical cancer only rather than considering all things that could be prevented and are known to 

be caused by HPV.

Dr. Dunne responded that she thought there were just different perspectives of the WG 

members in terms of the value of all outcomes that could be preventable and the indicated 

outcomes. That was why they showed indicated outcomes and all outcomes.

Dr. Sawyer pointed out that they do not do this for a lot of other illnesses. Pneumococcus 

causes pneumonia and meningitis, but they do not dissect the different illnesses it causes and 

decide which are the most worth preventing. 

Dr. Baker pointed out that the problem is that there are efficacy data for some anatomical sites 

but not others. However, she thought considering all outcomes was very helpful.

Dr. Marcy expressed concern about the slide that stated “next ACIP meetings” plural. He 

thought there should be a vote during the October 2011 meeting. No further information is 

needed for these considerations. He felt there were already ample data, and pointed out that 

Dr. Chesson was beginning to reshow slides he had shown a year previously. 

Dr. Baker thought the plan to update female uptake would be helpful in terms of that discussion.

While he knew it was unrealistic to think that there would be any data forthcoming regarding the 

vaccine and oropharyngeal malignancies, Dr. Meissner wondered whether everyone agreed 

that it was biologically plausible that the vaccine would have the same beneficial impact on 

oropharyngeal disease. 

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Dr. Markowitz replied that there are no efficacy studies, but there may be data from some 

studies assessing the infection.

Dr. Kreimer added that she is involved in the Costa Rica Vaccine Trial which is a publicly funded 

NIH vaccine trial evaluating the vaccine efficacy of the GSK vaccine. The primary aim was to 

assess infection at the cervix, but anal and oral specimen collection was added to that at the 

final randomized study visit. Because oral HPV infections are quite rare, the sample size will be 

limited, but they will be able to provide some proof of principle data over the next several 

months assessing just prevalence of oral HPV 16/18 infection in a vaccinated compared to an

unvaccinated arm. She stressed that because the study was not powered to assess oral, there 

will likely be inadequate power to reach a strong conclusion. Because this was implemented at 

the final study visit, oral persistence of infection will not be assessed. This is simply a one-time 

measure of oral HPV infection.

Dr. Duchin wondered whether there were any data that assess the antibody levels in the tissues 

of the oropharynx comparable to the data presented in the early stages of HPV vaccine 

development regarding the cervix, and whether the pathophysiology of the development of the 

cancer was similar. He also thanked the working group for being so responsive to the ACIP 

membership’s questions.

Dr. Kreimer responded that it was uncertain whether the pathophysiology of the cancers is 

similar, because in terms of the natural history of cancer, it is unclear whether it has a precancerous state. It is known that there is infection leading to cancer, but there is still a “black 

box” in the middle.

Dr. Wharton wondered whether anatomically oropharyngeal cancers started whether they 

initiated in the transition zone, or whether this was known.

Dr. Kreimer replied that she would say that is where they initiate because the tonsillar crypts has 

exposed epithelium.

Dr. Keitel wondered whether the age of diagnosis of people with HPV positive oropharyngeal 

cancer the same as the age of diagnosis of HPV negative oropharyngeal cancer. She also 

wondered whether the oropharynx can be sampled, or whether there was anything inhibiting the 

detection of DNA.

Dr. Kreimer responded that there is a difference in age of earlier diagnosis for the HPVassociated cancers by a couple of years. It is significant that the HPV-positive cancers are 

diagnosed at an earlier age. Measurement of oral HPV in the oral region is actually quite 

complicated because it is difficult to directly sample the tonsils due to the gag reflex. The 

investigators have worked to optimize specimen collection and processing for oral HPV DNA 

analysis

Dr. Baker noted that the recommendation for collection of culture specimens for Group A 

streptococcal pharyngitis is based on good studies, but this recommendation is hardly ever 

followed. It is quite difficult to collect a good sample because of the gag reflex in children, even 

with three people holding them down. 

In terms of risk factors, Dr. Keitel pointed out that marijuana use was not discussed at length. 

She requested insight into why that might be an independent risk factor. 

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Dr. Kreimer replied that in the graph contrasting HPV positive and HPV negative head and neck 

cancers, in HPV positives there is a dose response trend with marijuana use. These data were 

adjusted for sexual behaviors; however, there could still be residual confounding due to sexual 

behaviors. Researchers are following up on this hypothesis and investigating this topic 

currently. 

Dr. Englund reported that the WG members and CDC have tried very hard to provide the ACIP 

membership with answers to their questions, but have also offered continuous feedback to 

stimulate everyone’s memory about how far things have come since the vaccine was licensed 

over 5 years ago. They want to have institutional memory within ACIP and to understand the 

progress that has been made, and that opinions have changed.

Dr. Markowitz thanked Dr. Englund, who was rotating off as the HPV Vaccine Working Group 

chair. She has been a great chair and provided sound advice and guidance as the group dealt 

with many difficult issues over the last few years. 

Dr. Baker congratulated the WG and those at CDC for being very responsive to the ACIP 

membership’s questions the last couple of meetings. 

Dr. Sawyer said one of the figures that was presented that stuck with him was that HPV cancers 

in males account for 7000 cases per year compared to 14,000 in women. Half as much is not a 

trivial number, so he thought rather than continuing to try to decide whether males should be 

immunized, they should call the question.

Dr. Schaffner (NFID) felt that institutional memory was about to be diluted and new members 

will join. If there is going to be a vote during the October ACIP meeting, he wondered if any 

plans were being considered to bring the new members up to date on some of these very 

“pregnant” issues.

Dr. Markowitz replied that they will plan to summarize all critical data that have been presented 

during past meetings.

Dr. Pickering added that when there are new members, CDC conducts orientation sessions with 

them before their first meeting to bring them up to speed on all issues. A couple of new 

members have been involved either as liaisons or members of working groups, so they are 

current on the issues.

Discussion

No public comments were offered on the first day of the June 2011 meeting.

Day 1 Public Comments

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June 23, 2011

Centers for Disease Control and Prevention (CDC)

Dr. Wharton reported that during the March 2011 Immunization Conference, CDC presented an 

updated economic analysis of the return on investment of childhood immunizations. This 

analysis was last done in 2005. Given that a number of new vaccines have been added to the 

immunization program since that time, it was important to update it. The new model adds 

information for pneumococcal conjugate 7-valent vaccine, hepatitis A, rotavirus, and the second 

dose of varicella vaccine to the series of vaccines given through age 6 years. It also includes 

updated healthcare costs, vaccine prices, vaccine coverage, and annual births to 2009 figures. 

The bottom line of this new analysis was that the return on investment for vaccination of children 

born in one year in the US through age 6, according to the ACIP recommended childhood 

immunization schedule, is 20 million illnesses prevented; 42,000 premature deaths averted; 

$13.6 billion in medical costs saved; $59 billion total savings; an average of $3 medical savings 

for every $1 spent; and an average of $10.2 total medical and societal savings for every dollar 

spent.

Regarding the Vaccine Toolkit, on June 9, 2011 there was a special issue of Health Affairs, 

which was presented with a special issue on Vaccines and Immunization. That issue included 

an article by CDC and HHS staff on parental acceptance and vaccine concerns. There have 

been other recent publications in this area as well. The way CDC views this issue is that in the 

US, reinforcing the skills of clinicians to help them better address parental concerns is a key 

approach to improving vaccine acceptance and sustaining high immunization coverage. NCIRD 

has worked with the American Academy of Pediatrics (AAP) and other key partners, including 

FDA and NIH, to develop a set of updated health communication tools to improve provider care 

and interactions related to immunizations. These materials grew out of formative research 

conducted with parents in several parts of the country, as well as in-depth interviews with 

doctors and nurses. New materials have been developed to address a variety of issues. The 

materials available so far are on the website at the Vaccine Toolkit URL, and other materials are 

still being developed. CDC is very excited about this, and hope that they will be useful for the 

people who have to have these conversations every day in the office. 

Centers for Medicare and Medicaid (CMS)

Linda Murphy reported that CMS has worked on an interim upgrade for the administration fees, 

which are making their way through clearances. The hope is to have the information published 

in July 2011. They are still working on the larger regulations. Once published, she will 

distribute a notice to ensure that ACIP members are aware of it.

Department of Defense (DoD)

Jesse Geibe offered DoD’s gratitude for the support provided by CDC and ACIP during the 

development process of adenovirus vaccine that DoD will begin administering in the near future, 

particularly with the development of the vaccine information statement.

Agency Updates

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Department of Veterans Affairs (DVA)

Dr. Kinsinger reported that about half of the DVA clinical facilities ordered high dose influenza 

vaccine this year totally about 173,000 doses. They do not have records on how many of those 

doses were actually used, but the sites were surveyed and it was determined that there was a 

lot of variability. Some sites used the vaccine a lot, while other sites were confused and 

uncertain as to when and for whom high dose vaccine should be administered. More guidance 

about using high dose influenza vaccine would be very helpful as those data become available. 

They noticed a decrease in uptake of influenza vaccine by healthcare professionals this year, 

although DVA is not quite sure why and wondered whether others had noticed a similar trend. 

There is some concern about the side effects from the H1N1 vaccine, so there may be some 

residual uncertainty about influenza vaccine among DVA healthcare professionals. They hope 

to put a system in place in the fall that will allow them to track uptake very easily.

Food & Drug Administration (FDA)

Dr. Wellington Sun provided a synopsis of the vaccines that have been licensed by FDA since 

the February 2011 meeting. The adenovirus vaccine for ages 17 to 50 years for the military, a 

FluZone® intradermal formulation, Menactra® supplement for 9 months to 23 months, and 

Zostavax® were approved. Regarding interference amongst bacterial vaccines, FDA also 

approved the change in prescribing information for Menactra® and Boostrix® based on a study 

conducted about co-administration. Basically, there appears to be some interference from an 

antibody standpoint between Menactra® and Boostrix® in the pertussis assays. It is not clear 

what this means. There is no correlate of protection, but that phenomenon was observed in coadministration. He encouraged those interested to read that label. 

Health Resources and Services Administration (HRSA)

Dr. Evans reported that a final rule was published on June 22, 2011. Four vaccines have been 

added to the program since 2004 (e.g., hepatitis A, trivalent influenza, meningococcal, and 

HPV). When new vaccines are added to the program, they are put in a footnote until final 

rulemaking is undertaken. Formal rulemaking was undertaken, with the opportunity to add 

injuries, and these four vaccines will now be listed in separate box categories. No associated 

injuries were added at this time. In the future, the Institute of Medicine Committee on Vaccines 

and Adverse Events will be releasing its much anticipated paper, which is approximately 50% 

longer than in 1991 and 1994. This is why it is taking longer to clear and publish. It is expected 

that from this report, there may be opportunities to add injuries to some of these vaccines. The 

report will cover varicella, influenza, both hepatitis vaccines, meningococcal, HPV, DTaP, MMR 

in various combinations. It will cover 12 vaccines total, and is quite an ambitious effort. This 

major effort was sponsored in part by CDC. HRSA looks forward to discussing the results of 

this report during the October ACIP meeting. Perhaps the IOM will be able to present at that 

time as well.

Indian Health Services (IHS)

Amy Groom reported that approximately 73% of IHS’s healthcare personnel had received 

influenza vaccine, which was about the same as it has been for the past couple of years. While 

they are happy with this percentage, they believe they can do better and are considering 

implementing a mandatory influenza vaccination policy as well as other vaccines recommended 

for healthcare personnel. This policy is currently being review by their Chief Medical Officer. 

IHS is working to organize a stakeholders meeting with the American Indian community and 

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providers to assess national vaccine plan implementation issues. A concerted effort is also 

being made to assess adult vaccination within Indian adult services. There is a vaccination 

program for children, but adult vaccine coverage is variable. With all of the healthcare reform 

activities that are ensuring access to adult vaccines for the remainder of the population, they 

want to better assess what is occurring in IHS health facilities. They will be conducting a survey 

to determine which facilities are providing the recommended vaccines and what issues there 

may be. They have had a lot of success with pharmacists providing immunizations at various 

sites, so a concerted effort is being made to inform pharmacists of the goals pertaining to adult 

vaccination.

National Institutes of Health (NIH)

Dr. Nesin reported that NIH joined other agencies and organizations in commemorating the 30th

anniversary of the first reported cases of AIDS. Dr. Fauci, director of the National Institute of 

Allergy and Infectious Diseases (NIAID), issued a statement that is located on the NIH website. 

He also co-authored Thirty Years of HIV and AIDS: Future Challenges and Opportunities was 

published in the Annals of Medicine [Carl W. Dieffenbach and Anthony S. Fauci, Ann Intern Med 

May 31, 2011 E-345; published ahead of print May 31, 2011]. There is also a slide show on 

public health advances. The Vaccine Research Center celebrated its anniversary and hosted 

the anniversary symposium. The objective was to describe the advances in the last 10 years. 

The speakers were Dr. Collins, Dr. Fauci, and many of the NIAID faculty investigators. NIAID 

supports studies of new vaccine candidates and licensed vaccines, so there are studies 

underway in Phase 1 or Phase 2 for candidates for malaria, dengue, et cetera. Studies are also 

conducted in populations that require protection such as pregnant women. All of the protocols 

can be reviewed on the website. 

National Vaccine Program Office (NVPO)

Dr. Grabowsky thanked everyone for their indulgence, indicating that he was tardy due 

to engagement of a rehearsal operation exercise earlier in the morning in which they 

practiced transferring decision-making authority from Washington to Atlanta. The 

National Vaccine Plan was released in February. NVPO continues to write the 

implementation plan with some engagement activities. NVPO is well underway in terms 

of implementing priority areas such as the methodology for identifying vaccines and 

vaccines.gov has been launched. The Adult Immunization Working Group of the 

National Vaccine Advisory Committee released its report, and will vote on the safety 

report of that committee in September 2011. The Interagency Influenza Task Force is a 

high priority of Dr. Koh. 

National Vaccine Advisory Committee (NVAC)

No report.

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Discussion Points

Dr. Baker commented that she had reviewed the new health communication tools to improve 

provider care and interactions related to immunizations and found them to be outstanding. She 

inquired as to whether the updated report on the impact of vaccines had been or would be 

published.

Dr. Wharton responded that information was included in an MMWR article, which could be 

provided to ACIP members, and a peer-reviewed publication is being prepared. 

Introduction

Jeff Duchin MD

Chair, General Recommendations Working Group

Dr. Duchin reminded everyone that the vaccine safety monitoring system reflected a small 

increase in seizures. This was discussed during the February 2011 ACIP meeting. Because of 

the observation of a potential increase in febrile seizures associated with PCV, CDC leadership 

asked the General Recommendations Work Group to establish a subgroup to evaluate the 

problem. The terms of reference for this subgroup were to: 

 Review data on the risk for febrile seizures after seasonal trivalent inactivated influenza 

vaccine (TIV) and pneumococcal conjugate vaccine (PCV13/7) in children aged 6 through 

23 months

 Describe what is known about the causes, preventive measures, and clinical significance of 

febrile seizures

 Present options to ACIP for any action(s) related to the use of these vaccines for the 2011-

2012 influenza season

 Describe what is known about incidence of febrile seizures in association with childhood 

vaccines alone and in combination (including influenza, pneumococcal, pertussis-containing 

vaccines, MMR, MMR-V)

 Describe whether vaccination against influenza provides protection against febrile seizures 

 Provide a framework for determining when vaccine-associated febrile seizures should lead 

to a change in recommendations for administration of one or more vaccines

General Recommendations: Febrile Seizures

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Although the analysis of the significance of this observation is on-going, the risk appears to be 

lower than was initially estimated. During this session, presentations included a clinical review 

of febrile seizures; review of current data on association of febrile seizures with TIV and PCV; 

benefits of TIV and PCV (morbidity prevented; potential impact of missed doses); policy options; 

and communication considerations. The Febrile Seizures Subgroup Work Group concluded that 

no change in recommendation for simultaneous administration of TIV and PCV is indicated at 

this time. Additional data collection and analyses are underway, and information for healthcare

providers and parents will be developed. 

Clinical Aspects of Febrile Seizures

Harry L. Keyserling, MD

Professor of Pediatrics

Emory University School of Medicine

Dr. Keyserling explained that a febrile seizure is defined as a seizure with fever >38°C in 

children age 6 months through 6 years with no CNS infection, no prior history of epilepsy or 

afebrile seizures, or metabolic disturbances. Febrile seizures are quite common. 

Approximately 2% to 5% of children have a lifetime risk of developing febrile seizures. Of these, 

97% are simple febrile seizure defined as generalized seizure lasting less than 15 minutes with 

no recurrence in the following 24-hour period. Complex febrile seizure make up 3% of febrile 

seizures defined as focal, lasting greater than 15 minutes, and/or recurrent within 24 hours. It is 

thought that complex febrile seizures are probably related to underlying CNS problems. In 

terms of the pathophysiology, the mechanism for fever causing a seizure is unknown. The fever 

can be from any sources (e.g., infection, vaccines, environmental). It is probably not a cytokine 

phenomenon, but is truly an increase in body temperature. The fever induces an abnormal, 

sudden, excessive electrical discharge of neurons. It is known that genetic factors are 

important. Children with febrile seizures have a family history in first degree relatives of 10% to 

20%. Many genetic markers have been identified that correlate with febrile seizures.

In terms of the epidemiology, Berg assessed children in what Dr. Keyserling considered the premodern vaccine era before MMR and other vaccines from 1960 through 1967. This was a 

population-based study of an HMO from which 18,000 children were followed. The investigators 

assessed febrile and non-febrile seizures. Of the seizures, 70% were febrile, in the age group 

of 12 through 23 years of age about 90% were febrile, and 10% were admitted to the hospital. 

Regarding underlying cause, syndromic causes not laboratory-confirmed infections, 15% were 

roseola (some reports indicate that 30% to 40% of children below 20 years of age have roseola 

as the cause of febrile seizures), about 50% were upper respiratory infections, and about 15% 

were gastrointestinal disease [van den Berg BJ et al: Pediatr Res 1969;3:298-304]. 

Another important point is that even though during the period of life from 6 to 60 months of age 

children might have 25 to 50 febrile episodes, recurrences of febrile seizures occur in about 

50% of children. Even in children with febrile seizures, the majority of the time febrile illnesses 

will not induce a febrile seizure and about 40% of the time the fever itself is the first indication to 

the parents that the child is ill.

Moving to the period from 1997 to 2006, a Vaccine Safety Data Link study showed that acellular 

pertussis vaccine was not associated with febrile seizures; whereas earlier studies of whole cell 

pertussis vaccine had shown an association. There was a very similar pattern to the earlier 

study. The incidence of seizures peaks at about 15 months of age [Huang, W.-T. et al. 

Pediatrics 2010;126:263-269].

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An important question regards the sequelae or potential outcomes of simple febrile seizures. 

There are no significant sequelae for simple febrile seizures. There appears to be no decline in 

IQ, no developmental disorders, and no behavior disorders associated with febrile seizures. 

There is an increased risk of epilepsy and risk of recurrence of febrile seizures, and there are 

some theoretical risks (e.g., injury, aspiration, cardiac arrhythmias). There are approximately

100,000 to 200,000 febrile seizures per year in the US. From one emergency room report, in 

children in the age range of 12 to 23 months, about 1% of emergency room visits are related to 

the first simple febrile seizure. There really have not been any reports of significant injury, 

aspiration, or cardiac arrhythmias, so these could be rare events. It is important to remember 

that those in this age group are not swimming or driving. Toddlers fall down frequently, so the 

theoretical risk of having a problem related to physical manifestations of the motor activity from 

a seizure and loss of consciousness in this age group generally is not large.

Two population-based studies have addressed whether any significant brain damage occurs. 

The first showed that children with simple febrile seizures have approximately the same risk

(1%) of developing epilepsy by the age of 7 years as the general population. Another study 

showed that children who have had multiple simple febrile seizures, are younger than 12 

months at the time of their first febrile seizure episode, and have a family history of epilepsy are 

at a slightly higher risk (2.4%) of developing epilepsy by 25 years of age. This increase may be 

a coincidence rather than causal. In terms of risk of recurrent febrile seizure, a child who has 

one febrile seizure has a 30% chance of having another one, a 20% chance of having two, and 

about a 5% chance of having 3 seizures. 

With regard to what occurs when a child is evaluated for a febrile seizure, the American 

Academy of Pediatrics (AAP) recently published new recommendations. Basically, the 

recommendation was to do nothing in terms of laboratory or imaging evaluations and to 

consider doing a lumbar puncture to evaluate the cerebral spinal fluid if the patient has evidence 

of CNS infection, or for children less than 12 months of age who have not been immunized with 

Hib and pneumococcal vaccines. An EEG, electrolytes, complete blood count, and 

neuroimaging are not recommended. In terms of treatment, continuous or intermittent 

anticonvulsant therapy is not recommended. While anticonvulsants decrease the risk of 

recurrence by 80% to 90%, there is significant toxicity. Phenobarbital has been associated with 

a decreased IQ and behavioral disorders. Therefore, the recommendation is that even though 

pharmacological intervention works, there is more risk than benefit. Antipyretics offer no 

benefit. 

In terms of additional issues, certainly when a child has a febrile seizure it is stressful to the 

family, daycare center staff, and anyone else witnessing the event. There are also the costs of 

medical evaluation. Most of the time the parents bring their child in themselves; however, 

occasionally an ambulance is needed for which there is a fee, and the cost of an ER visit can 

vary depending upon the work-up but can be as high as $2,000 for the evaluation.

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Safety Data Update

Jerome I. Tokars, MD, MPH

Immunization Safety Office (ISO)

Division of Healthcare Quality Promotion

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention (CDC)

Dr. Tokars presented updated analyses on febrile seizures following a trivalent inactivated 

influenza vaccine (TIV) based on data from the VSD. Regarding the methods, data were 

obtained from 8 managed care organizations within the VSD. Self-controlled analyses 

compared the number of cases on days 0 to1, which is the risk interval, to days 14 to 20, which 

is the control interval. Here, day 0 is the day of vaccination. Febrile seizures are initially 

identified using automated data seeking the ICD9 code for convulsion (780.3). Chart 

confirmation ensures febrile seizure. Data come from inpatient and emergency departments, 

and outpatient data are excluded. Only the first event in 42 days is collected to assist in 

identifying incident cases. 

In February 2011, data were presented to ACIP that the VSD had identified an increased risk of 

seizures on days 0-1 post-vaccination among children 6 through 59 months of age who received

their first dose of TIV. Most had received other vaccines, most commonly 13-valent 

pneumococcal conjugate vaccine (PCV13). Questions about the risk of febrile seizures after 

TIV included the following:

 Was the risk in 2010-11 higher than in past influenza seasons?

 What was the role of concomitant vaccines?

 What age groups were affected?

 What is the attributable risk?

 What is the effect of first versus the second dose of TIV?

The attributable risk per 100,000 in 12 through 23 month old children was found to be very high 

in children who received both TIV and PCV13. There is some evidence of elevated risk in those 

who received only one or the other of the vaccines, but the confidence interval overlaps with 

zero, so these are not statistically significant findings and are probably not clinically important. 

During the February 2011 ACIP meeting, it was reported that the largest excess risk was in 12

through 23 month old children who received a concomitant first dose of TIV and PCV13 (+/- 

other vaccines). The attributable risk was reported to be 61 (95% CI 13 to 109) per 100,000 

vaccinees or approximately 1 excess febrile seizure in 1640 children who received both

vaccines. Since that time, additional data for the 2010-2011 influenza season have been 

received, and a chart review of cases after TIV was completed. There has been an updated 

calculation of the attributable risk for first dose TIV. For children who received TIV with or 

without PCV13, chart-confirmed febrile seizure data were used. For children who received 

PCV13 only, non-chart confirmed data were used with an estimated chart confirmation rate. 

There are also data on the second dose of TIV. Dr. Tokars emphasized that these are 

preliminary data.

