DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION

Advisory Committee on 

Immunization Practices (ACIP)

Summary Report

February 25-26, 2009 

Atlanta, Georgia 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 25-26, 2009

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Table of Contents Page

Acronyms 4 

Agenda 6 

Wednesday, February 25

Welcome and Introductions 9 

Anthrax Vaccines

BioThrax® (Anthrax Vaccine Adsorbed): 

Reduced Dose / Route Change Study—Immunogenicity Results 

Draft Recommendations for Route /Schedule of Anthrax Vaccine Adsorbed (AVA)

13

15

Hepatitis Vaccines

Hepatitis A Vaccination among Contacts of Internationally Adopted Children 17

Influenza Vaccines 

Introduction

Influenza Surveillance Update

27

28

Rabies Vaccine 38

Update: Pertussis Vaccines Work Group 45

Pneumococcal Vaccines

Use of PPSV23 for Prevention Of Pneumococcal 

Pneumonia during an Influenza Pandemic

An Economic Analysis for use of PPSV23 for Prevention of 

Pneumococcal Pneumonia during an Influenza Pandemic

Update on PCV13 Pediatric Phase 3 Trial Results

Use of Pneumococcal Vaccines: VFC Vote

45

53

59

65

Measles, Mumps, and Rubella 74

General Recommendations 74

Human Papillomavirus (HPV) Vaccines 

Introduction80 

Update on Bivalent HPV Vaccine: 

AS04 Adjuvant Mechanisms of Action and Safety Meta-Analysis 

Burden of HPV Related Disease in Males

Update on Quadrivalent HPV Vaccine: Efficacy Data in Males

80

81

84

87

Vaccination of Immigrants and Refugees 92

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Public Comments 94

Thursday, February 26

Pediatric Haemophilus Influenzae B Cases in Minnesota, 2008-2009 94

Agency Updates

CDC / CCID / NCIRD

Center for Medicare and Medicaid Services (CMS)

Department of Defense (DoD)

Department of Veteran’s Affairs

Food and Drug Administration (FDA) 

Heath Resources and Services Administration (HRSA)

Immunization Safety Office (ISO)

National Institutes for Health (NIH) 

National Vaccine Program Office (NVPO)

National Vaccine Advisory Committee (NVAC)

Indian Health Services (I HS)

100

to

103

Meningococcal Vaccine 

Update: Meningococcal Work Group

Meningococcal Conjugate Vaccine Post-Licensure Safety Update:

 Vaccine Adverse Event Reporting (VAERS)

104

107

Update: Herpes Zoster (Shingles) Vaccine

Update: Herpes Zoster (Shingles) Vaccine

National Provider Survey Regarding Barriers to Implementation of Zoster Vaccine

111

113

Vaccine Supply 119

MMRV Vaccine Safety Updates 

Introduction

Update on Work Group Activities for Developing 

Policy Options for MMRV Vaccine Use 

 Provider Survey Regarding Opinions on the Use of MMRV Vaccine

122

122

128

Polio: Update on the Global Polio Eradication 

Initiative and Domestic Policy Issues

131

Update: Yellow Fever Vaccine Work Group 139

Public Comment 140

List of Members and Other Participants 141

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AAFP American Academy of Family Physicians

AAP American Academy of Pediatrics

ACIP Advisory Committee on Immunization Practices

AGS American Geriatrics Society

ALS Amyotrophic Lateral Sclerosis 

ATP According to Protocol

AVA Anthrax Vaccine Adsorbed 

AVWG Anthrax Vaccine Work Group 

BLA Biologics License Application

BOI Burden of Illness

CAIS Childhood / Adolescent Immunization Schedule

CAIV-T Cold-Adapted Influenza Vaccine

CCID Coordinating Center for Infectious Diseases

CDC Centers for Disease Control and Prevention

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

(AAP)

CIN Cervical Intraephithelial Neoplasia

Centers for Medicare and Medicaid Services

DBD Division of Bacterial Diseases (of NCIRD)

DGMQ Division of Global Migration and Quarantine

DHQP Division of Healthcare Quality Promotion

DoD Department of Defense

DSMBs Data Safety Monitoring Boards

DSTDP Division of Sexually Transmitted Diseases Prevention [of NCHHSTP]

DVA Department of Veterans Affairs

DVBID Division of Vector-Borne Infectious Diseases

DVD Division of Viral Diseases (of NCIRD)

DVH Division of Viral Hepatitis (of NCIRD)

DVRD Division of Viral and Rickettsial Diseases

FDA Food and Drug Administration

GBS Guillain Barré Syndrome

GID Global Immunization Division

GMCs Geometric Mean Concentrations 

GMTs Geometric Mean Titers

GSK GlaxoSmithKline

HICPAC Healthcare Infection Control Practices Advisory Committee 

HepA Hepatitis A

HepB Hepatitis B

HHS Department of Health and Human Services 

Hib Haemophilus influenzae B 

HMO Health Maintenance Organization

HPV Human Papillomavirus

HRIG Human Rabies Immune Globulin

HRSA Health Resources and Services Administration 

HZ Herpes Zoster

ID Influenza Division (of NCIRD)

IDSA Infectious Disease Society of America

IgG Immunoglobulin G

IgM Immunoglobulin M

IHS Indian Health Services

ILI Influenza-Like Illness

IND Investigational New Drug

IOM Institute of Medicine

ISD Immunization Services Division (of NCIRD)

Acronyms

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

ITT Intent to Treat

MCO Managed Care Organization 

MCV4 Meningococcal Conjugate Vaccine

MDH Minnesota Department of Health

MMRV Measles, Mumps, Rubella, Varicella

MMWR Morbidity and Mortality Weekly Report

mOPV1 Monovalent Polio Vaccine Type 1

NACCHO National Association of County and City Health Officials 

NACI Canadian National Advisory Committee on Immunizations 

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

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

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

Diseases

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

CDC/CCID)

NIH National Institutes of Health

NIS National Immunization Survey

NVAC National Vaccine Advisory Committee 

NVPO National Vaccine Program Office

OCSO Office of the Chief Science Officer

OD Office of the Director (of CDC)

ODCER Office for Disease Control and Emergency Response (Of China)

P&I Pneumonia and Influenza

PCV Pneumococcal Conjugate Vaccine

PEP Post-Exposure Prophylaxis

PhRMA Pharmaceutical Research Manufacturers of America

RCA Rapid Cycle Analysis

SAGE Strategic Advisory Group of Experts 

sBLA Supplemental Biologics License Application

SHEA Society for Healthcare Epidemiology of America

SMEs Subject Matter Experts

VAERS Vaccine Adverse Event Reporting System

VFC Vaccines for Children

VSD Vaccine Safety Datalink

VZV Varicella-Zoster Virus

WG Work Group

WHO World Health Organization

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MEETING OF THE ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES (ACIP)

Centers for Disease Control and Prevention

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

February 25-26, 2009

AGENDA ITEM PURPOSE

 

 

 

 

 

PRESIDER/PRESENTER(s)

Wednesday, February 25, 2009

8:00

 

Welcome & Introductions Dr. Dale Morse (Chair, ACIP)

Dr. Larry Pickering (Executive 

Secretary, ACIP; CDC)

8:30 Anthrax Vaccine

• BioThrax® (Anthrax Vaccine Adsorbed): reduced 

dose/route change study – immunogenicity results 

• Draft recommendation for route/schedule of Anthrax 

Vaccine Adsorbed (AVA) 

Information 

Information

Discussion

Vote

Dr. Robert Hopkins (Emergent 

BioSolutions)

Dr. Jennifer Wright 

(CDC/CCID/NCIRD/DBD)

8:55 Hepatitis Vaccines

• Hepatitis A vaccination among contacts of 

internationally adopted children 

 

Information

Discussion

Vote

Dr. Mark Sawyer (ACIP, WG Chair)

Dr. Sandra Chaves and Dr. Cindy 

Weinbaum 

(CDC/CCID/NCHHSTP/DVH)

9:55 Break

10:25 Influenza Vaccines

• Introduction 

• Influenza surveillance update 

• Antiviral resistance 

• 2009 influenza vaccine recommendations 

Information

Discussion

Vote

Dr. Kathy Neuzil (ACIP, WG Chair)

Dr. Anthony Fiore 

(CDC/CCID/NCIRD/ID)

11:25 Rabies Vaccine Information

Discussion

Dr. Paul Cieslak (ACIP, WG Chair)

Dr. Charles Rupprecht 

(CDC/CCID/NCZVED/DVRD)

12:10 Update: Pertussis Vaccines Work Group Information Dr. Mark Sawyer (ACIP, WG Chair)

Dr. Jennifer Liang 

(CDC/CCID/NCIRD/DBD)

12:15 Lunch

1:15 Pneumococcal Vaccines

• Use of PPSV23 for prevention of pneumococcal 

pneumonia during an influenza pandemic 

• An economic analysis for use of PPSV23 for prevention 

of pneumococcal pneumonia during an influenza 

pandemic 

• Update on PCV13 pediatric phase 3 trial results 

• Use of pneumococcal vaccines 

Information

Discussion

Information

Discussion

Information

VFC Vote

Dr. Matthew Moore 

(CDC/CCID/NCIRD/DBD)

Dr. Mark Messonnier 

(CDC/CCID/NCIRD/ISD)

Dr. Peter Paradiso (Wyeth)

Dr. Jeanne Santoli 

(CDC/CCID/NCIRD/ISD)

2:35 Measles, Mumps and Rubella

• Proposed changes in MMR vaccine evidence of 

 immunity requirements for healthcare personnel 

 

Information

Discussion

Dr. Jane Seward 

(CDC/CCID/NCIRD/DVD/OD)

Ms. Amy Parker 

(CDC/CCID/NCIRD/DVD/EB)

3:05 Break

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3:20 General Recommendations

• Storage and handling of immunobiologics 

• Vaccination of people with altered immunocompetence 

Information

Discussion

Vote

Dr. Ciro Sumaya (ACIP, WG Chair)

Dr. Andrew Kroger 

(CDC/CCID/NCIRD/ISD)

 

 

 

4:05 Human Papillomavirus (HPV) Vaccines

• Introduction 

• Update on bivalent HPV vaccine: ASO4 adjuvant 

 mechanisms of action and safety meta–analysis 

• Burden of HPV related disease in males 

• Update on quadrivalent HPV vaccine: efficacy data in 

 males 

• Work Group plans for upcoming recommendations

Information

Information

Information

Information

Discussion

Dr. Janet Englund (ACIP, WG Chair)

Dr. Tom Verstraeten (GSK)

Dr. Mona Saraiya 

(CDC/NCCDPHP/DCPC)

Dr. Rick Haupt (Merck)

Dr. Lauri Markowitz 

(CDC/CCID/NCHHSTP/DSTDP)

4:55 Pediatric Haemophilus influenzae B Cases in Minnesota, 

2008-2009

Information

Discussion

Ms. Kris Ehresmann (ACIP, MDH)

Dr. Jeanne Santoli 

(CDC/CCID/NCIRD/ISD)

5:15 Vaccination of Immigrants and Refugees Information

Discussion

Dr. Martin Cetron/Dr. Katrin Kohl 

(CDC/CCID/NCPDCID/DGMQ)

5:30 Public Comment

5:45 Adjourn

Thursday, February 26, 2009

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

8:30 Agency Updates (CDC/CCID/NCIRD, CMS, DOD, DVA, 

FDA, HRSA, IHS, ISO, NIH, NVAC, NVPO)

Information

 8:45 Meningococcal Vaccine

• Update: Meningococcal Work Group 

• Meningococcal conjugate vaccine post-licensure 

 safety update - Vaccine Adverse Event Reporting 

 (VAERS) 

Information

Information

Discussion

Dr. Carol Baker (ACIP, WG Chair)

Dr. Angela Calugar (CDC/OD/OCSO)

 9:15 Update: Herpes Zoster (Shingles) Vaccine

• Update: herpes zoster (shingles) vaccine 

• National provider survey regarding barriers to

 implementation of zoster vaccine 

Information

Information

Dr. Rafael Harpaz 

(CDC/CCID/NCIRD/DVD)

Dr. Allison Kempe 

 (University of Colorado)

9:55 Vaccine Supply Information 

Discussion

Dr. Jeanne Santoli 

(CDC/CCID/NCIRD/ISD)

10:10

 

Break

10:40 MMRV Vaccine Safety

• Introduction 

• Update on Work Group activities for developing policy 

options for MMRV vaccine use 

• Provider survey regarding opinions on the use of MMRV 

vaccine 

• Discussion 

Information

Information

Information

Discussion

Dr. Jonathan Temte 

 (ACIP, WG Chair)

Dr. Mona Marin 

(CDC/CCID/NCIRD/DVD)

Dr. Allison Kempe 

 (University of Colorado)

Dr. Jonathan Temte

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11:25 Polio: Update on the Global Polio Eradication Initiative 

and Domestic Policy Issues 

Information

Discussion

Dr. Steve Wassilak

(CDC/CCID/NCIRD/GID)

Dr. Gregory Wallace 

(CDC/CCID/NCIRD/DVD)

12:10

 

Update: Yellow Fever Vaccine Work Group Information Dr. Carol Baker (ACIP, WG Chair)

12:15 Public Comment

 

12:30 Adjourn

Welcome & Introductions

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Dr. Dale Morse (Chair, ACIP)

Dr. Larry Pickering (Executive Secretary, ACIP; CDC)

Dr. Richard Besser (Acting Director, CDC)

Dr. Samuel L. Katz (ACIP Liaison Representative, Infectious Diseases Society of America) 

 

Dr. Dale Morse, Advisory Committee on Immunization Practices (ACIP) Chair, welcomed those 

present and called the meeting to order at 8:00 a.m. 

Dr. Larry Pickering, ACIP Executive Secretary, extended his welcome to those in attendance. 

With great pleasure and gratitude, he introduced Dr. Richard Besser, Acting Director of the 

Centers for Disease Control and Prevention (CDC). Dr. Pickering noted that Dr. Besser had 

worked with and had been involved in the career development of several of the committee 

members, and that he had been intimately involved in ACIP activities. Dr. Besser then 

presented a special award.

Dr. Besser stressed what a privilege and an honor it was to deliver the opening remarks during 

this meeting of the ACIP. As a general pediatrician, he said he has benefited greatly from the 

work of ACIP, and as the Acting Director of CDC and a long-term CDC epidemiologist, has 

appreciated the scientific deliberations that the ACIP has undergone to develop very thoughtful 

recommendations. He then presented an award to Dr. Samuel L. Katz, pointing out that CDC 

and ACIP were honored during this meeting to offer appreciation to Dr. Katz, who has 

contributed enormously to ACIP in several capacities, and who likely holds the record for 

longest running involvement with ACIP’s activities from 1982 to the present. 

Dr. Katz served as a voting member of the ACIP from 1982 through 1993, which included 

chairmanship of the committee from 1985 through 1993. This period was notable for 

remarkable progress in vaccinations to prevent invasive Haemophilus influenzae type b (Hib), 

the leading cause of pediatric meningitis in the United States (US) at the time. Dr. Katz played 

a key role in leading the ACIP constructively and rapidly to assess the controversy on the 

strategy and effectiveness of the Hib polysaccharide vaccine, as well as moving ahead with 

prompt recommendations for use of the newly licensed Hib conjugate vaccine, which eventually 

led to a 99% decrease in this devastating disease. During his tenure as chair, Dr. Katz played a 

major role in evaluating the safety of the whole cell pertussis vaccine and set the stage for 

transition to acellular pertussis vaccines. Also during his tenure, Dr. Katz guided the ACIP 

through an extensive evaluation of the need for a second dose of the MMR vaccine, which was 

recommended in 1989 following almost a decade of deliberations. 

Since 1998, Dr. Katz has represented the Infectious Diseases Society of America (IDSA) as 

liaison member to the ACIP. In this capacity, Dr. Katz has participated actively as a member of 

several ACIP workgroups where his years of experience in vaccine research and 

implementation of immunization programs have proved invaluable in the development of options 

for policy recommendations. After graduating cum laude from Harvard Medical School, Dr. Katz 

completed his medical internship at Beth Israel Hospital and his pediatric residency at 

Massachusetts General Hospital and Boston Children’s Hospital, where he also served as a 

research fellow in virology and infectious diseases. He then became a staff member at 

Children’s Hospital and worked with Nobel Laureate John Enders for twelve years. Together, 

they developed the attenuated measles virus vaccine currently used worldwide. 

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Early in his career, Dr. Katz became fascinated with the measles virus and was instrumental in 

developing a vaccine for the disease using cell culture techniques and egg inoculations. In fact, 

after fastidiously preparing safety tested material for use in humans, he first inoculated himself 

and then his colleagues in the laboratory. After a series of clinical trials proved the vaccine 

effective and safe, it was licensed in 1963. By 1968, the incidence of measles plummeted to 

low levels. Once the vaccine was proven to be effective domestically, Dr. Katz was eager to 

see its success taken globally, conducting studies that contributed to the use of measles 

vaccines internationally. As well as chairing the ACIP, Dr. Katz previously chaired the 

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

Book Committee; the vaccine priority study of the Institute of Medicine (IOM); and several World 

Health Organization (WHO) and National Institutes of Health (NIH) panels. He also chaired the 

committee that in 2000 declared that measles was no longer endemic in the US. 

For 22 years, Dr. Katz was Chairman of Pediatrics at Duke University. In addition to mentoring 

students and residents for over two decades, Dr. Katz established an exchange program with 

Oxford University and provided training for an annual succession of residents from the American 

University of Beirut. Graduates of this program hold positions in the Food and Drug 

Administration (FDA), CDC, NIH, university departments, state health departments, research 

institutes, and in private practice. Dr. Katz has shared numerous scientific activities with his 

wife of many years, Dr. Catherine Wilfert, also an infectious disease expert who is currently the 

senior technical advisor to the CEO of the Elizabeth Glazer Pediatric AIDS Foundation, and who 

preceded Dr. Katz as ACIP chair during the 1980s. 

Tremendous gratitude was expressed to Dr. Katz for his years of tireless dedication, enthusiasm 

for the work, and his unfailing good humor. In his work with ACIP, he has been remarkable, not 

only for his graciousness and inclusiveness, but also for his effective committee management 

abilities. Dr. Katz brings a unique mix of skills and attributes that include expertise in virology

and vaccinology, modesty and team spirit, and an ability to translate basic scientific knowledge 

into sensible public health policy. Dr. Besser concluded that it gave him great pleasure to 

present an award to Dr. Katz for his tremendous accomplishments, which read, “Advisory 

Committee on Immunization Practices, Centers for Disease Control and Prevention. In 

recognition of the invaluable service of Samuel L. Katz, MD, ACIP member 1982-1993, ACIP 

chair 1985-1993, ACIP liaison representative 1998-present.” 

Dr. Katz thanked CDC and ACIP, noting that this award was totally unexpected. He said he had 

enormously enjoyed his years working with ACIP in various capacities, and in getting to know 

many of the CDC staff members. He quipped that while many of his colleagues send their best 

and brightest to the National Institutes of Health (NIH), he always sends his to CDC. Those 

present thunderously applauded Dr. Katz.