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First dose TIV recipients age 6 through 59 months (N=206,174) from August 2010 through 

February 2011 included 40,375 (20%) 6-11 month olds; 60,677 (29%) 12-23 month olds; and 

105,122 (51%) 24-59 month olds. TIV+PCV13 +/- other vaccines were received by 57,197

(28%) children; TIV+non-PCV13 vaccines were received by 37,364 (18%) children; and TIV 

only was received by 111,613 (54%) children. The number of cases identified by ICD-9 codes 

was 32 in the risk interval and 34 in the control interval. Available for chart review were 30 in 

the risk interval and 31 in the control interval. There were 27 chart-confirmed cases in the risk 

interval and 26 in the control interval. There were 25 chart-confirmed seizures in the risk 

interval and 22 in the control interval [Chart confirmation rate for risk interval 25/30 (83%), for 

control interval 22/31 (71%), for both combined 47/61 (77%)]. The reason that many of these 

are not confirmed as febrile seizures appears to be because of a lack of documentation, so 

there are more seizures than can be definitely described as febrile seizures with confidence. 

In terms of the characteristics of the TIV recipients with chart-confirmed febrile seizures in the 

risk interval (N=25), 21 (84%) were diagnosed in the emergency department and 4 (16%) were 

diagnosed in the inpatient setting. Of the 25 cases, 8 (32%) had a prior history of seizures, 5 

(20%) had a family history of seizures, 5 (20%) had a concurrent URI (including 2 otitis media, 1 

pharyngitis), 1 (4%) had a concurrent UTI, 17 (68%) received concomitant PCV13, and 17 

(68%) received concomitant DTaP. In the data presented in February 2011, slightly more 

children had received PCV13 than DTaP, while in the updated data 13 received both PCV13 

and DTaP. While they have data on PCV13, data have not yet been received on DTaP.

Updated attributable risk estimates of febrile seizures were calculated in 9 categories by age 

group and receipt of concomitant PCV13. The primary finding is that the highest elevation in 

attributable risk continues to be in children 12 to 23 months of age who have received both 

vaccines. The attributable risk is in the range of 42; however, there is also some evidence of an 

increase in attributable risk in the other age groups who received both vaccines, and some 

evidence of increased risk in the 12 to 23 month old children who received only TIV or only 

PCV13. These findings are based on generally low numbers stratified into the 9 categories. In 

terms of first versus second dose of TIV, the number of children who received TIV+PCV13 +/- 

other included 5,476 children. This is roughly only one-tenth of the number who received first 

dose of TIV+PCV13. The number of cases in the risk (n=2) and control (n=3) intervals were 

small. Because of the small numbers, the estimate of risk of the second dose of TIV is really 

not feasible.

In response to the questions that were raised about the risk of febrile seizures after TIV, in 

terms of whether the risk in the 2010-11 season were higher than in past influenza seasons, risk 

was risk was primarily seen in the 2010-11 season. Regarding the role of concomitant 

vaccines, risk is highest when TIV given with other vaccines. Concomitant PCV13 versus DTaP

were received equally by cases. Data are currently not available to evaluate DTaP. However, 

PCV13 was new for 2010-11 season, and increased risk of febrile seizures was not found after 

TIV in prior years when DTaP was used. With respect to the affected age group, there are 

limited data to define an age group-specific risk. Current analyses show that the highest 

attributable risk in the 12 through 23 month group and there is some evidence of risk in the 6 

through 11 month age range. The updated attributable risk estimate for 12 through 23 month 

olds when TIV is given concurrently with PCV13 is 42 (95% CI 3,81) per 100,000 or 1 per 2375 

vaccinees. The caveats are that the measures are of TIV administered with PCV13 

concomitantly versus no vaccine, not versus TIV and PCV given at separate visits. The 

confidence interval is wide, and focusing on a single point risk estimate may be misleading. In 

terms of the question regarding the effect of first versus second dose of TIV, the limited number 

of second dose vaccinees and few cases limit the ability to compare effects. 

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Further work to address this issue includes an alternate modeling approach to calculate the 

attributable risk using a larger dataset to estimate the baseline risk; assessing the effect of 

DTaP; comprehensively studying recommended childhood vaccines and febrile seizures; and 

continuing to monitor during the 2011-2012 season. 

Burden of Disease Information / Next Steps 

Andrew Kroger M.D., M.P.H.

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Regarding the burden of influenza among children in the US, Dr. Kroger reported that 

complications include respiratory issues (otitis media, sinusitis, croup, pneumonia—viral and 

secondary bacterial), musculoskeletal (myositis, rhabdomyelitis), cardiac (myositis, pericarditis), 

neurologic (seizures, encephalopathy, encephalitis), and exacerbation of chronic conditions 

(asthma, cardiac failure). Hospitalization rates from influenza vary with season and age group. 

Estimates from 2003-04 through 2007-2008 in children less than <6 months of age were 9 to 30 

per 10,000/year, in children 6-23 months 3 to 11 per 10,000/year, and in children 2-4 years 1 to 

4 per 10,000/year. For children <5 years, estimated direct costs were $40 to $160 million for 

hospitalizations and $60 to $270 million for emergency department visits. Mortality varies with 

season, with the highest mortality in the youngest children. In the 2003-2004 season mortality 

in children < 6 months was 0.88 per 100,000/year, in children 6-11 months 0.59 per 

100,000/year, in children 1 year of age 0.77 per 100,000/year, and in children 2 years of age 

0.35 per 100,000/year [Dawood F et al. J Pediatr 2010; 157(5):808-14; Fairbrother G et al. 

Vaccine 2010;28(31):4913-4919; Bhat et al. N Engl J Med 2005;353:2559-2567].

Regarding influenza-associated pediatric deaths by week of death from 2007-2008 through 

2010-2011, for the week ending June 11, 2011 FluView showed that influenza mortality like 

influenza disease follows a seasonal pattern as would be expected. Therefore, seasonality is 

critical in terms of a vaccination policy. 

An association of febrile seizure with influenza, particularly Influenza A, has been noted. Chung 

et al (Hong Kong) found that influenza A was associated with 17.6% of 923 hospitalized febrile 

seizures over 5 years. Chiu et al (Hong Kong) showed that in 1997 and 1998, influenza A 

accounted for 10.8% and 21.7% of febrile seizure admissions, respectively (35% and 44% 

during periods of peak flu activity). Kwong et al (Hong Kong) found that 19.5% of children 

admitted with influenza A developed febrile seizures. Van Zeijl et al (Netherlands) noted a 

positive seasonal correlation between peak influenza activity and febrile seizure presentation. 

In a retrospective cohort study of children hospitalized with lab-confirmed influenza (LCI) during 

4 seasons (2000-2004), Newland et al (Philadelphia) found that of 435 patients 6 months 

through 4 years of age, 27 (6.2%) had seizures meeting definition of simple febrile seizure [Chiu 

SS et al. Pediatrics 2001;108:1-7; Kwong KL et al. Pediatr Neurol 2006;35:395-399; Chung B et 

al. Arch Dis Child 2007;92:589-593; Van Zeijl et al. J Pediatr 2004;145:800-805; Newland J et 

al. J Pediatr 2007;150(3):306-310].

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2010-2011 ACIP recommendations for influenza vaccination for children aged ≥6 months are as 

follows [MMWR 2010;59:1-62]: 

 Annual vaccination recommended for all persons ≥6 months 

 For children 6 months through 8 years receiving seasonal influenza vaccine for the first time, 

two doses are required to ensure adequate immune response

 Doses must be administered a minimum of 4 weeks apart

 Schedule determined to some extent by time of year (vaccine becomes available 

approximately in September)

 Optimal protection afforded by administration of both doses early in season

In terms of the US burden of pneumococcal disease following introduction of 7-valent 

pneumococcal conjugate vaccine, data from a national ambulatory medical care survey showed 

a drastic reduction in invasive pneumococcal disease. Even at this point, in all age groups there 

were still 4 million illness episodes. There were 445,000 hospitalizations for communityacquired pneumonia, with >90% of these hospitalizations occurring among persons >5 years 

old, and there were 22,000 deaths. The annual direct costs totaled $3.7 billion and totaled $7.7 

billion including indirect costs. In children less than 5 years of age there were 1,050,000 illness 

episodes, a total of 1,132,000 antibiotic courses, and 42,000 hospitalizations [Huang, Vaccine 

2011;29:3398-412]. This is relevant because protection of vaccine is relied on for herd 

immunity and reduction of disease in all age groups.

The 13-valent pneumococcal conjugate vaccine was introduced into the routine schedule in 

March 2010. This replaced PCV7, which was associated with prevention of 211,000 cases of 

invasive pneumococcal disease between 2000 and 2007 (Pilishvili JID 2010). The 13-valent 

vaccine was recommended for all children at 2, 4, 6, and 12-15 months. The relevance of a 

booster dose in the second year of life is that is confers additional individual protection over 

primary series, it is likely important for mucosal immunity (pneumonia, otitis), and it is 

considered important for reducing transmission to other age groups. Most developed country 

schedules include a booster dose, though some use only 2 doses (“2+1” schedule) in the first

year. 

Invasive pneumococcal disease is also seasonal. Data from that Active Bacterial Core (ABC) 

surveillance system from 1998-2008 showed that the percentage of cases is highest in the 

months of September through April, similar to influenza disease in some respects. Again, there 

will be somewhat of a window in which vaccination needs to be administered in order to target 

the vaccination for the prevention of disease. In terms of the importance of vaccinating various 

age groups, the highest incidence rate is in the age group 12 through 15 months of age (24 

cases per 100,000). To wait until 16 to 18 months would involve missing the peak incidence in 

the earlier age group [CDC, Active Bacterial Core surveillance, unpublished].

The WG realized that it was limited in the amount of safety data available, although safety data 

are continuing to be received on an on-going basis. The influenza vaccination season will arrive 

in September as well, and the WG is aware that something must be done about this in terms of 

having a message about the safety data. Thus, part of the working group’s task was to 

determine what type of data are available to warrant any kind of changes in the nature of the 

message. Data are available that assess the risk of febrile seizures with simultaneous 

vaccination, the amount of simultaneous vaccination with TIV and PCV, and the dose number

for the fourth dose of PCV13 (as opposed to 5th dose following a recent 4th dose after first 

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birthday) and for dose number 1 versus 2 of TIV. Data are needed regarding the risk of febrile 

seizures with simultaneous versus non-simultaneous vaccination, and for the context of 

simultaneous vaccination with other vaccines. 

Regarding the rate of simultaneous vaccination, National Immunization Survey data were 

assessed to get a sense of how often simultaneous vaccination occurs. Children age 12

through 23 months who were vaccinated in one influenza season (2008-2009 season) were 

included in the assessment. The number of children who received PCV and TIV simultaneously

totaled 471,296 that season. This is basically a population-based estimate of simultaneous 

vaccination rate using a 4 million birth cohort equaling 12%. With an attributable risk of 

(42/100,000) 198 febrile seizures might be expected in a typical season due to simultaneous 

vaccination. However, an important caveat is that the seasons are not typical. In the 2010-

2011 season, for example, there was a specific formulation of TIV and a mix of PCV7 and 

PCV13. It is difficult to draw long-term conclusions based on current data.

The number needed to vaccinate to prevent one hospitalization from influenza ranges from

1031 to 3050 at 50% vaccine efficacy in children 6 through 23 months of age [Lewis EN, Griffen 

MR, Szilagyi PG, et. Al. Pediatrics, 2007]. This is an important statistic from the perspective of 

trying to come up with some type of risk-benefit calculation of simultaneous vaccination. 

Interpretation of true efficacy can vary. The paper by Lewis et al addresses this. This raises the 

question: How much risk of influenza infection and invasive pneumococcal disease are we 

willing to take with delayed vaccination, in order to prevent the occurrence of febrile seizures?

In terms of the potential contribution of other vaccines, there was a past recommendation to 

select MMR + varicella instead of MMRV for the first dose in children 12 through 47 months

based on an attributable risk of febrile seizures of approximately 40/100,000. Current VSD data

suggest that other vaccines might have elevated risk as well. Chart-reviewed cases of febrile 

seizures suggest that simultaneous TIV and DTaP have risks comparable to TIV and PCV13 

(number of cases 17). DTaP is not even on the table for messaging due to lack of data.

There have been some attempts in the WG at consensus, and there were later attempts at 

consensus following the publication of the handouts. The working group WG feels that the 

issues regarding febrile seizure need to be addressed through messaging; however, this does 

not necessarily require an ACIP vote. The data are still pending, but some important 

information can still be placed in messaging, including a statement about the general risk of 

febrile seizures; information about the benefit of prevention of influenza / invasive 

pneumococcal disease (burden of disease); information for the provider regarding additional 

criteria which must be met to make the decision to give simultaneous vaccination or to defer

(e.g., children at risk for invasive disease; no family history of febrile seizures; if family history, 

consideration of antipyretics). There was fairly strong consensus among WG members that if a 

decision was going to be made to delay one of the doses, delaying of PCV13 is preferable. 

During the February 2010 ACIP meeting, revisions were made to the General 

Recommendations on Immunization stating that there is no evidence to suggest that antipyretics 

should be given prior to or during administering a dose of the vaccine. The question remains: 

Should antipyretics be given after vaccination before fever occurs? This has been discussed, 

and there are opinions on both sides of the issue. 

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Discussion Points

Dr. Keitel inquired as to what form the messaging would take and how it would be presented.

Dr. Kroger replied that a policy note is an option, although that would not have an ACIP 

recommendation behind it. The thinking is more along the lines of information for the website, 

and the content for this is being developed. There is also discussion about whether there are 

specific groups for which a delay might be permissible. Whether the Vaccine Information 

Statement (VIS) is being discussed in terms of whether this is a suitable medium for 

dissemination of this type of information. While used by providers, VIS information is intended 

for parents. There is a long turnaround time to revise a VIS. It can take months to make a 

revision to a VIS, which is a disadvantage because there is a short turnaround time for the 

upcoming influenza season. Given that the data are variable and it is unclear what to predict in 

various seasons based on the different formulations of vaccines and seasonality variance with 

respect to severity, it is unclear whether a long-term turnaround time for the VIS will be 

applicable for this influenza season. There is fairly solid certainty that information will be 

included in the website.

Regarding the association of influenza disease with febrile seizure, Dr. Cieslak asked whether 

there was a way to estimate the risk of febrile seizure following an actual episode of influenza. 

That would be one of the easiest ways to address relative risk. While hospitalizations were 

mentioned, a nice direct comparison of risk of febrile seizures would be an easier message.

Dr. Kroger responded that the data are limited to hospitalizations, but there are data that include 

risk of hospitalization for influenza and how many of those have had febrile seizures. 

Dr. Marcy requested further information regarding why the cohort is 12 to 23 months when most 

children receive their combination vaccine at 12 to 15 months.

Dr. Tokars clarified that Dr. Marcy was referring to the fact that the data are currently divided 

into three groups, one of which is 12 through 23 months of age. While the data could be divided 

into other groups, the question regards whether there is a clear reason for doing that versus 

what might be referred to as “epidemiologic gerrymandering” because there is a higher relative 

risk in one group. Certainly, the dose of PCV would be given during that timeframe. It is not 

clear whether the best way to analyze the data is to hyper-stratify it into smaller and smaller 

categories. Even if there was a higher relative risk on one category, possible due to small 

numbers, it is not clear how much credence this could be given. Rather than stratification, 

another approach is to use a regression analysis that does not cut things into small categories, 

which is how this was approached.

Dr. Chilton expressed concern about the possibility of recommending the use of acetaminophen 

to families with a history of febrile seizures, given that as Dr. Keyserling noted, acetaminophen 

is not successful in preventing febrile seizures and one study indicated that it could decrease 

response in patients simultaneous given a pneumococcal vaccine and acetaminophen. 

Dr. Kroger clarified that Dr. Chilton was referring to the study in The Lancet that discussed the 

effect of antipyretics on the pneumococcal vaccine. Those data were presented to ACIP prior to 

publication, and Dr. Kroger thought it was after the vote but prior to the publication of the 

general recommendations. His recollection of the discussion was that one of the challenges of 

interpreting that paper was interpreting the clinical relevance of the results with respect to 

pneumococcal conjugate vaccine. The wording was clarified in the general recommendation to 

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state that there is no evidence to support the use of antipyretics. That change was in part due 

to the fact that based on the data, antipyretics do not seem to prevent febrile seizures in those 

who have previously experienced a febrile seizure. More papers are anticipated to be published 

on the topic of antipyretics. Although he did not know the specific results, Dr. Kroger indicated 

that they are assessing immunogenicity and antipyretics and it seems to be tipping the other 

way from the results in the other article.

Dr. Baker reported that Dr. Pickering had shown her an article pertaining to the potential for 

overdose of acetaminophen, which raised an additional caution for this situation.

Dr. Sawyer expressed concern about focusing on an adverse event from a vaccine without 

focusing sufficiently on the benefit of the vaccine or the risks of not vaccinating. He called 

attention to the background materials provided to the ACIP membership that discusses why 

children fall behind on their vaccine schedule. The primary reason those 9 to15 months of age 

fall behind is failure to receive simultaneous vaccination when in their doctor’s office. They run 

the risk of contributing to this issue by suggesting that simultaneous vaccination might be 

problematic. Careful consideration must be given to the balance in communication and 

emphasizing the risk of not being vaccinated.

In terms of messaging, Dr. Baker inquired as to the plans of partner organizations with respect 

to separate communication efforts from or communication efforts in collaboration with CDC on 

this matter. 

Dr. Brady (AAP) replied that given the current information, it is reasonable not to make any 

major changes either in communication or otherwise since there is insufficient information to 

make a strong statement. If by some chance there is a change, AAP could utilize a number of 

methods to inform the pediatric community (e.g., blasts, briefs, on line, et cetera). He concurred 

that the worst course of action would be to send a message that would suggest that delaying 

vaccination is a better strategy than preventing disease. It is already difficult to ensure that 

children are vaccinated on time, and the risk of disease is worse than the risk of febrile seizure. 

Dr. Baker emphasized that the risk of disease is much greater than the risk of any adverse 

events based upon the data.

Dr. Campos-Outcalt (AAFP) concurred that any communications should address relative risks, 

putting the risk of febrile seizure in context with disease. 

Dr. Englund agreed and thought that for ACIP to recommend that providers discuss febrile 

seizures during a visit would be harmful to the process. If such a recommendation were to be 

made, it should be done on the day the child is born since the risk of febrile seizure is a 

common childhood event and the vast majority are not associated with vaccines. 

Dr. Temte thought much had been made about sometimes over-responding to signals. He 

acknowledged their wonderful colleagues at the VSD who are establishing a great deal of 

expertise in responding to potentially harmful signals. The question regards whether to couple 

the assessments of an exposure and the potential outcome with a concomitant evaluation of 

febrile seizures within the VSD in terms of harms versus benefits. Some of the discussion 

pertaining to influenza regarded the fact that influenza alone could cause febrile seizures. 

Perhaps immunization to prevent influenza could prevent febrile seizures. In retrospect, it is a 

wash or actually a benefit. 

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Dr. Judson agreed with the general sentiment that had been expressed, and thought the issue 

of antipyretics to be subsidiary. He thinks that it is important to distinguish between antiinflammatory and non-anti-inflammatory antipyretics, because there is a theoretical possibility 

that anything that reduces inflammation can also reduce the beneficial inflammatory immune 

response to the vaccine versus the acetaminophen. 

Dr. Duchin pointed out that as they got involved in the subject of long-term issues pertaining to 

febrile seizures and vaccines, it would be extremely beneficial to hear the results of studies on 

febrile seizures. CDC has several networks in place that would be appropriate to assess this 

type of problem. 

Dr. Jenkins noted that while she did not know the general procedure for development of 

informational materials involving lay audiences, she thought it was important to strike the right 

balance in terms of protection versus risk. She suggested that parents could offer beneficial 

feedback. 

Dr. Pickering thanked those in the Immunization Safety Office (ISO) for their hard work 

regarding this activity. This has been a phenomenal gathering of data. Regarding Dr. Tokar’s 

slide #11 titled “Characteristics of TIV Recipients with Chart Confirmed Febrile Seizures in the 

Risk Interval,” the table indicates that 5 children had URIs and 1 child had a UTI, which is 6 

children or 25%. He wondered what the consideration was for excluding children with these 

confounders from the analyses. Clearly, they could have fever due to the underlying medical 

condition, and exclusion could change the findings.

Dr. Tokars responded that these are children in the risk interval, so there could also be children 

in the control interval who have these diseases as well. In fact, these are the febrile seizures 

that would be due to URI and not vaccine. This would be referred to as non-differential 

misclassification, which would bias the results toward the null. It is possible that if these were 

excluded, there would be higher risk. One reason for not doing this is that there has been 

difficulty obtaining data on certain information regardless of whether a child had fever. If people 

continue to be excluded, there will be such a small set of data, the investigators will not be able 

to say anything about the issue. That is the trade-off.

Dr. Paridiso (Pfizer) pointed out that the group under consideration received TIV with or without 

PCV because those were the signals assessed. If 75% of the children also had DTaP and 90% 

had one other vaccine, it was not clear how those would be teased out. He suspected that if 

they considered TIV+DTaP and 75% of the children had DTaP, it would result in the same 

answer as TIV administered with other concomitant vaccines. He wondered how that would be 

taken into consideration with multiple vaccinations.

Dr. Tokars responded that the current data do not include children who received DTaP and not 

PCV13 or TIV. When those data are received, it may be possible to unravel some of this. 

However, if most of the children received all three vaccines simultaneously, it becomes an 

unanswerable question. They really cannot speculate beyond what the data show. Vaccines 

other than these three are down the list in terms of frequency, so it does not appear that they 

belong in the mix in terms of figuring out what is occurring. 

Dr. Duchin pointed out that in past years when children received TIV, DTaP, and PCV7, this risk 

was not observed. Circumstantial evidence has changed. In addition to the formulation of the 

influenza vaccination is the addition of PVC13. 

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Dr. Coyne-Beasley noted that in terms of crafting the messaging, there will be people who 

present with low-grade fever or children with no contraindications merely because the media 

influences them not to acquire the vaccine.

Dr. Tan (AMA) supported many of the statements regarding balancing of the message. He 

reminded everyone that this all began because of the reports of febrile seizure in Australia. He 

congratulated the VSD for its ability to respond and provide data, and for reassuring everyone 

that the US has a system that works.

Introduction

Mark Sawyer, MD

Chair, Hepatitis Working Group

Dr. Sawyer reported that the Hepatitis Working Group continues to discuss the issue of 

Hepatitis B vaccination in persons with diabetes, and wanted to determine whether the ACIP 

membership received adequate information to prepare them for a potential vote on this topic 

during the October 2011 meeting. 

The WG discussion in 2009 about this term of reference was initiated because of continuing 

outbreaks of hepatitis B among adults with diabetes. In recent years, these outbreaks have 

been identified among older adult residents of long-term care facilities, particularly assisted 

living facilities. Outbreaks were tied to lapses in infection control practice, primarily during 

assisted blood glucose monitoring. Lapses during other care practices also might contribute. 

Patient-to-patient transmission has been the major mode of transmission. A person with chronic 

hepatitis B infection is the source of the virus for others, through lapses in infection control. 

Residents of these facilities are usually older adults, and they suffer substantial morbidity and 

high fatality rates from acute hepatitis B. They also may have high rates of chronic infection, 

which contributes to a reservoir for further transmission. Outbreaks have continued, despite 

infection control guidance for long-term care facilities since 2005.

The WG has had extensive discussions covering a wide range of topics since 2009. 

Presentations have been given on this topic at 5 ACIP meetings, and to the Healthcare Infection 

Control Practices Advisory Committee (HICPAC). A number of CDC/FDA/CMS initiatives have 

been undertaken during this time to provide additional infection control guidance, to alert the 

patients and the public about these concerns, and to encourage development of improved 

diabetes care devices, and updated patient guidance has been posted on the CDC and 

American Diabetes Association (ADA) websites.

This session included updates on incidence of acute hepatitis B by diabetes status and age, 

economic analyses of a program for vaccinating adults with diabetes, and proposed 

recommendations from the Hepatitis Working Group.

Hepatitis B Vaccines

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Update of Hepatitis B Incidence Among Persons with Diabetes 

Meredith Reilly, MPH

Division of Viral Hepatitis

National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention 

Centers for Disease Control and Prevention

Ms. Reilly presented an update on the estimated incidence of acute hepatitis B among adults 

with and without diabetes. The updated analysis included additional diabetes data provided by 

the Emerging Infections Program (EIP) sites following the February ACIP meeting. Before 

presenting the updated estimates, Ms. Reilly briefly reviewed the methods used to estimate 

annual acute hepatitis B incidence. The numerator consisted of confirmed acute hepatitis B 

cases from four EIP sites in 2009 and 2010. Cases in persons less than 23 years were 

excluded because vaccination coverage is likely high among this age group. In the analysis 

presented in February, 31% of cases had unknown or missing diabetes status and these cases 

were excluded from that analysis. To address the cases with missing diabetes data, the EIP 

sites were asked to attempt to determine the diabetes status of these cases. Over the past 

several months, the analysis was updated with new data that resulted from the EIP sites’ efforts. 

The proportion of cases with unknown diabetes information decreased from 31% to 18% by 

early June 2011. As suggested by ACIP in February, the remaining cases with unknown 

diabetes status were classified as “persons without diabetes.” The denominator was 

determined using 2009 state based Behavioral Risk Factor Surveillance System (BRFSS) data 

along with the New York City (NYC) Community Health Survey for self-reported diabetes status 

among adults 23 years or older.

During 2009 to 2010, 331 reported acute hepatitis B cases aged 23 years or older were 

reported in the four EIP sites. Of these, 49 (14.8%) had a diabetes diagnosis, 282 (85.2%) of 

cases had either no documented diagnosis of diabetes or no diabetes information, 224 (67.7%) 

cases or 2/3 of these were documented as “no diabetes,” and there was no diabetes information 

for 58 cases (17.5%).

Data on the number and percent of acute hepatitis B cases by age group and diabetes status 

highlight differences in diabetes prevalence among acute hepatitis B cases between younger 

and older age groups. Of acute hepatitis B cases, 12.6% of those 23 to 59 years of age had 

been diagnosed with diabetes, and 26.4% of those aged 60 years and older had been 

diagnosed with diabetes. Comparing these figures to the general population across the four EIP 

sites, 5% of adults aged 23 to 59 years, and 18% of adults aged 60 years and older, had been 

diagnosed with diabetes. Overall, the EIP case report data indicated that approximately 15% of 

acute hepatitis B cases had been diagnosed with diabetes, higher than the 8% estimated 

diabetes prevalence among the general population of the four EIP sites.

The overall incidence of acute hepatitis B among adults with diabetes was 2.1 per 100,000 

compared with 1.1 per 100,000 for adults without diabetes. The rate ratio of 1.9 was statistically 

significant. For adults aged 23 through 59 years of age, the rate ratio comparing acute hepatitis 

B incidence among adults with diabetes to adults without diabetes was statistically significant at 

2.6. For adults aged 60 years and older, the rate ratio was 1.6, but was not statistically 

significant.

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To summarize, additional data on diabetes status resulted in higher incidence estimates and 

similar rate ratios compared with results presented to ACIP in February 2011. Updated 

estimates were included in the economic analysis to be presented during this session. Rate 

ratios of 2.6 for adults aged 23 through 59 years and 1.5 for adults aged 60 years and older 

were used in the model. Since then, additional data resulted in a slight increase in the rate ratio 

to 1.6 for adults aged 60 years and older. To strengthen the analysis, additional EIP sites have 

agreed to evaluate the diabetes status of their acute hepatitis B cases reported during 2009 and 

2010. Additional data are expected over the next few months.

Discussion Points

Dr. Keitel asked whether there was any additional information about other behavioral risk factors 

that could be associated with acquisition of acute hepatitis B.

Dr. Reilly responded that the investigators compared some of the reported risk factors that the 

sites collect routinely (e.g., two or more sex partners, MSM, sexual contact, IDU, household 

contact) by diabetes status and did not find any significant differences between the two groups. 

For most risk factors, the groups without diabetes had a slightly higher rate of reporting those 

risk factors.

Dr. Pickering inquired as to whether there were any data on the incidence or prevalence of 

hepatitis C between the two groups.

Dr. Reilly responded that for this study, hepatitis C was not assessed.

Dr. Cieslak noted that hepatitis C is usually asymptomatic and surveillance for it is abysmal. 

Cost-Effectiveness of Hepatitis B 

Vaccination Among Persons with Diabetes

Thomas J. Hoerger, PhD

Public Health Economics Program

RTI International

Dr. Hoerger indicated that the study question was relatively simple: What is the costeffectiveness of hepatitis B vaccination among adults aged 20 through 59 years with diabetes in 

the United States? The perspective taken for this study was to assess the direct medical costs 

(e.g., the cost of vaccination minus the costs averted by vaccination), and will also examine 

QALY adjusted life years gained. 

The main intervention strategy is the use of hepatitis B vaccine in adults aged 20 through 59 

with diagnosed diabetes, which potentially includes up to 8.4 million persons. The reason the 

study focused on those aged 20 through 59 is because there is evidence of declining vaccine 

efficacy, especially after age 60, and because the preliminary analyses showed that there are 

very high cost-effectiveness ratios at higher age groups. Also examined was the alternative 

strategy of vaccinating all adults age 20 year and older with diagnosed diabetes, which includes 

about 17.2 million persons. The difference between this and the main intervention is the 

addition of vaccinations for individuals 60 and older. The time frame for the intervention is one 

year, so it was assumed that everyone would take up the vaccine within a year. The analytic 

horizon to assess the saved medical costs and QALYs gained is the remaining life expectancy 

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of the target populations. As is recommended for cost-effectiveness studies, a 3% annual rate 

was used for discounting.

The analytic method was cost-utility analysis (CUA), which is a specific type of costeffectiveness study. Now it is becoming so common that CUAs and cost-effectiveness analysis 

are used almost interchangeably. What makes it a CUA is that the changes in QALYs are being 

assessed as the denominator in the incremental cost-utility ratios (ICURs): 

(vaccine cost + administration cost) – (cost of illness averted by vaccination)

_____________________________________________________________

Change in QALYs

The summary outcome measure is QALYs gained which accounts for patient utility in a health 

state and the number of years in the health state. Deaths are accounted for by assigning a 

utility value of zero in the years when the person is deceased. All costs are in year 2010 

dollars.

A decision tree is used in the analysis for acute infections. At the branch that says “susceptible” 

there is a probability of infection or no infection. Of acute infections, about 30% are 

symptomatic and 70% are asymptomatic. Of those who have symptomatic disease, about 38% 

are hospitalized and the rest are not. If they are not hospitalized, they do incur some costs for 

outpatient care but they recover. Among the hospitalized cases, about 4% are fulminant 

infections and some of those require liver transplants. Among those who do and do not receive 

liver transplants, there is a possibility of death. For asymptomatic cases, about 6% will become 

chronic infections [Acute model structure and parameters based on Zhou et al..,2003 and Kim et 

al., 2006].

In terms of transitions after chronic infection, chronic hepatitis is important because it can lead 

to compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma (HCC), and liver 

transplantations and death. Probabilities are included in the model for all of these 

complications. This model is run to calculate how many people have these various 

complications [Chronic model structure and parameters based on Zhou et al., 2003 and Kim et 

al., 2006].

One of the key factors in this analysis is the incidence among adults with diabetes by age group. 

One of the primary factors is that account is taken of the hepatitis B incidence ratio among 

persons with diabetes versus those without diabetes. EIP sites’ hepatitis B incidence ratio for 

diabetes was 2.6 until age 60 at which time it is 1.5. The calculated incidence per 100,000 

diabetes increases until around age 35 to 39 and then begins to decline based on these 

numbers from the surveillance. It is also important to account in the analysis for the fact that 

those cases are only coming from individuals who are susceptible, so also taken into account is 

the fact that some people already have been naturally infected with hepatitis B infection and 

some individuals have already been vaccinated.

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For the incidence among susceptible adults with diabetes, existing vaccine coverage is taken 

into account and is relatively high for younger age groups and declines as individuals become 

older. Also taken into account is the prevalence of previous HBV infection based on individuals 

who have diabetes. Again, the incidence rates are higher among the relatively younger age 

groups. Vaccination program inputs include 10% coverage with a 3-dose series, a private 

vaccine price per dose of $52.50, a CDC vaccine price per dose of $28.00, administration costs 

per dose of $14.42, lifetime direction of protection, and no adverse events since the vaccine is 

generally considered to be very safe. The uptake rate of 10% is based on indirect evidence 

about what might occur if there is a recommendation that these groups be vaccinated; there are 

three pieces of indirect information. One of these is the difference in vaccination rates between 

people who are currently recommended for vaccination and those who are not currently 

recommended to receive vaccination. A second piece is estimates from manufacturers of the 

increase in demand that would occur if people with diabetes were recommended for care, and 

the third is based on the uptake rate for DTaP vaccination. The analysis can be viewed as a 

one-time catch-up program with all susceptible adults with diagnosed diabetes offered 

vaccination and a 10% take-up rate. Vaccine efficacy estimates are based on a CDC review of 

vaccine efficacy studies in adults and persons with diabetes. There is certainly evidence from 

this review that efficacy rates fall as age rises, especially after age 65. 

The cost inputs for the various complications include the following:

Variable Cost

Outpatient costs for symptomatic $402 

Hospitalization for non-fulminant $12,034 

Hospitalization for fulminant $19,481 

Chronic hepatitis $1,824 

Inactive carrier $402 

Compensated cirrhosis $7,402 

Decompensated cirrhosis $46,864 

Hepatocellular carcinoma (HCC) $40,334 

Liver transplantation (1st yr) $378,229 

Liver transplantation (subsequent yr) $36,725 

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The Health Utility Index is based on a product of baseline value for persons with diabetes and 

utilities for hepatitis states and is as follows:

Susceptible / Immune 0.75

Inactive carrier 0.74

Chronic hepatitis 0.71

Compensated cirrhosis 0.62

Decompensated cirrhosis 0.41

HCC 0.37

Liver transplantation 0.65

Another assumption made is that there is no cost for visits incurred either by patients or 

physicians because these vaccination will be administered during visits for diabetes-related 

care. There are relatively frequent visits for persons with diabetes, so vaccinations can simply 

be added on to those visits. Also incorporated in the model are background diabetes mortality 

rates [Kim et al., 2006]. The relative risk of death for persons with diabetes is approximately 2 

for most age groups [Geiss et al., 1995; Gregg et al., 2007; 2011 Diabetes Fact Sheet], but it is 

lower for age groups 75 and older [McBean et al., 2004]. This may be important because many 

deaths occur in these age groups. In terms of one-way sensitivity analyses, low and high 

clinically relevant values based on the literature are used. For probabilistic sensitivity analyses, 

input values are drawn from all distributions simultaneously, 1000 draws are run, and 95% 

credible intervals are calculated. 

In terms of the results, the main analysis focuses on vaccinating persons aged 20 through 59, 

but also assessed are cases prevented by vaccinating those 60 and older. For example, 

vaccinating 10% of persons 20 through 59 years will prevent 5071 acute infections over the 

course of these persons’ remaining lifetimes. Of these, about 1521 would be symptomatic, 

leading to prevention of 555 hospitalizations, 23 fulminant cases, 9 transplants, and 16 

fulminant deaths. Given that about 6% of acute cases lead to chronic infection, about 304 

chronic cases will be prevented and corresponding complications including 175 cases of 

cirrhosis, 67 cases of decompensated cirrhosis, 40 HCCs, 6 transplants, and 141 deaths. For 

the age group 60 and above, the numbers are much lower.

Turning to cost utility results with a 10% take-up rate, the results for the main intervention 

include $110,172,395 in program costs; $22,681,172 in medical costs saved; $87,491,223 in net 

cost; 1,489 discounted QALYs saved; and a cost per QALY of $58,762. The results do mask 

differences between different age groups. The cost per QALY is about $6,000 for the youngest 

age group of 20-29; it is about $57,000 per QALY for 40 to 49; and $249,000 per QALY for 50 to 

59 years. As noted, the main analysis focuses on the 20 to 59 age groups, but the older age 

groups are shown to illustrate that the cost-effectiveness ratio really increase in those groups. 

There are three major factors that drive the result that cost-utility ratios rise with age, including 

fewer years at risk because life expectancy is shorter, lower hepatitis incidence risk after ages 

35-39, and declining vaccine efficacy. Regarding the cost utility of vaccinating those individuals 

older than 60, for the entire population of 20 and older, the cost-utility ratio is $159,633 per 

QALY. In just the oldest age group, this goes up much higher to over $2 million per QALY. 

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The following diagram shows the sensitivity analysis. Some related variables are grouped in the 

diagram, with all variables in the group set to their low values and then to their high values. 

Effects of individual inputs from the group are generally very small. Ordering in parentheses 

indicates which value of the input parameter leads to a lower cost-utility ratio and which value 

leads to a higher cost-utility ratio. For example, high complication cost values lead to lower 

cost-utility ratios and low complication cost values lead to higher cost-utility ratios. For the 

discount rate, zero percent leads to the low value and 5% leads to high value. In the case of the 

hepatitis B incidence ratio for diabetes, it is the high value which is from the 95% confidence 

interval of 4.3:

To understand how sensitive the results are, low and high clinically relevant parameters are 

included. In many of these cases, for example in the case of complication costs, all of the low 

values and all of the high values were grouped together to come up with this calculation. 

Again, for the probabilistic sensitivity analysis, input parameters were drawn from appropriate 

distributions and the model was run 1000 times. The 95% percent credible interval is based on 

the 2.5 and 97.5 percentile values for each output variable. Note that the median, 2.5 

percentile, and 97.5 percentile results for different variables may not come from the same model 

run (e.g., the 2.5 percentile value for QALYs saved may come from a different model run than 

the 2.5 percentile cost per QALY saved). Especially important is the cost per QALY ($56,681) 

for which the probable interval rises from $18,442 to $129,082 per QALY. As in most studies, 

there is uncertainty of the cost-utility ratio.

A number of other analyses were also done. One of these assessed the base case for age 20

through 59 years using the lower CDC price ($28 per dose) rather than the higher private 

patient price ($52.50 per dose). This led to a lower cost per QALY of $31,000. Unfortunately, 

the percentage of adults who received hepatitis B vaccine at the CDC price is unknown. The 

impact of take-up rate on costs, QALYs, and ICUR was assessed for ages 20–59 at the private 

price. This showed that QALYs gained also rise proportionately with uptake-up rate. As 

uptake-up rate increases, the cost of the program increases, but the ICUR remains the same 

because net costs (the numerator in the ICUR) and QALYs gained (the denominator) increase 

proportionately. In addition, a qualitative analysis was done of the overlap with current 

recommendations. Some adults aged 20–59 with diabetes are already recommended for 

vaccination. Of these, 15% have chronic liver disease, severe kidney disease, or high-risk 

behavior for infection. This rises to 24% if health-care personnel are also included. The impact 

on cost-utility ratios is uncertain. However, if all persons with diabetes have same incidence 

and same complication rates cost-utility ratios do not change. Because vaccination rates are 

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moderately higher in recommended groups, program costs and QALYs gained could decline by 

less than 24% if these groups are excluded from the analysis.

The main analysis focuses on vaccinating persons with previously diagnosed diabetes. Another 

analysis projected the cost of vaccinating persons diagnosed with diabetes in the future. This 

projection requires a number of strong assumptions: (a) age-specific incidence and prevalence 

rates for diabetes will remain constant in future years; (b) 95% of persons younger than 20 will 

be vaccinated prior to entering the model; (c) the take-up rate will be 10% in the year that a 

person is diagnosed with diabetes, and no additional vaccination will occur after the year when 

diagnosis occurs. Key insights from these analyses are that program costs for vaccinating 10% 

of incident diagnosed diabetes cases are considerably lower than the one-time, catch-up costs 

of vaccinating 10% of prevalent diabetes cases in the main analysis. This occurs because there 

are more prevalent cases than incident cases (8.4 million prevalent cases aged 20-59 vs. 1.2 

million incident cases). This accounts for the largest share of the difference. Also, incident 

cases tend to be younger than prevalent cases, and thus are more likely to have been 

previously vaccinated. In addition, annual undiscounted program costs are likely to fall in future 

years as younger cohorts with higher previous vaccination rates age upwards. The cost-utility 

ratios for individual age groups are the same in this analysis as in the main analysis. Thus, 

program costs fall in later years because younger cohorts have high rates of previous 

vaccination. Cost-utility ratios for individual age groups do not change.

There are limitations and possible impacts on incremental ICURs. The analysis is necessarily 

based on simulation model. Some inputs are uncertain. For example, incidence of hepatitis B 

may be underrepresented (ICURs ↓), and incidence ratio estimate assumed that cases with 

unknown diabetes status did not have diabetes (ICURs ↓). Costs do not include public health 

costs for outbreak control (ICURs ↓). Benefits from reduced transmission or herd immunity are 

not included (ICURs ↓). The analysis assumes that vaccinations will be provided during 

regularly scheduled visits for diabetes care (ICURs ↑). The main analysis does not account for 

lower vaccine cost (CDC price) for immunizations in public sector (ICURs ↓).

In summary, adults with diabetes have higher hepatitis B incidence rates than adults without 

diabetes. Vaccination provides protection, but efficacy declines with age. The cost-utility ratio 

for vaccinating adults with diabetes ages 20 through 59 years is $58,762 per QALY, which is the 

private price. The cost-utility ratio rises with age. Take-up rate affects program costs and 

QALYs gained, but does not affect the cost-utility ratio.

Discussion Points

Regarding the assumptions made on the costs, Dr. Keitel requested additional information 

about screening for susceptibility before vaccination, diagnosis of acute hepatitis, testing for 

response to vaccination, and on-going screening for HCC and people with chronic hepatitis, 

liver biopsy for consideration of treatment, and treatment of chronic hepatitis. 

Dr. Hoerger replied that almost all of those variables were assessed either in the sensitivity 

analyses or the costs in the main analysis. The one cost he heard that was not included was 

testing for susceptibility for hepatitis before vaccination. One sensitivity analysis assessed 

revaccination for adults, especially in the age group 60 through 69, after vaccination. That had 

a very small effect on the QALYs gained and had a very high cost-utility ratio. 

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Regarding the incidence of diabetes, Dr. Duchin thought he heard Dr. Hoerger say that a 

potential increase in the incidence of diabetes in the future. He wondered whether that was 

because it was believed that the population who would age and get diabetes is also the 

population that has been immunized. 

Dr. Hoerger responded that this was a question of simplicity in not trying to load up the analyses 

with somewhat difficult to determine trends in incidence. If he had to bet, he would say that the 

incidence is going to rise given recent trends in diabetes.

Dr. Duchin’s understanding is that diabetes incidence is increasing, and he wondered whether 

that would significantly change the results of the analysis.

Dr. Hoerger replied that it would increase the cost of the program, but it would also increase the 

benefits of the program. Those two effects would cancel out in the cost-utility ratios. The cost 

per QALY gained is not going to be affected as much by the incidence of diabetes.

Regarding the realities of new programs and new costs in the current deficit environment, Dr. 

Judson pointed out that when something like this is attempted at the state level where programs 

are often level or trickling down and they cannot deficit spend, nothing is accomplished. When 

he went before the state legislature to try to sell a universal mandatory school entry 

immunization for hepatitis B, they required a fiscal note stating what it would cost, what it would 

accomplish, and who would pay for it. The sensitivity to vaccine costs are being dealt with all of 

the time with the new hepatitis B vaccine. When their state law was passed, he thought the cost 

of hepatitis B vaccine in 1994 was $8. At $28 dollars, things are clearly not moving in the right 

direction. Diabetes is a risk marker, not a risk factor. Probably the sole exception is in the longterm care areas where breaches in hospital infection control are occurring.

Ms. Ehresmann commented that as a member of the working group, one of the challenges they 

are struggling with the issue of cost-effectiveness is the dramatic change that occurs after 60 

years of age. While cost-utility is important, by the same token they do not want to suggest that 

those over 60 years of age are not worth the vaccine. 

Dr. Baker suggested that this is an issue that is more broad than hepatitis B immunization. 

Dr. Whitley-Williams (NMA) wondered whether the analyses took into account the prevention of 

secondary infections. While that may be more difficult to assess, it would drive up the benefit in 

terms of savings in medical costs.

Dr. Hoerger replied that the potential reduction of transmission or herd immunity effects were 

not taken into consideration. 

It was not clear to Dr. Plotkin in the sensitivity analysis whether the vaccine effectiveness 

variable was based on the upper likely limits of the effectiveness of the current vaccine, or 

whether consideration was given to the possibility (which is real) of newer vaccines that are 

more effective in the elderly. That is, does it take into account possible improvement?

Dr. Hoerger responded that the sensitivity analysis was based on the review that assessed 

existing vaccines, and does not take into account possible improvements.

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Next Steps: Proposed Recommendations

Dr. Trudy Murphy

National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention 

Centers for Disease Control and Prevention

Dr. Murphy reported that the ACIP Hepatitis Working Group, after reviewing an extensive body 

of information, has weighed infection control practice as the major strategy for prevention of 

hepatitis B and other bloodborne infections among adults with diabetes. While everyone would 

like to promote infection control, the WG concluded that infection control alone is probably not 

the solution to preventing most hepatitis B infections in this vulnerable population in the near 

future, particularly among younger people who have diabetes and may not be in an institution 

setting where there is oversight and control. Given this, the WG proposed two 

recommendations for vaccinating adults with diabetes for the full ACIP membership, taking into 

account the cost-effectiveness analysis.

To review, there are ACIP recommendation categories with the new GRADE system. A 

Category A recommendation applies to all persons in an age or risk group, and suggests 

wording such as “recommend,” “recommend against,” “should,” and “should not.” A Category B 

recommendation is one that encourages individual decision-making based on weighing 

desirable and undesirable effects. Suggested Category B wording includes words like “may 

vaccinate,” and “suggest against vaccination.” The working group has begun to frame the 

recommendation in this format, but had not completed the GRADE formatting before this 

meeting. Each of the two proposed recommendations would include Category A and B 

proposed wording. The following represents an overview of the two proposals:

In Option 1, hepatitis B vaccination is recommended for unvaccinated adults with diabetes who 

are <60 years of age (Category A). Individual clinical decision making is recommended for 

vaccination among unvaccinated adults with diabetes who are ≥60 years (Category B). In 

Option 2, hepatitis B vaccination is recommended for unvaccinated adults with diabetes 

(Category A). Individual decision-making (Category B) is recommended for vaccinating frail 

elderly adults with diabetes, and for post-vaccination testing, with revaccination for nonresponding adults with diabetes who are less likely to respond (e.g., those ≥ 60 years). The 

actual wording proposed by the working group is as follows:

Option 1: Category A

Recommend 

• Hepatitis B vaccination is recommended for unvaccinated adults with diabetes who are 

<60 years of age. The hepatitis B vaccination series can be safely given to persons of 

any age, but current hepatitis B vaccines are less efficacious and less cost-effective in 

older adults. Therefore, the hepatitis B vaccine series should be completed as soon as 

feasible after diabetes is diagnosed. 

Option 1: Category B

Recommend individual clinical decision making

• Decisions to vaccinate adults with diabetes who are ≥60 years of age should incorporate 

consideration of the particular adult’s likelihood of acquiring hepatitis B virus infection, 

including the risk posed by an anticipated need for assisted blood-glucose monitoring; 

the likelihood of experiencing chronic sequelae or other complications if infected; and the 

decline in immunologic response to hepatitis B vaccine with advancing age.

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Option 2: Category A

Recommend

• Hepatitis B vaccination is recommended for unvaccinated adults with diabetes. The 

hepatitis B vaccination series should be completed as soon as feasible after diagnosis 

since vaccine effectiveness declines with advancing age. 

Option 2: Category B

Recommend individual clinical decision making

• Providers are encouraged to use clinical judgment to determine the suitability of hepatitis 

B vaccination for frail elderly adults with diabetes.

Option 2: Category B

Recommend individual clinical decision making

• Revaccination with 3 additional doses of hepatitis B vaccine generally increases the 

proportion of non-responding adults who achieve a protective level of antibody to 

hepatitis B surface antigen (anti-HBs, ≥10mIU/mL). For adults in whom a reduced 

response to the initial series might be expected (e.g., adults ages ≥60 years, obesity), 

revaccination would be medically appropriate. If revaccination is planned when a 

protective level is not achieved, testing for anti-HBs is recommended 1-2 months after 

completion of the initial hepatitis B series.* 

*MMWR 2006;55 (RR-16):26-29 (Appendix A)

Each option might include additional guidance, such as the following:

Available data do not confirm an advantage to any specific hepatitis B vaccine, dosage 

or approved schedule for adults with diabetes. No additional hepatitis B vaccination is 

recommended for adults with diabetes who received a complete series of hepatitis B 

vaccine at any time in the past.