At this time, Dr. Morse officially opened the meeting, thanking Dr. Besser for taking time out of 

his busy schedule to address the committee and present the award to Dr. Katz. He pointed out 

that one of the perks of being an ACIP member and attending these meetings is to bask in the 

wisdom of the icons in the world of immunization. Dr. Sam Katz is one of those icons and while 

he is not a giant in height, he is a giant in stature, and his comments and actions have 

prevented untold illnesses and saved many lives. Due to his many accomplishments, it was 

only fitting that they honor Dr. Katz for his career of service to CDC and ACIP, although that 

paled in comparison to how his presence, comments, and actions honor the agency and 

committee more. 

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Dr. Pickering indicated that Dr. Besser’s remarks were being circulated around the room for 

those who wanted to sign them and / or write their thoughts to Dr. Katz. He reminded everyone 

that the “Call to Order Bell” was given to ACIP by Dr. Katz in 1993, so every time they ring it, 

they will forever think of him. 

He pointed out several individuals who were to be present throughout the meeting to assist with 

meeting functions (Antonette Hill, Natalie Greene, Tamara Miller, Stephanie Renna, and Suzette 

Law) and he reviewed housekeeping issues. In addition, he referred participants to the ACIP 

website (www.cdc.gov/vaccines/recs/acip), noting that copies of the handouts distributed to 

ACIP members were available on the table outside the meeting room for members of the public, 

that slides used during the meeting would be posted on this site where they would be available 

approximately one week following the meeting, and that the minutes of the meeting would be 

posted within approximately 90 days following the meeting. ACIP Recommendations, Notice to 

Readers, and other information related to immunization and ACIP activities also can be found 

on this site. CDC has updated its vaccine safety web site (www.cdc.gov/vaccinesafetv). 

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

contact Tom Skinner. Dr. Pickering noted that their long-time friend and colleague, Curtis Allen, 

had taken another position outside CDC. He also welcomed visitors from China’s Office for 

Disease Control and Emergency Response (ODCER) Dr. Zijian Feng, Director; Dr. Luzhao 

Feng and Dr. Xuesong Pei.

Dr. Pickering congratulated ACIP’s immediate past chair, Dr. Jon Abramson, who was 

nominated and chosen to serve as a representative from the Americas to the Strategic Advisory 

Group of Experts (SAGE). Dr. Abramson served from 1999 to 2003 as an ACIP liaison 

representative from AAP, as an ACIP member from 2003 to July 2007, and as ACIP chair from 

2005 until July 2007. 

He welcomed new member Dr. Linda Kinsinger from the National Center for Health Promotion 

and Disease Prevention (NCHPDP), who has been chosen to represent the Department of 

Veteran Affairs (DVA) as the Ex Officio Member. Ex officio members Dr. Gus Birkhead from the 

National Vaccine Advisory Committee (NVAC) and Dr. George Curlin from NIH were unable to 

attend this ACIP meeting. It was noted that Dr. Gellin would present the NVAC update, while 

Ms. Carolyn Deal and Ms. Barbara Mulach were in attendance on behalf of Dr. Curlin. Liaison 

representatives Dr. David Salisbury from the Department of Health in the United Kingdom (UK), 

Dr. Alexis Elward from the Healthcare Infection Control Practices Advisory Committee 

(HICPAC), and Dr. Joanne Langley from the Canadian National Advisory Committee on 

Immunizations (NACI) were also unable to attend this meeting. 

To avoid interruptions during the meeting, Dr. Pickering requested that all business not directly 

related to discussions of ACIP be conducted in the hall to avoid disturbing people in the 

audience, and that all cell phones be turned off or placed in the vibrate mode to avoid 

disruption. He stressed the importance of all members remaining throughout the meeting to 

maintain a quorum, requesting that appointed members return from breaks and lunch in a timely 

manner to participate in the meeting to help facilitate an efficient and productive meeting. In 

addition, he reminded everyone that the ACIP charter gives the Executive Secretary, or his 

designee, the authority to temporarily designate ex officio members as voting members. This 

would occur only if there were fewer than eight appointed members available, or qualified to 

vote due to financial conflict of interest. If necessary, the ex officio members would be formally 

requested to vote when necessary. If this occurred, they would be asked to disclose any 

potential conflicts of interest.

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The ACIP home page URL is www.cdc.gov/vaccines/recs/acip. The website is updated at 

frequent intervals with the current version of the meeting agenda, meeting minutes, and 

presentations, as well as ACIP recommendations and other information related to 

immunizations and ACIP activities. CDC continues to update its vaccine safety web page for 

which the URL is www.cdc.gov/vaccinesafety. Since the last meeting the Rotavirus Vaccine 

Recommendations have been published in the Morbidity and Mortality Weekly Report (MMWR) 

The adult and childhood immunization schedules also have been published. The adult schedule 

was published in the Annals of Internal Medicine for the second year in a row, as well as in the

American Family Physician Journal and the MMWR. The interactive catch-up immunization 

schedule has been updated to reflect the 2009 childhood schedule. A standardized list of 

vaccine abbreviations has been posted to the ACIP website. Dr. Bill Atkinson will ensure that 

the vaccine abbreviations will be included in the Pink Book, and these will be included in the 

Red Book. 

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

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

deliberation of a specific agenda item. Comments from the public may be received during open 

discussions depending on the amount of time available. Dr. Pickering requested that those who 

planned to make public comments sign in at the registration table at the rear of the auditorium 

where Antonette Hill would record their name and provide information on the process. Those 

who registered prior to the meeting were instructed to check the list to ensure that their names 

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

audience to use when addressing the committee. Dr. Pickering requested that anyone making 

comments identify himself or herself and organization before comments were made. He 

stressed that both CDC and the public believe in a transparent process for information gathering 

and decision-making. To ensure such transparency during the public comment session, CDC 

believes that it is important to understand the context of an individual’s comments. For this 

reason, CDC encourages people at the beginning of comments to advise the committee of any 

financial relationship that he or she may have with any company or any organization that is 

likely to be impacted by the topic being discussed. For example, the financial information may 

include the company’s or organization’s payment of travel, lodging, or other expenses in 

connection with attendance at the meeting. Likewise, CDC encourages individuals at the 

beginning of their statements to advise the committee if they do not have any such financial 

relationships. Although encouraged, choosing not to address the issue of financial relationships 

prior to making comments would not preclude individuals from speaking.

As in previous ACIP meetings, a review of vaccine safety issues and a discussion of the vaccine 

supply of recently approved vaccines were included in the agenda.

With respect to disclosures, Dr. Pickering explained that the goal in appointing members to the 

ACIP was to achieve the greatest level of expertise while minimizing the potential for actual or 

perceived conflicts of interest. To summarize conflict of interest provisions applicable to the 

ACIP as noted in the ACIP Policies and Procedures Manual, members of the ACIP agree to 

forgo 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 granted limited conflict of interest waivers. Members who conduct vaccine 

clinical trials or serve on data safety monitoring boards may serve as consultants to present to 

the committee on matters that relate to those specific vaccines. However, they are prohibited 

from participating in deliberations or votes of the committee on issues related to those specific 

vaccines. Regarding other vaccines of the affected company, a member may participate in 

discussions with the proviso that he or she abstains on all votes related to vaccines of that 

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company. ACIP members who may have a potential financial conflict of interest should make 

this conflict known by disclosing all of their vaccine-related financial interests and related 

activities.

Regarding applications for membership appointment, the ACIP Secretariat solicits applications 

throughout the year for candidates to serve as ACIP members. Detailed instructions for 

submission of names of candidates may be found on the ACIP website. Applications may be 

submitted at any time during the year. Materials in support of the next cycle of applications for 

ACIP membership, which begins in July 2010, are due no later than November 15, 2009. ACIP 

meeting registration dates are established for security reasons. The CDC complex is a secured 

environment and pre-registration for meetings is posed on the ACIP website. This preregistration is time-sensitive for international visitors, given that the Office of Security and 

Emergency Preparedness (OSEP) is required to pre-approve access for all non-US citizens 

visiting CDC facilities. Dr. Pickering requested that everyone register early for the June 24-25, 

2009 meeting by visiting the ACIP website. 

Dr. Pickering then turned the meeting over to Dr. Morse, who welcomed members and

requested that any conflicts of interest be indicated. The following conflicts of interest were 

declared: Dr. Marcy is serving as a consultant to Merck through April 2009; Dr. Englund is 

receiving research support from Novartis, MedImmune and sanofi pasteur; Dr. Meissner 

indicated that payments are made to Tufts Medical Center by Wyeth and MedImmune. All other 

ACIP members present declared that they had no conflicts of interest. 

BioThrax®: Reduced Dose / Route Change Study—Immunogencity Results

Robert Hopkins, MD, MPH, TM

Vice President, Clinical Development US

Emergent BioSolutions Inc.

Dr. Hopkins expressed his gratitude to the ACIP for permitting Emergent BioSolutions to discuss 

some of the immunogenicity results from the trial conducted and sponsored by CDC. His 

involvement was to interact with the Food and Drug Administration (FDA) in implementing the 

recent labeling change pertaining to route and schedule that occurred with the FDA approval on 

December 11, 2008. With regard to the clinical trial, Dr. Hopkins described the study design 

and objectives, populations and analytic datasets, the non-inferiority criteria, and the 

immunogenicity results from the following time points:

 









At Week 8: After 0-2-4 wks SQ vs. 0-2-4 wks IM

At Week 8: After 0-2-4 wks SQ vs. 0-4 wks IM

At Month 7: After 0-2-4-26 SQ vs. 0-2-4-26 IM

At Month 7: After 0-2-4-26 SQ vs. 0-4-26 IM

Anthrax Vaccine

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The trial was a randomized placebo controlled double blind multi-center study conducted in the 

US at five academic institutions. There were seven study arms. The first arm (A) was the 

previously approved subcutaneous (SC) route and schedule, six doses over eighteen months 

followed by two additional booster doses at months 30 and 42. The second arm (B) was the 

same schedule using intramuscular (IM) route administration. The next three arms (C) were 

combined for the purposes for this analysis. This arm examined the IM route, dropped the twoweek dose, and evaluated different booster schedules. These arms will be further investigated 

and analyzed in the 43-month analysis that will be conducted by CDC later in 2009. The last 

two arms (D) were saline placebo given IM and subcutaneous. Dr. Hopkins’ discussion during 

this ACIP meeting was limited to two time points: Week 8 and Month 7 following each 

vaccination. 

As outlined in the study protocol drafted in 2002, the primary study objectives were to: 1)

demonstrate that BioThrax® (Anthrax Vaccine Adsorbed) administered by the IM route elicits 

antibody responses that are non-inferior to that achieved by the currently licensed schedule 

(Group A vs. Group B); and 2) to demonstrate that BioThrax® (Anthrax Vaccine Adsorbed) 

administered by the IM route and containing fewer numbers of doses (no 2-week dose) elicits 

antibody responses that are non-inferior to that achieved by the currently licensed schedule 

(Group A vs. Group C). The primary study endpoints included: Geometric Mean Concentrations 

(GMCs): Anti-PA specific IgGl; Geometric Mean Titers (GMTs): Anti-PA specific IgG; and 

seroconversion: ≥ 4 fold rise in anti-PA specific IgG titer. 

There were two primary study populations: 1) Intent-to-treat (ITT) population, which included 

those subjects who received at least one dose. This was used for safety; and 2) According to 

Protocol (ATP) population, which consisted of those subjects who at a particular time point must 

have received all injections up through that time point; injections within the windows defined by 

the protocol; the correct agent administered by the correct route according to subject’s assigned 

study arm; and the correct injection volume (0.3 mL or greater considered valid). Dr. Hopkins 

noted that immunogenicity analyses included data from blood draws that occurred within 

defined windows at a particular time point. 

Non-inferiority criteria were established prospectively in the study. With respect to 

immunogenicity analyses performed at Week 8 and Month 7, for GMC and GMT the criteria for 

non-inferiority of comparisons were based on the mean antibody GMC / GMT ratio (Group A 

/Group X). Non-inferiority was achieved (passed) when the upper 97.5% confidence limit was < 

1.5. For seroconversion criteria for non-inferiority of comparisons was based on differences in 

rates of a four-fold rise in antibody titer (Group A – Group X). Non-inferiority was achieved 

(passed) when the upper 97.5% confidence limit was < 0.10. Baseline values below LLOQ 

were set to 1⁄2-empirical LLOQ to calculate post-vaccination four-fold rise in titer.

Regarding the Week 8 Response: SQ (0-2-4 Wks) versus IM (0-2-4 Wks), the point estimates 

for IM were somewhat lower for both GMCs as well as GMTs; however, all three primary end 

points met the criteria. For the Month 7 Response: SQ (0-2-4-26 Wks) versus IM (0-2-4-26 

Wks), the point estimates were somewhat higher for the IM route of administration versus 

subcutaneous, and all non-inferiority criteria were met. In the Week 8 Response: SQ (0-2-4 

Wks) versus IM (0-4 Wks) in which the two-week dose was dropped and there was a change to 

an IM route of administration, there was a drop in the point estimates for the IM route and the 

dropping of the two-week dose (Group C versus Group A), and the prospective defined noninferiority criteria was not passed for GMCs and GMTs. However, the criteria were passed for a 

four-fold rise seroconversion. In Group C, with the dropped two-week dose and move to IM 

route administration, non-inferior criteria are easily passed for all end points. Again, the IM 

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route, as well as dropping the two week dose, have point estimates that are numerically higher 

and easily pass the non-inferiority criteria for all three endpoints. 

In conclusion with respect to immunogenicity for this trial, at Week 8 Group B (IM 0-2-4-26 

weeks) was non-inferior to Group A (SQ 0-2-4-26 weeks) for all three primary endpoints. Group 

C (IM 0-4 weeks) was non-inferior to Group A (SQ 0-2-4 weeks) for the percentage with a fourfold rise in titer but not non-inferior to Group A for GMC and GMTs. At Month 7 Group B (IM 0-

2-4-26 weeks) was non-inferior to Group A (SQ 0-2-4-26 weeks) for all three primary endpoints. 

Group C (IM 0-4-26 weeks) was non-inferior to Group A for all three primary endpoints. Thus, 

the elimination of the Week 2 dose did not impact the immune response following the 6-month 

vaccination.

With respect to the approved labeling that occurred on December 11, 2008, these results 

essentially allowed a change from 6 doses to 5 and a change from SQ to IM administration. 

The recommended dosing schedule is now 0, 1, 6, 12, 18 months with annual boosters. The 

route of administration is now intramuscular, unless when medically indicated, such as in 

persons with coagulation disorders or receiving medications that affect coagulation (e.g., 

Coumadin® / Warfarin), the subcutaneous route may be used.

Draft Recommendations for the Pre-Event Use of Anthrax 

Vaccine Adsorbed (AVA): Route of Administration Number of Doses

Jennifer Gordon Wright, DVM, MPH

ACIP Anthrax Vaccine Work Group

On behalf of the Anthrax Vaccine Work Group (AVWG), Dr. Wright thanked the ACIP for giving 

her and Dr. Hopkins the opportunity to present the final piece of this statement and the AVWG’s 

final recommendation. She recognized all of the AVWG members, especially the two ACIP 

members Drs. Morse and Beck.

Dr. Wright reminded everyone that in October 2008, ACIP voted to approve approximately 20 

recommendations for the use of Anthrax Vaccine Adsorbed (AVA) both pre-event and postexposure. During this meeting, she explained that the AVWG would be requesting an ACIP 

vote on the route change and dose reduction recommendation. This would allow the workgroup 

to finalize the statement, a draft copy of which all ACIP members received for review on 

February 3, 2009. Comments were received from most of the ACIP members and the AVWG 

was working to finalize the document, with plans for submission to the MMWR in the near 

future. 

The workgroup reviewed the dose reduction and route change data, and the data were

previously presented to ACIP in their entirety on several occasions. The workgroup’s position 

was that IM administration, as presented to the ACIP in October 2008, was associated with 

fewer injection site adverse events than subcutaneous administration. IM administration also 

elicited an immune response equivalent to that elicited by subcutaneous administration. 

Removing the second priming dose administered at Week 2 had no negative impact on immune 

response in the pre-event regimen. Therefore, the workgroup presented the following draft 

recommendation for pre-event use of AVA for consideration by ACIP, “ACIP recommends 5 IM

doses administered at day 0, week 4, months 6, 12, and 18, followed by annual boosters. 

Subcutaneous administration is allowable only when medically indicated, such as in persons 

with coagulation disorders.” At this time, there was no recommendation to change the dose or 

the route recommendation for the use of AVA in the post-exposure setting. 

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Discussion

Dr. Marcy noted that based on Page 23 of the statement that 6,000,000 doses were 

administered and presuming that in the Army all 5 doses were given to everybody, it appeared 

that approximately 1.2 million personnel received AVA. With that in mind, he wondered whether 

anyone was concerned about the 25 deaths, three of which were due to Amyotrophic Lateral 

Sclerosis (ALS). To Dr. Marcy, this seemed like a high number of ALS cases.

Col Cieslak replied that the number of personnel receiving doses was greater than 1.2 million. 

Not everyone received all of the doses. Many personnel left the military after receiving only 2 or 

3 doses. He thought it was probably closer to 1.9 to 2 million personnel who received at least 

some doses. He then looked up the incidence of ALS per year in the general population, 

reporting that this appears to range between 1.4 and 2.7 per 100,000. Rounding that off to 2, in 

a population of 2 million, 40 cases of ALS would be expected. While that is not controlled for 

age and the military is a younger population than normal, the 3 ALS deaths did not appear to be 

unusual. 

Also troubled by the number of ALS cases, Dr. Temte looked up the incident rate in the general 

population. Given that there is usually a fairly short latency between onset and death in ALS, 

the numbers seemed to him to be within what could probably be expected with the number of 

doses administered.

With respect to the post-exposure, inhalational situation, Dr. Lett requested clarification about 

what would remain under Investigational New Drug (IND) Protocol versus what constituted 

licensed use.

Dr. Wright responded that licensure is only for pre-event use. Post-exposure use at 0, 2, and 4 

weeks administered subcutaneously is under an IND. The group that holds the IND is in the 

process of submitting a request to the FDA for consideration to change to IM administration. 

She believed a ruling was expected in April 2009. 

Dr. Cieslak requested information about the subjects who were in this trial and their 

demographics (e.g., age, sex, and race).

Dr. Wright replied that the subjects in this trial were 1,563 US civilians. Across the study 

groups, the subjects were approximately 50/50 male and female, approximately 80% 

Caucasian, and the majority were less than 30 years of age. The next highest age group were 

40 to 50 years old.

Motion: Pre-Event Use of AVA Recommendation

Dr. Neuzil made a motion to approve Option 1 Pre-Event Use of AVA Recommendation as 

written. Dr. Baker seconded the motion. The motion carried with 15 affirmative votes, 0 

abstentions, and 0 negative votes. 

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Overview

Dr. Mark Sawyer, Chair 

ACIP Hepatitis Workgroup

Dr. Sawyer introduced the first action item brought to the ACIP by the Hepatitis Vaccine 

Workgroup, which was formed in the Fall of 2008, and on which Drs. Cieslak and Ehresmann 

also serve. Liaisons represented on this workgroup include: American Academy of Pediatrics 

(AAP), National Association of County and City Health Officials (NACCHO), Infectious Disease 

Society of America (IDSA), American Geriatrics Society (AGS), Healthcare Infection Control 

Practices Advisory Committee (HICPAC), Society for Healthcare Epidemiology of America

(SHEA). Expert contributors include: Brian McMahon, Rafi Ahmed, and Myron Levin. CDC 

staff include: Sandra Chaves, Cindy Weinbaum, and Trudy Murphy. 