The majority preference of the working group is Option 1. The rationale is that Option 1 

recommends vaccination for age groups achieving the highest rates of protection, that is, up to 

age 60 years. An advantage of covering adults to age 60 years is that the recommendation 

includes 68% of adults with new diabetes diagnoses. By contrast, covering adults to age 50 

years, but not ages 50 through 59 years, would be more cost-effective, but would include less 

than 38% of adults with a new diabetes diagnoses. The working group felt that the increased 

cost for including ages 50 through 59 years could be justified by the larger proportion of adults 

with diabetes who could be protected. Option 1 was also favored by the working group 

because, although not encouraging vaccination at ages 60 and older, it does not place a barrier 

to vaccinating older adults, which might be a consideration in some situations (e.g., an 

outbreak). Option 1 is silent on revaccination for non-responders, which is done at high cost. 

The most important reason that WG members moved to favor Option 1 over Option 2 was the 

considerably lower cost of Option 1, approximately $58,000 per QALY saved.

A minority of the WG continued to favor Option 2 primarily because it protects more adults with 

diabetes. Option 2 is simple and it is consistent with other hepatitis B vaccine 

recommendations, which do not make distinctions by age for who should or should not be 

vaccinated. Option 2, while recommending vaccination of all adults with diabetes, encourages 

individual clinical decisions for vaccinating frail elderly adults, who generally have limited life 

expectancy and may have poor response to vaccination. It also discourages post-vaccination 

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serology except when revaccination of non-responding adults would be medically appropriate. 

Option 2 is associated with considerably higher cost at approximately $159,000 per QALY 

saved, and this estimate does not include post-vaccination serology or revaccination.

In conclusion, Dr. Murphy indicated that during the October 2011 ACIP meeting, anticipated 

topics on the matter of hepatitis B include additional incidence data; vaccine efficacy data from 

older adult residents in institutional (outbreak) settings; information on how a hepatitis B 

vaccination program for adults with diabetes might be implemented; and GRADE analysis of the 

strength of evidence for a proposed recommendation. She then invited input on the proposed 

recommendations. 

Discussion Points

Dr. Baker inquired about the WG’s plans in terms of the timing of a vote.

Dr. Murphy replied that the WG wants to ensure that the ACIP membership feels that they are 

ready for a vote. This could be done as early as October 2011. The GRADE analysis has 

already been completed.

Dr. Marcy did not understand including the decline in immunological response to hepatitis B 

vaccine with advancing age. There is one immunizer and one elderly person. It was not clear 

how that relationship would be influenced by a population observation, given that a provider will 

not know whether a person is in the 30% failure rather than 70% acceptance group.

Dr. Murphy responded that this is a very important question that the working group has spent a 

great deal of time discussing. Some members of the working group are involved in nursing 

home administration and geriatrics. They informed the working group that they find it difficult to 

acquire consent from older adults with dementia, and many LTC residents have a short life 

expectancy. Some of the wording proposed has been provided by those working group 

members. An attempt has been made to try to identify the key factors that would result in 

favoring vaccination or not.

Dr. Marcy did not feel that the proposed wording did this. It offers an excuse not to give the 

vaccine if a provider wants to save money. He was very concerned about including this.

Dr. Murphy pointed out that this was part of the rationale behind the Option 2 approach. She 

invited other input about how this might be addressed.

Dr. Cieslak clarified that the cost of the vaccine does not vary by age or anything else. It is 

three doses at $58.50 per dose plus some administration fees. Based on the cost-utility 

analysis and the prices reach millions of dollars per QALY saved, the reason is that at some 

point, it is very unlikely that some people will benefit from the vaccine because of lesser risk of 

being exposed to the virus during remaining years of life, risk of progressing to chronic disease, 

and to a lesser degree, lesser chance of responding to the vaccine.

Dr. Marcy emphasized that he was talking about one individual with a needle and one person 

with a deltoid—not a population.

Dr. Cieslak stressed that everything done in medicine is based on assessing risk across 

populations.

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Dr. Duchin suggested that there was some language that could bring some clarity to the intent; 

that is, age is not the only indicator of physiological robustness. Clinicians need to consider the 

likelihood that the patient would respond to the vaccine as one factor in making a decision. He 

said he liked Option 1, but it was not clear why it did not include language about the 

consideration for post-vaccination testing in that option as well. Age is not the only factor that 

should determine the type of counsel given in the recommendation.

Dr. Murphy replied that the major reason it was not included in Option 1 was the cost of testing 

plus revaccinating those persons who do not respond. This would be a complete second series.

Dr. Duchin clarified that he was not suggesting that testing be recommended, but that advice be 

given about when testing would be appropriate post-vaccination. For instance, even patients 

under the age of 60 can have conditions for which post-vaccination testing might be indicated. 

Dr. Meissner inquired as to whether there are data regarding the ability of individuals over 60 to 

respond to a second series of hepatitis B vaccine.

Dr. Murphy replied that there are limited data, which suggest that individuals over 60 do respond 

and that overall response may be as high as 80% with three additional doses. However, the 

data are so limited that it is difficult to have great confidence in them.

To avoid problems that have been observed with respect to insurance coverage regarding 

recommendations that say “may,” Dr. Doskey (AHIP) recommended that the working group 

should use more definitive language in the recommendation that is put before the full ACIP 

membership for a vote.

Dr. Baker said she thought that not only insurance companies, but also physicians have 

problems interpreting the word “may.” 

Dr. Schaffner (NFID) observed that it is recognized that immunizing adults is more elaborate 

than immunizing children in many ways, and offers more challenges. One of the challenges is 

that ACIP’s recommendations for adults are too complicated to remember and implement. He 

strongly endorsed simplicity. If they want diabetics to be immunized, then ACIP should 

recommend immunizing and should not include a lot of qualifications around that 

recommendation. Doctors’ decisions in these types of circumstances are difficult, and if they 

are worrying about which patients might get hepatitis B, they are going to think about sex and 

drugs. They are not going to think about the issues that brought this to ACIP’s attention. He 

found it a particular paradox that older patients, especially those who are cared for in nursing 

homes or other facilities—the very group that brought this to ACIP’s attention—is now not being 

recommended for vaccination.

Regarding Option 1, Dr. Schmader (AGS) pointed out that providers, particularly those in the 

nursing home setting and assisted care facilities, are going to need a lot more education about 

what the risks are and who should or should not receive the vaccine. It would be simpler to 

state that persons in nursing homes with diabetes should receive the vaccine. Regarding 

Option 2 and the use of the term “frail elders,” the definition of “frail” is highly debated in the 

geriatrics literature and that alone would suggest removal of that term. The somewhat accepted 

term for frailty is “geriatric syndrome,” which is characterized by fatigue, easy exhaustion, 

muscle weakness, low muscle mass and physical inactivity. Many individuals in nursing homes 

are not frail. They do not meet that definition and still might benefit from the vaccine. His 

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suggestion was to remove the word “frail” and include language that would address the concept, 

which he was happy to discuss off line. 

Dr. Fryhofer (ACP) indicated that they care for the majority of individuals who would be 

excluded if only those under 60 are vaccinated. She agreed that this must be kept simple. 

Everyone knows what diabetes is, and if it is too complicated, the goal will not be accomplished. 

Americans are living longer, though not necessarily living better. That means as people grow 

older, increasingly more Americans are likely to end up in a nursing home situation unable to 

control excretions; therefore, possibly putting more people at risk if someone is hepatitis B 

positive. Increasingly more people are going to develop diabetes.

Dr. Baker pointed out that there are many people in their 80s and 90s who are functionally like 

her 60-year old grandmother was who was less functional because of her cardiac disease.

Dr. Duchin raised the issue that when ACIP makes a recommendation, even in the context of 

children, the recommendation is usually made for an age cohort with the understanding that that 

cohort will be protected into the future. In the context of hepatitis B and using a cutoff of 60 

years of age, he did not think the intent was that adults would not be protected when they reach 

nursing home age. The cohort will age up and successive cohorts will be protected. The 

question regards whether to immunize everyone immediately. For instance, when an age frame 

is chosen with respect to childhood vaccinations, there is always some discussion about catchup and whether that is cost-effective.

Dr. Marcy said he thought pediatricians’ goal was to immunize as many of their cohort as 

possible. The goal of the nursing homes, which are not all “Hyatt Hotels,” is to save as much 

money as possible. If nursing homes can find an excuse not to immunize, they will use that 

excuse. 

Dr. Duchin emphasized that vaccination should begin younger so that as people age into the 

nursing home, they are already protected. 

Dr. Moore (AIM) supported Option 2 and endorsed simplicity, with the caveat that the individual 

providers consider the vulnerability of the patient. Programmatically, AIM runs into tremendous 

difficulty trying to help adult healthcare providers implement recommendations. In addition, one 

third of people develop diabetes after the age of 60. It is incorrect to think that everyone is 

aging into the over 60 population protected.

Dr. Baker also said she liked Option 2 for its simplicity.

Dr. Temte wondered for those over the age of 65 who qualify for Medicare whether this would 

be a Part D or Part B vaccination. 

Dr. Linda Murphy (CMS) replied that she did not have information on Medicare because she 

works strictly with Medicaid. However, she requested that someone email her the question and 

she would follow-up.

Dr. Chilton pointed out that several years ago in deciding whether he should sign up for longterm care insurance, he determined that information appears to show that his likelihood of being 

in long-term care for very long is low. This supports Option 1 in that those in nursing home care 

are unlikely to be there long, and if they are infected with hepatitis B, they are unlikely to have 

clinical manifestations of that.

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Dr. Murphy indicated that the figures differ somewhat for nursing homes and for assisted living 

facilities where people do have a longer longevity. She did not know whether long-term 

insurance covers assisted living in terms of longevity of stay. Most of the outbreaks that have 

occurred in the last five years have been in assisted living facilities, which have the least 

regulation. 

Dr. Cieslak did not believe the WG had any data at all for the population that led to the 

discussion in the first place on either the incidence of hepatitis B among diabetics in long-term 

care, or efficacy of the vaccine among diabetics in long-term care. 

Dr. Baker inquired as to whether any studies were planned that would address Dr. Cieslak’s 

comments.

Dr. Murphy replied that a limited amount of data would be presented during the October 2011 

ACIP meeting regarding long-term care vaccine efficacy among residents in outbreak settings. 

Based on the provisional data she has reviewed thus far, it aligns with current estimates. She 

knew of no plans to try to determine incidence in these facilities.

Introduction

S. Michael Marcy, MD

Chair, Pneumococcal Vaccines Work Group

Dr. Marcy reminded everyone that the 13-valent pneumococcal conjugate vaccine (PCV13) is 

proposed to be used for prevention of pneumococcal disease (including pneumonia and 

invasive disease) in adults ≥50 years of age, specifically prevention of disease caused by S. 

pneumoniae 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F. Accelerated approval was 

applied for in December 2010, with a decision anticipated in October 2011. Licensure is to be 

based on demonstration of non-inferiority of opsonophagocytic assay (OPA) response to PCV13 

versus currently licensed 23-valent pneumococcal polysaccharide vaccine (PPSV23).

The Pneumococcal Vaccines Working Group’s terms of reference are to:

 Review data on immunogenicity, safety, efficacy, and cost-effectiveness of pneumococcal 

vaccines in adults

 Determine whether available data for adult PCV13 immunogenicity and cost-effectiveness 

are sufficient to determine value of vaccination of adults

 Develop a revised statement for use of pneumococcal vaccines if it is determined that a new 

policy statement including adult PCV13 recommendations is needed; however, policy 

options for use of PCV13 among adults were not presented during this meeting

13-Valent Pneumococcal Conjugate Vaccine (PVC13)

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Evidence reviewed to date includes immunogenicity and safety results from Pfizer’s Phase III 

studies, and cost-effectiveness and public health impact of different adult pneumococcal 

vaccination strategies. Evidence to be reviewed during upcoming calls includes updated 

PCV13 immunogenicity and safety data, and new data on PCV13 immunization for high-risk 

adults. Evidence that will not be available to ACIP prior to the anticipated licensure includes 

efficacy of PCV13 against invasive disease, pneumococcal pneumonia, and all-cause 

pneumonia (Netherlands, results 2012), and indirect effects among adults of PCV13 use in 

children.

During this session, presentations were delivered on the public health and economic impact of 

routine PCV13 vaccination of adults ≥50 years of age, an update on the epidemiology of 

pneumococcal disease among adults in the US, and considerations for 13-valent pneumococcal 

conjugate vaccine use among adults.

Public Health and Economic Impact of PCV13 in US Adults ≥50 Years of Age

David Strutton, PhD, MPH

Pfizer, Inc.

Dr. Strutton reported on the public health and economic impact that Pfizer has estimated for 

Prevnar 13® in adults over the age of 50. Prevnar 13® is the same product currently used in 

pediatric population (Prevnar®) which was launched approximately 10 to 11 years ago in the US 

and has had a tremendous impact on public health. Prevnar 13® covers 6 additional 

pneumococcal serotypes. The analysis presented takes into account impact of Prevnar®. The 

23-valent polysaccharide vaccine (PSV23) is currently recommended for all adults older than 65 

years of age. About two-thirds of that population has been vaccinated. It is also recommended 

for adults 18 to 64 years of age at high risk for pneumococcal disease, about a third of whom 

have been vaccinated. This analysis focuses on an age-based recommendation for all 

individuals 50 years of age and above. The idea is that Prevnar 13® could be recommended for 

all adults older than 50 years of age regardless of previous history of vaccination with 

pneumococcal polysaccharide vaccine. 

The study question addressed was the expected public health and economic impact of PCV13 

use in US adults age ≥50 years. This was evaluated using a microsimulation model depicting 

risks and costs of invasive pneumococcal disease (IPD) and all-cause non-bacteremic 

pneumonia (NBP). Clinical outcomes and economic costs were evaluated over a lifetime in US 

adults age ≥50 years under two alternative vaccination strategies: 1) Use of PCV13 in all adults 

age ≥50 years at model entry, and no subsequent revaccination compared to the current 

recommendation for the polysaccharide vaccine. Revaccination scenarios with Prevnar 13® at 

5 or 10 year increments were also examined; and 2) Use of PPSV23 per current ACIP 

recommendations. Alternative strategies for use of PCV13 and PPSV23, as well as a strategy 

of no routine vaccination, also were considered.

The clinical outcomes and economic costs were projected over a specified period of interest for 

alternative vaccination strategies and included expected total cases of IPD and non-bacteremic 

pneumonia (NBP), total life years, total deaths due to IPD and NBP, total medical care costs for 

IPD and NBP, total value of morbidity / mortality-related work loss, and total costs of 

vaccination. In terms of the inputs for the model, baseline rates of IPD were based on 2006 

Active Bacterial Core surveillance (ABCs) data (Pfizer Inc., data on file). Serotype coverage for 

PPSV23 (67%) and PCV13 (45%) were based on 2008 ABCs data. Baseline rates were 

adjusted to account for the potential indirect effects that Prevnar 13® would have on the 

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pediatric program. This was done in a manner consistent with the model for the pediatric 

program. Serotype-specific changes for 6 serotypes unique to Prevnar 13® were assumed to 

be same as for Prevnar ® serotypes. For NBP data from the literature were used for rates of 

all-cause inpatient NBP based on “confirmed” all-cause hospitalized (non-bacteremic) CAP 

cases. Rates of all-cause outpatient NBP were based on “presumptive” all-cause ambulatory 

CAP cases from the literature. Again, rates were adjusted to account for the potential indirect 

effects of Prevnar 13® pediatric program would have on the rates of both hospitalized and outpatient pneumonia. This was also done in a consistent framework, as was done with the 

PCV13 pediatric program evaluation for ACIP a couple of years ago. 

In terms of effectiveness for invasive pneumococcal disease and pneumonia for the two 

different vaccines under evaluation, for all data points, data from the literature, input from a 

series of advisory boards conducted over the past two years, and expert opinion generated from 

those advisory boards were utilized. For the polysaccharide vaccine, effectiveness against 

invasive pneumococcal disease would be highest in the youngest, healthiest group in this 

population. Vaccine effectiveness wanes by time since vaccine receipt, with increasing age, 

and by risk status.

Vaccine effectiveness data against invasive pneumococcal disease for the conjugate vaccine 

were primarily based on the PCV7 data in pediatric population. The estimates were used from 

the clinical trial for Prevnar® and they were adjusted for age, time since vaccine receipt, and 

risk group using a similar framework as was used for the polysaccharide vaccine. In terms of 

the decline with time since vaccine receipt, the rate was assumed to be 50% from what was 

used for the polysaccharide vaccine. It was also assumed that subsequent doses of the 

conjugate vaccine would be as effective as the first dose after accounting for the time that has 

passed and any risk changes incurred since the initial vaccination. 

Estimates for the immunocompromised patients in the adult population, data were derived from 

the pediatric program from an analysis of the impact of Prevnar® on HIV positive and HIV 

negative patients. Vaccine effectiveness was assumed at 91% for the youngest, healthiest 

cohort in this model. That wanes over time and by age of risk. Based on a study conducted in 

HIV positive patients in Malawi, 71% effectiveness was used in the youngest age group that is 

high risk (50-64/High-Risk). The data available are based on this study which showed a 74% 

efficacy against vaccine type invasive disease with Prevnar® in HIV positive people [French. N 

Engl J Med 2010;362:812-22]. This corroborates the estimates used in the model.

For the polysaccharide vaccine, data were used from the literature on potential effectiveness 

against pneumonia. All studies that had some level of blinding showed that the polysaccharide 

vaccine does not work on pneumonia. This assumption is consistent with the model that was 

presented in February 2011 by Drs. Smith and Zimmerman. For the conjugate vaccine, data 

were again used from the pediatric program and those were adjusted by age, time, and risk in a 

similar fashion as was done for invasive pneumococcal disease. For hospitalized pneumonia, 

effectiveness estimates were started at 25% and were waned over time, age, and risk. Based 

on the same study from French, the point estimate of effectiveness against all-cause pneumonia 

in the 50-64/Low-Moderate Risk group is 25%. This suggests that the methodology is 

reasonable and corroborates the approach used. 

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The pneumonia effectiveness estimates are critical in this model, and this is a point that drives 

the difference between the two vaccines. There are no clinical trial data from Prevnar 13® in 

adults on pneumonia yet, so the best data available were used. There are a number of ways 

this can be approached. The model presented in February 2011 by Drs. Smith and Zimmerman 

approached this by trying to estimate the percentage of pneumonia that is pneumococcal, the 

serotype coverage that would reflect the coverage for Prevnar 13® and an estimate of 

effectiveness. The model presented during this session by Dr. Strutton approached it in a 

different fashion by assessing the effectiveness level observed in the pediatric program and in 

immunocompromised adults to corroborate the levels of effectiveness being assumed. Since 

this is a critical component of the model and there is no certainty in the estimates used, a 

number of sensitivity analyses were conducted, including one in which the level of effectiveness 

was reduced by 50% as a starting point and everything was waned over time from there.

Key parameters used in the model included the following:

 Population demographics from 2007 US Census and 2006 NHIS [US Census Bureau. 

Available at: http://www.census.gov/population/www/projections/popproj.html [accessed July 

15, 2009; and National Center for Health Statistics. 2006 Health Interview Survey]

 Medical costs of invasive pneumococcal disease and inpatient pneumonia were from the 

2005 Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample (NIS)

[Agency for Healthcare Research and Quality. Available at: www.hcupus.ahrq.gov/nisoverview.jsp [accessed June 22, 2008].

 Medical costs of outpatient pneumonia were based on unpublished healthcare claims data 

and published case-finding algorithm for CAP [Colice. Chest 2004;125:2140-2145].

 Price per dose of PCV13 was assumed to be $108, and price per dose of PPSV23, $49 

[Redbook. Monvale, NJ: Medical Economics, Inc. July 2010].

 Vaccine administration cost was assumed to be $17 [RBRVS. Salt Lake City, UT: Ingenix 

Inc. 2009].

 Future life years and costs were discounted at 3% per year and were expressed in US 

dollars for 2009.

In terms of the cost of pneumonia, the investigators feel that these estimates are conservative. 

For inpatient pneumonia, they do not take into account the effect of re-hospitalization rate, 

which has been estimated to be 20% within a 30-day period. Also, in terms of work loss 

productivity, the estimates used are relatively conservative based on a new research project just 

completed and submitted to IDSA this year. From a societal perspective, these estimates are 

expected to be relatively conservative. 

To account for some of the uncertainties in the model development, a series of sensitivities 

analyses were conducted. The sensitivity of the expected net impact of PCV13 versus PPSV23 

to selected model changes was explored, each in turn. Effectiveness of PPSV23 was assumed 

to persist for a maximum of 5 years, and alternatively, for 1 year. Herd effects were assumed to 

be higher by 50% in each year of the modeling horizon. The effectiveness of PCV13 against allcause pneumonia was assumed to be higher by 20%, and alternatively, lower by 20% and 50%. 

The cost of vaccination was assumed to be higher by 10% of the cost of patient visits ($1.88, 

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based on reimbursement for 5-minute evaluation of established patient). The cost-neutral 

threshold of effectiveness of PCV13 against all-cause pneumonia was also examined.

With regard to the public health impact estimated that Prevnar 13® would have if transitioning 

from the current recommendation for the polysaccharide vaccine for those 50-64 years of age at 

high risk and everyone over ≥65 years to an age-based recommendation for Prevnar® for 

everyone 50 years of age and older in the US. This model estimates that there would be 

reductions approaching 19,000 cases of invasive pneumococcal disease; 840,000 cases of 

inpatient pneumonia; 650,000 cases of outpatient pneumonia; and about 74,000 untimely 

deaths over the remaining lifetime of the adult population 50 years of age and above. This is 

based on a one-time vaccination with Prevnar 13®. The economic consequences of that public 

health impact from a payer perspective, not taking into account lost productivity, absenteeism, 

or presenteeism, the model estimates that transitioning from the current polysaccharide 

recommendation to the Prevnar 13® recommendation would result in cost savings of $6.4 billion 

over the remainder of the lifetime of this adult population. If lost productivity is taken into 

account, the economic consequences would be savings of $11.7 billion dollars for this 

population. There is a lot of uncertainty in the model, so a probabilistic sensitivity analysis was 

run in which the simulation of the model was run 100 times. When this model was simulated 

over a range of estimates for the various inputs, 99 of 100 estimates ended up in the cost 

saving quadrant.

A couple of scenarios were run for potential revaccination programs, including an every 10-year 

revaccination program for Prevnar 13®, which would lead to a greater reduction in disease and 

a substantial reduction in untimely deaths, as well as additional cost savings. From a payer 

perspective, the cost savings would approach $10 billion. From a societal perspective, cost 

savings would approach $20 billion. When the revaccination program is adjusted down to 5 

years, the public health impact continues to rise. Under reasonable assumptions concerning 

vaccine effectiveness and cost, use of PCV13 in all adults age ≥50 years, in lieu of the current 

strategy for use of PPSV23, would yield fewer cases of disease and lower overall costs.

There are some limitations to the model. Perhaps the area of greatest uncertainty concerns 

assumed effectiveness of vaccination with PPSV23 and PCV13 against all-cause pneumonia. 

Estimates for PPSV23 are based on data from a modeling study that incorporated expert 

opinion and data from a case-control study, a meta-analysis of relevant trial data, and 

assumptions in other modeling exercises. Estimates for PCV13 were based on data from trials 

of PCV7 in children. Effectiveness of PCV13 was assumed to wane at 50% of rate for PPSV23. 

Another area of parameter uncertainty concerns clinical burden of all-cause pneumonia, as 

these estimates are based on published data from a single study in a single geographic area.

Discussion Points

Regarding non-bacterial pneumonia, Dr. Baker wondered whether the data on all-cause 

community-acquired pneumonia (CAP) were from ICD-9 codes or ICD-9 codes plus chart

reviews in terms of the number of cases every year. She also wondered what percent was 

estimated that would be caused by the pneumococcal serotypes in the 13-valent vaccine for 

inpatient or outpatient CAP.