The Hepatitis Workgroup’s terms of reference are to determine the advisability and extent of 

hepatitis A vaccination recommendations for families adopting children from other countries; 

review data from recent hepatitis B outbreaks among diabetics in institutional care to determine 

whether vaccination is appropriate; review data related to long-term immunity of hepatitis B 

vaccine to determine if additional vaccine doses are necessary and if so, under what dosage 

and schedule; and review hepatitis A vaccine long-term immunity to determine whether updating 

recommendations is warranted. 

Hepatitis A Among Contacts Of Internationally Adopted Children

Sandra Chaves, MD, MSc 

Division of Viral Hepatitis

NCHHSTP / CDC

During this session, Dr. Chaves described the morbidity of hepatitis A associated with 

international adoption by providing some examples of recent cases, discussed some 

background features of hepatitis A virus infection, and discussed the characteristics of 

international adoptees. 

In June 2007, CDC was notified of a case of fulminant hepatitis A in a 51-year-old grandmother 

of 12-month old adopted twins. The twins were not jaundiced, but were both confirmed to have 

hepatitis A by IgM testing (anti-HAV IgM+). This case prompted further investigation, with 20 

cases of hepatitis A in non-traveling contacts of international adoptees identified from six

different states between 2006 and 2007 [Fischer et al., Clin Infect Dis. 2008 Sep 15;47(6):812-

4]. 

In 2008, CDC learned about hepatitis A in both non-traveling parents of an international adoptee

in Minnesota. This child was an 18-month old who was non-jaundiced, but who was confirmed 

to have hepatitis A by IgM testing (anti-HAV IgM+). Both parents were hospitalized due to 

hepatitis A, were sick for almost two months, were too ill to care for their child, were too ill to

work, and had substantial medical care costs [International Adoption Medicine Program, MN – 

Cynthia R. Howard]. Also in 2008, CDC was informed of a community spread of hepatitis A 

related to an international adoptee. This child was a non-jaundiced 10-month old who was 

confirmed to have hepatitis A by IgM testing. Overall, 12 cases of hepatitis were associated 

with this outbreak, all in non-traveling contacts. Of these, 6 were household members (attack 

rate 100%), 4 cases resulted from contact with household members who attended the local 

Hepatitis Vaccines

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elementary school (3rd and 5th grades), there was documented exposure in a pre-kindergarten 

class, 2 cases were identified among extended family members, and 2 adult cases were 

hospitalized (one with fulminant hepatitis). Two vaccination clinics were set up in response to 

this outbreak [Maine State Health Department, unpublished data]. 

In January 2008, another cluster of hepatitis A in non-traveling contacts of an international 

adoptee was reported to CDC. Two children, aged 8 and 14 months, were adopted. The 14-

month old was not jaundiced, but was confirmed hepatitis A by IgM. Both parents, who were 

vaccinated before travel following ACIP recommendation, did not become ill. However, there 

were 3 hepatitis cases among 5 non-traveling household contacts for an attack rate of 60%. IG 

and immune globulin (IG) and vaccine were offered to the close contacts to control the spread 

of infection.

In summary, international adoptees have been recognized as an important source of hepatitis A 

for their unvaccinated, non-traveling contacts in the US. In fact, international adoption as a 

source of infection for hepatitis A is likely to be underestimated, primarily due to the incomplete 

ascertainment of cases. Based on surveillance, it is known that cases of hepatitis A are 

substantially underreported. Moreover, the current hepatitis A surveillance system does not 

capture international adoption as a risk factor. 

With respect to transmission of hepatitis A, the incubation period is 4 weeks on average. The 

range is 2 to 8 weeks (~60 days). The greatest period of communicability is approximately 2 

weeks before jaundice. In the US, transmission is most common by person-to-person contact, 

especially in household settings [Bell BP et al. J Infect Dis 1998;178(6):1579-84]. The highest 

risk of hepatitis is associated with infected children in diapers ages 0-3 years [Hadler S et al. J 

Infect Dis 1982; 145: 255-61]. In fact, infected, non-jaundiced children under age 6 have been 

described as the most likely source of hepatitis A for adults without any other risk factors [Staes 

CJ et al. Pediatrics 2000;106(4):E54; Smith PF et al Epidemiol Infect 1997; 118:243-52].

In terms of the probability of symptomatic (jaundice) hepatitis A virus infection by age, up to 

70% of children under the age of 6 may be infected without having jaundice, but are a source of 

infection for other age groups. Of children ages 6 to 17 years, 20% to 50% could also be 

infected without jaundice [Armstrong GL et al. Pediatrics 2002;109:839–45]. The severity of 

hepatitis A increases by age. The overall fatality rate of hepatitis A is considered to range 

between 0.3% to 0.6%, but is at least 3 times higher (1.8%) among adults 50 years and older 

[Adapted from MMWR 2008; 57 SS-2]. The estimated cost of a case of hepatitis A, based on 

2004 US dollars, ranges from $800 to $300,000 if a patient requires a liver transplant due to 

fulminant hepatitis. In terms of the public health costs, one reported case is estimated to cost 

approximately $700, excluding outbreak control (e.g., vaccination clinics) [Rein et al.; Pediatrics, 

2007].

In summary, approximately 70% of infected children <6 years, and approximately 20% to 50% 

of infected older children are not jaundiced. The incubation period can be as long as 8 weeks or 

approximately 60 days. Diaper-wearing aged children are the most efficient source of 

transmission to older age groups. Death and hospitalization due to hepatitis A is more likely to 

occur among infected adults. 

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With regard to the at-risk population of contacts of international adoptees, hepatitis A vaccine 

was first available in the US in 1995. ACIP recommendations targeted vaccination for children 

in high endemic areas, and high risk groups, e.g., travelers (1996 &1999). Nationwide 

childhood immunization for 12-23 month olds was recommended in 2006. Although the 

program has primarily targeted children, a strong herd immunity effect has been described 

related to hepatitis vaccine [Samandari et al.Vaccine, 22 (2004) 4342-50].

There was a dramatic decrease of hepatitis A incidence among the US population from the prevaccine era to 2007. Due to lack of circulation of virus and the herd immunity effect of the 

vaccine, adults are now less likely to be exposed to circulating virus and, therefore, may be 

more susceptible to hepatitis A [NNDSS, CDC unpublished]. Based on the National Health and 

Nutrition Examination Survey (NHANES) conducted from 1999-2004, less than 40% of adults 

ages 20 to 59 have markers of immunity to hepatitis A. While hepatitis A infections decreased 

in all age groups in the US, over 60% of adults 20-59 years of age are susceptible. In addition, 

this is the age group most likely to be adoptive parents. 

The annual number of internationally adopted children coming to the US from 1998-2008, 

estimated from immigrant visas issued to orphans, is approximately 18,000. Of these 

internationally adopted children ages 0-17 years old, it is estimated that 40% are under 1 year of 

age, 85% are under 5 years of age, and 16% are 5 years and over. Countries with the greatest 

number of adoptions have changed over time. For instance, in 1990 South Korea was the most 

common source for US adoptions. Russia and China became preeminent in international 

adoption in the late 1990s. More recently, countries such as Guatemala and Ethiopia made 

their adoption process easier, so they became a popular destination for international adoption. 

For example, in 2003 only 135 children were adopted into the US from Ethiopia. In 2008, 

almost 2,000 children came from Ethiopia. While it is impossible to predict which country 

international adoptees will come from in any given year, Dr. Chaves considers all countries in 

which international adoptions occur to be endemic for hepatitis A. [Source: 

http://adoption.state.gov/news/total_chart.html].

In terms of the medical requirements for internationally adopted children, before admission into 

the US, children must undergo a medical examination in their country of origin by a US State 

Department designated physician. Basically, the examination focuses on serious physical or 

mental defects and there is no screening for hepatitis A virus (HAV) infection. Since 1997, 

international adoptees 10 years of age or younger are exempt from immunization requirements

for entry into the US [Immigration and Nationality Act: October 21, 1997].

To estimate the risk of hepatitis A transmission for international adoptees, CDC has reached out 

to adoption clinics in the country that are screening this population routinely for hepatitis A. 

Data pertaining to the seroprevalence of antibody to hepatitis A among international adoptees 

under age 6, by their country of origin and at their first medical encounter, show that 50%-70% 

of children coming from Ethiopia have been exposed to hepatitis A by the time they turn 6. In 

Russia and China, infection may be acquired at a later age. While this illustrates that the risk of 

infection will vary by age and by country of origin for adoptees, it would be very difficult to 

predict infections based on these parameters [Data unpublished: Cincinnati Children's Hospital 

Medical Center, Mary Staat; and University of Minnesota, International Adoption Medicine 

Program, Cindy Howard]. Three adoption clinics have tested more than 600 internationally 

adopted children for Anti-HAV IgM+ [Cincinnati, Ohio 2006-2008; Lexington, Kentucky 2007-

2008; Minneapolis, Minnesota 2008]. Data from these facilities demonstrate that most of the 

IgM+ children are clustering around younger ages, most of them under age 6. However, there 

are also IgM+ children ages 6-17. The percentage range of IgM positivity among adoptees of 

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all ages across these three clinics varied from 1.1% to 6.5% [Data unpublished: Cincinnati 

Children's Hospital Medical Center, Mary Staat; A Caring Touch Pediatrics & International 

Adoptions, Lexington, Shawn Taylor; and University of Minnesota, International Adoption 

Medicine Program, Cindy Howard]. In summary, approximately 18,000 internationally adopted 

children come from hepatitis A endemic countries every year. Most of them will be exempt from 

immunization requirements before entry in the US. Of these international adoptees, 1.1% to 

6.5% are infectious or may be infectious on arrival in the US based on the data from these three 

clinics. 

Using the information available, the risk of hepatitis A among close contacts of international 

adoptees was estimated. The assumptions used to estimate risk of hepatitis A infection among 

close contacts of international adoptees ages 0 to17 years were that 18,000 children will arrive 

in the US every year from endemic countries and each adoptee will have, on average, 7 

contacts for a total of 126,000 people at risk. Based on the NHANES data, it was assumed that 

50% of these contacts may be susceptible to hepatitis A, varying from 30% to 90% for the 

sensitivity analysis. A 30% baseline estimate was used for attack rate, with 10% to 50% used 

for the sensitivity analysis, which is likely to be a conservative assessment. Although a much 

higher attack rate was reflected in one example earlier in the presentation. The assumption for 

the proportion of infectious adoptees on arrival in the US was 1.2% at baseline and 0.6% to 

3.9% in the sensitivity analysis. This estimate took into account the rates of IgM positivity that 

was observed from the adoption clinics and was corrected by using a 60-day window period for 

risk of infection, with 60 days being the upper limit of the incubation period. 

Given these assumptions, 136 cases of hepatitis A associated with international adoption could 

occur every year ranging from 113-1,031. The risk of hepatitis A was estimated at 106 cases 

per 100,000 among contacts exposed to an international adoptee during the first 60 days after 

arrival in the US, which could range from 90 to 819 per 100,000. Thus, the rate of infection in 

this group is substantially higher than the incidence of hepatitis A in the US in 2006 which, was 

estimated to be 1.2 per 100,000 [MMWR 2008; 57 SS-2]. However, there are limitations in the 

risk assessment that must be considered. The risk of transmission may vary by age of adopted 

child (highest among children in diapers ages 0-3 years), by country of origin of the adopted 

child, and by time of arrival of the adopted child related to the infectiousness period. In addition, 

the estimate of number of close contacts (e.g., denominator) may not be accurate. 

Dr. Chaves concluded that international adoptees come from countries endemic for hepatitis A. 

A substantial proportion of US adults are susceptible to hepatitis A and are, therefore, at risk for 

severe disease. Adoptees with unrecognized hepatitis A virus infection, on arrival in the US, are 

a source of hepatitis A for their close contacts. Current recommendations for pre-exposure 

hepatitis A vaccination do not address non-traveling close contacts of international adoptees. 

Proposed Recommendation

Cindy Weinbaum, MD MPH

Division of Viral Hepatitis

NCHHSTP / CDC

Advisory Committee on Immunization Practices

On behalf of the Hepatitis Vaccine Work Group, Dr. Weinbaum posed the following question to 

the full ACIP, “Should current ACIP guidelines include hepatitis A pre-exposure prophylaxis for 

non-traveling contacts of international adoptees from areas of high and intermediate hepatitis A 

virus endemicity?” The current recommendation covering prospective adoptive parents 

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traveling to foreign countries states, “All susceptible persons traveling to or working in countries 

that have high or intermediate Hepatitis A endemicity should be vaccinated or receive IG prior to 

departure” [MMWR, 2006/Vol.55/No. RR-7]. Making the new recommendation would rely on the 

previously published map that appeared in the 2006 ACIP guidelines. Basically, countries with 

intermediate or high endemicity of hepatitis A include most of the world except for North 

America, Western Europe, Australia, New Zealand, and Japan. The workgroup presented two 

options for this recommendation:

Option 1

Recommend hepatitis A vaccination for all previously unvaccinated non-traveling persons who 

anticipate having close personal contact with an international adoptee, within 60 days of arrival 

of the adoptee in the US, when the adoptee is from a country of high or intermediate endemicity 

and under age 6 years. 

Option 2

Recommend hepatitis A vaccination for all previously unvaccinated non-traveling persons who 

anticipate having close personal contact with an international adoptee, within 60 days of arrival 

of the adoptee in the US, when the adoptee is from a country of high or intermediate endemicity. 

Partners would be needed to facilitate provider awareness and vaccine uptake among parents 

including: US Department of State, adoption clinics, adoption agencies, travel agencies, 

American Academy of Pediatrics (AAP), and American Academy of Family Physicians (AAFP). 

Many adoption clinics already recommend that contacts of adoptees be vaccinated, and are 

giving advice to adoption and travel agencies that are subsequently advising adoptive parents. 

Also important to consider is the financial burden of vaccination that would be added to the cost 

of adoption. The cost of adoption was estimated at $20,000, but ranges between $20,000 and 

$30,000 for the family. The cost contributed by vaccinating 7 contacts (the average number of 

contacts estimated by the model) at a cost of $140 in the private sector for 2 doses plus an 

administration fee would represent 3% to 5% of the total costs of an adoption. 

The following advantages and disadvantages are associated with each of the proposed options, 

with Option 2 being supported by the majority of the Hepatitis Vaccines Workgroup: 

Option 1: Advantages and Disadvantages 

Advantages:













Children <6 years likely to be non-jaundiced (~70%)

HAV transmission efficient; high attack rates in susceptible close contacts

>85% of international adoptees are <6 years

Less costly than recommending hepatitis A vaccine for contacts of all-aged adoptees

Disadvantages: 

Will not prevent cases associated with older adoptees

Recommendation for target age group may be more difficult to implement

Option 2: Advantages and Disadvantages

Advantages: 

•

•

•

•

•

Acute hepatitis A infection can occur in any age group

> 20% not jaundiced with acute infection

Patients are infectious prior to onset of jaundice

All-age recommendation easier to implement 

Would prevent cases associated with older adoptees

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Disadvantages: 

•

•

~15% increased vaccination costs

Older adoptees more likely to be immune to hepatitis A; are less likely to have 

asymptomatic infection

The current definition of “Close Personal Contact” in the context of post-exposure prophylaxis is, 

“Close personal contact. Hepatitis A vaccine or IG should be administered to all previously 

unvaccinated household and sexual contacts of persons with serologically confirmed hepatitis 

A. In addition, persons who have shared illicit drugs with a person who has serologically 

confirmed hepatitis A should receive hepatitis A vaccine, or IG and hepatitis A vaccine 

simultaneously. Consideration also should be given to providing IG or hepatitis A vaccine to 

persons with other types of ongoing, close personal contact (e.g., regular babysitting) with a 

person with hepatitis A [MMWR 2007;56(41):1080-1084]. 

Close personal contact. Hepatitis A vaccine [or IG] should be administered to all previously 

unvaccinated household [and sexual] contacts [of persons with serologically confirmed 

hepatitis A. In addition, persons who have shared illicit drugs with a person who has 

serologically confirmed hepatitis A should receive hepatitis A vaccine, or IG and hepatitis A 

vaccine simultaneously. Consideration also should be given to providing IG or hepatitis A 

vaccine to] and to persons with other types of [ongoing,] close personal contact (e.g., 

regular babysitting) with [a person] adoptees from countries of high or intermediate 

endemicity of [with] hepatitis A. 

The underlined words would be retained from the current definition of “Close Personal Contact, 

italicized words would be removed, and the remainder of the words represent new language 

that would need to be added to make the definition applicable to this recommendation.” That is, 

“Close Personal Contact” would be defined as, “Hepatitis A vaccine should be administered to 

previously unvaccinated household contacts and to persons with other types of close personal 

contact; for example, regular babysitting, with adoptees from countries of high or intermediate 

endemicity of hepatitis A. 

Discussion

With respect to the three clinics, Dr. Morse requested clarification regarding whether the IgM 

positive children were all asymptomatic. It seemed that there was a significant rate of positivity 

in the older age groups. 

Dr. Chaves responded that this was correct, although she was not certain whether this was also 

true for the Lexington clinic, given that they had only recently collected these data. She thought 

two were asymptomatic and two actually developed symptoms. Given that the Lexington clinic 

did not provide all of the data provided by the other two clinics, she also did not know whether 

there was anything different about these children that differed in terms of where they came from 

geographically. It may reflect the country of origin. 

With regard to the anti-HAV IgM, Dr. Sumaya inquired as to what type of test was used, whether 

it was commercially available, and if done in a reference lab whether there was validation. 

Dr. Chaves responded that while they did not have information on test sensitivity of the tests 

used in the study described, it is a commercially available test. This is in the context of a 

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population that can have a hepatitis infection without symptoms, and who come from countries 

where prevalence of disease is higher.

Dr. Judson pointed out that targeting this vaccine in a way that is going to be cost-effective is 

obviously difficult because such small groups have been tested, there are variations in age and 

country of origin, and from time to time secular trends are probably changing as well. Another 

issue pertaining to cost regarded when the vaccine patents expire. 

Peggy Reynolds (GSK) responded that her understanding was that vaccines never come off 

patent.

Merck clarified that it is what goes into making a vaccine, not simply the intellectual property that 

is involved in the foundation of it. It is the technical know-how which is not really covered by 

intellectual property that is generally considered proprietary information. Given the significant 

expense that goes into developing a vaccine, there is no reason to believe that it could be made 

in a more cost-effective or lower price than the currently available vaccines. 

Dr. Temte asked the Workgroup to consider two additional insertions of language: 1) Include 

language that endorses many other groups’ approach to providing universal testing for children 

coming from intermediate and high endemic areas; 2) Based on a case in his clinic of a child 

coming from Ethiopia, and despite prompt warnings about not placing this child in daycare prior 

to the time that serologies came back, 50-60 children and adults had to be immunized. With 

that in mind, include language to suggest that children should not be placed in day care 

situations until serologies are known.

Dr. Weinbaum indicated that the workgroup considered an option of testing all children adopted 

from other countries.. The group basically concluded that for close contacts, by the time the test 

was done and the results were received, exposure would have already occurred. The 

workgroup would likely consider the recommendation of not placing a child in a daycare 

situation until the seriologic results were known. 

Dr. Temte clarified that the suggestion was not to supplant the recommendation for 

immunization of close contacts, but as an addition to suggest that children adopted 

internationally from intermediate to high areas of endemicity be tested. Once that language is 

published, at least some insurers will cover the cost and some physicians will be inspired to do 

the testing. While there are several adoption clinics throughout the country that do a very good 

job, there are many practitioners in rural settings who have no knowledge about what to do. 

The backing of ACIP would lend credence to what they do. 

Given that approximately half of the people ACIP was proposing to immunize were adults, Dr. 

Poland (ACP) extended ACP’s partnership support. He was surprised that the number of 

contacts was just 7, particularly given that many of these children go into preschool. He 

seconded Dr. Temte’s suggestion to add more language about placement in daycare / 

preschool settings. In addition, he thought perhaps other examples should be included in 

addition to babysitters, such as preschool workers. In addition, he wondered whether a costbenefit analysis had been done.

Dr. Chaves responded that it was a learning process to understand how international adoption 

occurs and the dynamic of receiving and spending time with the child. Various adoption clinics 

that engage in pre-consultation before adoption say that in most cases they suggest that 

children not be placed in day care as soon as they arrive in the country. The clinics’ reasoning 

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behind this is that it is very important to have at least one of the caretakers with the child for the 

first three months or so to develop an emotional bond. The University of Minnesota interviewed 

almost 2,000 adoptive parents and found that this issue was addressed with parents. Less than 

10% were going to place their child with a caregiver for the first three to four months. The article 

describing this survey was included in members’ packages. In the examples provided during 

her presentation, the siblings were infected and were attending school before it was known that 

they were infected with hepatitis A. Although the analysis was not yet complete, the group 

examined cost-effectiveness and did not believe it would be cost-effective based because there 

would be very few cases to prevent, a small population at risk, and a short period of risk for 

those in contact. 

Dr. Sawyer stressed that it was very difficult to develop a formal cost-effectiveness analysis, and 

noted that the workgroup discussed this extensively. He explained that the slide showing the 

estimate of number of cases among contacts at roughly 100 per 100,000 was meant to compare 

to the previous cost-effectiveness discussions regarding the general recommendation when 

overall rates were approximately 20 per 100,000, in which case it was considered to be costeffective. 

If trying to stop hepatitis A before it was introduced into the US, it seemed to Dr. Beck that Dr. 

Temte’s recommendation seemed appropriate. Of concern to him was that they were relying 

upon the good auspices of people to acquire vaccinations after the child was already in the US. 

To him the hook was the child. It seemed more appropriate to make vaccination part of the 

entire adoption package (e.g., anyone who will be exposed or potentially will be exposed to the 

child should be vaccinated before the child arrives). If one child could affect 50 or more other 

children and their caretakers, such as in the preschool setting, this would mean an additional 

large number of people who could geometrically impact many other people. It seemed that this 

would also have an impact on cost-effectiveness.

Dr. Weinbaum reminded everyone that the preferred proposal from the workgroup was to 

recommend vaccination of all who would be expected to have contact with the child (within 60 

days of arrival) as soon as possible after the adoption is planned, prior to the arrival of the child. 

For example, this would include a babysitter who would begin taking care of the child within 60 

days of after arrival in the US. This person should be vaccinated as soon as the adoption is 

planned if they are known at that time.

Dr. Baker suggested revising the language because it appeared to recommend that people be 

vaccinated within 60 days after arrival rather than prior to arrival.

Dr. Ehresmann stressed that it was important for this recommendation to specifically address 

non-traveling close contacts. Recently in Minnesota a physician interpreted the 

recommendation as pertaining only to those who were traveling and did not vaccinate a nontraveling mother of an international adoptee. The mother subsequently developed hepatitis A. 

She also thought the estimation of 7 close contacts was very conservative. Minnesota has 

experienced a number of outbreaks of hepatitis A associated with international adoptees. In 

one situation, the grandparents were exposed. The grandfather worked in a group home as a 

cook where everyone had to be prophylaxed. There was one case of fulminant hepatitis A in 

one of the group home members who nearly needed a transplant. This has significant impact 

when it occurs. From the public health department’s perspective, an exposure / outbreak takes 

a great deal of time and attention and the impact is considerable. 

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Dr. Temte noted that the upper Mid-West has had many international adoptees. Wisconsin and 

Minnesota are greatly over-represented. He sees many of these families in his practice and 

finds them to be highly motivated. If he suggests vaccinations, this is the one group that will 

comply. He agreed that better language was needed to clarify that at least the first dose should 

be completed at least two weeks prior to the arrival of the child. Even a single dose within two 

weeks is highly effective in preventing hepatitis A. 

Dr. Poland clarified that he favored the intent of the recommendation, but stressed that the 

committee must be consistent in their efforts. A complete cost-benefit analysis should be 

conducted. The average out-of-pocket expense for an adoption is approximately $40,000. 

Each cost that is added is not trivial. Wording in ACIP recommendations typically states 

something about being cost-effective or not and might include wording such as, “Hepatitis A 

vaccination is recommended for those who wish to avoid becoming ill with Hepatitis A.” For the 

sake of consistency and because these recommendations tend to set precedent, he thought the 

committee should be consistent in its approach.

Dr. Englund pointed out that adoption itself is not cost-effective and these parents clearly realize 

this. This is indeed a specific and highly motivated group of people. They need the best 

medical advice possible regardless of whether cost-effectiveness is known. While costeffectiveness information should be pursued, she did not believe ACIP should wait for costeffectiveness information to make a recommendation. As someone who cares for many foreignborn adoptees, she strongly agreed with Option 2, with the revision of the language to make it 

clearer about vaccination of potential contacts “prior to arrival.” She also thought the 

recommendation should address adoptees of any age, given that there are no firm birth records 

for children from some countries and many come from orphanages where the risks are even 

greater. Therefore, the recommendation should not be restricted to adoptees under the age of 

6. 

With respect to the travel medicine aspect, Dr. Grogg pointed out that frequently, families return 

to the country. Grandparents who did not go originally may not have been vaccinated. With 

that in mind, he supported Option 2 with the proposed wordsmithing.

Dr. Duchin (NACCHO) requested further information regarding the clusters described by Dr. 

Chaves with respect to how many had an indication for vaccination already.

Dr. Chaves responded that most of the clusters were in areas that did not have a 

recommendation for vaccination from the earlier ACIP recommendation, so many of these 

children missed the opportunity to be vaccinated. There were no children born in the cohort of 

children to be vaccinated based upon the 2006 recommendation. Based on the Minnesota 

article, the workgroup learned that most of the adult contacts (88%) of adoptees who actually 

travel to their adoptee country of origin were vaccinated before departure. There is room for 

improvement in terms of the recommendation to vaccinate travelers, but the uptake is 

reasonably good already.

Dr. Sawyer summarized the workgroup’s discussion about Option 1 versus Option 2 with regard 

to the age cutoff. He thought it was fair to say the majority opinion was that Option 2 was 

preferred because it was simpler and for the reasons that had already been raised. However, a 

significant number of workgroup members preferred Option 1 on the strength of the costeffectiveness considerations (e.g., it would reduce the costs somewhat, although only by about 

15% overall).

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Ms. Stinchfield (NAPNAP) stressed that there is vaccine fatigue from a clinical standpoint. 

Therefore, simple is better, and with that in mind she supported Option 2. 

Dr. Neuzil pointed out that this is a safe and effective vaccine and a small captured population. 

She also supported Option 2, reminding everyone that this issue came to light because a 

grandmother died. Referring to the map shown earlier about the effective decline in hepatitis A 

incidents in the US in the last 10 years, she wondered whether there were any plans to 

systematically examine the remaining cases, particularly the severe cases, to determine who 

these are to better target prevention / elimination efforts.

Dr. Chaves responded that while it was early to discuss elimination of hepatitis A - there are 

currently no catch-up vaccination recommendations - the epidemiology of hepatitis A has 

changed significantly since the introduction of the vaccine. CDC / Division of Viral Hepatitis is 

looking at the national surveillance system for hepatitis A to understand and address the current 

risk factors. Approximately 60% of reported hepatitis cases do not know where they contracted 

the disease.

John Ward, Chief, Division of Viral Hepatitis, added that death certificates reflect that those who 

are dying from hepatitis A tend to be adults with pre-existing liver disease. 

To clarify that the “within 60 days statement” Dr. Sawyer suggested the following revision to the 

proposed wording: “Hepatitis A vaccination is recommended for previously unvaccinated, nontraveling persons who anticipate close personal contact with an international adoptee during the 

60 days following the arrival of the adoptee in the United States when the adoptee is from a 

country of high or intermediate endemicity.” With additional input from other members, Dr. 

Sawyer suggested that the last sentence be changed to read, “Ideally, the first dose of Hepatitis 

A vaccine should be administered at least two weeks prior to the arrival of the adoptee.”

Dr. Ehresmann commented that most close contacts will not be identified until after arrival of a 

child, and that a recommendation for post-exposure prophylaxis following exposure would be 

sufficient. Therefore, it was not clear why the recommendation needed to read “two weeks prior 

to arrival.”

Dr. Englund disagreed. These children often arrive at the airport with 40 people there to greet, 

hug, and kiss them. They will know who the potential close contacts are because they have to 

make their airplane reservations at least two weeks ahead of time. Perhaps a new babysitter 

will also have been hired ahead of time. The recommendation must be clear for providers and 

parents. 

Dr. Plotkin suggested removing the word “non-traveling” because some travelers will not have 

been vaccinated. Perhaps it should read “unvaccinated persons.”

Dr. Sawyer responded that the primary emphasis of this recommendation was to focus on nontravelers. There is an existing recommendation for travelers to be immunized, so they should 

be careful not to dilute or shift the focus away from that.

Dr. Baker thought everyone agreed that ideally the contacts should be fully immunized before 

arrival; therefore, she was comfortable with the language proposed by Dr. Sawyer. 

Dr. Morse suggested taking a short break to flesh out the wording, to be able to reach 

consensus. 

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Following a 20-minute break to further develop Option 2 wording, Dr. Weinbaum indicated that 

the group proposed a preamble to better define who this recommendation addresses, “Persons 

who will have close personal contact with the adoptee during the first 60 days following arrival of 

the adoptee in the US should be identified.” The actual recommendation language would state, 

“Hepatitis A vaccination is recommended for all previously unvaccinated persons who anticipate 

close personal contact with an international adoptee from countries of high or intermediate 

endemicity during the first 60 days following arrival in the US.” In addition, the recommendation 

would include the wording, “The first dose of hepatitis A vaccine should be administered as 

soon as adoption is planned. Ideally, the first dose of hepatitis A vaccine should be 

administered at least two weeks prior to the arrival of the adoptee.” This recommendation 

would also refer to the currently existing recommendations for travelers and for post-exposure 

prophylaxis. The post-exposure prophylaxis recommendations would apply to those individuals 

who are not vaccinated two weeks prior to the arrival of the adoptee.

Motion: Hepatitis A Among Contacts Of Internationally Adopted Children

Dr. Ehresmann made a motion to approve Option 2 Hepatitis A Among Contacts Of 

Internationally Adopted Children with the newly suggested revisions to the language. Dr. Temte 

seconded the motion. The motion carried with 14 affirmative votes, 1 abstention, and 0 

negative votes. 

Introduction

Kathy Neuzil, MD, MPH

Chair, Influenza Vaccine Workgroup

Dr. Neuzil introduced the session on Influenza Vaccines. This session included an update on 

workgroup activities, the influenza season, antiviral resistance issues, and highlights and 

changes for the 2009-2010 influenza vaccine recommendations. The Influenza Vaccine 

Workgroup has been very busy in the last few months. The group has engaged in discussions 

on a number of topics, including: influenza activity, improved vaccines for older adults, vaccine 

safety issues, and adult vaccination recommendations. During this time, they heard 

presentations from the manufacturers as well. 

Influenza Vaccines

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Influenza Surveillance Update, Antiviral Surveillance, 

and 2009 Influenza Vaccine Recommandations

Anthony Fiore, MD, MPH

CDC / CCID / NCIRD / ID

Dr. Fiore first presented on the influenza positive tests reported to CDC from the WHO / 

National Respiratory and Enteric Virus Surveillance System (NREVSS) collaborating 

laboratories through February 14, 2009. As of Week 6, there were 1313 (24.4%) specimens

positive for influenza virus among specimens submitted for testing from persons with acute 

respiratory illness. The types and sub-types thus far in this season have been dominated by 

influenza A(H1N1), with some influenza Bs appearing in the past few weeks, and relatively little 

influenza A(H3N2) thus far. Based on pneumonia and influenza mortality surveillance 

conducted in 122 US cities using weekly reports from death certificates, the past influenza 

season (2007-2008) was well above the epidemic threshold during the peak influenza season. 

This has not yet occurred in the current season.

Pediatric deaths for laboratory-confirmed influenza have been a reportable disease since 2004. 

Thus far in this season only 9 deaths have been reported. Of these 9 deaths, 6 were in children 

who had bacterial co-infection. Death reporting typically lags behind by one to two weeks, so 

unfortunately more reports of death can be anticipated. With respect to the hospitalization 

surveillance data from the Emerging Infections Program Surveillance, this season hospital 

laboratory-confirmed influenza is being reported for hospitalizations in all age groups. At the 

time of this presentation, an increase in persons hospitalized for laboratory-confirmed influenza 

was just beginning in hospitalization surveillance. This also tends to be a somewhat lagging 

indicator of influenza activity, so an additional increase would be expected over the next few 

weeks. With respect to the percentage of visits for influenza-like illness (ILI) reported by the US 

Outpatient Influenza-like Illness Surveillance Network (ILINet), conducted among over 2,000 

central providers across the US, reports have exceeded the seasonal baseline over the last 

several weeks. 

Influenza activity is reported to CDC by state and territory epidemiologists each week. The 

following map reflects week 6. At this time, 24 states were reporting wide-spread activity, while 

the majority of the rest of the states were reporting regional or local activity. At this time last 

year, all of the states were reporting widespread activity with the exception of Florida: 

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CDC laboratories do strain characterization of the influenza viruses that are submitted to the 

agency. From October 2008 through February 14, 2009, 390 viruses have been characterized. 

The bulk of the viruses characterized are Influenza A(H1N1) [n=239]. Of these, 239 (100%) are

similar to A/Brisbane/59/2007 (2008-09 vaccine strain). This includes H1N1 resistant to

oseltamivir. Influenza A(H3N2) was characterized in 37 cases, of which 37 (100%) were similar 

to A/Brisbane/10/2007 (2008-09 vaccine strain). Of the total characterized, 114 were Influenza 

B. Of these, 33 (29%) were in the B/Yamagata lineage, similar to B/Florida/04/2006 (2008-09 

vaccine strain); and 81 (71%) were in the B/Victoria lineage. With respect to Influenza B, there 

are always some strains that do not match the vaccine because over the last 10 years there has 

been co-circulation of the two major influenza B lineages. 

The major issues thus far in the current influenza season has been resistance to antivirals

among influenza viruses. In October 2008, CDC was concerned about antiviral resistance 

among the (H1N1) viruses. Over the course of the season, the majority (264 of 268) Influenza 

A (H1N1) viruses tested have been resistant to oseltamivir. All influenza A (H1N1) viruses were 

sensitive to zanamivir. All H1N1 resistant to oseltamivir were sensitive to adamantanes 

(rimantadine and amantadine). All 51 influenza A (H3N2) viruses were sensitive to oseltamivir 

and zanamivir, and resistant to adamantanes. All 110 influenza B viruses tested were sensitive 

to oseltamivir and zanamivir. 

With regard to oseltamivir resistance, data suggested that development of resistance is 

probably not driven by oseltamivir use. There is no correlation between oseltamivir use and 

prevalence of resistance by country [WHO 2008]. Most persons with H1N1 infections have no 

exposure to oseltamivir [Hauge Emerg Infect Dis 2009; Dharan JAMA 2009]. From a clinical 

perspective, oseltamivir-resistant viruses are similar to oseltamivir-sensitive viruses in terms of 

transmissibility, virulence (severity of illness and types of complications) [Hauge Emerg Infect 

Dis 2009; Dharan JAMA 2009], and antigenic similarity to the 2008-09 vaccine strain. 

As a result of this large increase in oseltamivir resistance among the (H1N1)s that has been 

observed in the current influenza season, CDC issued interim guidance in late December 2008. 

The rationale for “CDC’s Interim Guidance for Use of Antivirals in the Treatment and Prevention 

of Influenza, 2008-09 Season” was that oseltamivir-resistant H1N1 is the most commonly 

isolated virus thus far; clinicians need to know that oseltamivir alone might not effectively 

prevent or treat influenza; and there are no rapid tests for influenza A sub-typing or antiviral 

resistance testing. Key points made by this guidance are that local influenza surveillance data 

and influenza diagnostic testing can help with physician decision-making regarding the choice of 

antiviral agents for their patients. Treatment with zanamivir or a combination of oseltamivir and 

rimantadine (amantadine acceptable in place of rimantadine) is preferable in some situations

(influenza subtype is likely to be H1 or unknown). Oseltamivir-resistant H1N1 strains are 

antigenically similar or identical to the strains in the vaccine. 

CDC has conducted additional activities with regard to the oseltamivir resistance issue. 

Enhanced viral surveillance has been developed in partnership with state public health labs. 

Throughput and timeliness of antiviral testing in CDC labs have been increased. Updates are 

made through FluView (weekly) and the MMWR. The issues have been discussed with antiviral 

manufacturers. ACIP workgroup activities for antiviral recommendations are to monitor antiviral 

resistance data; consult and coordinate with antiviral experts and medical professional 

organizations; develop draft ACIP recommendations for antiviral treatment and 

chemoprophylaxis; present to the full ACIP in June 2009; and publish a separate ACIP guidance 

before the 2009-10 season. 

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Dr. Fiore shared highlights in the proposed vaccination recommendations from the ACIP for the 

2009-2010 season. Strain selection occurred in the past two weeks, first at the WHO meeting 

on February 11, 2009 and then during the Vaccines and Related Biologic Products Advisory 

Committee (VRBPAC) meeting the week prior to ACIP’s February meeting. The selections 

were as follows:







An A/Brisbane/59/2007 (H1N1)-like virus (same as 2008-2009) 

An A/Brisbane/10/2007 (H3N2)-like virus (same as 2008-2009) 

A B/Brisbane/60/2008-like virus (new; this is a Victoria lineage virus which is different 

from the Yamagata virus that is currently in the vaccine)

Some sections of the prevention and control of influenza draft vaccine recommendations have 

been revised to update them according to new data. The age or risk groups recommended for 

annual vaccination remain unchanged. Approximately 84% of the US population currently is 

recommended to receive annual influenza vaccination. The permissive recommendation will be

continued for persons not specifically targeted (e.g., healthy adults ages 19-49 who do not have 

a contact-based recommendation). Vaccination is recommended for “All persons who want to 

reduce the risk of becoming ill with influenza or of transmitting it to others.” Full implementation 

of annual vaccination for all children ages 6 months through 18 years is now expected, rather 

than “if feasible.” 