Dr. Strutton replied that the hospitalized pneumonia estimates were based on ICD-9 codes and 

a chart review. This is why the one particular dataset was selected for the estimates of burden. 

The outpatient visits are just presumptive CAP based on coding and no chart review. The 

previous model shown in February estimated the percent of pneumonia that was pneumococcal 

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and the serotype coverage; whereas, the model presented during this session approached the 

effectiveness estimates based on the evidence of the level of effect in the pediatric program, 

which was corroborated with the HIV positive estimate from French. These were two different 

approaches, and this is why such a dramatic range was estimated in the analysis.

Regarding the efficacy of Prevnar 13 against non-bacteremic pneumonia, it was not clear to Dr. 

Cieslak how well pediatric data could be extrapolated to adult populations given the variety of 

causes of pneumonia. The reduction in HIV infected adults did not appear to be statistically 

significant, so it is entirely possible that there is zero protection against non-bacteremic 

pneumonia. 

Dr. Strutton clarified that this was a point estimate. The estimates were not totally based on the 

Malawi data. It was also based on the pediatric program, which would represent patients with 

an immature immune system and assessed the level of effect of Prevnar® on pneumonia in that 

population. That was then applied to the adult population beginning with healthy 50 year olds. 

That was then waned by age, time, and risk. In lower ages, years of immunoscenence was 

estimated at lower levels for a starting place for an effectiveness estimate on pneumonia, and 

that would wane again over time following the time since receiving the vaccination. The 

investigators recognize that this is a limitation, which is why they tested such a dramatic range 

down to cost neutrality, which was a 60% reduction in the preliminary estimate. That was waned 

again by age, time, and risk. 

As a member of the WG, Dr. Duchin found it very difficult to interpret this study because of the 

scarcity of data on vaccine effectiveness versus non-bacteremic pneumonia and vaccine 

effectiveness against non-bacteremic pneumonia. Although this was a very interesting 

exercise, Dr. Duchin found it very difficult to translate this into anything that could lead to action 

until there are further data on these critical points. 

Dr. Turner (ACHA) wondered how recipients of the polysaccharide were handled in the model, 

and whether they would also receive the conjugate and if this was accounted for in the model. 

In addition, Prevnar 13 is missing 10 antigens versus the polysaccharide. He wondered if the 

model accounted for the effect that those residual 10 may cause some disease in the conjugate 

recipients. 

Dr. Strutton responded that it was assumed that receipt of the conjugate vaccine would not be 

based on previous receipt of polysaccharide. In terms of the 10 residual antigens, serotype 

coverage was based on the current serotype coverage for the two vaccines, for which the 

conjugate had a lower serotype coverage because there are less serotypes in that vaccine. For 

pneumonia, it was based on an all-cause estimate, so it did not take into account the serotype 

specific effects. They did try to estimate the serotype coverage and the percent that is 

pneumococcal in terms of pneumonia, which fit within the range of estimates included in the 

sensitivity analyses.

Dr. Paradiso (Pfizer) indicated that in all of the trials in which they have assessed invasive 

disease and pneumonia, an impact on invasive disease is observed in the 75% to 100% range 

depending upon the population being studied. For all-cause pneumonia, a lesser effect is 

observed because all-cause pneumonia can be many things. The percent of pneumonia that is 

pneumococcal is never really known; however, the impact can be assessed for all-cause 

pneumonia. What is reassuring about the data in HIV positive adults is that it looks exactly like 

the data for children, with 75% effectiveness against invasive disease and about 25% against 

all-cause pneumonia. Although it did not achieve significance in the model, the pattern is 

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almost exactly the same. The serotype coverage was 50%, so for PCV7 in the Malawi 

population, there was 50% serotype coverage and a 25% reduction in disease. This implies 

that approximately 50% of the pneumonia was pneumococcal. This can be reverse calculated. 

While the exact number is unknown, the data in children has consistently been between 20% 

and 40% reductions in all-cause pneumonia. That corresponds to an invasive disease efficacy 

of approximately 75% to 95%. 

Current Epidemiology of Pneumococcal Disease in Adults

Tamara Pilishvili, MPH

Respiratory Diseases Branch, 

National Center for Immunizations and Respiratory Diseases

Centers for Disease Control and Prevention

Ms. Pilishvili reminded everyone that the current recommendation for 23-valent pneumococcal 

polysaccharide vaccine (PPSV23) is for the following groups [MMWR 1997; 46(RR-8):1-24]:

 All adults 65+ years

 Persons 2 to 64 years with:

→ chronic cardiovascular or pulmonary disease 

→ functional or anatomic asplenia

→ chronic liver disease or alcoholism

→ cerebrospinal fluid leak

→ diabetes mellitus

→ cochlear implant 

→ immunocompromising conditions

 Persons 2 to 64 years old living in high risk settings (long-term care facilities)

 Persons 19 to 64 years who smoke cigarettes (added last year)

 Persons 19 to 64 years with asthma (added last year)

ACIP does not recommend routine revaccination with PPSV23 for persons age 65 years or 

older. However, for persons who previously received PPSV23 before age 65 for one of the 

high-risk indications, revaccination is recommended if it has been ≥5 years since first PPSV 

dose. In addition, revaccination with a second dose is recommended for immunocompromised 

adults and adults with aspelnia.

The 7-valent pneumococcal conjugate vaccine used in children since late 2000 has dramatically 

reduced the incidence of invasive infections in this country in the vaccine target age group, as 

well as adults of all age groups through herd effects. The herd effect has ranged from 22% to 

50% reductions observed in 2010 when compared to pre-vaccine baseline [Moore, IDSA, 2009 

& ABCs unpublished data]. The age distribution of pneumococcal disease has changed since 

PCV7 introduction with children contributing less to the overall disease burden. Despite the 

large reductions observed among adults due to herd effects, a high burden remains, especially 

for older adults. Among older adults age 65 and older, there are an estimated 36 cases per 

100,000 in the US. 

In terms of the serotype-specific changes in the incidence of invasive disease among adults, 

invasive disease caused by the serotypes in the 7-valent conjugate vaccine formulation has 

virtually been eliminated. At the same time, there have been increases in all non-PCV7 

serotypes. Most of these increases were driven by a single serotype (19A), especially in 

children, but also in adults. Increases have also been observed in invasive infections that are 

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caused by serotypes included in the 23-valent formulation (excluding the serotypes in the 7-

valent formulation). Increases have occurred in invasive infections that are caused by these 

serotypes despite long-term availability of the 23-valent vaccine and modest increases in 

vaccine coverage in recent years [ABCs unpublished data, continuous sites].

Regarding the herd effects of pneumococcal conjugate vaccine (PCV7) on pneumonia among 

adults in the US, three studies evaluated the impact of PCV7 introduction on adult pneumonia 

burden. All three studies were conducted using administrative data. Grijalva and colleagues 

(2007) found small but not statistically significant reductions in the incidence of all-cause and 

pneumococcal pneumonia in adults 40 to 64 years of age and 65 years of age or older. Up to a 

25% reduction, but not statistically significant, was observed in pneumococcal pneumonia 

hospitalizations. Nelson and colleagues (2008) found no consistent reductions in adults with 

presumptive hospitalized and presumptive outpatient pneumonia. This is the study that was 

mentioned earlier in which ICD-9 codes were used to identify cases of pneumonia, followed by 

validation through chart and chest radiograph reviews. A newer study by Simonsen and 

colleagues (2011) found different results in which fairly large reductions were observed in 

pneumococcal pneumonia at 34% and 54% depending upon the age groups, and these were 

significant. These studies differ in data sources that were utilized, case definitions applied, 

methods of data analysis, and time points at which vaccine impact was evaluated. 

In terms of what can be concluded about whether there are herd effects of PCV on nonbacteremic pneumonia, the current studies rely on ICD-9 codes and are subject to limitations. 

First, pneumonia cases are subject to misclassification. In addition, the trends are being 

examined based on administrative datasets, so changes in coding practices, admission criteria, 

and culturing practices may impact these trends. The key message in assessing whether there 

are herd effects of conjugate vaccine use on non-bacteremic pneumonia using the current data 

systems available is that it is difficult to measure the magnitude of the effect given the current 

data systems. However, based on what is known about the contribution of pneumococcus to 

non-bacteremic pneumonia, it can be concluded that the herd effect of PCV13 on nonbacteremic pneumococcal pneumonia is biologically plausible.

Adults with chronic and immunocompromising conditions are at highest risk for pneumococcal 

disease. CDC unpublished data evaluated trends in invasive disease before and after the 7-

valent vaccine introduction by race groups and by presence of indications for the 23-valent 

polysaccharide vaccine. The study observed significant reductions in overall disease for all comorbid and race groups. The infections caused by 7-valent vaccine serotypes have been 

virtually eliminated for all co-morbid and race groups. However, increases have been observed 

in the non-PCV serotypes for all groups and the increases have been most dramatic among 

blacks with immonocompromising and chronic conditions that are indications for 23-valent 

vaccine. Similar data for adults age 65 years and older show virtual elimination of the 7-valent 

vaccine serotypes as causes of invasive disease, but increases in non-vaccine serotypes for 

this age group were most dramatic among both race groups with indications for the 23-valent 

vaccine [Muhammad et al. Manuscript in preparation]. Despite large reductions in 

pneumococcal disease rates observed for all race and co-morbid groups, there are still 

disparities in disease rates after 9 years of 7-valent vaccine use. 

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Given the observed changes in pneumococcal disease in adults after 7-valent vaccine 

introduction, what is the current distribution of serotypes that are causing invasive disease? 

The 13-valent serotypes cause from 50% to 59% of invasive disease among healthy adults and 

38% to 46% of invasive disease among adults with co-morbid conditions. Coverage provided 

by 13-valent vaccine decreases by age and presence of co-morbid conditions. The additional 

11 serotypes that are included the 23-valent vaccine composition account for anywhere from 

20% to 30% of invasive disease. 

In summary, large herd effects on invasive pneumococcal disease from PCV7 use in children 

are still evident among adults. Pneumococcal disease burden remains high among adults 50 

years of age or older with an estimated 27,000 IPD cases of invasive pneumococcal disease; 

4000 deaths; 374,000 outpatient visits; 194,000 emergency department visits; and 1.4 million 

hospital days due to pneumonia among adults 65 years or older. Racial disparities in disease 

burden remain despite dramatic PCV7 herd effects. No population level effects of PPSV23 

have been observed on invasive pneumococcal disease or non-bacteremic pneumonia despite 

increased coverage.

Considerations for PCV13 Use Among Adults, Summary of

Immunogenicity and Efficacy, and Cost-Effectiveness Studies

Tamara Pilishvili, MPH

Respiratory Diseases Branch, 

National Center for Immunizations and Respiratory Diseases

Centers for Disease Control and Prevention

As noted earlier, it is anticipated that the 13-valent pneumococcal conjugate vaccine (PCV13) 

for adults will be licensed toward the end of 2011 in the US. The proposed indication is for 

prevention of pneumococcal disease, including pneumonia and invasive disease, in adults 50 

years of age and older for disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 

6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. Licensure will be based on demonstration of noninferiority of OPA response to PCV13 compared to PPV23. A confirmatory trial will be 

conducted with pneumonia as the primary endpoint, and will be submitted as a post approval 

supplement. Key factors to consider for PCV13 use among adults include immune response, 

efficacy, herd effects from pediatric PCV13 program, potentially preventable disease burden, 

and cost-effectiveness. Key factors to consider for PCV13 use among adults in terms of 

immune response are whether immunogenicity is non-inferior to the currently licensed vaccine 

(PPV23), and there are no established serologic correlates of protection for pneumococcal 

disease in adults. 

There are a number of published immunogenicity studies in the US with head-to-head 

comparisons of a single dose of PCV versus PPSV23, and these studies differ in age groups, 

prior PPV vaccination, and time points of serology [Goldblatt (2009), De Roux (2008), Dransfield 

(2009), Scott (2008), Ridda (2009), Miernyk (2009), Feikin (2001), Crum-Cianflone (2010), 

Penaranda (2010). All of these studies conclude that a single dose of the 7-valent vaccine was 

better or as good as the polysaccharide vaccine. Serotype-specific IgG levels were higher or as 

high for some serotypes of the 23-valent vaccine. Only one of the studies used the 13-valent 

vaccine formulation, and the sample size was 15 in each arm. Some of these studies show that 

for select serotypes, an improvement was observed in response to the conjugate vaccine 

compared to the polysaccharide vaccine. For example, the Goldblatt study showed that for 3 of 

the 7 serotypes in common the response was superior, for one of the serotypes (19F) in the 23-

valent vaccine the response was superior than the 7-valent, and for the remaining serotypes 

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there was no difference observed. In the absence of serologic correlates of protection for 

adults, OPA assumes a greater role since it measures functional antibody responses elicited by 

vaccine. The De Roux, Dransfield, Scott, and Miernyk studies also evaluated the OPA results 

and compared the results to the ELISA IgG levels, and the OPAs did not change the 

conclusions of these studies. Similar results were found in studies that focus on HIV positive 

adults [Feikin (2001), Crum-Cianflone (2010), Penaranda (2010)]. These studies demonstrate 

that serotype-specific IgG levels and OPA activity, where it was measures, were similar after a 

single dose of the 7-valent or polysaccharide vaccine. The Crum-Cianflone study showed that 

response to PCV for 3 out of 4 serotypes measured at 1 month post-dose was superior for the 

7-valent vaccine as compared to the 23-valent vaccine. However, when the response was 

measured at 6 months post-dose, for all 4 serotypes measured, the response was equivalent for 

the 7-valent and 23-valent vaccines.

The results of the Phase III immunogenicity studies of PCV13 versus PPV23 were presented to 

ACIP in February 2011. In summary of these studies, non-inferior immune response post-dose 

1 for PCV13 compared to PPSV23 was demonstrated for all common serotypes. In 

pneumococcal vaccine naive adults, 9 of 13 serotypes showed a statistically greater response. 

In adults pre-immunized with PPSV23 >5 years prior, 11 of the 13 serotypes showed a 

statistically greater response. There was improved response when PCV13 was given as the 

first dose with sequential vaccination one year apart. When two doses of PCV13 given one 

year apart were compared to one dose of PPV23 followed by PCV13 one year later, for 10 of 13 

serotypes statistically greater response was observed. When PCV13 was given first followed by 

PPV23 or PPV23 was given first followed by PCV13, 11 of 13 serotypes statistically greater 

response was observed.

Another factor to consider is the efficacy of conjugate vaccines among adults; however, limited 

data are available. The only study is the double-blind, placebo-controlled clinical efficacy trial 

conducted in Malawi among HIV-infected (88%) adolescents and adults who recovered from 

documented invasive pneumococcal disease (N=496). Two doses of the 7-valent were given in 

this trial, and the trial demonstrated 75% efficacy against vaccine serotype invasive disease and 

25% efficacy against all-cause pneumonia (although not statistically significant). This is a very 

different population in Africa, so it is unclear whether these results can be extrapolated to the 

US population. These are the only data pertaining to efficacy against invasive disease among 

adults.

There are no data on efficacy of the vaccine against non-bacteremic pneumonia; therefore, the 

direct efficacy of the vaccine in adults is not known. There is an on-going trial in the 

Netherlands that will provide crucial data on the efficacy against pneumonia. That study 

involves 85,000 community-dwelling, pneumococcal vaccine naïve adults >65 years of age. 

The primary objective is efficacy against the first episode of vaccine serotype communityacquired pneumonia, and the secondary objectives are efficacy against non-bacteremic vaccine 

type CAP, vaccine type IPD, all pneumococcal CAP, and death. The safety profile will also be 

assessed. The occurrence of the primary outcome, vaccine type CAP, will be established on 

three criteria: clinical definition of CAP, chest radiographic interpretation consistent with 

pneumonia, and determination of pneumococcal serotype. Determination of serotype will rely 

primarily on culture, but there will be two additional diagnostic techniques used (e.g., PCR and 

antigen tests that were evaluated prior to inclusion in the study). The results from this study will 

not be available for the next 1 to 2 years.

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Also important to discuss are the potential herd effects of PCV13 and preventable disease 

burden in adults. Regarding the rank order of IPD serotypes among adults >65 years of age in 

2010, the three most common serotypes are 19A, 7F, and 3. These are included in the 13-

valent formulation and account for over one-third of invasive infections among adults in this age 

group. The remaining most common serotypes are either covered by the 23-valent vaccine 

(22F, 9N, 11A) or they are not covered by any of the vaccine formulations. There is a similar 

picture in terms of rank order for adults 50 to 64 years old, except that 7F causes more 

infections [CDC, unpublished, 2010].

Given the data, the question is: will PCV13 use in children reduce disease in adults similar to 

what was observed with the use of 7-valent vaccine use in the US? PCV7 introduction led to 

near elimination of vaccine type IPD among adults of all age groups. Carriage and transmission 

for some PCV13 serotypes is similar to PCV7 serotypes (types 19A, 7F, 6A). Serotype 1 is 

rarely carried, so it unclear if vaccinating children will reduce type 1 disease. Efficacy of PCV13 

may not be similar to PCV7 for some types (types 1 and 3). The key message is that the herd 

effects of PCV13 are likely to be observed, given the PCV7 experience.

Cost-effectiveness must also be taken into account. Given the high cost of the vaccine and the 

availability of the two vaccines for adults soon, studies are needed to identify the most costeffective strategies for vaccinating adults using these two vaccines. One cost-effectiveness 

analysis was presented by Dr. Strutton during this session. Another model was presented in 

February 2011 and these data were updated based on incorporation of the comments received 

from the ACIP membership and working group members. As a reminder, a decision modeling 

technique was used, which was employed to examine 6 different pneumococcal vaccination 

strategies with the conjugate vaccine and the 23-valent vaccine. The model followed a 

hypothetical US cohort of 50 year olds yearly until death. Detailed assumptions and inputs of 

this model were presented during the February ACIP meeting. As a reminder, the key 

assumptions included the following: 

 Base case:

→ Assumptions regarding PCV13 effectiveness against IPD and non-bacteremic 

pneumonia (modified Delphi panel)

→ Herd effects of PCV13 against non-bacteremic pneumonia were modeled based on 

the point estimates from Grijalva et al

→ Vaccine uptake was modeled based on observed vaccine uptake for the 23-valent 

vaccine, which is 60.1% adherence for age 65 and older and 33.9% for co-morbiditybased uptake

 Worst case:

→ Assumed the lowest PCV effectiveness against noninvasive pneumonia (modified 

Delphi panel)

→ Age-based vaccination uptake = 60.1%, co-morbidity-based uptake = 33.9%

 Changes since the February ACIP presentation include

→ Real vaccine uptake instead of 100% uptake

→ Assumption of herd effects against non-bacteremic pneumonia

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Regarding the public health impact of the vaccine strategies, PPSV strategies prevented more 

invasive disease than strategies that used only the 13-valent vaccine, while strategies that used 

2 scheduled doses of the 13-valent vaccine prevented more non-invasive pneumonia. In the 

base case sensitivity analysis, results were most sensitive to variations in vaccine effectiveness 

estimates and herd effects from the pediatric use of the 13-valent vaccine that were assumed 

for non-invasive pneumonia. With respect to incremental cost-effectiveness analysis results 

under base case and worse case assumptions, only strategies were included that were not 

eliminated by strict or extended dominance. Compared to no vaccination, 13-valent vaccine 

given as a substitute for the 23-valent vaccine using current recommendations cost $28,900 per 

QALY gained. 13-valent vaccine given routinely at 50 and 65 years of age cost $45,100 per 

QALY gained compared with a strategy of substituting PCV13 in the current recommendation. 

A strategy of PCV13 given at the ages of 50 and 65, followed by a dose of polysaccharide at the 

age of 75 years cost $496,000 per QALY gained. The other two strategies, use of 

polysaccharide vaccine with current recommendations as well as a dose of the conjugate 

vaccine given at 50 and followed with a dose of polysaccharide given at the age of 65, were the 

dominated strategies in the base case and were excluded. In the worst case analysis, the 

current recommendation strategy with the 23-valent vaccine is no longer dominated and is 

favored, costing $34,000 per QALY gained. 13-valent vaccine substituted in the current 

recommendations costs $131,000 per QALY gained, and the other strategies had prohibitively 

high cost-effectiveness ratios.

In terms of the cost-effectiveness analysis summary, the models show that PCV13 in adults 

could be highly cost-effective. However, both models rely heavily on assumptions about indirect 

effects of PCV13 on non-bacteremic pneumonia. The current PPSV strategy is favored if 

PCV13 effectiveness is low against non-bacteremic pneumonia. Results are sensitive to 

assumptions regarding PCV13 effectiveness against noninvasive pneumonia, PPSV 

effectiveness against invasive pneumococcal disease, and that herd immunity effects on the 

likelihood of PCV13-type disease.

In conclusion, PCV13 provides immune responses that are, for some serotypes, greater than for 

PPV23 in both vaccine naïve and previously immunized adults. However, the clinical relevance 

is unclear without a correlate of protection. Revaccination with PCV13 does not appear to lead 

to diminished response. Cost-effectiveness and public health impact estimates of PCV13 

strategies rely on assumptions of burden of vaccine-preventable disease after herd immunity 

impact and efficacy against non-bacteremic pneumonia. Data on efficacy against non-invasive 

pneumonia and herd effects of pediatric PCV13 use pending completion of those studies. No 

data are available on duration of protection.

In terms of whether there is a role for PCV13 use among adults, the pros are that there is a 

large, potentially preventable burden of adult disease. Efficacy against pneumonia in children 

suggests possible efficacy against non-invasive pneumococcal pneumonia among adults. 

There is no evidence of population-level prevention with PPV23. The cons are that the potential 

herd effects of PCV13 use among children may limit the utility of PCV13 among adults. There 

are no efficacy data against pneumonia, and there are limited data on efficacy against adult 

invasive pneumococcal disease (PCV7 only).

The next steps are to evaluate relevant new data as they become available, including data from 

the efficacy trial against pneumonia (CAPITA); the impact of pediatric PCV13 program on 

disease burden and serotype distribution among adults; and additional immunogenicity data 

from Phase III studies (adults 18-49 years old, high-risk adults, and long-term persistence of 

immune response). Consideration will be given to revision of the ACIP recommendations as 

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these additional data become available, and the evidence will be reviewed to consider PCV13 

for high-risk adults.

Discussion Points

Dr. Baker inquired as to when information would be available about the pediatric effects of 

Prevnar 13®, when data would be available from the Netherlands trial and how long the followup is post-immunization to detect pneumonia.

Dr. Pilishvilli responded that the ABCs data are being examined in real-time to assess the 

pediatric effects on herd immunity. These data are not complete and consistent results have 

not yet been observed. Based on what has been observed with the 7-valent vaccine, after there 

is one year of complete data available, there should be some indication of whether there is a 

herd effect. 

Dr. Paradiso (Pfizer) added that recruitment for the pneumonia trial occurred through two 

influenza seasons, or over two years. Follow-up has been two years after that, and some 

subjects will be followed for three years. This is a case accrual endpoint, so that data are not 

analyzed until there are enough cases for all of the endpoints. These data are estimated to be 

available in about early 2013 for a primary endpoint. Consideration is being given to whether an 

interim analysis can be done; however, they do not want to jeopardize the endpoint by doing 

this so they have to be careful.

Dr. Marcy noted that in that week’s Vaccine, he thought he saw something about 6C, which is 

beginning to cause more problems in pediatrics and is the fourth leading cause of adult invasive 

disease.

Dr. Paradiso (Pfizer) replied that the data indicate that 6A, B, and C are related serotypes that 

are part of the same serogroup. 6B was in the 7-valent vaccine and cross protective antibody 

can be made against 6A, so by functional activity, killing of 6A is not as good as killing of the 

homologous strain. Some impact has been seen on 6A even with Prevnar® introduction. It 

turns out that 6B antibody does not kill 6C. On the other hand, the data that were published 

showed that the antibody of 6A does, in fact, kill 6C. In vitro, looking at OPA activity, it does 

look like those two are more closely related and there is potential for cross reactivity. However, 

there are only in vitro data at this point. 

Dr. Cieslak pointed out that the two cost-analyses gave pretty different results, one with cost 

savings to society across a broad range of assumptions and the other always costing money 

and sometimes costing a lot of money. He requested an explanation of the differences in the 

model or inputs that explain the differences in outputs. 