Revisions of vaccine immunogenicity and effectiveness background sections, with respect to 

immunogenicity among hospitalized persons, support will be included for routine vaccination of 

hospitalized persons [Berry et al, Vaccine 2001; Gurfinkel Eur Heart J 2004]. Some of CDC’s 

colleagues in the quality assurance arena suggested that ACIP should be more clear in the 

guidance about its support for routine vaccination of persons who have vaccine indications 

during hospitalization. With regard to reductions in laboratory-confirmed influenza among infants 

born to vaccinated women, support will be included for vaccination of pregnant women [Zaman 

et al, N Engl J Med 2008]. Regarding reductions in absenteeism or illness in vaccinated 

populations, support will be included for community-level indirect benefits with increased 

vaccine use in younger persons [King et al, Pediatrics 2008; Kwong et al, PLoS Med 2008]. . 

As part of the expansion of the safety background section, information has been added about 

ocular and respiratory symptoms that can occur following the trivalent inactivated influenza 

vaccine (TIV). The rationale for this is that ocular and / or respiratory symptoms after TIV are 

described in some prescribing information statements and are noted in some clinical trials; 

however, they are not adequately discussed in ACIP influenza vaccine statements. With 

respect to the US experience with ocular or respiratory symptoms after TIV, persons with red 

eyes and / or one or more respiratory symptoms after TIV are reported each year to the Vaccine 

Adverse Event Reporting System (VAERS). Fortunately, these are typically acute and mild selflimited reactions, which likely occur at low frequency. 

Also described in the safety background section is oculorespiratory syndrome (ORS) after TIV. 

This was initially described as a syndrome occurring after a single TIV formulation in Canada 

during the 2000-2001 season that was discussed in 2004 and with the ACIP in the past. ORS 

study case-definitions include acute onset after TIV of a variety of ocular and / or respiratory 

symptoms (e.g., bilateral red eyes, cough, hoarseness, sore throat, facial edema, wheezing, 

difficulty breathing or swallowing, or chest tightness) that are typically acute, mild, self-limited, 

reactions occurring within 24 hours after TIV. Most published information on ORS is based on

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•

the Canadian experience during and after the 2000-2001 influenza season. This was 

associated with one product in 2000-01. Although it was reported after a variety of products in 

subsequent years, it was less frequent. Hoarseness, ocular soreness / itchiness and cough 

were the only symptoms significantly associated with vaccination in one placebo-controlled 

study. ORS can recur with TIV in following seasons, but many people were revaccinated 

without incident. The pathogenesis is uncertain. Some US VAERS reports meet screening 

criteria for ORS, including some before and after the 2000-01 season. Less than 2% of reports 

after TIV were for ORS-like symptoms occurred in 2008-09. 

With regard to draft revaccination information and additional plans for ocular and respiratory 

symptoms, the proposed wording for the ACIP statement is, “Guidance on influenza vaccination 

in subsequent seasons for persons who have had ocular and respiratory symptoms is under 

consideration by ACIP.” Additional consideration is needed regarding how to distinguish 

immediate hypersensitivity from ORS or other causes of ocular or respiratory symptoms. There 

are on-going discussions with the CDC Immunization Safety Office, Clinical Immunization 

Safety Assessment (CISA) Network consultants, FDA, manufacturers, and ACIP influenza 

vaccine workgroup. Plans for the June 2009 ACIP meeting are to expand the presentation and 

possibly request an ACIP vote on revaccination guidance if warranted, and to include the 

evaluation of VAERS reports among persons vaccinated with TIV during 2007-08 and 2008-09 

with ocular and respiratory symptoms meeting screening criteria for ORS. 

Vaccination recommendations for children and adolescents will include full implementation of 

universal recommendations: 

• All children aged 6 months through 18 years should be vaccinated annually. 

• Children and adolescents at higher risk for influenza complications should continue to be 

a focus of vaccination efforts, including those:

–

–

–

–

–

–

–

aged 6 months through 4 years;

who have chronic pulmonary (including asthma), cardiovascular (except 

hypertension), renal, hepatic, hematological or metabolic disorders (including 

diabetes mellitus);

who are immunosuppressed (including immunosuppression caused by 

medications or by human immunodeficiency virus);

who have any condition (e.g., cognitive dysfunction, spinal cord injuries, seizure 

disorders, or other neuromuscular disorders) that can compromise respiratory 

function or the handling of respiratory secretions or that can increase the risk for 

aspiration;

who are receiving long-term aspirin therapy who therefore might be at risk for 

experiencing Reye syndrome after influenza virus infection;

who are residents of chronic-care facilities; and,

who will be pregnant during the influenza season.

Note: Children aged <6 months cannot receive influenza vaccination. Household and 

other close contacts (e.g., daycare providers) of children aged <6 months, including 

older children and adolescents, should be vaccinated. 

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There are no changes in the adult recommendations, which will remain as follows:

• Annual vaccination against influenza is recommended for any adult who wants to reduce 

the risk of becoming ill with influenza or of transmitting it to others. 

• Vaccination is recommended for all adults in the following groups, because these 

persons are either at higher risk for influenza complications, or are close contacts of 

persons at higher risk:

–

–

–

–

–

–

–

–

–

persons aged >50 years;

women who will be pregnant during the influenza season;

persons who have chronic pulmonary (including asthma), cardiovascular (except 

hypertension), renal, hepatic, hematological or metabolic disorders (including 

diabetes mellitus);

persons who have immunosuppression (including immunosuppression caused by 

medications or by human immunodeficiency virus); 

persons who have any condition (e.g., cognitive dysfunction, spinal cord injuries, 

seizure disorders, or other neuromuscular disorders) that can compromise 

respiratory function or the handling of respiratory secretions or that can increase 

the risk for aspiration;

residents of nursing homes and other chronic-care facilities;

health-care personnel;

household contacts and caregivers of children aged <5 years and adults aged 

>50 years, with particular emphasis on vaccinating contacts of children aged <6 

months; and,

household contacts and caregivers of persons with medical conditions that put 

them at higher risk for severe complications from influenza.

Discussion

With regard to the ocular and respiratory symptoms, Dr. Baker inquired as to whether CDC 

planned to conduct viral surveillance in these children. It seemed to her that some noninfluenza virus might be causing these symptoms.

Dr. Fiore responded that further studies planned largely pertain to examination of the safety 

databases and consultation with a variety of allergists and others about revaccination. He knew 

of no plans at this point to study other potential causes. 

Dr. Sawyer pointed out that healthcare workers often state the vaccine makes them sick. It 

appeared that the revisions would emphasize more clearly known side effects versus newly 

recognized side effects. With that in mind, he made a plea that the revisions be made very 

clear so as not to come across as addressing newly identified side effects. He also inquired as 

to whether the language concerning ORS would clearly distinguish respiratory symptoms 

related to LAIV. 

Dr. Fiore responded that both of these issues would be addressed and that LAIV has its own 

section. 

Dr. Neuzil indicated that the working group discussed this extensively. They raised some of the 

same concerns about proactively addressing this issue. There are a number of placebo 

controlled trials of influenza vaccine, which show that large percentages of the population have 

a headache and cough regardless of whether they receive vaccine or placebo. The difficulty is 

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that some of the specific symptoms were not asked in many of these large studies, so the 

working group is relying on the Canadian experience and the passive databases. She 

encouraged members to read the language that is proposed in the MMWR to determine 

whether they struck a balance. 

Peggy Reynolds (GSK) indicated that in approximately one month, the results would be 

published of a placebo controlled trial of the FluLavalTM TIV Vaccine (n=7500) for which ORS 

signs and symptoms were prospectively solicited. No significant difference was found between 

the vaccine and placebo groups. GSK would be happy to provide those data to the working 

group.

Dr. Temte pointed out that zanamivir is basically unavailable this year. He also had heard of a 

quadrivalent vaccine, and requested further information about this. In addition, the 

recommendation for up to 18 has been wonderful, given that he no longer has to think about 

who should be vaccinated in his practice. With that in mind, he wondered when they would 

simply recommend universal coverage.

With regard to zanamivir Dr. Fiore, CDC discussed availability with the manufacturer, GSK, 

before the season began and during the season. GSK has greatly increased the amount of 

zanamivir available to the US market; however, there appears to be a disconnect between what 

is ordered and what is available at the local level. He encouraged those experiencing difficulties 

to contact GSK to learn about availability. Shortages can be reported to the FDA. Regarding 

the quadrivalent vaccine, CDC engaged in discussions during the FDA Advisory Board meeting 

the week before the ACIP meeting about a quadrivalent vaccine. This information will be 

presented to the workgroup and the full ACIP as merited. The initial results suggest that there 

would be some modest benefits from the addition of a B strain that represents the B strain from 

each of the lineages. There are many other issues to work through with regard to licensure, 

safety, et cetera. Given the continued interest in this, Dr. Fiore believed that these discussions 

would continue with the FDA. The workgroup continues to discuss universal adult immunization 

recommendations. As indicated in the October 2008 ACIP meeting, the workgroup preferred to 

see how the universal childhood vaccination recommendation played out, and to gather 

additional information pertaining to why adults currently recommended for and who have access 

to vaccination do not acquire vaccines. 

Dr. Cieslak wondered about the wisdom of dubbing ocular respiratory syndrome as a syndrome 

when it seems instead to be a minor side effect. He also wondered whether comments should 

be made on the potential differential effectiveness of why the attenuated influenza virus vaccine 

seemed to show a difference in the Belshe study, which is a randomized head-to-head placebo 

controlled trial.

With regard to the ORS, Dr. Fiore encouraged ACIP members to review an updated draft, which 

he planned to send them shortly, in which he thought they had struck a better balance between 

describing a variety of different ocular and respiratory symptoms that can occur at a relatively 

low frequency after TIV, with the Canadian experience which might be somewhat different 

because it was elicited by the one year when ORS was associated with one manufacturer. With 

regard to LAIV versus TIV, the randomized controlled trial from Belshe for 2004-2005 influenza 

season shows that LAIV had a better efficacy than TIV in children between the ages of 6 

months and 6 years. There are also other randomized controlled studies in young adults, such 

as Arnold Monto’s, that showed that TIV has better efficacy among young adults. There is no 

LIAV preference from a labeling point of view at this point. 

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Paul Offit reinforced Dr. Fiore’s communication with regard to supply and availability of 

zanamivir in the marketplace. GSK has more than ample supplies to satisfy current and future 

demand in this season’s antiviral marketplace. Challenges at the start of the season in early 

January occurred with encouraging wholesalers and retail pharmacies to order zanamivir and 

put it on their shelves. He reassured everyone that this situation has been largely resolved. 

On-going challenges are occurring with thousands of independent pharmacies; however, that 

situation is improving each day. 

Dr. Neuzil pointed out that the LAIV issue has been discussed in the past. The references are 

continually updated, so the workgroup has been provided with the Belshe study and others. 

One difficulty with regard to influenza is that it changes from year to year and there are three 

strains in the vaccine. Anytime a one-year study is reviewed, there is no evidence of efficacy for 

all three strains. 

Dr. Marcy requested that the dashes be removed from age groups, given that these are 

confusing. For example, it is not clear whether 6 months-5 years means up to the 5th birthday or 

through 5 years. 

Dr. Pickering responded that they are in the process of doing away with dashes. These have all 

been removed from the childhood immunization, and will be removed from all ACIP statements. 

They will no longer be used in the Pink Book or the Red Book either. 

Dr. Sumaya inquired as to whether CDC was quantitatively following the sites where vaccine is 

administered (e.g., public health facilities, private physician offices, pharmacies, et cetera) to 

determine where there are any trends, consequences, et cetera. 

Dr. Fiore responded that CDC gathers information through coverage data overall. There is a 

particular focus in the ISD on studying school-based vaccination recommendations to better 

understand best practices, barriers, et cetera. That has been the major focus of a Request for 

Application (RFA) that was published during the past season. In some of the coverage 

information, CDC does identify where people received their vaccines. 

Dr. Meissner pointed out that the 1% or 2% of the H1 strains that are resistant to adamantanes, 

and isolates that are resistant to both oseltamivir and adamantanes, pose a major issue for a 

patient who cannot tolerate zanamivir (e.g., an intubated patient). If increasing oseltamivir 

resistance was not related to oseltamivir use, he wondered what CDC thought was driving this 

increased resistance pattern.

Dr. Fiore responded that in past seasons there has been a fair amount of oseltamivir resistance 

among H1N1 viruses on the order of 10% to 15%. This has not been observed during the 

current season. Last season, there was an 11% or so resistance to oseltamivir. In the past, 

resistance has been observed among H1N1s to adamantanes on the order of 10% to 15%. 

This season, whatever is currently circulating seems to have dropped that particular resistance 

pattern. CDC is concerned that there could be H1N1s that are resistant to both classes of 

antiviral drugs (e.g., neuraminidase inhibitors and adamantanes). Such viruses have 

sometimes been observed in global surveillance. The potential for this is one of the reasons for 

the advice that if zanamivir cannot be used, rather than simply switching to an adamantane if 

there is thought to be an H1N1, both oseltamivir and one of the adamantane drugs should be 

used. With regard to what drives resistance if not oseltamivir use, emphasis has always been 

placed on the role of antigenic drift, but beyond that, input is needed from virologists. 

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Dr. Katz (IDSA) inquired as to what data CDC has related to uptake by hospital and clinic 

workers.

Dr. Fiore responded that CDC has no information for the current influenza vaccination season 

about health care workers at this point. There are a number of initiatives being implemented in 

hospitals and other systems, the results from which have been presented at the National 

Immunization Conference, and which have described ways in which uptake has increased 

beyond the national level of approximately 40%. CDC will receive national level data on 

healthcare worker coverage of influenza vaccine sometime in the summer, which will reflect 

2008.

James Turner (ACHA) called Dr. Fiore’s attention to an article by Dr. Ed Ellinger of the 

University of Minnesota published in early December in the Archives of Pediatric and 

Adolescent Medicine that discusses decreased absenteeism on college campuses and better 

academic success among vaccinated college students. For parents spending $20,000 to 

$40,000 a year for students to attend college, it is worth the $25 to have them vaccinated. In 

terms of vaccine effectiveness, the University of Virginia has a close population of 20,000 

students. They know who is and is not vaccinated, and they can track vaccine effectiveness. 

During the poor match, they experienced approximately 30% effectiveness, but are approaching 

60%-70% effectiveness this season with A strains. Anticipating the need for zanamivir, the 

college contacted local pharmacies and the hospital to ensure that an ample supply was 

available for this community.

Regarding vaccine effectiveness, Dr. Fiore indicated that this season CDC and partners are 

working to develop rapid vaccine effectiveness estimates. However, they are at the mercy of 

the influenza season. It was only in the past few weeks they had begun to observe an increase 

in activity.

Dr. Poland (ACP) pointed out that no one really knows what leads to antiviral resistance. ACP 

is attempting to publish an editorial in Clinical Infectious Diseases in the next few weeks. 

Resistance occurs against a background of use and abuse of single antiviral drugs. It may well 

have been a de novo mutation, but it occurs against a background in which there is mutational 

and selective pressures due to antivirals. He shared the concerns raised about ORS in terms of 

highlighting this as a seemingly “now we’re concerned” type of side effect. While he knew that 

was not the intent, he cautioned the committee to use careful wording to stress that this was 

based on observations made in a limited timeframe and with respect to one product and a 

couple of lots. While the ACIP has functionally said that there should be universal 

immunization, there seems to have been a reluctance to state this out loud. At this point, there 

is basically a universal recommendation for influenza vaccine with three tiers: the tier of those 

who are at greatly increased risk of morbidity and mortality, the tier of contacts, and the tier of 

everybody else who wishes to avoid all the consequences. The three reviewers who reviewed 

the editorial insisted that a call be put forth for universal immunization, particularly given what is 

occurring with antiviral resistance. He suggested including health care providers in any surveys 

conducted regarding implementation.

Dr. Neuzil agreed that ACIP is encouraging vaccination for the entire population. The concern 

that has arisen is that regardless of how these recommendations are made (e.g., by high risk, 

age-based, et cetera) the vaccination rates continue to be dismal. Thus, there is nothing to 

suggest that going to a universal recommendation will actually result in improved vaccination 

rates. This is why the working group made the intentional decision to review the effects of 

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various recommendations, and to attempt to obtain further information on coverage to better 

understand why coverage rates are not where they should be.

Tamara Lewis (AHIP) offered a plea from front line administrators who are trying to deal with the 

expanded recommendations and are seeking assistance with surveillance. While the National 

Immunization Survey (NIS) offers the ability to examine what is occurring with young infants, 

there are not good measures for the school-aged child to better understand what is occurring 

locally. In the interim, people look to the Behavioral Risk Factor Surveillance System (BRFSS) 

for information; however, on the BRFSS website the only information available is on those over 

65 years of age. Even in the adult population it is not clear at the local level what is occurring.

 

David Kimberlin (AAP Red Book) indicated that the National Institute of Allergy and Infectious 

Disease’s (NIAID’s) Collaborative Antiviral Study Group recently convened a meeting on 

antiviral resistance. The summary of this is that virologists do not understand this much better 

that anybody else. In terms of the emergence of resistance of oseltamivir on such a widespread 

scale, it truly does not seem to be related to use of oseltamivir, given that it also occurred in 

countries with very low utilization of oseltamivir. While there may be a rationale for dual 

therapy, and he certainly understood CDC’s recommendations on December 19, 2008, more 

information is needed on safety, pharmacokinetics, and efficacy in terms of whether these 

classes of drugs can be used together safely without any type of antagonism. Secondly, the 

use of rimantadine and amantidine is the same sort of situation that zanamivir has posed in that 

many pediatricians are experiencing difficulty in acquiring these two drugs. 

Regarding immunization rates in school aged children and surrogate markers, Phil Hosbach

(sanofi pasteur) pointed out that claims data could be used to ascertain a private sector number. 

Anecdotally from the experience they have had during the pre-booking season for influenza, the 

needle has not moved much with pediatricians in terms of preparing to implement the 

recommendation for 9- to 10-year olds. He seconded Dr. Poland’s advice to include health care 

providers in any surveys conducted regarding implementation.

Patricia Whitley-Williams (NMA) inquired as to whether any increases had been observed in 

vaccine coverage, particularly among underrepresented minorities in the older age adult 

population. She also wondered where there had been any narrowing of the health disparities 

gap that exists in influenza burden of disease, particularly among adult minority populations. 

She encouraged the working group to continue to consider these issues, particularly as 

recommendations are changed. She also supported a universal recommendation.

Dr. Fiore responded that he would probably need to develop a presentation and consult with his 

colleagues about this topic, particularly with regard to coverage and ISD. 

Dr. Bell added that CDC collects disparities information from the National Health Interview 

Survey (NHIS) every year (e.g., coverage by race, ethnicity, and age group). The previous 

season’s findings were published in the MMWR last fall. 

Dr. Chilton wondered whether information about the current problem with oseltamivir resistance 

had had any impact on the use of this particular agent.

Dr. Fiore responded that CDC plans to study this. They recently had a survey sent out through 

the Emerging Infections Network asking members of that network what drugs they were using 

and whether they had seen the interim guidance. They could conduct surveys similar to those 

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that were administered regarding the adamantanes. However, it is difficult to quickly change 

course. 

Dr. Judson inquired as to whether all inactivated vaccines are now thimerosal-free. While this is 

not an issue for ACIP scientifically, it remains an issue in the public. Perhaps at some point it 

would be beneficial to be able to state that no influenza vaccines contain thimerosal.

Dr. Fiore responded that the multi-dose vial of the inactivated vaccines still contain thimerosol. 

There are numerous thimerosal-free or trace thimerosal presentations in single use vials. Live 

attenuated vaccine does not contain thimerosal. 

Phil Hosbach (sanofi pasteur) reported that this year, sanofi pasteur will have the capability of 

making 30,000,000 doses of thimerosal-free influenza vaccine based upon demand. For the 

2010-2011 season, they anticipate being able to make 50,000,000 doses thimerosal-free, or 

virtually all of sanofi pasteur’s supply in the US.

Peggy Reynolds (GSK) reported that all FluarixTM doses will be thimerosal-free by the next 

season, and they anticipate that all FluLavalTM will be thimerosal-free by the season after that.

Malik Manzoor (CSL Biotherapies) reported that they plan to have 10,000,000 doses in 2009, 

80% of which are thimerosal-free. They have the capacity to switch to 20,000,000 thimerosalfree doses over the next two years.

With the expansion of recommendations, Dr. Temte noted that Wisconsin has observed a near 

linear increase in vaccine utilization from 2002, with the one exception of 2004 with the 

shortage. They are over 1,000,000 doses in the registry this year for the first time ever. Most of 

their vaccine (95%) is being provided between August and December. At the end of December, 

people stop seeking vaccines. Thus, they must do a better job of educating people about the 

ability to acquire vaccines beyond that timeframe.

Dr. Fiore responded that each of the last three years, there has been an Influenza Vaccination 

Week. This past season it was in mid-December and encouraged people to vaccinate through 

January and February. This season was a great example of why vaccinating later in the 

vaccination season would be effective, given that influenza really did not appear in most 

communities prior to that and has not appeared in some communities until January or February. 

Dr. Morse commended the working group on continuing its efforts with respect to adult 

immunization. He thought a strong case was made in October 2008 to move forward with a 

universal recommendation based on disease burden, safety, efficacy, and cost-benefit. While 

he understood the rationale behind further assessing feasibility, he expressed his hope that the 

search for the best did not become the enemy of the good. 

Motion: 2009 Influenza Vaccine Recommendations 

Dr. Baker moved to approve the 2009 Influenza Vaccine Recommendations as stated. Dr. 

Chilton seconded the motion. The motion carried with 14 affirmative votes, 1 abstention, and 0 

negative votes. 

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Introduction

Paul Cieslak, MD 

Oregon Public Health Division

ACIP Committee Member

Dr. Cieslak explained that the Rabies Vaccine Work Group came into existence largely as a 

result of potential difficulties with the rabies vaccine supply. Since 2007, the availability of 

human rabies vaccine remains much less than ideal, for a variety of complex, interrelated 

reasons. Increased public health demand and seasonal limitations in vaccine supply over the 

past two years have created a very volatile public health environment. A variety of public health 

strategies have prevented the development of a true shortage.

A draft of interim recommendations prepared by a national working group on human rabies 

prevention, in the event of a forecast shortage of biologics used in prophylaxis, was previously 

distributed to ACIP. Use of alternative schedules, such as the elimination of the 5th (final dose) 

of vaccine in a naïve patient during prophylaxis, was one of the recommendations proposed by 

that working group. Based upon a review of the draft document by ACIP members, the 

suggestion was made to evaluate this option for more routine use, regardless of a vaccine 

shortage.

The focus of the ACIP Rabies Work Group was to review the available evidence related to a 

proposal for eliminating the last dose of rabies vaccine during post-exposure prophylaxis; 

provide a draft document to the ACIP for review of any altered schedule, based upon the data; 

discuss the findings during the February 2009 ACIP meeting; and prepare a statement for 

consideration of a vote at a future ACIP meeting, which is likely to be presented during the June 

2009 ACIP meeting.

In conclusion, Dr. Cieslak thanked the members of the workgroup, without whose expertise and 

a variety of disciplines, consideration of this particular topic would not have been possible. 

Human Rabies Biologics: Consideration of a Reduced 

Vaccine Schedule in Post-Exposure Prophylaxis

Charles E. Rupprecht, VMD, MS, PhD

National Center for Zoonotic

Vector-Borne & Enteric Diseases

Dr. Rupprecht reported that the sources of the evidence for the Rabies Vaccine Workgroup 

were based upon preliminary studies, basic studies on rabies virus pathogenesis, applied 

immunization principles and kinetics, published literature on human clinical trials, 

epidemiological surveillance data in the US and abroad, and consultation with industrial and 

international and national subject matter experts (SMEs). 

As an acute, progressive encephalitis, due to highly neurotropic RNA viruses, the modern 

rationale for preventive prophylactic action in rabies focuses upon timely intervention against the 

initial events in viral pathogenesis, prior to invasion of the central nervous system. The 

recommended rabies post-exposure regimens emphasize the early provisions of wound care 

and passive immunity (e.g., infiltration of rabies immune globulin at the bite site), combined with 

Rabies Vaccines

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administration of rabies vaccine, to stimulate the development of active immunity in the days 

following exposure. 

The rapid induction of rabies virus neutralizing antibodies during prophylaxis is accepted as a 

critical surrogate for predicting successful survivorship. In a review of clinical trials of rabies 

vaccination, all healthy individuals developed detectable rabies virus neutralizing antibodies by 

Day 14. No significant differences were documented between a 4- versus a 5-dose rabies 

vaccine schedule in the amount of detectable rabies virus neutralizing antibodies produced 

using temporal serological comparisons. In comparison of studies using 4 doses of vaccine, 

when given in a regimen that included rabies immune globulin, equivalent outcomes were 

found.

No record of failure of human post-exposure prophylaxis has been identified in the U.S. since 

the advent of modern cell culture vaccines and immune globulins 30 years ago. Worldwide, the 

clear majority of documented cases of human rabies cases have occurred in patients who either 

did not receive any post-exposure prophylaxis, or for whom there were documented substantial 

delays in the initiation of prophylaxis and / or significant deviations from current 

recommendations; no failures have been attributable to an absence of the last (fifth) vaccine 

dose in prophylaxis.

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

of rabies vaccines. Such research on basic immune response and efficacy outcomes with a 

variety of species has provided significant inferences to human clinical trials. Models from 

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

potent vaccine are not critical if timely intervention occurs after experimental infection, including 

the use of immune globulins. In fact, all current biologics have first been used with surrogates 

from comparative animal models, and no animal models have demonstrated greater efficacy of 

5 versus 4 doses. Provided that wound care, infiltration of immune globulin, and at least the 

‘prime-boost’ vaccination scheme are given, the same outcome is observed in a variety of 

species: no evidence suggests the necessity of a 5th dose.

Preliminary assessments support the positive national health benefits associated with a reduced 

schedule of rabies vaccination. Overall, there is no anticipation that changing the current 

recommended schedule of 5 vaccine doses to 4 vaccine doses during rabies post-exposure 

prophylaxis would substantially alter the health economics of rabies prophylaxis. Recognizing 

that there are no national or international comparative clinical human trials that specifically 

compared 4 versus 5 doses, the work group’s approach had to be inferential based on a review 

of published and unpublished studies related to rabies virus pathogenesis, experimental animal 

studies, human clinical trials, and national and international epidemiologic surveillance data. 

The work group concluded that based upon the available evidence in toto, no additional cases

would result from a reduced schedule of 4 vaccine doses applied during post-exposure 

prophylaxis, compared to the status quo recommendations of 5 vaccine doses. After discussion 

and deliberations of the ACIP on the provided evidence, a vote should be considered at the next 

meeting based upon the draft document prepared by the rabies working group. 

The work group recognizes that the 2008 ACIP recommendations did not take reduced doses

into consideration. Considering lag times, the work group began work in 2005 to produce the 

2008 recommendations. Nearly an entire year passed with the additional deliberations, 

clearance processes, et cetera after the primary vote and acceptance by ACIP the prior year. In 

addition, the supply limitations gave the group a new appreciation for the utility of dose-saving 

measures. Similarly, they do not wish to focus upon this as any conflict with label per se as 

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opposed to a focus upon the evidence for support of any reduced schedules in the future. No 

substantive data have been produced internationally or nationally from the FDA, industry, or at 

the WHO Collaborating Center level that would suggest that a reduced dosing schedule from 5 

to 4 would lead to any more cases. In regards to compliance issues, the work group recognizes 

from sentinel studies in the US that compliance with 5 doses is not 100%. In fact, from one 

retrospective study in New York, approximately 3% to 5% of patients did not report for the fifth

dose. Extrapolating that across the US population, there have been no documented 

repercussions. Similarly, in enzootic dog rabies countries where compliance is less because of 

travel distances and because of cost, there have been no associated epidemiological 

repercussions from the reduction of 5 to 4 doses. 

Discussion

Dr. Morse thought a highly convincing argument had been made to go to 4 doses. He reminded

everyone that this was only one component of a multi-faceted approach to address the potential 

shortage of vaccine should it arise, and to reduce the potential overuse of vaccine. If ACIP 

recommends this reduction Dr. Morse wondered whether it would be implemented, given that it 

is licensed as a 5-dose regimen. Given the 5-dose series will be printed on the package insert, 

it is possible that this may be viewed as off-label use. 

Norman Baylor (FDA) clarified for the record that while the FDA has a representative on this 

working group, the agency cannot endorse off label use. The package insert states 5 doses 

and until data are presented by the manufacturers to change that to 4 doses, the FDA cannot 

change the package insert as doing so would be inconsistent with the label as licensed. 

Dr. Judson wondered whether anyone had compared the use of neutralizing antibody immune 

surrogate.

Dr. Rupprecht stressed that they had to appreciate the historical legacy that 5 to 6 doses were 

better than 14-21 doses. Vaccines have certainly improved over nerve tissue vaccines that 

continue to be used in the developing world. Based on all of the available evidence, the 

inclusion of wound care, infiltration of immune globulin, and at least the prime boost strategy are

much more important than the necessity for 5 doses. The median incubation period for US 

cases is 35 days, which calls into question the scientific utility of a dose at day 28 when most

people are not demonstrating illness at one month. While they cannot compel industry to 

change labels and recognize that there is a potential perceived conflict with FDA, on the basis of 

the data that industry and FDA have shared, there have been no substantive public health 

repercussions. 

Dr. Cieslak pointed out that there are no data that either the 4th or the 5th dose is needed, so it 

might be a bridge too far to change the recommendation in that regard. There are no data to 

suggest what percentage of physicians would follow a recommendation for a reduced schedule 

if the FDA labels were not changed. 

Dr. Rupprecht reminded everyone that many practicing physicians were not even aware of the 

current ACIP recommendations. Part of the outreach is at least to get the recommendations in 

place into the hands of the stakeholders.

Dr. Morse noted that Canada’s committee recommended changing a different rabies issue, 

although this may not be implemented. 

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Dr. Pickering added that the “bat in the bedroom” recommendation was changed in Ottawa so 

that it does not appear as a risk criterion. 

Dr. Rupprecht pointed out that this working group has many issues to address (e.g., bat in the 

bedroom, risk assessments, stockpile issues, et cetera). The potential reduction in doses was

simply the first issue the working group undertook for resolution. Similarly, the working group 

feels that even with its limitations, the 2008 attempt at an evidence-based approach is an 

improvement from the previous 1984 ACIP recommendations, which also included the utility of 

intradermal vaccination a full two years before it was actually licensed. 

With respect to the question of 5 versus 4 versus 6 doses, Dr. Decker (sanofi pasteur) 

summarized what the package insert currently states with respect to indication, “WHO 

established a recommendation over 6 intramuscular doses based on [various studies that are 

listed]. Studies conducted at the CDC have shown that a regimen of 1 dose of human rabies 

immune globulin (HRIG) and 5 doses of human diploid cell rabies vaccine (HDCV) induce 

excellent antibody response. Based on this data, ACIP recommends a 5 dose regimen . . .” The 

US already deviates from WHO recommendations based on studies conducted by CDC. There 

are no studies to support further deviation. This proposal was not an accommodation merely for 

a shortage, but a permanent change in routine recommendation, which is an entirely different

issue. sanofi pasteur fully expects that the FDA would not find it reasonable to change the 

package insert based on inferences with no specific studies. There is going to be incredible 

confusion if ACIP makes this recommendation and the label remains the same. There is a legal 

regulatory issue and a clinical practice issue. From a clinical standpoint, a clinician might 

reasonably assume that 4 doses are more than enough in the US system giving of HRIG, but as 

a matter of law, that is not adequate. The law must be complied with. As a matter of 

faithfulness to the procedures ACIP has followed in the past, this recommendation is not the 

basis on which they have made prior statements and is not what is embodied in the current 

package insert. 

Dr. Rupprecht responded that the committee was cognizant of these nuances from an 

administrative and regulatory standpoint for a long time, and took the evidence-based approach 

based upon ACIP discussion regarding the utility based upon the evidence in toto of 4 versus 5 

doses or other reduced schedules. They also recognize that no one can compel a manufacturer 

to change a label.

Clement Lewin (Novartis Vaccines) indicated that a 4-dose regimen is not on the label for 

RabAvert®. Novartis has not generated the data to support the 4-dose schedule. As a 

company, Novartis does not promote or support off label use, nor are they planning to collect 

clinical data to justify the change in the label that Dr. Decker discussed. If ACIP makes this 

change, Novartis will continue to tell anyone who calls in that the currently licensed regimen is 5 

doses. 

Dr. Plotkin commented that if this recommendation is put into effect, there will be a problem with 

regard to testing for antibody. There is a problem with immunosuppression, HIV, and perhaps 

people who receive the vaccine in the fatty tissue. Thus, he anticipated that there would be 

more demand for antibody testing. Perhaps some information about that should be included in 

any statement made regarding the 4th dose.

Dr. Rupprecht responded that the information supplied to ACIP members does recommend 

antibody testing, and that until additional supportive data become available, particularly for the

immunocompromised, the current regimen of 5 doses should be continued.

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Dr. Sawyer encouraged the committee to consider making a recommendation that is off label as 

long as the data support it; however, as a clinician who deals with this question in talking to 

pediatricians about whether to give prophylaxis, this is a very stressful and emotional topic. For 

local public health authorities or clinicians to follow an off label recommendation, there must be 

very strongly stated data and language in the recommendation. Therefore, he encouraged the 

committee to be very clear about the points that had been raised in the draft statement. He 

thought they would clearly have to show that in the US, where everyone receives immune 

globulin, a 4-dose regimen is still likely to be successful and there will be no significant change 

in antibody titer.

Dr. Rupprecht replied that in regard to the immunosuppression issue, for example, with rabies 

immune globulin (RIG) as to the possibilities for interference from some of the licensed products 

used in the US, there are prior data showing a lack of interference of HRIG in regard to those 

doses. In addition, the working group believes that there will be some additional information 

coming out from an alternative product in the near future that will also support those claims. 

Dr. Marcy said he thought most Americans contracting rabies would acquire it overseas. He was 

very concerned last year about the statement that post-exposure prophylaxis is a medical 

urgency not a medical emergency. This has implications for those who are traveling because a 

travel insurance company has to expend $50,000 to fly somebody back to the US. Otherwise 

they have to get nerve tissue vaccine and no rabies immune globulin is available.

Dr. Rupprecht clarified that this was a statement inserted in 2008 after the ACIP review and 

vote; however, the working group will be considering additional language based upon updating 

the recommendations. The implicit rationale behind that was to allow time for risk assessments 

as opposed to everybody receiving prophylaxis or any of the other strategies currently used. It 

is not clear whether prophylaxis is needed at all. The working group will consider alternative 

strategies.

Dr. Lett inquired as to whether the FDA would consider amending the package insert language 

to describe the ACIP recommendation or endorsement, given that it already states that the 

ACIP has recommended a schedule that is one dose different from the WHO’s schedule. 

Dr. Baylor (FDA) responded that they would not do so unless the manufacturers submit data 

supporting the 4-dose regimen. It has been the FDA’s practice to drop the ACIP 

recommendations from the label if they are inconsistent with the data FDA has reviewed to 

support the indication.

Dr. Duchin (NACCHO) agreed with the recommendation put forward. While he thought the 

evidence presented was convincing, the discrepancy between the package label and the ACIP 

recommendation would likely create problems with respect to implementation. Therefore, he 

urged everyone to reconcile this before creating a final statement.

Dr. Decker (sanofi pasteur) indicated that to satisfy FDA requirements to effectuate a label 

change, sanofi pasteur would first have to decide that they wanted a label change. That is not a 

foregone conclusion because it was not clear to them whether dropping the 5th dose was 

prudent. Assuming they did agree, they would first have to determine what such a study would 

cost, and they would have to prioritize it. Many good projects are already going undone due to 

the lack of resources. This label change effort would delay or defer something else, so they 

would have to weigh whether it is important to do. They only engage in about half of the 

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projects each year that would like to already. If it did become prioritized, it would take 

approximately three years from the day the decision is made to go forward to the day that there 

is actually a decision from the FDA about a label change. This is a highly effective vaccine for 

an otherwise fatal disease. There may be a difference in antibody levels downstream. The 

literature shows instances of people developing rabies years after exposure who are not 

prophylaxed, so it is not clear they would answer the question that a critic might raise, which is 

the most important aspect in determining whether someone has zero risk of disease later. 

Dr. Rupprecht acknowledged that there are fundamental fears about rabies that the working 

group appreciates. He reiterated that there was none of the international SMEs consulted, 

including the SMEs from Novartis and sanofi pasteur, provided any data demonstrating the 

utility of 5 versus 4 doses. There are differences between administrative and regulatory issues, 

the evidence based upon the literature, what is understood about the disease, basic 

immunogenicity, the way forward for additional manufacturers and additional products, et cetera

on the basis of the evidence. The working group does not wish to prolong the discussion about 

a conflict between the evidence and the label because these are two different arenas.

Clement Lewin (Novartis Vaccines) indicated that Dr. Rupprecht was correct on subject matter 

experts who were consulted. It was his understanding that the SMEs communicated that there 

are no data to support 4 doses. There is clinical data to support 5 doses. Novartis does not 

disagree with the scientific conclusions that Dr. Rupprecht shared; however, in practical terms,

this will create an issue for practitioners because the ACIP recommendation will conflict with the 

product insert. 

Dr. Chilton pointed out that there is a conflict in the labeling and in the recently published 

statement for rotavirus vaccine in the age at last dose, so there is precedent for differences 

between the FDA and the ACIP recommendations.

Having been on the Anthrax Working Group, Dr. Morse pointed out that it took years to reduce 

the number of doses based on clinical data. It seemed as though there was strong evidence for 

4 doses, but without the clinical data, it will take numerous years to make this change. One of 

the issues driving this discussion was the potential for a vaccine shortage. He requested that 

the vaccine manufacturers comment on supply. 

Joel Ward (UCLA) noted that over the decades, this committee had faced an issue many times 

in which there has been a discrepancy in a published precedent or the data used to develop the 

drug inserts. ACIP should develop some policy issues regarding how to deal with these 

generically. 