Dr. Pilishvilli responded that there is a methodology difference. One model follows a cohort of 

50 year olds over a lifetimes; whereas, the other assesses the population of 50 and above. 

Some of the inputs are also different. The input for efficacy against pneumonia is more 

conservative, so the estimation in the Pittsburgh model was to calculate the contribution of 

pneumococcal disease to overall pneumonia and then apply the projected vaccine efficacy and 

the relative contribution of the serotypes. So, this actually comes up with a much smaller 

proportion of what the vaccine types of pneumococcal disease will be for all-cause pneumonia. 

Another difference is that outpatient cases were not included in the Pittsburgh analysis. 

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Dr. Zimmerman added that one of the major differences in what was presented in February 

versus what was presented during this session was the difference in the ceiling. For modelers, 

that is an interesting theoretical perspective: What ceiling should be included in a costeffectiveness analysis? While 100% is sometimes used in policy circles, it is almost never 

achieved. Certainly for adult vaccinations, 100% is not achieved. So, 60% was used because 

that was the time point with the vaccination rate against pneumococcal disease according to the 

NHIS. The critical issue is the proportion of pneumonia that is due to pneumococcous. That is 

to say, Pfizer used the generally accepted 30%. CDC is funding research on this topic, which is 

another critical issue. If it is substantially less, if 15% of pneumonia was attributable to 

pneumococcous, that will make it much more expensive. If it is closer to 50%, the vaccine will 

be much more cost-effective. This issue is critical, but will not come from CAPITA because the 

population is different from that of Northern Europe. 

Dr. Judson pointed out that the literature has varied over the years in terms of the extent to 

which any of the pneumococcal vaccines prevent non-bacteremic pneumococcal pneumonia in 

the different age groups. A number of those studies were reviewed during this session; 

however, he was still left lacking a best estimate in terms of the efficacy of PCV7 to prevent 

non-bacteremic pneumococcal pneumonia. 

Dr. Pilishvilli responded that there are no data on the efficacy of the conjugate vaccines against 

non-bacteremic pneumonia. That is a crucial piece of data that is missing, and is one of the 

reasons that the working group felt that this is why it is difficult to develop policy options at this 

time. The assumptions to which Dr. Zimmerman referred are also based on what is known 

about the contribution of pneumococcous to overall all-cause pneumonia. Based on the 

literature, this is anywhere from 25% to 30%. The estimates incorporated in the Pittsburgh 

model assumed, in addition to the contribution of pneumococcoal pneumonia that there will not 

be 100% efficacy against all pneumococcal pneumonia and the contribution of the vaccine types 

to pneumococcal pneumonia. 

Dr. Turner (ACHA) said he was still obsessing over the serotypes that are not included in 

PCV13 that are included in the polysaccharide. Knowing that if the polysaccharide was given 

after the conjugate and the shared antigens could be boosted in addition to getting the benefit 

from the non-shared antigens, he wondered why they did not analyze a model of giving the 

conjugate at age 50 and the polysaccharide as a booster at age 60 or 65.

Dr. Zimmerman responded that they did analyze this scenario because a priori was exactly that 

schedule, but it did not come up as either making as much public health impact, or as being 

cost-effective. It is included in the public health models, but is not included in the costeffectiveness models because it drops out due to the dominance and extended dominance 

conventions. To respond to Dr. Judson’s earlier question, in the Pittsburg model, the efficacy 

among 50 year olds to the conjugate vaccine against vaccine type non-invasive pneumonia 

started at age 50 at 74% and in 10 years was down to 41%. Those are very midrange, sober

estimates and the investigators thought that instead of back-calculating, they simply asked the 

direct question so that the Delphi panel would not have to back-calculate the percentage of 

pneumonia and the percentage of serotypes. 

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Dr. Paradiso clarified that there is no controversy about conjugate vaccine efficacy in any trial 

that has ever been done in any age group assessing invasive disease or pneumonia. The 

models of public health impact focus on addressing the current US disease burden after 30 

years of using the vaccine in over 65 year olds and high risk groups down to 50, and a serotype 

coverage after those 30 years of using that vaccine where 65% to 70% of the population has 

received that vaccine. So, the impact on the serotype distribution of disease has not changed 

with the use of polysaccharide, as has been seen with the conjugate vaccine. The 

immunogenicity and immunological mechanisms are very different than with the polysaccharide 

vaccine. This is observed in terms of not only the response, but also the response to 

subsequent boosting and the existence of memory. As was mentioned, more data will be 

shared with the working group over the next months that assess boosting over time and 

memory responses. It is important to look at the whole picture of trying to address a burden that 

is very high.

Dr. Grabenstein (Merck) emphasized that assumptions are essential in those models. One 

meta-analysis showed zero percent efficacy of the polysaccharide vaccine for non-bacteremic 

pneumonia. There is another meta-analysis that shows that there is 70%. There is an RCT 

from Japan for non-bacteremic pneumonia showing 60% efficacy. It depends upon which 

studies go in or out of the meta-analyses. When numbers range from 0% to 70%, the logical 

approach is to do a sensitivity analysis on the efficacy for the polysaccharide vaccine against 

pneumonia, which he had not seen in any of the presentations and which he recommended 

doing. 

Discussion

Introduction

Wendy Keitel, MD

Advisory Committee on Immunization Practices 

Dr. Keitel reported that since the last ACIP meeting, the working group has convened a 

teleconference approximately every other week as necessary to discuss a number of topics 

related to several new vaccines in terms of safety, efficacy, and immunogenicity. The WG has 

also been drafting the guidelines for use of influenza vaccine for the upcoming season. The 

decision was made this year not to develop an extensive document discussing influenza as well 

as the guidelines, but instead to provide an abbreviated document that would highlight the 

strains; the recommendations for the number of doses, particularly in children; and the 

administration of inactivated influenza vaccination to persons with a history of egg allergy.

During this session, presentations were delivered regarding influenza activity, influenza vaccine 

distribution and coverage, vaccine effectiveness, Fluzone® High-Dose, Fluzone® Intradermal, 

and influenza vaccine and egg allergies.

Influenza

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Influenza Vaccine and Egg Allergy

John M Kelso, MD

Division of Allergy, Asthma, and Immunology

Scripps Clinic

Dr. Kelso discussed the issue of administering influenza vaccine to patients who have egg 

allergies, which has heretofore been a contraindication to immunization. He indicated that he 

was presenting on behalf of the Clinical Immunization Safety Assessment (CISA) 

Hypersensitivity Working Group, which consists of 9 allergists/immunologists, 6 CISA principal 

investigators, fellows, and CDC ISO. This group reviewed egg allergy and influenza vaccine 

over 9 months or longer to ultimately reach consensus conclusions.

Under consideration is the approach to a patient who has had an immediate-type allergic 

reaction to the ingestion of eggs, but who has never received the influenza vaccine. If a patient 

has already had an apparent immediate-type reaction to this or any vaccine, the approach 

would be very different and would include skin testing with the suspect vaccine and vaccine 

ingredients. Patients who have IgE-mediated egg allergy have a theoretical risk of anaphylaxis 

if injected with influenza vaccines containing egg protein. Withholding influenza vaccine from 

egg-allergic recipients has very real risk, namely the morbidity and mortality associated with the 

disease. Influenza vaccine contains measurable quantities of egg protein as ovalbumin. The 

question is: Does this cause systemic reactions when injected into egg-allergic patients? 

Seventeen published studies have involved over 2600 egg-allergic subjects getting influenza 

vaccine without any serious reactions (e.g., no respiratory distress or hypotension), and with 

only a low rate of minor reactions (e.g., hives, mild wheezing). So, the answer appears to be 

no. With regard to patients with severe egg allergy, most studies have specifically included

patients with histories of severe anaphylaxis (n > 200) with egg ingestion, and these patients 

also tolerate the vaccine. So, even these patients do not appear to be at risk of serious 

reaction. In terms of whether skin testing with the vaccine will help predict a reaction, in a few 

studies, vaccine was withheld from patients with positive prick or intradermal skin tests. In the 

majority of studies where skin testing was done, vaccinated skin test positive subjects had no 

reactions, or no greater rate of reactions than skin test negative subjects. The rate of reactions 

is the same whether skin testing is included in the protocol or not. In one very large study 

conducted at Boston Children’s Hospital, for a few years skin testing was part of their protocol 

for giving influenza vaccine to children and for subsequent years this testing was removed from 

their protocol. Their overall rate of reaction to the vaccine was very low regardless of whether 

skin testing was part of the protocol. Thus, skin testing with the vaccine is not helpful. Another 

cautious approach to this were studies that were conducted early on that divided the dose (10% 

and if no reaction after 30 minutes 90%) vaccine was administered. In those studies that divide 

the dose, the vast majority of patients ultimately tolerate the 10+90% vaccine dosing. Studies 

with single dose also report no serious reactions. These patients ultimately receive the full 

dose, so dividing the dose appears to be unnecessary.

The reason no serious reactions are being reported appears to relate to the amount of egg 

protein that is present in the vaccine. What is actually being measured in terms of “egg protein” 

is ovalbumin, which is one of the protein constituents of eggs. It is the most important allergen, 

and is the protein to which patients make IgE antibody. Ovalbumin is measured by immunologic 

assays and is the surrogate for the total egg protein content of the vaccine. In the studies 

reporting the ovalbumin level, vaccines used have contained as much as 0.7 mcg per 0.5 mL 

dose without serious reactions, so at least that much is tolerated. That is, the vaccines 

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available for administration contained up to this much ovalbumin and there were no reactions, 

so it is known that at least amount is fine. To put this into perspective, the absolute smallest 

amount of ovalbumin that anyone has ever eaten that caused any sort of objective sign was 130 

mcg. Three of the five manufacturers report the maximum amount of ovalbumin in the package 

insert, and two of the five provide the information on request. The claimed amounts are all 

below 0.6 mcg per 0.5 mL dose. The measured amounts in independent laboratories are 

usually much lower than the claimed amounts. The one outlier has been Fluzone®, which is of 

particular concern because that is the only vaccine approved for children under age 3. Between 

the 2009-2010 and 2010-2011 vaccines, even the Fluzone® vaccine contains considerably less 

ovalbumin. There is reason to believe that this will be the case going forward. 

It is very likely that there is just not enough ovalbumin in the vaccine to cause a reaction. 

Therefore, the consensus conclusions of CISA were that: 

1. Egg allergy of any severity (including anaphylaxis) is not a contraindication to the 

administration of influenza vaccine, but rather a precaution. 

2. Patients who report that they are egg-allergic should be referred to an allergist, where the 

current status of the patient's egg-allergy (often outgrown) can be assessed by history and 

skin or blood tests for IgE antibody to egg. 

3. Skin testing egg-allergic persons with influenza vaccine prior to administration is not 

required because of its low sensitivity and specificity in predicting serious reactions to 

vaccine administration. 

4. Dividing the dose of vaccine is also not required because the majority of even severely eggallergic patients can tolerate the full vaccine dose without severe reaction.

5. Influenza vaccine should be administered to those who are egg-allergic in a setting where 

anaphylaxis can be recognized and immediately treated should it occur and patients should 

remain under observation for at least 30 minutes after vaccination.

Administering Influenza Vaccine to Egg Allergic Recipients: 

A Focused Practice Parameter Update

Dr. Matthew Greenhawt

University of Michigan Medical School

An Arbor, Michigan

Dr. Greenhawt reviewed the following practice parameters for administering influenza vaccine to 

egg allergic recipients:

• Summary Statement 1. Egg allergic patients generally should receive influenza vaccinations 

because the risks of not vaccinating outweigh the risks of vaccinating. 

• Summary Statement 2. Persons with a history of suspected egg allergy who need an 

influenza vaccination should be evaluated by an allergist/immunologist with expertise in food 

and vaccine allergy.

• Summary Statement 3. Skin testing (prick and/or intradermal) with the influenza vaccine 

itself in egg allergic individuals does not reliably identify patients who are at increased risk of 

reacting to the vaccine because of their egg allergy. 

• Summary Statement 4. Administration of influenza vaccines to egg allergic individuals 

should be performed by clinicians experienced in recognizing and managing anaphylaxis 

and in a setting equipped to manage potential adverse reactions (including anaphylaxis).

• Summary Statement 5. Egg allergic patients who receive influenza vaccine should be 

observed for at least 30 minutes after receiving the last dose of vaccine.

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• Summary Statement 6. Both the single-dose and 2-dose (10%, 90%) methods are 

appropriate for administering influenza vaccine to egg allergic individuals.

NIAID Recommendations for the Vaccination of 

Egg-Allergic Individuals with Seasonal Influenza Vaccines 

Matthew J. Fenton, Ph.D.

Chief of the Asthma, Allergy, and Inflammation Branch

On Behalf of the Division of Allergy, Immunology, and Transplantation (DAIT), NIAID, NIH

Dr. Fenton noted that NIAID’s recommendations for vaccination of egg-allergic individuals are 

largely consistent with ACIP draft language. A white paper was prepared in January 2011, 

which the ACIP membership had an opportunity to review. NIAID recommends administration 

of seasonal influenza vaccine (TIV) to egg-allergic individuals with a medical history limited to 

egg protein-induced hives and/or angioedema. Such individuals will not require two-step dosing 

or skin testing with the vaccine prior to TIV vaccination, but should remain under observation for 

at least 30 minutes following vaccination. Individuals with a history of anaphylaxis to egg 

proteins can safely receive the TIV vaccine using a 2-step or multi-step challenge protocol, but 

the use of very low ovalbumin- (OA-) containing vaccines (preferably <0.1 mcg/ml) is critical. 

This differs from the presentations by Drs. Kelso and Greenhawt. It is certainly quite possible 

that this category of high risk patients could receive the single dose of vaccine safely, and it may 

prove to be unnecessary in almost all cases not to use a multi-step protocol. However, the 

published data to date really only include just over 200 subjects with a history of anaphylaxis, 

which NIAID feels that larger studies really be needed to make a less conservative 

recommendation at this point. At this time, NIAID think the data published to data are very 

encouraging and hope that additional studies will address this issue. There are virtually no data 

at this point on TIV vaccination of egg-allergic patients with uncontrolled asthma, and such 

patients should not receive the vaccine until a further risk assessment has been performed. 

NIAID agrees with Drs. Kelso and Greenhawt that skin prick testing with the TIV vaccine should 

not be relied upon to distinguish between groups that are more versus less at risk of systemic 

reactions (e.g., Chung et al 2010). Prospective studies are needed to determine if the risk of 

TIV-induced severe reactions in very young egg-allergic children is different than that in older 

children, adolescents, or adults. Vaccine manufacturers should be encouraged to make OA 

content available to the CDC for dissemination and use by health care professionals. This 

recommendation is made in part to aid in the ease by which these data can be obtained by 

healthcare professionals. In some cases, the ovalbumin limits are noted by the manufacturer, 

while in some cases the manufacturer must be contacted. In many cases, the actual lot to lot 

ovalbumin content can be far more than what is stated as the maximum allowable ovalbumin 

concentration. A history of reactions to any vaccine represents an additional risk group, but one 

that is likely to involve sensitivities to vaccine components other than egg proteins. NIAID 

recommends that individuals with a history of severe reactions to any vaccine should be 

referred for further risk assessment. 

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Three additional studies reported subsequent to the NIAID white paper after January 2011 are 

consistent with the recommendations and the comments made by Drs. Kelso and Greenhawt 

and include the following: 

 Webb et al performed 285 single-dose vaccinations (OA content of up to 1.4 mcg/ml) in a 

group that included individuals with a history of severe egg allergy (23%). There were no 

systemic reactions in any of these vaccinated individuals.

 Owens et al performed a retrospective chart review of children with egg allergy (64 patients,

96 total vaccinations) who received the TIV (OA content of up to 1.4 mcg/ml) by a two-step 

protocol. There were no episodes of anaphylaxis and all observed reactions were mild 

cutaneous symptoms.

 Howe et al performed both a 5-year retrospective chart review of children (135 patients) who 

received the TIV (OA content of up to 1 mcg/ml) and a prospective study (69 egg-allergic 

children and 14 non-egg-allergic children) that included children with a history of 

anaphylaxis. There were no serious reactions observed in either study. In the prospective 

study, 12 of 13 patients with a history of anaphylaxis tolerated TIV given as a single dose. 

Discussion Points

Dr. Baker requested that Dr. Fenton define “uncontrolled asthma” and expressed concern that 

the largest risk group of children for influenza complications is comprised of asthmatics, and 

NIAID was basically stating that these children should not receive influenza vaccine.

Dr. Fenton responded that this referred to a severe group of asthmatics on oral Prednisone and 

high doses of inhaled steroids who have very poor lung function. 

Dr. Kelso responded that there is no definition per se, but those who have poor lung function at 

the time they are evaluated should not receive the vaccine until they are treated appropriately 

with steroids and other agents, and their pulmonary functions returns toward the normal range.

Dr. Baker pointed out that someone with pulmonary function of less than 75% would be at the 

highest risk of having influenza complications. 

Kelly Moore (AIM) requested clarification regarding whether the recommendation meant “egg 

allergic” children with uncontrolled asthma, or just uncontrolled asthma. She also wondered 

whether “egg allergic” referred only to those with anaphylaxis or a broader category of children 

with “uncontrolled asthma.” 

Dr. Fenton confirmed that the recommendation refers to “egg allergic” children with 

uncontrolled asthma. The recommendation also refers to a broader group, not just those who 

are egg allergic with anaphylaxis. 

Dr. Baker stressed that the point of the presentation was to tell them that egg allergic children 

may have completely outgrown their egg allergy or do not have severe reactions. Children with 

severe asthma are a very high risk group. She also highlighted the fact that the speculation that 

the risk of being vaccinated and triggering a full-blown anaphylactic episode could be greater 

than the risk of someone with impaired lung function being susceptible to influenza infection is 

not backed up by data. 

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Dr. Marcy suggested using “moderate persistent” or “severe persistent” rather than 

“uncontrolled” because there are case definitions for those. He also wondered why they would 

send anyone to an allergist, given the statements that history and skin testing do not matter. He 

emphasized that language should be included at the outset of the recommendations that 

providers must be prepared to handle serious reactions. 

Dr. Kelso clarified that the recommendation indicates that skin testing with the vaccine to predict 

whether someone is going to react when it is injected into them is not helpful, because even 

patients with positive skin tests go on to receive the vaccine uneventfully. That is different from 

using skin testing to egg with a commercial extract of egg to confirm someone’s current egg 

allergy. Regarding the case definition, Dr. Kelso thought “uncontrolled” came out of the allergy 

literature on giving allergy immunotherapy injections. In the case of influenza vaccine, patients 

are being injected with things that they are known to be allergic to. About .5% to 1% of 

injections will result in a systemic allergic reaction and anaphylaxis. In that case, someone with 

fully controlled asthma is more likely to have a bad outcome from an anaphylactic event. In the 

case of allergy shots, patients are asked about their level of symptoms in terms of their asthma 

and sometimes a pulmonary function test is administered prior to giving an allergy shot. In the 

case of influenza vaccine, the same would be true. If someone’s asthma was poorly controlled, 

and they happen to be unlucky enough to have an anaphylactic event on top of that, they could 

have a worse event. No patients thus far have had any serious reactions. It still seems to be a 

reasonable step not to administer the vaccine to someone who may be allergic to ovalbumin. 

He sympathized with the quandary about definitions, but even the allergy world and the asthma 

guidelines moved away from “mild, moderate, persistent” to “fully controlled” or well-controlled” 

asthma, which could easily be discerned by history. 

Dr. Marcy inquired as to the protocol: should the skin test be positive to egg?

Dr. Kelso replied that this merely establishes whether the child is egg allergic. Because egg 

allergy is typically outgrown, the child would be given an egg challenge to confirm this. Once a 

child has outgrown their egg allergy, giving him / her influenza vaccine would be no different 

than giving it to any other child.

While she did not have a problem with the idea itself, Dr. Baker expressed concern about 

placing a recommendation to refer someone to an allergist in the middle of influenza-specific 

recommendations, given that it is very misleading. Also, if a patient is referred to an allergist at 

the beginning of influenza season, it may be the middle of influenza season before they are 

actually able to get an appointment. She suggested a cost-effectiveness study on the benefit of 

referrals to allergists and pulmonary function tests for asthmatics. If pediatricians or family 

practitioners know ovalbumin content, this information should be disseminated at the beginning 

of the influenza season and hopefully the content should be below the threshold. It is difficult 

enough to vaccinate children without adding more barriers. 

Dr. Judson agreed with Dr. Baker. While he thought Dr. Kelso’s presentation was clear, logical, 

and helpful, he did not think it supported the strong wording. Item 3 stating that “Skin testing 

egg-allergic persons with influenza vaccine prior to administration is not required . . .” sounds 

soft versus “not indicated” or “not recommended.” People should not be thinking about getting 

tested at the time they are ready to receive their influenza vaccine. Item 4 includes a further 

qualifier in the statement, “Dividing the dose of vaccine is also not universally required . . .” This 

may deter a physician or healthcare provider who is ready to immunize. 

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Dr. Kelso agreed, pointing out that these statements came out of the consensus process. His 

vote was “absolutely not required; don’t need to divide the dose.” The equivocation about 

whether it is necessary or helpful to divide the dose in certain high risk patients is dealt with the 

language. He provided the conclusions of CISA, which then has developed actual 

recommendations for ACIP to consider, which should answer questions about who should be 

referred to an allergist, dividing the dose, et cetera. This will apply to a very small percentage of 

patients who might actually be referred, and will leave the vast majority able to be vaccinated 

without concern about these considerations.

Dr. Keitel pointed out that they had heard three different position statements from three different 

organizations. The working group wrestled with the language as well. The Influenza WG 

considers ascertaining whether a person is allergic to eggs to be a separate issue. She 

suggested reviewing the language the WG developed. 

Dr. Grohskopf read the following guidance from the WG pertaining to influenza vaccination of 

persons with egg allergies:

 Egg allergy may be confirmed by a consistent medical history of adverse reactions to 

eggs and egg-containing foods, plus a skin and/or blood testing for IgE antibodies to egg 

proteins.

 Individuals who have experienced less severe reactions to egg (hives only) may receive 

influenza vaccine with the following additional measures: 

a) as studies published to date involved use of TIV, TIV rather than LAIV should be 

used;

b) vaccine should be administered by a healthcare provider who is familiar with the 

subject of egg allergy and who is able to ascertain the ovalbumin content of the 

vaccine available to him/her; 

c) vaccine with an ovalbumin content ≤0.6 mcg/dose should be used; 

d) vaccine recipients should be observed for at least 30 minutes for signs of a 

reaction following administration of each vaccine dose. 

 Other measures, such as dividing and administering the vaccine by a two-step approach 

and skin testing with vaccine are not necessary.

 Persons who may be at higher risk for severe reaction and who should be referred for 

further risk assessment prior to receipt of influenza vaccine:

a) Those who report having had reactions to egg involving such symptoms as 

angioedema, respiratory distress, lightheadedness, or recurrent emesis; 

b) Or who required epinephrine or other emergency medical intervention;

c) Particularly those which occurred immediately or within a short time following egg 

exposure (minutes to hours).

Dr. Baker suggested that the egg allergy information should appear at the end, given that this is 

a recommendation about influenza vaccine. Otherwise, it will be extremely confusing to 

practicing physicians. Expecting pediatricians or family practitioners to know the egg ovalbumin 

content is completely unrealistic.

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Dr. Sawyer clarified that the Influenza Working Group language does not contain language 

pertaining to asthma and uncontrolled asthmatics. Given the comments during this session, it 

seemed that this language should be included. In the rare chance that a vaccine recipient with 

uncontrolled asthma should have a severe reaction, based on the experience of the allergy 

group that they are more likely to have a bad outcome, ACIP should not take an extra chance 

on that. 

Dr. Baker emphasized that they are more likely to have a bad outcome from influenza.

Dr. Sawyer clarified that he was not saying they should not be influenza immunized, but was 

saying that they should be influenza immunized by someone who is an expert in severe allergic 

reactions.

Dr. Grohskopf responded that such language was included in the recommendation at one time, 

but the clinical opinion from some WG members that they thought they would be able to judge 

that. She was not adverse to adding the language back, but requested input from other working 

group members regarding their opinions.