With regard to supply, Clement Lewin (Novartis Vaccines) indicated that based on current 

projects and forecasts for demands in the marketplace, Novartis Vaccines believes that it can 

supply enough vaccine for pre-exposure prophylaxis and for selected first responders (e.g., 

veterinarians, students, animal control officers, et cetera). Novartis is currently not supplying for 

travelers for pre-exposure prophylaxis, but continues to evaluate the situation. In terms of longterm supplies, Novartis is upgrading its facility in Marburg, Germany. The new building is 

scheduled to be complete in 2010 and to start production in 2011, which will result in a 

significant increase in capacity.

Dr. Rupprecht indicated that there is one update for pre-exposure for travelers. Currently, 

individuals posted in enzootic rabies countries, because of the lack of pre-exposure 

vaccinations, are recommended to receive whatever local vaccines are available even if they 

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are not on the ACIP list or licensed in this country rather than receive no pre-exposure

whatsoever. 

Phil Hosbach (sanofi pasteur) indicated that sanofi pasteur is currently providing post-exposure

product only. They have made public announcements that their facility is in the midst of a 

planned shut down for upgrades. They have built a stockpile, but are reaching the end of it due 

to ins and outs of the other manufacturer. They are currently at post-exposure doses, with state 

health department assistance and screening only. The new facility is expected to be on-line and 

approved by the FDA in the second half of 2009. 

Dr. Decker (sanofi pasteur) added that in a shortage situation there is substantially more 

flexibility in how sanofi pasteur responds. A deviation from the package insert can be handled 

much more easily in the context of a temporary shortage recommendation. They cannot handle 

a permanent ACIP change that conflicts with the package insert.

Dr. Gellin recognized that off label recommendations in this medical environment is not a simple 

thing to do. As part of the body of evidence to make the case for dropping the fifth dose, health 

economics was addressed. There is no question that less of something with an equal result is 

beneficial. He agreed that they should also develop a general framework for dealing with these 

issues regardless of the topic. 

Dr. Pickering reminded everyone that the FDA licenses vaccines and ACIP recommends those 

vaccines without typically wandering too far from the FDA licensures. He said he felt very 

uncomfortable in doing that, particularly for large population recommendations. With smaller 

issues such as in sub-groups of travelers and post-exposure to hepatitis A, there have been 

differences from the labels. However, as a general rule it is not a good idea for ACIP to differ 

from FDA indications for vaccines. 

Dr. Judson pointed out that one problem was that pharmaceutical manufacturers would never

have as a high priority determining the minimal effective dose of anything. If ACIP had to rely 

upon manufacturers to go back to the FDA with an application to change the label to lower the 

dose to a new minimal effective does, it was not likely to happen. This leaves ACIP either to go 

against the label or go against the FDA to meet the practicalities of limited supply. 

Clement Lewin (Novartis Vaccines) responded that Novartis was not declining to move forward 

with a label change request because they would lose money. They view rabies vaccine and the 

investment in terms of the cost per series and the value that they create by immunizing. 

Clearly, there is an advantage to fewer doses and there are actually savings that might be

recouped. The challenge and concern is that there is a significant investment in capacity, as 

well as competing priorities. Given that the investments that both companies have made, it 

appears that the supply will be sufficient. 

Dr. Friedland (GlaxoSmithKline) commented on the statement about manufacturers not being 

interested in establishing a minimum effective dose in that he though it was an overgeneralization and was not accurate. Speaking for his company and others, they are interested 

in finding vaccines that prevent and eliminate disease for children and all age ranges. The 

approach is to find the proper dose.

Dr. Marcy emphasized that this issue was going to continue to arise. Last October, they were 

informed that there was a reduction in the dose of rotavirus vaccine with RotaTeq® from 3 to 2

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doses based on South American studies. It was his understanding that there are also on-going 

studies with HPV vaccine to support moving to 2 instead of 3 doses. 

Dr. Katz indicated that there was no difference in the dosimetry of rabies vaccine for a 2-month 

old who is exposed versus a 200-pound adult. Speaking from personal experience, his 

granddaughter was exposed at 2 months to a rabid bat that the cat brought in the house. She 

received the full series of rabies vaccine (5 doses). He was convinced that if anyone conducted

antibody studies, they could save vaccine also by having reduced doses depending on size and 

weight similar to other products. Influenza vaccine is given at a reduced dose to children in the 

first years of life. Perhaps the same could be done with rabies.

Dr. Decker (sanofi pasteur) indicated that manufacturers conduct studies to develop improved 

versions of products, with the intent to get the license changed. The problem was that the

rabies vaccine process was flowing backwards with the functional indication of a 

recommendation without any studies. He emphasized that he totally agreed with Dr. 

Rupprecht’s review of the literature as to what would be clinically reasonable. If someone asked 

him as a clinician, this would be his response. However, in the regulatory environment

changing a package insert is a major endeavor that will take years. The change will not occur

without an explicit study demonstrating satisfactory criteria on a pre-agreed endpoint that the 

change is adequate. It is not clear whether such a study could be conducted other than in 

Thailand, India, or elsewhere where rabies is so endemic an experiment could be conducted

among people who have been bitten by rabid animals. 

Dr. Baylor noted that moving forward with newer vaccines, the doses can be optimized at that 

point. It is very difficult to go backwards with old vaccines. 

Dr. Cieslak pointed out that all of these concerns have been discussed in the working group,

which has come far in terms of reviewing the data. The working group members believe the 

data are compelling and feel an obligation to place them before the committee in June 2009. 

Mark Sawyer, MD

University of California, San Diego

Chair, ACIP Pertussis Vaccines Working Group

Dr. Sawyer indicated that his sole purpose was to introduce the new Pertussis Vaccines 

Workgroup, which is in the process of begin formed. The background is that pertussis remains

the least well-controlled reportable bacterial vaccine-preventable disease in the US. There is a 

series of ACIP statements for infants and young children, adolescents, adults, and pregnant and 

postpartum women that refer to use of various products with pertussis vaccine in them.

The Pertussis Vaccines Workgroup’s terms of reference are to: 1) review existing statements on 

infants and young children (1997), adolescents (2006), adults (2006), and pregnant and 

postpartum women and their infants (2008) and consolidate these into a single statement; and 

in the process of doing so 2) review new data on Tdap, including effectiveness of ACIP 

recommendations with respect to uptake of recommendations and barriers to uptake, interval 

between Td booster and Tdap, reactogenicity, use of vaccine for pregnant and breastfeeding 

women, and vaccinated healthcare workers and the need for post-exposure prophylaxis. 

Update: Pertussis Vaccines Workgroup

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The workgroup includes the following members and continues to take suggestions for any 

additions: ACIP: Mark Sawyer (Chair), Carol Baker, Lance Chilton; CDC: Jennifer Liang 

(Lead), Nancy Messonnier, Thomas Clark, Stacey Martin, Tami Skoff, Lucia Tondella, William 

Atkinson (ISD), Beth Hibbs (ISO); Liaisons: Richard Beigi (ACOG), Geoffrey Evans (HRSA), 

Theresa Finn (FDA), Stanley Gall (ACOG), Christine Hahn (CSTE), Harry Keyserling (SHEA), 

Tom Koinis (AAFP), Sarah Long (AAP); and Consultants: Scott Halperin (Canada), Bruce 

Meade. 

Use of PPSV23 for Prevention of Pneumococcal

Pneumonia During an Influenza Pandemic

Matthew R. Moore, MD, MPH

Commander, USPHS

CDC / CCID / NCIRD / RDB

During this session, Dr. Moore discussed the use of PPV23 for prevention of pneumococcal

pneumonia during an influenza pandemic, specifically focusing on the role of this vaccine in 

critical infrastructure personnel. To set the stage, he explained that he would present a model 

used to estimate the burden of PPV23-type pneumococcal pneumonia among critical 

infrastructure personnel during an influenza pandemic and that, after his presentation, he would 

pause to answer questions about the specifics of the model. Next, Dr. Messonnier would 

present a cost-effectiveness model of PPV23 use in this same population during a pandemic.

The reason this issue is important is because it is known that pandemic influenza infection 

predisposes individuals to secondary bacterial pneumonia [Brundage, Lancet Infect Dis 2006]. 

Also known is that Streptococcus pneumoniae (pneumococcus) was identified in approximately 

50% of secondary bacterial pneumonia cases and about 20% of deaths in 1918 [Soper, JAMA 

1918; Morens, JID 2008]. Currently recommended pneumococcal vaccines were not available 

during any of the 20th Century influenza pandemics. Therefore, pneumococcal vaccines may 

play a role in reducing morbidity and mortality during the next pandemic. 

The ACIP Pneumococcal Working Group considered three policy options regarding this issue. 

The first was to assume that a pandemic will occur in the near future, and to expand the current 

recommendations for use of PPV23 as soon as possible. This posed some challenges such as 

thinking through the target groups that would be involved and the benefit in vaccinating those 

target groups, the programmatic challenges of expanding target groups, and concerns about revaccination and the potential issue of hyporesponsiveness. The second option recognized by 

the working group was to encourage implementation of the current recommendations 

[http://www.pandemicflu.gov/vaccine/pneumococcal.html], which has essentially been done. 

This document is posted on the influenza website, which advocates for continuing to use 

polysaccharide vaccine according to the current recommendations. The third option, the topic 

of this discussion, is to administer PPV23 to critical infrastructure personnel targeted for prepandemic influenza vaccine when a pandemic is actually declared. This has several 

advantages. The first is that this is a relatively young, healthy population that is likely to 

respond robustly to PPV23. Programmatic efficiency would also result from administering prepandemic influenza vaccine. In addition, this particular approach fulfills the planning objective of 

maintaining critical response functions during a pandemic.

Pnuemococcal Vaccines

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Dr. Moore stressed that he wanted to be clear and careful about distinguishing between 

pandemic influenza vaccine and pre-pandemic influenza vaccine. Pandemic influenza vaccine 

is manufactured after sustained person-to-person transmission has been identified. It is 

targeted against a novel influenza A virus, which may not necessarily be H5N1. The objective 

of the pandemic influenza vaccine program is to minimize morbidity and mortality by providing 

an opportunity for the entire US population to be vaccinated. Pre-pandemic influenza vaccine is 

manufactured and stockpiled before a pandemic begins, and is targeted against strains that 

have pandemic potential, such as H5N1. Currently, HHS’s goal is to stockpile 20 million 2-dose 

regimens with an objective to maintain critical response capabilities during a pandemic rather 

than vaccinating the entire country. It is really this particular program with which PPV23 would 

be coupled, and it is these 20 million individuals who the working group wanted the committee 

to consider vaccinating with PPV23. 

To better understand how great the problem might be during a pandemic, the working group 

took a relatively simple approach to estimate the burden of pandemic-associated pneumococcal 

pneumonia among these 20 million critical infrastructure personnel. The following method was 

used to make this estimation: 

20 million personnel

X 

influenza attack rate

X 

secondary bacterial pneumonia

attack rate

X 

% due to 23 pneumococcal serotypes

included in PPV23

= 

expected cases of PPV23-type

pneumococcal pneumonia

attributable to influenza

This is a multiplicative rate-based model. The assumptions, which were many, were based

whenever possible upon the published literature and the current pandemic plan. The working 

group considered “best case,” “worst case,” and “base case” scenarios that incorporate the 

lowest morbidity and mortality, the highest morbidity and mortality, and estimates in between 

these two extremes, respectively. Then they had to factor in the potential effects of several

interventions that were not available during previous pandemics (e.g., antiviral prophylaxis and

treatment, non-pharmaceutical interventions, pre-pandemic influenza vaccine, and reduced 

incidence of pneumococcal pneumonia as a result of routine childhood use of pneumococcal 

conjugate vaccine (PCV7). Some programmatic assumptions also had to be made. The first 

was that a pre-pandemic program will actually be implemented at the time a pandemic is 

declared. It was also assumed that this program would target 20 million critical infrastructure 

personnel (e.g., healthcare workers, water and electrical workers, and other individuals). Also 

assumed was that all 20 million of these individuals would be between the ages of 20 and 64 

years, and that two doses of pre-pandemic influenza vaccine would be administered to all 20 

million personnel. 

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In addition, it was assumed that the program would allow for simultaneous administration of 

PPV23 to each of those individuals as they arrived for their first dose of pre-pandemic vaccine. 

Decisions also had to be made about the epidemiology of pandemic influenza, assuming that in 

the absence of any of the interventions available in the 20th Century that attack rates of 

influenza would be similar to that of previous pandemics. It was also assumed that attack rates 

of pandemic influenza may be reduced through the use of anti-viral prophylaxis, nonpharmaceutical interventions, and pre-pandemic influenza vaccine. Finally, the assumption was 

made that reductions in the influenza attack rates would be proportionate to the effectiveness of 

the interventions themselves and the proportion of the target population that actually receives 

them. That is, if a particular intervention is 50% effective for an individual and if 50% of the 

population receives that intervention, the population would experience a 25% reduction, in 

relative terms, in the influenza attack rate. 

Virtually of the assumptions were derived from either the published literature or existing 

pandemic plans rather than expert opinion. Assumptions were made about the effectiveness of 

antiviral prophylaxis, coverage with antiviral prophylaxis, the effectiveness of pre-pandemic 

vaccine, and coverage with pre-pandemic vaccine. Assumptions also had to be made about 

secondary pneumococcal pneumonia during an influenza pandemic. 

Thus, it was assumed that in the absence of interventions, attack rates of secondary 

pneumococcal pneumonia would be similar to those in previous pandemics. Also assumed was 

that attack rates of secondary pneumococcal pneumonia might be reduced through the use of 

antiviral treatment of persons who have pandemic influenza because it is known that people 

who are treated with antivirals and have seasonal influenza infection have a reduced risk of 

lower respiratory tract complications that require antibiotics. It was also assumed that attack 

rates of secondary pneumococcal pneumonia would be reduced proportionate to reductions in 

pneumococcal pneumonia observed since the introduction of 7-valent conjugate vaccine, and 

that the distribution of serotypes causing secondary pneumococcal pneumonia would be similar 

to the distribution of serotypes causing invasive pneumococcal pneumonia in 2007.

To estimate secondary bacterial pneumonia attack rates in the presence and absence of 

treatment with neuraminidase inhibitors for 20 million critical infrastructure personnel, for the 

base case it was assumed that 15% of individuals who develop pandemic influenza infection will 

go on to develop secondary bacterial pneumonia and about half of those cases will be caused 

by pneumococcus. Reductions were incorporated related to the introduction of PCV7 in 

children and herd effects in adults. Also assumed was that the proportion of PPV23 serotypes 

would be similar to that observed in 2007 (~78%). 

The next step was to enter all of these assumptions into a software package that allowed them 

to do thousands of simulations of various combinations of the different assumptions to better 

understand what is really the most likely situation to occur given this very broad range of 

assumptions. Most of the estimates are below 100,000 cases. That is, it seems unlikely that 

there would be more than 100,000 cases of PPV23 type pneumonia during an influenza 

pandemic in the population of 20 million critical infrastructure personnel. The most likely 

estimate was approximately 35,000 cases of PPV23 type pneumococcal pneumonia in this 

population of 20 million critical infrastructure personnel. Beginning with that number of 35,000 

cases, consideration was given to how much of that could actually be prevented with 

polysaccharide vaccine. This raised another tricky question with respect to what should be 

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assumed about pneumococcal vaccine effectiveness in this population of young, healthy 

individuals who are exposed to pandemic influenza infection. 

The working group reviewed the literature, finding that there really are no data on the 

effectiveness of this formulation of this vaccine for this population (e.g., young, healthy, but 

high-risk) during an influenza pandemic. Going back approximately 30 years, studies of PPV14 

in South African gold miners suggest 76% efficacy against vaccine-type pneumonia. Studies of 

PPV23 in the elderly suggest 50-85% effectiveness against vaccine-type bacteremia, but not 

necessarily pneumonia. Thus, the working group decided to assume a very broad range of 

effectiveness from 20% to 80% and applied this to all vaccine type pneumococcal pneumonia

(e.g., invasive and non-invasive); that is, they did not distinguish between bacteremic and nonbacteremic pneumococcal pneumonia. 

With regard to the number of 20-64 year-olds needed to vaccinate to prevent a case of vaccinetype pneumococcal pneumonia is as follows:

Age Group, 

Years

 Assumed PPV23 Vaccine Effectiveness

20 50 80

20-49 3,749 1,499 937

50-64 5,644 2,258 1,411

This assumes base case model-derived estimates of 31,903 total cases of pneumococcal 

pneumonia, and that approximately 75% to 80% were caused by PPV23 types. Even with a low 

vaccine effectiveness of approximately 20%, approximately 3,000 to 6,000 individuals would 

need to be vaccinated to prevent a single case of PPV23 type pneumonia. Obviously, as 

vaccine effectiveness increases, the number needed to vaccinate decreases. Therefore, if this 

vaccine were 80% effective in this young, healthy population that is heavily exposed to influenza 

infection, the number needed to vaccinate would be approximately 1,000 to 1,500. This was 

somewhat of a surprise to the working group, as they were not so optimistic that the numbers 

needed to vaccinate were going to be so low. However, this may have to do with how this 

phenomenon of secondary pneumoccocal pneumonia is thought about. If beginning with a 

population that has a pandemic influenza attack rate of between 20% to 30%, even after 

incorporating all of the other interventions, the risk to this population of developing secondary 

pneumococcal pneumonia is sufficiently high that the numbers needed to vaccinate are actually 

lower than expected. 

The working group went on to estimate the preventable burden of PPV23-type pneumonia in the

absence of all influenza interventions (e.g., antiviral prophylaxis or treatment, nonpharmaceutical interventions, or pre-pandemic vaccine). Using the same range (20% to 80%), 

the working group estimated the number of individual cases that might be prevented (~5,000 to 

20,000), hospitalizations that could be prevented (~700 to 3,000) and deaths that could be 

prevented (~300 to 1,100). 

With respect to what is driving these estimates, the estimate of pre-pandemic influenza vaccine 

effectiveness is really the most important driver. As that effectiveness increases, the likely 

benefit of PPV23 decreases considerably. Similarly, if the secondary bacterial pneumonia 

attack rate is higher than the 15% estimated, an increased benefit of polysaccharide vaccine 

would be expected. If the proportion of those cases caused by pneumococcus is higher, a 

modestly increased benefit would be expected of polysaccharide vaccine. If the influenza attack 

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rate is higher for any reason, that increases the benefit of PPV23. Somewhat to the working 

group’s surprise pneumococcal polysaccharide vaccine effectiveness is not the most important 

driver. 

With regard to whether there could be a role for PCV13, which is under development. Licensure 

is being sought for use in children, but it may be licensed for adults at some point as well. This 

same model can be used to estimate the burden of PCV13 type pneumonia. 

In conclusion, the working group thinks that a rate-based model can be used to estimate the 

burden of pneumococcal pneumonia during an influenza pandemic. The group’s best estimate 

is that about 35,000 cases of secondary pneumococcal pneumonia caused by these 

polysaccharide vaccine types could occur among 20 million critical infrastructure personnel 

during the next influenza pandemic. The use of polysaccharide vaccine during a pandemic 

really could have substantial public health benefits, especially if the influenza interventions are 

ineffective or if they are unavailable, and even with relatively low polysaccharide vaccine 

effectiveness.