Dr. Kelso said he was inclined not to include such language in terms of simplification and the 

small numbers of patients to whom this might apply. However, he was not averse to inclusion of 

this language if it was necessary to achieve consensus. The wording put forth by the working 

group regarding referral to an allergist should address the residual concerns about patients with 

particularly severe allergy and dose division. All current vaccines meet the ovalbumin criteria. 

Dr. Baker stressed that language about ovalbumin should be removed.

Dr. Greenhawt indicated that a large portion of immunologists feel that this is very concerning, 

although he does not particularly agree. Regarding the study that established 1.2 as the safe 

level, this is a by-product of what happened to be distributed in the last year. This is something 

they could live with because it is largely moot. 

Dr. Temte inquired as to the prevalence of egg allergy in the general population, the prevalence 

of uncontrolled asthma in egg-allergic patients, and the likelihood he would see one of these 

patients in the next 40 years. 

Dr. Kelso replied that the prevalence of uncontrolled asthma in egg-allergic patients is thought 

to be, at most, about 1% in children. This is much less common in adults. The vast majority of 

toddlers who are egg-allergic will no longer be egg-allergic by the time they are school-aged. In 

children who have food allergies, there would be a higher incidence of asthma in general 

because atopic diseases tend to coexist. However, the percentage of those children who would 

also happen to have poorly controlled or uncontrolled asthma would be very small. Moreover, 

poorly controlled asthma is not a diagnosis, but is a temporary condition. Everyone’s asthma 

can be well-controlled with the appropriate medication regimen. 

Dr. Cieslak viewed people as being vaccinated in three settings, including the routine setting of 

a grocery store, a physician’s office capable of handling some reactions, or an allergist’s office. 

He thought it would be most useful for the guidelines to succinctly spell out, based on 

information a patient is likely to disclose, which of those three paths they should be sent down. 

He was thinking about standing orders that physicians would be signing in terms of potential 

reactions. 

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Dr. Baker indicated that pharmacies in Houston are more likely to have emergency equipment 

available because they give more immunizations than physicians’ offices.

Dr. Greenhawt said the academy probably would not recommend that egg-allergic children go to 

Walgreen’s or CVS. Given the level of evidence and monitoring, it makes the most sense for 

them to be vaccinated in their doctor’s office. Although the risk may not be that great and may 

not be in excess of the typical patient, this is not the typical patient. These patients need some 

special forethought. 

Dr. Cieslak thought that some patients would state that they have an egg allergy because their 

mother told them once that they once had a reaction, or some will say they vomited after they 

were vaccinated or after they had eggs once. It would be nice if they could narrow this down to 

the smallest group that needs to be sent to an allergist’s office. 

Dr. Greenhawt thought the academy’s position would be that someone who says they are 

allergic to eggs should be seen by an allergist. Some patients will actually have an allergy and 

others will not. He sees both types of patients every day. In their guidelines, they did not want 

to get into the issue of stating where to acquire the vaccine. The goal is to increase access to 

influenza vaccine in persons who say they are allergic to eggs. 

Dr. Keyserling (SHEA) expressed concern about how much variation there is within one 

manufacturer from lot to lot. He wondered whether ovalbumin content disclosure is a regulatory 

issue in terms of lost release criteria and if so, whether a statement could be made about not 

releasing a lot with over 0.7 micrograms.

Dr. Sun (FDA) responded that the amount of ovalbumin is a lot specification. He thought it was 

in the range of what had been shown, but there is variability between manufacturers as shown 

in the data.

Dr. Baker pointed out that there is also variability in the recommendations in that one states less 

than 1.2 and the other less than 0.6 micrograms. 

Phil Hosbach (sanofi pasteur) pointed out that manufacturers try to improve the process over 

time. As they have developed the high dose and interdermal vaccines, sanofi pasteur has had 

some incremental and process changes over the last couple of years, including equipment 

changes. Those changes were validated and submitted to and approved by FDA. Ovalbumin is 

not a release criterion for a final vaccine. However, following some of the changes they have 

tested some of the lots and these were found to be at a level of 0.1 micrograms per dose or 

less. Therefore, sanofi pasteur feels that the ovalbumin content has been significantly reduced 

through that purification process. 

Dr. Chilton supported removing ovalbumin content from the discussion if it is no longer an issue. 

It would be very difficult for him in his practice to evaluate that each time he received a new lot 

of vaccine. He also preferred not to include anything about “uncontrolled asthma,” especially if 

it is not clearly defined. He has patients who require albuterol two or three times a week and he 

does not know whether that is poorly controlled or not. 

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Dr. Keitel pointed out that individuals who can eat eggs are not egg-allergic. There is the 

separate issue of whether a person is egg-allergic and needs to be evaluated for egg allergies, 

which needs to be separated from influenza vaccine. In her opinion, if someone has an egg 

allergy, she would prefer that they received influenza vaccine in a doctor’s office. She agreed 

with moving the statement from the beginning to the end. 

In the spirit of keeping things simple, Dr. Jenkins thought it would be useful to devise a set of 

three or four questions for practitioners to consider to help them determine whether to 

administer an influenza vaccine to a child, or to refer them to an allergist. 

Dr. Baker wondered why the working group used the wording “may receive influenza vaccine” 

versus “should.”

Dr. Brady (AAP) pointed out that since these recommendations pertained to the current season 

and there was no ovalbumin issue at this time, this should be removed from the 

recommendation. Language could be included in the text that describes the overall concern 

about ovalbumin. In addition, people order vaccines late in the year. If there a situation in 

which ovalbumin content exceeds the threshold, practitioners need to know that before they 

order. It is too late at this time to address this because people have already placed orders.

Dr. Baker recapped that they had heard some good suggestions, but these were not included in 

the recommendations presented. The first bullet should be moved to be last, “may” should be 

“should,” and language about ovalbumin should be removed. 

Dr. Sawyer said he had not heard a complete answer to his concern about asthmatics. He 

heard from the NIAID group that children with uncontrolled asthma are at higher risk when they 

have an anaphylactic reaction for a bad outcome. If there is a population in whom a worse 

outcome can be predicted if they receive an influenza vaccination, it seemed to him that ACIP 

should call attention to this in its recommendations. 

Dr. Baker requested that Dr. Fenton clarify that this is theoretically possible, but that there are 

no data to support that children with uncontrolled asthma are likely to experience a worse 

outcome.

Dr. Greenhawt replied that Dr. Fenton had left, but said that as was stated previously by Dr. 

Kelso, there are soft data to suggest a worse outcome. It is the feeling that patients with 

uncontrolled asthma who receive an injection of something to which they are allergic will have a 

worse outcome.

Dr. Fryhofer (ACP) pointed out that administration of influenza vaccinations to egg-allergic 

patients is a new frontier, and she felt strongly that the recommendation pertaining ovalbumin 

should remain in the recommendation. Having the provider go through an extra step is 

reassuring. They also heard that Fluzone® is the only influenza vaccine recommended for 

children under 3 years of age, but it has the highest ovalbumin content. ACP has 0.6 

micrograms per dose in its recommendations. She thought they should clarify the size of the 

dose, and leave the numbers in.

Phil Hosbach (sanofi pasteur) clarified that milligrams per dose for the pediatric vaccine is less 

than 0.1 micrograms per dose. 

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Dr. Baker thought that 0.6 micrograms or less would simplify the recommendation for busy 

family practitioners and pediatricians.

Kelly Moore (AIM) expressed confusion about the LAIV being excluded, only because if 

ovalbumin is the issue with egg allergy, LAIV showed the least ovalbumin of any of the TIVs. 

She wondered what the thought process was regarding LAIV and children with egg allergy. The 

risk to children with uncontrolled asthma from influenza is among the highest risk for 

hospitalization and death. This cannot be overlooked in terms of missed opportunities with the 

broader group of egg-allergic children as opposed to those with anaphylaxis.

Dr. Keitel responded that LAIV was excluded was that no studies have been conducted with 

LAIV, and LAIV is administered by an alternative route. It is unknown whether administration 

via a different route will cause a reaction in patients with reactions to egg protein. 

Dr. Englund indicated that the most frequent complaint in pediatric offices is that people think 

they may have had a reaction to eggs. She thought the first bullet should state that the 

recommendation does not pertain to subjects who are not egg-allergic. If they eat eggs without 

incident, they are not egg-allergic and it will not be necessary to consider the rest of the list. 

She emphasized that busy people do not read the whole statement.

It seemed to Dr. Baker that a statement should be added to the first bullet such as, “Individuals 

who eat eggs are not egg-allergic.” For individuals who have reactions, she suggested stating 

“individuals who have reactions” rather than “less severe reactions” and then the rest. 

Dr. Pickering indicated that the sentence, “These are the final recommendations by ACIP” could 

be included there so that it would be read immediately before any of this is listed.

Dr. Baker suggested adding the screening questions that Dr. Jenkins requested to the 

statement.

Ms. Ehresmann noted that this is the only topic for which her agency received a call from an 

allergist to encourage support for this decision. She has never received a call from anyone 

else. She thought that there was overriding support for removal of the statement regarding 

ovalbumin content to make it less complicated. Because it is not an issue for the upcoming 

season, she proposed removing it. 

Dr. Cieslak asked whether the sentence that was moved to the end pertaining to skin or blood 

testing had anything to do with ACIP’s recommendation about whether to administer an 

influenza vaccination. If not, it should be scratched from the recommendation. Otherwise, the 

only place he could see that it mattered was for a population of children who were tested and 

found to be positive who never had a history of a reaction. 

Dr. Greenhawt responded that this would represent a significant population . 

Dr. Cieslak pointed out that those who are egg-allergic who have never had a reaction also 

need to be addressed in the recommendation. They should probably go to a doctor.

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Dr. Kelso responded that there are certainly children who are sensitized who make IgG 

antibodies to eggs who are positive by skin tests or blood tests, but whose parents do not know 

what happens when they eat eggs because they have never had eggs. They were sensitized 

through a respiratory route, skin contact, breast milk, or some other way. Some of those 

patients would react if they ingested eggs. In terms of simplifying matters, parents could simply 

be asked what happens when their child eats eggs. If the parents state that the child eats eggs 

uneventfully, they are not egg-allergic. If something more severe than hives occurs, further 

evaluation should be done. Screening for egg allergy can be done reliably by history. He 

agreed that it is true if an individual provider is not sure for some reason whether a patient is 

allergic to eggs, there are various mechanisms by which they can figure this out, including blood 

testing, sending them to an allergist, et cetera. 

Dr. Baker requested further input regarding whether to keep the language pertaining to 

ovalbumin in the recommendation.

Dr. Grohskopf replied that that the quantity had been expressed as either 1.2 mcg per mL or 0.6 

mcg per 0.5 mL dose, so it was not really inconsistent, but she will check. There has been a 

significant amount of discussion regarding ovalbumin. The reasons for keeping it in is because 

the information is available on some manufacturer package inserts but not all, and there may be 

variability from season to season and lot to lot. Therefore, it is difficult to make a blanket 

statement that would cover everyone in every circumstance. Hopefully in the future, the 

information will be more easily accessible such that the issue could be addressed for the 

majority of egg-allergic people who only have hives and may be missing out on getting 

vaccinated. The information can be simplified.

Dr. Brady (AAP) emphasized that this is a recommendation for this year, and there will be 

another one next year. As most people mentioned, most people look at the recommendations. 

Ovalbumin is not an issue this year, so perhaps it could be removed from the recommendations 

but included in the text so that people are aware that it is important but is not an issue this year. 

If it is included as a recommendation, everyone who has already ordered vaccine is going to be 

confused and may not immunize someone if they do not know that ovalbumin content.

Dr. Sun (FDA) pointed out that many of the package inserts have already been printed for the 

current year’s influenza vaccine. The package inserts state that egg allergy is a 

contraindication, so he is not sure how to deal with this issue. However, he did believe that 

there could be confusion and that further deliberation is required. 

Dr. Baker thought it was the same as having an off-label recommendation for compelling 

reasons. Often practitioners cannot find the package insert much less find a magnifying glass to 

read it. Therefore, she did not think the package insert would pose a major barrier. 

Motion 

Ms. Ehresmann made a motion to accept the recommendation as modified based on the 

discussion and with removal of the ovalbumin statement, and with the understanding that the 

recommendations pertain to this year and must be re-evaluated each year. Dr. Cieslak

seconded the motion. The motion carried with 13 affirmative votes, 0 negative vote, and 1 

abstention. 

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Influenza Activity Update

Lisa Grohskopf, MD, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Grohskopf reported that the vaccine virus strains would be the same as those in the 2010-

2011 vaccine, and would include the following:

 A/California/7/2009 (H1N1)-like 

 A/Perth/16/2009 (H3N2)-like

 B/Brisbane/60/2008-like

A new intradermally-administered TIV, Fluzone Intradermal® manufactured by sanofi pasteur) 

was licensed in May 2011. This vaccine is indicated for persons aged 18-64 years. It is 

administered intradermally via a single-dose, prefilled microinjection syringe. Is an alternative to 

other seasonal vaccines for the indicated age group, and there is no preferential 

recommendation.

There working group has had some discussion regarding the number of doses for children 6 

months through 8 years of age. This is was somewhat complicated in 2009 by the pandemic 

2009 H1N1 virus. Children in this age group do not develop full immunity with the initial dose of 

vaccine in the first season it is administered. In past seasons, 2 doses have been required 

during the first season a child in this age range receives influenza vaccine. In order to simplify 

things this year and because the vaccine virus strains for the coming season are the same as 

for this past season, the algorithm proposed is to ask whether a child received at least one dose 

of the 2010-2011 seasonal influenza vaccine. If so, one dose should be administered for 2011-

2012. If unsure or at least one dose was received, two doses should be administered. This is 

depicted in the following diagram upon which ACIP members ultimately voted:

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Discussion Points

Dr. Keitel proposed that these recommendations be accepted with the caveat that a footnote be 

included on the algorithm that relates to Option 2 that regards whether a child received an 

influenza vaccine before 2010 and had the monovalent H1N1. If so, they will only need one 

dose for 2011-2012. Dr. Jenkins seconded the motion.

Dr. Sawyer wondered why a footnote when there is a different version of the algorithm diagram 

that includes that scenario and seemed clearer to him than putting them in the footnote.

Dr. Keitel responded that there was a robust discussion about the selection of the option. The 

simple Option 1 was favored by the majority of the WG members.

Dr. Sawyer emphasized that although the other option was more complicated, it is the reality. 

He thought placing it in a footnote made it even more difficult. Therefore, he disagreed with the 

majority opinion of the WG because many children received monovalent H1N1 vaccine and 

seasonal influenza vaccine in 2009-2010.

Ms. Ehresmann expressed confusion with regard to whether they were voting on the diagram.

Dr. Baker clarified that they were voting on the antigen content and the simple diagram.

Dr. Englund inquired as to what AAP had chosen. If there are different diagrams, there will be 

confusion.

Dr. Baker said she thought the intent for AAP was to be in concert with ACIP.

Dr. Englund supported the simpler diagram, but thought that adding a footnote, even as a 

separate diamond above made more sense than the complicated version of the diagram.

Dr. Pickering indicated that Dr. Bernstein from AAP wrote both of these documents. The feeling 

was that the simpler one would be better, and the two groups try to harmonize whenever 

possible. 

Dr. Sawyer said his concern was that if someone followed the simpler diagram but did not read 

the footnote, they would make the wrong decision regarding whether a child needs two doses. 

Complexity or not, that is the situation.

Dr. Baker clarified that they were voting on the antigen content, the simpler diagram, and either 

a traditional footnote or additional diamond as suggested during the discussion.

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Motion 

Prior to the discussion, Dr. Keitel proposed that the recommendations be accepted with the 

caveat that a footnote be included on the algorithm that relates to Option 2 regarding whether a 

child received an influenza vaccine before 2010 and had the monovalent H1N1. If so, they will 

only need one dose for 2011-2012. Dr. Jenkins seconded the motion. Following the 

discussion, Dr. Baker recapped that they were voting on the antigen content, the simpler 

diagram, and either a traditional footnote or additional diamond as suggested during the 

discussion. Dr. Judson added that he would include the “minimum of 4 weeks apart” in a box 

for the two doses. The motion carried with 9 affirmative votes, 3 negative votes, and 1 

abstention. 

Dr. Baker concluded that they could leave it to the wisdom of the CDC lead staff and WG 

members to make this as clear and simple and possible to reflect the discussion, working off of 

the simple diagram.

Fluzone Intradermal® (Influenza Virus Vaccine)

David R. Johnson, MD, MPH

Senior Director, Global Medical Affairs

sanofi pasteur

Dr. Johnson reminded everyone that ACIP recommends annual influenza immunization for 

everyone 6 months of age and older. For the first time, ACIP recommendations include healthy 

adults 19 through 49 years of age. Given that young adults have traditionally been hard to 

capture with vaccination, strategies for extending the reach of influenza immunization are 

needed. Fluzone® Intradermal is a new vaccine option for adults 18 through 64 years of age. 

This may contribute to an increase in immunization rates. Influenza vaccination coverage rates 

are still below national goals, especially among young adults, including those who have high risk 

conditions. It is hoped that the intradermal vaccine will help to improve this situation. 

The presentation of antigen to dendritic cells induces a robust immune response. The vaccine 

comes in a simple, easy to use microinjection system that results in reduced volume and less 

antigen. The skin plays a key role in immune function. The intradermal vaccination exploits the 

skin, the body’s first line of defense in recognizing and eliminating invading organisms. The skin 

is rich in dendritic and other immune cells. Because of extensive blood vasculature and 

lymphonic network, the skin facilitates the traffic of these cells as well as antigens in and out of 

its dermal layer. The dendritic cells are the power house of the skin’s immune potential. It is a 

highly specialized antigentic cell that can stimulate a robust and long-lasting immune response 

to viral.

Tapping into the skin’s immune cells has been done for many years; however, this has usually 

been done through the Mantoux Technique, which can be cumbersome and uncomfortable for 

patients. Therefore, sanofi pasteur developed a new approach for intradermal delivery. Dr. 

Johnson instructed ACIP members to open the boxes provided to them that included a sample 

syringe. Fluzone Intradermal® utilizes a novel microinjection device, illustrated in the following 

diagram:

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This single-use glass syringe is prefilled with 0.1mL dose of vaccine. The syringe has a 30-

gauge, short-bevel needle permanently affixed to the end of the syringe. The depth of insertion 

limited to 1.5 mm from the skin’s surface. Dr. Johnson described how to utilize the syringe and 

to demonstrate had the ACIP members inject the vaccine into the orange sponges provided. 

Following administration, pressing hard on the plunger emits a needle sheath over the needle. 

In terms of the attributes of this system, the needle is 90% smaller than needles traditionally 

used for IM injections, and the short needle reduces the possibility of damage to nerves and 

blood vessels. The design of the device ensures consistent delivery of the vaccine into the 

dermal layer regardless of a patient’s age, gender, muscle mass, or body-mass index (BMI). 

The microinjection system is easy to use such that only minimal training is needed. In addition, 

there is nothing to prepare. The device is essentially ready to go from the box to the injection. 

Given the size of the needle, it is expected that patients will like being injected with the device 

even if they have avoided vaccination before because they do not like needles. The integrated 

needle shield may reduce contamination, injury, and infection in health-care personnel.

When comparing Fluzone Intradermal® vaccine with regular Fluzone®, some of the most 

striking differences are with respect to the antigen content, the injection volume, and the tiny 

needle. Fluzone Intradermal® contains 40% less antigen in an 80% smaller dose that is 

administered through a micro needle. Again, the product is an inactivated influenza virus 

vaccine indicated for active immunization of persons 18-64 years of age against influenza 

disease caused by influenza virus subtypes A and type B contained in the vaccine. Persons 18-

64 years of age should receive a single annual 0.1mL intradermal dose, and the recommended 

site is over the deltoid. This is an area where people are used to receiving a vaccination, and 

this area is preferred because here the skin has a uniformity in its thickness and is thick enough 

to allow reliable deposition of the vaccine into the dermal layer.

The safety and immunogenicity of Fluzone Intradermal® was evaluated in three trials. Dr. 

Johnson discussed the Pivotal Trial FID31, which was a multi-center, modified, double blind trial 

to assess the safety and immunogenicity of this product compared to standard Fluzone®. 

Fluzone Intradermal® induced GMT responses that were very similar to Fluzone® for all three 

strains. Seroconversion rates were similar, though they were somewhat lower for Fluzone 

Intradermal® with the B strain. For seroprotection rates, there was hardly any difference for all 

three strains. In terms of safety, participants were observed for 30 minutes in the clinic after 

vaccination. Participants recorded solicited injection-site and systemic symptoms on a diary 

card each day for 7 days following vaccination. Diary cards and unsolicited adverse events 

were reviewed by study staff during clinic visit 28 days after vaccination. SAEs and healthcare 

provider contacts were assessed by telephone 6 months after vaccination. As expected, 

injection site reactions were more common with Fluzone Intradermal® than Fluzone® because 

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the vaccine is injected just below the skin surface. However, these injection site reactions were 

generally mild to moderate and resolved within 3 to 7 days. The frequency of pain within the 7 

days post-vaccination was similar across the two vaccine groups, and despite the higher 

frequency of certain injection site reactions, the real-world experience suggests that these 

reactions are not that bothersome to the recipients of the vaccine. There was no material 

difference with respect to solicited systemic reactions between the two vaccine groups, which 

were typically mild to moderate and transient. Rates of immediate, unsolicited, and serious 

adverse events were similar in the two groups.

While Fluzone Intradermal® was licensed in the US in May 2011, it will not be available until the 

upcoming season. However, sanofi pasteur has some insight into how intradermal influenza 

vaccinations perform in the real-world through experience with licensed and used elsewhere 

(e.g., Intanza® in the Northern Hemisphere and Instivac ID® in the Southern Hemisphere). 

Satisfaction surveys were conducted in Australia and Argentina. Almost all respondents who 

received intradermal vaccine reported being either very satisfied or satisfied with their 

vaccination experience. Minimal pain with the injection, a quick administration process, and 

feeling reassured by the micro needle were frequently cited reasons for their satisfaction. When 

intradermal vaccine recipients were asked what they wanted to do next year for influenza 

vaccination, the vast majority reported that they wanted to receive the intradermal vaccine 

again. When the Argentinian sample was followed up 7 to 10 days later, they still felt the same 

way. The survey of Australian providers showed that they had liked their experience with 

intradermal vaccination. Most preferred administering it over an IM injection, and almost all said 

that they would definitely or probably recommend it to their patients next year.

In summary, Fluzone Intradermal® vaccine induces a robust immune response in adults 18-64 

years of age. Injection-site reactions are more frequent due to administration of influenza 

antigens into the dermal space, but not bothersome to vaccinees in routine clinical practice. 

The systemic safety profile, including unsolicited adverse events and severe adverse, is 

comparable to IM. The real-world experience demonstrates a high level of satisfaction with 

intradermal vaccination. The microinjection system is well-accepted by patients and providers 

due to the shorter needle length, smaller gauge, and lower antigen content compared with 

traditional IM vaccine. The system ensures consistent and accurate delivery of antigen into the 

dermis, whatever the patient’s physical characteristics. There is a simple administration 

technique that is easy to learn and is intuitive. The needle shielding system enhances safety.

Fluzone Intradermal vaccine is an attractive alternative to traditional IM vaccine and may help 

increase immunization coverage rates among adults®.

Discussion Points

Dr. Meissner noted that the microinjection system looked more complicated than the standard 

mechanism, and he wondered how much more expensive it is than using a standard needle and 

syringe.

Phil Hosbach (sanofi pasteur) responded that the price is very similar to prefilled syringes. It is 

about $1 to $2 more because the device is more expensive. 

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Fluzone High Dose Update

David R. Johnson, MD, MPH

Senior Director, Global Medical Affairs

sanofi pasteur

Dr. Johnson reminded everyone that while older adults comprise only about 15% of the US 

population, they make up 63% of influenza hospitalizations and account for 90% of influenzarelated deaths despite the fact that they have a vaccination coverage rate of nearly 70%. The 

risk of death and hospitalization from influenza clearly increases with increasing age. For those 

with high risk conditions, the risk of dying from influenza increases dramatically for older adults 

as evidenced by multiple studies. As HAI titers increase, the risk of infection decreases. Older 

adults do not make as much influenza antibody compared to younger adults. This difference in 

antibody response is likely responsible for influenza vaccine effectiveness being consistently 

lower in older adults compared to younger persons. With these issues in mind, sanofi pasteur 

developed Fluzone High Dose®. In many respects, Fluzone High Dose® is just like other 

currently licensed influenza vaccines. However, Fluzone High Dose® differs in that it contains 

four times more HA than standard influenza vaccines and it does not contain an adjuvant, 

antibiotics, gelatin, or preservatives. 

Three pre-licensure trials were conducted for Fluzone High Dose® involving thousands of 

patients. Given that the results were essentially the same across these trials, Dr. Johnson 

presented information on Pivotal Trial FIM05. FIM05 was a multicenter, randomized, doubleblind, controlled Phase III trial of Fluzone High-Dose® vaccine for older adults. The purpose 

was to compare the immunogenicity and safety of Fluzone High-Dose® vaccine (60mcg HA per 

strain) with standard-dose Fluzone® vaccine (15mcg HA per strain). This trial was conducted 

among medically stable persons ≥65 years of age living in the community. There were 3876 

subjects randomized to receive vaccine in a 2:1 ratio. Of those, 3851 were included in the 

immunogenicity analysis. Blood samples were drawn before and 28 days after vaccination, and 

serum samples were assessed for antibody to each of the 3 vaccine components by HAI testing 

using standard methods. 

As expected, the rates of injection site reactions were higher with the high dose, but these 

reactions were generally mild to moderate and were transient. For solicited systemic reactions, 

there was no material difference between the vaccine groups. Rates of immediate, unsolicited 

and serious adverse events and deaths were similar between the two groups. Two serious 

adverse events were considered to be vaccine-related, one in each group. Of the reported 

deaths, none occurred within 28 days of vaccination. Two endpoints were considered to assess 

superiority of Fluzone High-Dose®: GMT ratios and differences in four-fold rates. Typically, 

immune response would be considered superior if it was even minimally higher but statistically 

higher than the other response. However, for Fluzone High-Dose® it was necessary to 

demonstrate super superiority. That is, the lower bound of the 95% confidence interval for the 

GMT ratio had to exceed 1.5 instead of just 1. The lower bound of 95% confidence interval for 

the 4-fold rise rates had to be greater than 10 percentage points and not just greater than 0. 

Fluzone High-Dose® achieved super superiority for the A strains, and was superior for the B 

strain if considering the traditional measure but not if the measure established in this protocol 

was considered. Sub-analyses showed that Fluzone High-Dose® induced robust immune 

response regardless of age, gender, or cardiopulmonary disease history. 

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In summary, no important safety differences were observed between Fluzone® and Fluzone 

High-Dose®. Fluzone High-Dose® was more immunogenic than the standard dose Fluzone® 

and achieved overall immunogenicity compared to Fluzone®. Based on these results, Fluzone 

High-Dose® was licensed through FDA’s accelerated approval process in December 2009. Of 

those elderly who were vaccinated last season, about 10% received Fluzone High-Dose® 

vaccine. It has an established benefit under Medicare Part B, and has its own CPT code.

Regarding the post-approval experience, for the period July 1, 2010 through May 15, 2011, 

sanofi pasteur’s pharmacovigilance department received over 400 reports of adverse events 

associated with either Fluzone® or Fluzone High-Dose®. About 75% of reports were for 

Fluzone® and the remainder were for Fluzone High-Dose®. Most reported adverse reactions 

were non-serious. One possible reason for the higher rate for Fluzone High-Dose® compared 

to Fluzone® is increased reporting with a new vaccine in a special population. Age-related 

morbidities may also account for some of the increased adverse events. Further study revealed 

that nausea, vomiting, and diarrhea were included in the top 10 adverse events observed for 

Fluzone High-Dose®, but not for regular Fluzone®. 

Given this interesting signal, further investigation was done. The rate of nausea, vomiting, and 

diarrhea was about 13 cases per million doses. In most cases, these were non-serious and 

usually arose within 24 hours of receiving vaccination. Given the number of lots involved, this 

did not seem to be a lot-specific or lot-related issue. The investigators then turned to the public 

VAERS database to better understand this finding. VAERS data also showed an increase in 

adverse report rates for Fluzone High-Dose® compared to Fluzone®. Overall, the picture from 

VAERS appeared to be similar to what was observed in the sanofi pasteur safety database. 

Further investigation revealed that the rate of nausea, vomiting, and diarrhea stabilized at 

around 50 per million doses. Given the limitations to VAERS and reporting to sanofi pasteur’s 

database, the investigators reviewed an HMO database that covers 14 million persons in the 

US. Based on these data, regardless of the time after vaccination, the rates for provider visits 

for nausea, vomiting, and diarrhea were the same for high dose and other influenza vaccines. It 

remains unknown whether the increase in nausea, vomiting, and diarrhea reports represents a 

true difference or is a reporting artifact associated with the use of a new vaccine in a special 

population. Fluzone High-Dose® did not alter the likelihood of patients seeking healthcare with 

complaints of nausea, vomiting, and diarrhea. 

In response to the report of nausea, vomiting, and diarrhea, sanofi pasteur took a number of 

steps, including a thorough review of the manufacturing process. No quality issues were 

identified for lots associated with the reports, nor could any aspects unique to the production of 

Fluzone High-Dose® vaccine be implicated. Fluzone® and Fluzone High-Dose® are both 

manufactured in the same facility using equivalent licensed processes. Each report of nausea, 

vomiting, and diarrhea was followed up. This revealed that about 50% of persons experiencing 

nausea, vomiting, and diarrhea following Fluzone High-Dose® vaccine had pre-existing medical 

conditions or were using concomitant medications. The Post-Marketing Experience section of 

2011-2012 Prescribing Information was updated to read, “The following events have been 

reported during the post-approval use of Fluzone High-Dose®. Gastrointestinal Disorders: 

Nausea, vomiting, diarrhea.” The safety of Fluzone High-Dose® will continue to be monitored 

through sanofi pasteur’s safety database, VAERS, and on-going clinical trials.

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In summary, past season spontaneous and VAERS reports of nausea, vomiting, and diarrhea in 

2010-2011 occurred at higher rates with Fluzone High-Dose® vaccine than Fluzone®. Most 

cases were non-serious and self-limited. When considered in the context of number of vaccine 

doses distributed, these events remain relatively rare. Of note, this phenomenon was not 

observed pre-licensure or in large HMO database. Data collected and analyzed to date 

continue to support a favorable benefit / risk profile for Fluzone High-Dose® vaccine.

There are other on-going or planned studies for Fluzone High-Dose® vaccine. FIM07, the 

original post-licensure efficacy trial, was somewhat of a bust because it began the same year as 

pandemic H1N1. Therefore, no efficacy information is available from this trial. The information 

on safety will be available, and a larger efficacy study will be conducted (FIM12). Additional 

information will continue to be gained from other on-going trials (FIM09, GRC48). FIM12 will 

begin in the fall of 2011. This will be a multi-year, multi-center study of Fluzone High-Dose® 

vaccine versus Fluzone® vaccine to begin Fall 2011. The results are expected in approximately 

2014-2015. This will be a randomized, blinded trial with up to 26,000 subjects 65 years of age 

and older who will be recruited over two influenza seasons. Subjects will be randomized in a 

1:1 ratio to high-dose or standard-dose vaccine. Passive and active surveillance will be 

conducted for influenza-like illness, and confirmation will be made by culture or polymerase 

chain reaction. Serious adverse events and deaths will be monitored during each surveillance 

period. The super superiority criterion will be the lower bound of the 95% confidence interval for 

relative vaccine efficacy for high-dose compared with standard-dose (>9.1%).

To summarize the first year experience, Fluzone High-Dose® vaccine licensed under 

accelerated approval based on super superiority of antibody responses and the potential to 

address an unmet medical need. Unfortunately, the uptake of Fluzone High-Dose® during the 

past season is best described as limited at approximately 10% of doses among persons ≥ 65 

years of age. There is an obvious communication gap because what sanofi pasteur hears from 

many providers is the misperception that this vaccine is not recommended by ACIP. Postmarketing safety surveillance is consistent with pre-licensure studies, except that nausea, 

vomiting, and diarrhea were among the top 10 reported adverse events. Even so, nausea, 

vomiting, and diarrhea following Fluzone High-Dose® can be considered uncommon, and 

reported cases were typically not severe. Also, data from a large HMO showed no material 

difference in high dose and standard vaccine in healthcare visits for nausea, vomiting, and 

diarrhea. 

Discussion Points

Regarding the limited uptake, Dr. Baker wondered whether there was any trend toward what 

type of people experienced gastrointestinal symptoms.

Dr. Johnson replied that upon further examining the reported cases, they found that about 50% 

had high risk conditions or were taking medications that might have helped to explain these 

gastrointestinal symptoms.

Dr. Meissner inquired as to whether there would be any change in the wording of the CDC 

statement in regard to the high dose vaccine for the upcoming year.

Dr. Bresee responded that no change was expected this year, or until efficacy or effectiveness 

data are received that might warrant a change.

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Dr. Baker requested that Dr. Bresee respond to the comment that there is a misconception that 

ACIP does not think this is a good vaccine to use. 

Dr. Bresee replied that he was surprised by this because it is not the recommendation. It is not 

recommended as a preferential vaccination, which perhaps has been misinterpreted as a “no” 

recommendation. However, it is in the same tables as all of the recommended vaccines. 

Dr. Cieslak thought perhaps ACIP should recommended it as a preferential vaccine. A 25% 

better response to the H3N2 antigen seems like it might be significant unless they did not really 

believe that the 4-fold rise equals seroprotection. 

Dr. Englund believes that they need to see efficacy data, which she thinks will show something. 

However, she also believes that ACIP should not preferentially indicate anything without some 

data. Serologic data are very helpful and promising, but she did not think it was enough to give 

the vaccine preference. It was already given equivalency. She has heard this 

misunderstanding herself, but perhaps it shows that people are not reading the 

recommendation. 

Phil Hosbach (sanofi pasteur) noted that the VA was also confused and was seeking additional 

guidance. While they were not asking for a preference, it is clear when speaking with 

physicians that they believe ACIP does not recommend this vaccine. The only thing sanofi 

pasteur would ask is that when recommendations are published that it is clear that these are 

equivalent vaccines that are all recommended by ACIP.

Dr. Temte thought traditionally the challenge has been having sufficient vaccine to meet the 

needs of patients. In previous recommendations there have not been any distinctions between 

types even though there is some compelling data, especially in children, that live attenuated 

vaccine may work better than TIV. ACIP has been very careful not to designate any 

preferences until such time that both vaccine supply is fairly secure and there is good clinical 

outcome evidence that there is clear superiority, and that has to be shown over a number of 

seasons as opposed to just one.

For the record, Dr. Pickering noted that there were 9 ACIP members and 4 ex officios present at 

of the close of the meeting.

 

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Participant Roster

Last First Citizenship Organization

Alexa Pamela United States Pfizer

Allen Curtis United States Pfizer

ARCY Stephan Michael United States Advisory Committee on Immunization Practices

Armstrong Jennifer United States Glaxosmithkline

Ashley Don United States Pfizer Vaccines

Ault Kevin United States Emory University School of Medicine

AVILES-MENDOZA GUILLERMO J. United States National Vaccine Program Office (NVPO)

Bacott Tameeca United States Westchester College

Baker Carol J. United States Baylor College of Medicine

Bandell Allyn United States Medimmune

Barden Helen United States Meningitis Angels

Bardi Janna United States WA Department of Health

Baxter Bryan United States Novartis

Beaman Ann United States Avalon Catering

Bennett Echo United States National Meningitis Association

Berns Abby United States

National Association of County and City Health Officials 

(NACCHO)

Bibila Theordora United States Merck & Co., Inc.

Biega Lou United States Merck and Co. Inc.

Blalack Gary United States GlaxoSmithKline

Boyce Donna United States GlaxoSmithKline

Bozof Lynn United States National Meningitis Association, Inc.

Bradley Kimberly United States GlaxoSmithKline

Brady Michael United States Nationwide Children''s Hospital

Bresnitz Eddy United States Merck & Co., Inc

Brewer Katherine United States American Nurses Association

Brewre Katherine United States American Nurses Association

Burnworth Laura United States Children''s Healthcare of Atlanta

Burstin Stuart United States GlaxoSmithKline

Campos-Outcalt Doug United States American Academy of Family Physicians

Carter Laura United States Avalon Catering

Cary Donna United States sanofi pasteur

Chaney Mike United States GA Chapter, American Academy of Pediatrics

Chang Jean United States Dynavax Technologies

Cheek Jim United States Indian Health Service

Chesney Elizabeth United States Johns Hopkins School of Public Health

Chilton Lance United States University of New Mexico

Christophers Gerard United States Somers Manor Nursing Home Inc.

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Cieslak Paul United States Oregon Public Health Division

Clark Liana United States Merck & Company, Inc.

Claxton Isabelle United States GSK Vaccines

Clover Richard United States University of Louisville

Coelingh Kathleen United States MedImmune

Collier Antwon United States Albany Technical College

Conner Penny United States Georgia Immunization Program

Conway Catherine United States Avalon Catering

Cordell Laura United States sanofi pasteur

Coyne-Beasley Tamera United States Advisory Committee on Immunization Practices

Cullison Mark United States Merck and Co., Inc.

Dalrymple Donald "Dack" United States Dalrymple & Associates, LLC

Dana Adrian United States Merck Sharp & Dohme Corp.

Dasbach Erik United States Merck & Co., Inc.

Deal Carolyn United States National Institute of Allergy and Infectious Diseases

Decker Michael United States sanofi pasteur

Dinovitz Richard United States Nuron Biotech

Donnelly John United States Pfizer

Doskey Richard United States America''s Health Insurance Plans

Duchin Jeffrey United States Public Health - Seattle & King County

Egge Steven United States Merck and Co., Inc.

Ehresmann Kristen United States Minnesota Department of Health

Elward Alexis United States Healthcare Infection Control Practice Advisory Committee

Englund Janet United States Seattle Children''s Hospital

Erkman Brett United States Great Point Partners

Etkind Paul United States National Association of County and CIty Health Officials

Evans Geoffrey United States Division of Vaccine Injury Compensation, HRSA, HHS

Fernandez Carrie United States Pfizer

Florez Jorge United States IMMUNOPROTECTION

Fortner Angela United States Northeast Georgia Medical Center

Foster Stephan United States American Pharmacist Association

Friedland Leonard United States GSK

fryhofer sandra United States american college of physicians

Gaffoglio Diane United States Nancy Lee & Associates

Gall Stanley United States The American College of Obstetricians & Gynecologists

Gantt Lionel United States Iron Sharpens Iron

Gargano Lisa United States Emory University

Garman Patrick United States Military Vaccine (MILVAX) Agency

Gaskins Diana United States retired

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Geibe Jesse United States DoD (LNO to CDC & ex-officio ACIP member)

Gilmore Ruth United States GA EPIC program

Gonzales Tara United States MedImmune

Gould Philip United States Air Force Medical Support Agency

Grabenstein John United States Merck & Co., Inc.

Greenaway Richard United States Every Child By Two

Greenberg David United States sanofi pasteur

Grogg Stanley United States American Osteoapthic Association

Groom Amy United States CDC/Indian Health Service

Hahn Christine United States CSTE

Halbert Ron United States PriceSpective

Halsey Neal United States Johns Hopkins Bloomberg School of Public Health

Haupt Richard United States Merck Research Labs

Hazelwood Kim United States Georgia Public Health

Henry-Wallace Stephanie United States Cambridge Communications & Training Institute

Henzig Brian United States Safeway Inc.

Herrera Taracena Guillermo United States Glaxo Smith Kline

Hewlett Dial United States Pfizer

Heyward William United States Dynavax Technologies

Hoerger Thomas United States RTI International

Hosbach Philip United States sanofi pasteur

Howe Barbara United States GlaxoSmithKline

Huang Philip United States Merck & Co., Inc.

Humphrey-Franklin Donelle United States Ga Division of Public Health

Hunter Margie United States Dekalb Medical

Hutnick Natalie United States University of Pennsylvania

Iarocci Tom United States TIMD, LLC

Israel Zimra United States Pfizer Inc.

Jacobs Megan United States National Vaccine Program Office (HHS)

Janssen Robert United States Dynavax Technologies

Janusz Cara United States Pan American Health Organization

Johnson David United States sanofi pasteur

Johnson Erica United States APCO Worldwide

Judson Frank United States University of Colorado School of Public Health

Kagan Stephen United States Pfizer

Keitel Wendy United States Baylor College of Medicine

Keyserling Harry United States Society for Healthcare Epidemiology of America

Kimberlin David United States AAP

Kinsinger Linda United States Veterans Health Administration

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Kitchen Chester United States Merck & Co., Inc.

Knowlton Rachel United States sanofi pasteur

Konz John United States Merck

Krishnarajah Girishanthy United States GlaxoSmithKline

LaBenita Maribel United States Avalon Catering

Landry Sarah United States NVPO

LaRussa Philip United States Columbia University

Lawson Herschel United States CDC, Retired

Leach Patti United States Meade County Health Department

Lee Ingi United States Merck & Co.

Leger Marie-Michele United States American Academy of Physician Assistant

LEROY JUDY United States CLEMSON UNVERSITY

Lewin Clement United States Novartis Vaccines and Diagnostics

Lewin Susan United States None

Lewin Sylvana United States None

Li Xiaoming United States Merck Research Laboratories

Lievano Fabio United States Merck Sharp & Dohme Corp.

Lindert Kelly United States Novartis Vaccines and Diagnostics

Lyalin David United States Northrop Grumman - CDC Contract

Malhame Melissa United States Dynavax Technologies

Manzano Yecenia United States Meningitis Angels

MARONEY PATRICK United States sanofi pasteur

Martin J. Tyler United States Dynavax Technologies

Martin Maria United States sanofi pasteur

Mazur Marie United States CSL Biotherapies

McGuffin Colleen United States Merck

MEADE BRUCE United States Meade Biologics LLC

Meissner Cody United States Tufts Medical Center

Middleman Amy United States Baylor College of Medicine

Milley Frankie United States Meningitis Angels

Moburg Christeen United States MedImmune

Montero Jose United States New Hampshire Department of Health and Human Services

Moore Kelly United States Tennessee Department of Health

Moore Brandon United States I. D. R.

Mulach Barbara United States NIAID/NIH

murphy linda United States Centers for Medicare & Medicaid Services

Nesin Mirjana United States NIH/NIAID/DMID

Neuman William United States Pfizer Pharmaceuticals

NGUNDUE JEROME United States WALDEN UNIVERSITY

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Nicholson Jennifer United States Emory University

Offit Paul United States Children''s Hospital of Philadelphia

Owen Bill United States MedImmune

Paradiso Peter United States Pfizer

Parrino Janie United States Merck & Co., Inc.

Peter Georges United States Warren Alpert Medial School of Brown University

Peterson Diane United States Immunization Action Coalition

Plaskett Theresa United States Elizabeth Seton Pediatric Center

Plotkin Stanley United States Vaxconsult

Poland Greg United States Mayo Clinic

Pontani Dennis United States Pfizer Inc

Power Elizabeth United States Novartis Vaccines and Diagnostics

Purdy Jay United States Pfizer

Quinn Carrie United States private practice pediatrician

Quinn Jane United States GlaxoSmithKline

Read Jennifer United States NVPO

Redwood Lyn United States SafeMinds

Reeves-Hoche Mary Kate United States sanofi pasteur

Rein David United States RTI International

rennels margaret United States GlaxoSmithKline

Reynolds Megan United States Children''s Healthcare of Atlanta

Reynolds Joni United States Colorado Department of Public Health & Environment

Richardson López-Collada Vesta United States National Center for Children and Adolscentes Healt (CeNSIA)

Richmond Heather United States MedImmune

Ripley Millicent United States Avalon Catering

robbins patsy United States rite aid

Rosenbaum Sara United States George Washington University

Saah Alfred United States Merck & Co.

Sanyour Mark United States Novartis Vaccines

Sato Reiko United States Pfizer Inc.

Sattler Carlos United States Merck & Co., Inc.

Sawyer Mark United States UCSD School of Medicine

Schaffner William United States Vanderbilt University School of Medicine

Schmader Kenneth United States American Geriatrics Society

Schodel Florian United States Philimmune LLC

Schuler Christine United States University of North Carolina

Shaw Brian United States Sabin Vaccine Institute

Sheek-Hussein Mohamud United States Faculty Of Medicine

Sheffield Tamara United States Intermountain Healthcare

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Shelton Jerry United States Fuld and Company

Sherner James United States Pfizer

Shin Tom United States Baxter Healthcare Corporation

SIEVERT ALAN United States GA CHAPTER, AAP

Silber Jeffrey United States Merck & Co., Inc.

Silverstein Leonard United States GlaxoSmithKline Vaccines

Skjeveland Eric United States Merck Vaccines

Smith Susan United States Medscape

Snow Vincenza United States Pfizer Vaccines

Splete Heidi United States Pediatric News

Stephens David United States Woodruff Health Sciences Center, Emory University

Stinchfield Patricia United States NAPNAP

Strutton David United States Pfizer Inc.

Stuerke Stacy United States Merck Vaccine Division

Sullivan Gina United States GlaxoSmithKline

Sun Wellington United States Center for Biologics Evaluation and Research

Talkington Kathy United States ASTHO

Taylor Melinda United States Roanoke City and Alleghany Health Dept

Temte Jonathan United States ACIP

Thomas Lonnie United States Henry Schein, Inc

Thomas Sabrina United States DeKalb County Board of Health

Thompson Brad United States Pfizer

Titievsky Lina United States Pfizer Inc

Tobar Peter United States TOBAR LLC

Turner James United States American College Health Association

Vaupel Christine United States GlaxoSmithKline

Vaupel Logan United States no organization -- citizen

Verdecia Alonso Maykel United States Saint Francis Memorial Hospital

Vigliarolo Peter United States Cooney Waters

Wain Jennifer United States Northrop Grumman Corporation

Wallace Fred United States Fuld & Co

Warner Amy United States Take Care Health

Weston Wayde United States GlaxoSmithKline

Wexler Deborah United States Immunization Action Coalition

Whitley-Williams Patricia United States

University of Medicine & Dentistry of New Jersey-Robert Wood 

Johnson Medical School

Wu Lauren United States National Vaccine Program Office, DHHS

Yamauchi Terry United States Arkansas Children''s Hospital

Yarn Sandra United States GAAAP

Yeh Michael United States Novartis Vaccines

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Zahn Matthew United States Louisville Metro Department of Public Health and Wellness

Zimmerman Richard United States University of Pittsburgh

Zucker Jane United States NYC Dept. of Health and Mental Hygiene

Non-US Citizens

Asahi Kentaro Japan Pfizer Japan Inc.

Baehner Frank Germany Novartis Vaccines & Diagnostics

Biehn Brant Canada Dynavax

Dovali Claudia Mexico Novartis Vaccines & Diagnostics

Durrheim David Australia University of Newcastle

ElZein Majed Czech Republic Department Of Treasury pan Majed El Zein

Florez Jorge Colombia IMMUNOPROTECTION

Gomez Cesar Mexico Ministery of Health

Hein Pierre United Kingdom GlaxoSmithKline

Hollingsworth Rosalind United Kingdom Pfizer

IWAMA Masumi Japan sanofi pasteur KK

Kamiiya Hajime Japan

National Institute of Infectious Diseases Infectious Disease 

Surveillance Center

Kanaras John Canada Merck & Co., inc.

Kim Jonghee South Korea Korea Centers for Disease Control

LesterSwindell Mark United Kingdom Pfizer Inc

Mahmood Asif Canada sanofi pasteur

Omanio Roque Glenn Philippines Novartis Vaccines

Oselka Gabriel Brazil

National Technical Advisory Committee for Immunizations of 

Brazil

Park Kwang Suk South Korea Korea Centers for disease control & prevention

Rey Benito Gloria Janneth Colombia Instituto Nacional de Salud

Saddier Patricia France Merck & Co., Inc.

seo min jung South Korea korea centers for disease control & prevention

Tan Litjen Singapore American Medical Association

Tsuzuki Daisuke Japan sanofi pasteur Japan

UEMURA NOBUO Japan PMDA

YORK Laura Jean France PFIZER

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