Discussion

Joel Ward (UCLA) pointed out that one important factor not discussed was that those individuals 

who have pneumonia and high fever presumed to be due to influenza with respect to what 

proportion of those will have received antibiotics, in which case a significant proportion of 

potential pneumoccocal disease will have been treated by antibiotic prophylaxis and will not 

occur.

Dr. Moore responded that this model has also been used to estimate the number and types of 

courses of anti-bacterials that may be necessary during an influenza pandemic. However, 

consideration has not been give to what would occur if everyone was simply treated with 

antibiotic versus being vaccinated.

Dr. Cieslak requested clarity on where the 50% for Streptococcus pneumoniae causing 

secondary bacterial pneumonia came from. Based on the table presented in the pre-conference 

materials, this appeared to be more in the range of 20%. In addition, he wondered about 

serotypes, because his understanding of the pathogenesis had something to do with specific 

receptors induced on respiratory epithelium and the possibility that there is strong serotype 

specificity. Serotypes I, II, III, and IV are mentioned, but he was trying to make a connection 

between the 23 in the vaccine.

Dr. Moore replied that this may have been with a different serotyping scheme with respect to the 

pathogenesis of individual serotypes being more likely to cause pneumonia than others. The 

currently available epidemiology was used on invasive pnumococcal pneumonia and assumed 

that it was not really the serotype that made a difference. However, it may be that the individual 

influenza strain makes a difference. There is some evidence that the neuraminidase activity in 

individual influenza strains may make a difference in terms of the likelihood of developing 

secondary bacterial pneumonia of any kind. One of the assumptions is that the strains that 

would cause secondary bacterial pneumonia in a pandemic setting are the same strains 

currently circulating in communities throughout the US. In terms of the determination to use 

50% versus 20%, a judgment call had to be made in examining the different sources of 

information for the proportion of secondary bacterial pneumonia cases causes by 

pneumococcus, taking into consideration that some of the studies involved upper respiratory 

tract specimens only, some were from autopsy studies, and others were from sterile sites only.

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Dr. Duchin (NACCHO) inquired as to whether it was assumed that the vaccine would be equally 

protective against bacteremic and non-bacteremic pneumonia.

Dr. Moore responded that they assumed three point estimates for effectiveness against the 

combination of bacteremic and non-bactermic pneumonia. One way to think about that is that it 

is thought that roughly 30% of all pneumococcal pneumonia is bacteremic. If the vaccine 

effectiveness against that 30% is similar (~50% to 85% range) to that of PPV23 against 

bacteremia in the elderly, but there was essentially no effectiveness against non-bacteremic 

pneumonia, then the 80% effectiveness against 30% of diseases is essentially an overall 

effectiveness of 24%. Taking into account the broad range of 20% to 80% would account for 

the issue of bactermic versus non-bacteremic disease. 

Regarding the estimation of Streptococcus pneumoniae (S. pneumoniae) as a cause of 

pneumonia following influenza, Dr. Englund pointed out that over the past few years there has 

been a major predominance of Staphylococcus aureus (S. aureus) as opposed to S. 

pneumoniae. This may be related to high rates of pneumococcal vaccine coverage in the 

young, which may impact the nasal coverage in older individuals (e.g., over 21 years of age). 

She expressed concern that the pnuemococcal causes were overestimated.

Dr. Moore responded that this was a legitimate concern that the group had discussed 

extensively. The problem is that there is no population-based data on the incidence of 

Staphylococcus aureus (S. aureus) pneumonia. There is great concern that methicillin-resistant 

(MRSA) S. aureus in particular is more common; however, the group used a very broad 

sensitivity analysis that incorporated pneumococcal estimates from as low as 10% to as high as 

80%. It does not make that much of a difference, but when it comes to making planning 

decisions, especially with regard to anti-bacterials, careful thought has been given to the S. 

aureus situation. 

Dr. Meissner noted that the efficacy of anti-viral therapy assumption used of 65% to 70% might 

not be characteristic of a pandemic strain. If the efficacy rate were lower, that would lead to 

greater benefit from the vaccine.

Dr. Moore responded that essentially anything that increases the risk of pandemic influenza 

increases the benefit of PPV23.

If there is high efficacy against the pandemic influenza strain in this population of 20 million such 

that they acquire very little influenza, Dr. Morse pointed out that use of the pneumococcal 

vaccine will not prevent very much disease because this population does not have to get 

influenza to have the secondary pneumonia. Knowing that, would this formula be used for 

another population who does not receive the pandemic influenza vaccine? While it is easier to 

administer both at the same time, it may be wasted in terms of preventing very much disease. 

He wondered whether the model took this into consideration. 

Dr. Moore responded that this was approached from the standpoint of the objective of 

maintaining critical response functions early in a pandemic. Therefore, this group would not yet 

have had the opportunity to receive pandemic vaccine because it would not yet be available. 

Dr. Cieslak asked what the vaccine efficacy was against pre-pandemic influenza. Dr. Moore 

responded that this was 75%.

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Dr. Duchin (NACCHO) noted that the terminology of “pandemic influenza” was based on a 

1918-like scenario. He wondered whether this model would apply equally well to a 1957- or 

1968-like pandemic or if these seemed to have difference propensity to be associated with 

secondary bacterial pneumonia. 

Dr. Moore responded that the group essentially did not distinguish between the three 

pandemics. All of the data that could be found pertaining to all three pandemics were 

combined. The influenza attack rates, for example, are an amalgam of 1918, 1957, and 1968 

with no particular weighting. The one area where this may come into play is that for a variety of 

reasons, there are actually more data from 1918 than for 1957 or 1968. It is true that the 

likelihood of secondary pneumonia varied in the three scenarios, which pertained to the issue of 

where all of the assumptions came from. To keep the meeting moving forward, he offered to go 

over these in more detail off-line with anyone interested. 

Dr. Judson thought the major problem was that the assumptions used for the likelihood of an 

epidemic (e.g., which strain it would be, pathogenicity, secondary infections) keep changing / 

improving as knowledge improves. Originally everyone assumed that 1918 was the worst 

influenza virus anyone had ever observed; however, there is a fair amount of evidence to 

suggest that it was not necessarily a more pathogenic virus, spread more rapidly, and / or had a 

higher attack rate. Instead, there were no antibiotics and no one knew what was occurring. It 

appears that a large proportion of the deaths were later deaths owing to secondary bacterial 

infections. Over the course of the 20th Century, nature has shown that successful pandemics of 

influenza have become less fatal, with lower mortality rates. Everyone was completely thrown 

off by Swine Flu, which turned out not to be a pandemic at all. One reason for the lower 

pathogenicity or death rates in 1957 and 1968 could well have been that antibiotics were given 

as soon as someone presented with a febrile respiratory illness, which is continued currently to 

some extent. He did not believe that trying to equate H5N1 with 1918 was justified scientifically. 

In fact, that might be the least likely influenza virus to cause a pandemic because it has had 15 

years to do so. Many of these assumptions are based on facts that have changed. 

Dr. Moore responded that pandemic preparedness is a major priority for NCIRD and for CDC. 

The data referred to are not all from 1918. Some of it is from 1957 and 1968, while some of it is 

from as recently as the last few months in terms of analyzing autopsy specimens from those 

pandemics. He thought it was very important to make a decision about this vaccine, and this 

modeling was the way that they had tried to “tee up” the question for the full ACIP. Not only did 

they need to make a decision, a decision was going to be made regardless of whether it was 

based on data. While these are the data currently available, as data changes over time they 

can be incorporated into the model. 

Dr. Judson pointed out that the ability to detect, type, and sequence new viruses had become 

far superior to what it had been in the past. If a real new threat evolved, there would likely be 

much more time to respond to it. Moreover, the vaccine development research has reduced the 

cycle and uncertainty for vaccine development from 6 to 8 months to approximately 2 weeks, 

which would also affect how secondary or indirect ways of preventing influenza mortality might 

be handled.

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An Economic Analysis for Use of PPSV23 for Prevention of 

Pneumococcal Pneumonia during an Influenza Pandemic 

Mark L. Messonnier, PhD, MS

CDC / CCID / NCIRD / ISD

 

Dr. Messonnier indicated that this presentation had gone through the process of review as put 

forth in the guidance for economic studies to be presented to the ACIP that was adopted in 

2007 by the ACIP and implemented beginning in 2008. There were no conflicts of interest 

among any of the study participants. 

The study question was: What is the cost-effectiveness of using 23-valent pneumococcal 

polysaccharide vaccine (PPV23) during an influenza pandemic to prevent secondary 

pneumococcal pneumonia (SPP) caused by PPV23 serotypes among members of priority target 

populations responsible for fulfilling critical pandemic functions in the United States? A direct 

medical cost perspective was taken in this review.

The intervention strategy was the use of PPV23 for prevention of PPV23-type SPP in adult 

target populations responsible for fulfilling critical functions during an influenza pandemic

(N=20million). The intervention time frame was one year, a single pandemic occurrence. The 

analytic horizon included the remaining life expectancy of the people in the target populations. 

None of the effects of PPV23 beyond this pandemic year were included. Discounting all future 

outcomes was at a 3% rate. A cost-effectiveness analysis (CEA) was used, and as a summary 

measure, the cost-effectiveness ratios (CER) were used. The basic construction of the cost 

effectiveness ratio is the net cost divided by the outcomes of interest. In this case, this was as 

follows:

(vaccine cost + administration cost) – (cost of illness averted by vaccination) 

___________________________________________________________________

number of outcomes of interest

Health outcomes included SPP health outcomes (e.g., cases, number of hospitalizations, 

deaths, life-years saved (LYS), and discounted LYS) all from the PPV23-type infections. The 

epidemiological model was calculated as follows:

Cases of SPP attributable to influenza by age in target populations

= 

Target population by age 

X 

Age-specific influenza attack rate

X 

Age-specific secondary bacterial pneumonia attack rate

X 

Age-specific percent due to PPV23-type pneumococcus

X 

Age-specific reductions attributable to currently recommended interventions

(antivirals, nonpharmaceutical interventions, influenza and pneumococcal vaccines)

[calculations to this point represent baseline strategy]

X 

Age-specific reductions attributable to use of PPV23 in target populations

[these calculations represent intervention effects]

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The cost inputs used included hospitalization, outpatient, and program costs. These are taken 

from the published literature and publicly available resources, such as the DFC contract price 

list: 

Three types of sensitivity analyses are conducted on cost-effectiveness ratios: 1) a simulation 

to estimate the values of the cost-effectiveness ratios given the input variables used and 

distributions assumed for these; 2) a ranking of the variables that affect the cost-effectiveness 

ratio; and 3) estimation in the absence of any and the absence of all non-PPV23 interventions

that are included in the model.

Health outcomes were as follows:

9

Methods: Cost Inputs

Cost Category Age Base Lower1 Upper Base Source

Hospitalized pneumonia

15 to <45 $ 9,148 $ 7,319 $ 10,978 Ray, et al.3

45 to <65 $ 10,389 $ 8,311 $ 12,467

Outpatient2

20-64 yrs $ 272 $ 217 $ 326 Meltzer, et al.4

Program cost

Vaccine $ 18 $ 15 $ 20 CDC VFC Online Vaccine Price List5

Administration $ 12 $ - $ 20 Zhou, et al.6

Wastage 0.05 0 0.1 Assumed

1

 Lower and upper bound on dollars values assumed to be 80% and 120% of base case, respectively

2

 Calculated using averages or "most likely" in Meltzer et al. Table 3; direct costs only

3

Ray, et al., PIDJ, 25:6(June 2006) 494-501

4

Meltzer, et al., EID 5:5 1999

5 http://www.cdc.gov/vaccines/programs/vfc/cdc-vac-price-list.htm; accessed 2/5/09

6

Zhou et al., Pediatrics. 2002;110:653-661; J Infect Dis. 2004;189:S131-S145.

Health Outcome Outcome 95% CL

PPV23-type Pneumococcal pneumonia 

cases prevented 12,673 (8,927-91,863)

Hospitalizations prevented 1,827 (842-8,745)

Deaths prevented 700 (327-3,323)

Years of Life saved 27,280 (11,862-133,675)

Discounted Years of Life saved 15,773 (8,273-82,927)

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Cost Outcomes Dollars

Cost of the Program $ 608,295,000

Medical costs saved $ 19,657,861

Net Cost $ 588,637,139

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Cost outcomes included the following, based on base case values for input variables:

Summary measures included the following

Of the simulated cost-effectiveness ratios, 95% fall within a range of $6,000 to $80,000 per 

discounted life year saved. In terms of the relative magnitude effects of changing the input 

variables on the output variables (e.g., cost-effectiveness ratio), bacterial pneumonia attack rate 

(20-49), pre-pandemic vaccine effectiveness (20-49), and the PPV23-type infections (20-49) 

were the top three variables that had the most-effect on the estimated cost-effectiveness ratio. 

In terms of zero effect for non-PPV23 interventions that are included as part of the model, if it 

assumed that there is zero effectiveness of prophylactic use of neuraminidase inhibitors, the 

result is $28,954 / Discounted LYS. Reduction in the influenza attack rate from nonpharmaceutical interventions is $28,954 / Discounted LYS. If pre-pandemic flu vaccine efficacy

is zero, there is a greatly decreased Discounted LYS of $8,395. Reduction in SPP from 

treatment with neuraminidase inhibitors among those infected results in $24,593 / Discounted 

LYS. If all non-PPV23 are completely ineffective, the result is $2,396 / Discounted LYS. For 

comparison, which refers to the base case results, the result is $37,320 / Discounted LYS. 

Limitations of the study are that only direct medical costs are included. Productivity losses 

averted, direct non-medical costs, and other indirect costs are not included. The effects of 

PPV23 beyond its effectiveness in a pandemic even are not included. Adverse events that may 

occur from vaccination are not included. The assumption of linkage to pre-pandemic influenza 

vaccination is also a limitation. In terms of the relation of this analysis to other studies, there are 

no other studies of cost-effectiveness of vaccine interventions in this population. 

With respect to CDC peer-reviewers’ comments, two peer reviewers found no substantive 

problems with the methods or results. It was suggested that some additional sensitivity 

analyses be conducted with respect to the impact of failure of other interventions. Also noted 

was that the cost of stockpiling is not included in the analysis. In addition, it was pointed out 

that the value of use changes. This may vary during a pandemic versus an ordinary season. 

Health Outcome CE Ratio 95% CL

PPV23-type Pneumococcal pneumonia 

cases prevented $ 46,449 ($4,860 - $65,098)

Hospitalizations prevented $ 322,204 ($51,301 - $685,553)

Deaths prevented $ 840,741 ($135,875 - $1,771,196)

Years of Life saved $ 21,577 ($3,376 - $47,758)

Discounted Years of Life saved $ 37,320 ($5,865 - $80,359)

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Discussion

It appeared to Dr. Chilton that this analysis was based on 700 deaths prevented out of 20 million 

people, or an incidence of death of 3.5 x 10-3 percent, which is pretty low. Thus, the sensitivity 

of the model in determination of the value of the 700 lives is fairly high. In addition, he 

wondered whether giving PPV23 to these healthy young people would be borrowing from 

children. If indeed there is a hyporesponsiveness induced by PPV23 for those who receive the 

vaccine, it may be less effective when they turn 65 and are supposed to receive it anyway. 

Dr. Messonnier responded that the issue of hyporesponsiveness was one that the committee 

had discussed in the past. There are questions about exactly how relevant that issue is for 

routine vaccination. He thought vaccination of critical infrastructure personnel was a 

fundamentally different situation in that they were considering the vaccination of individuals who 

would be responsible for keeping society functioning during a pandemic versus thinking about 

whether to add additional indications for those under the age of 65. 

Dr. Chilton wondered then whether they were considering the wrong end point. If the end point 

was really keeping important workers at work during a pandemic, perhaps they should be taking 

the value of that into consideration rather than the value of their lives.

Dr. Messonnier replied that this model did not incorporate those types of costs, but if this was 

done, it would actually reduce the cost-effectiveness ratio and make things look even more 

favorable than they already did. 

In response to the hyporesponsiveness question, John Grabenstein (Merck Vaccines and 

Infectious Diseases) indicated that they had shown to the Pneumococcal Working Group a few 

months ago the responses to a third dose of PNEUMOVAX® 23 in 70- and 80-year old 

individuals. The responses to the third dose have been vigorous. He indicated that he would 

be happy to present numbers to the full ACIP at any time. 

Dr. Paradiso (Wyeth) wondered whether consideration had been given to a situation in which 

the pre-pandemic vaccine was not available (e.g., cannot make it or cannot make enough); 

whereas pneumococcal vaccines are already available. With that in mind, he also wondered 

whether they modeled no influenza and just polysaccharide. The real value of vaccinating this 

group beyond just vaccinating them was the societal benefit that would be gained, which is a 

very important part of the economic analysis. 

Dr. Messonnier responded that a broad sensitivity analysis was run with pre-pandemic vaccine. 

If pre-pandemic vaccine is simply not available or it is available but not effective, the costeffectiveness ratios decrease and the burden of pnuemococcal disease increases. 

Joel Ward (UCLA) stressed that the issue of antibiotic use was profound. In 1918 there were no 

antibiotics to be used. At best in 1957 approximately 10,000 units were given of various forms 

of antibiotics. If surveys were conducted currently, the findings would likely be that 90% of 

people are given broad spectrum antibiotics and that is probably an important reason for gram 

negative pathogens. The vaccine trials conducted that showed a reduction in pneumonia, 

primarily in children, were often conducted in populations where antibiotic use was not as 

profound as in developed societies. The benefit of the vaccine may be prolonged over 5 to 10 

years, in which case there is a benefit to society by virtue of immunizing a large number of 

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adults. The analysis being done is very difficult, given that the gain that they were attempting to 

measure was secondary versus primary. 

Dr. Poland (ACP) wondered whether the economic analysis used the proportion of invasive 

pneumococcal infection.

Dr. Messonnier responded that it is known from recent studies in elderly populations who 

receive polysaccharide vaccine that effectiveness against bactermia caused by the serotypes 

included in the vaccine is between approximately 50% to 85%. If it is assumed that roughly 

30% of pneumococcal pneumonias are bactermic, the 50% to 85% would apply to the 30% that 

are bactermic and could bring the overall effectiveness down to as low as roughly 20%. The 

estimates of vaccine effectiveness are against all vaccine type pneumococcal pneumonia 

whether bactermic or not.

Dr. Poland (ACP) noted that in earlier studies, in younger people in some unusual settings who 

received the vaccine there was prevention of non-bactermic pneumonia.

Dr. Messonnier replied that this was where the 80% came from. 

Doug Campos-Outcalt (AAFP) inquired as to whether the working group considered and listed 

potential harms. For example, when people are vaccinated it sometimes alters their behavior. 

They might take fewer precautions than usual. There is a series of other potential harms that 

could occur and he wondered whether any consideration was given to this at all.

Dr. Messonnier responded that adverse events associated with vaccines were not included in 

this or in the calculations from the first presentation. This vaccine is believed to be very safe in 

young people. The goal was to estimate how great the problem might be during the next 

pandemic, and subsequently to bring the question to the full ACIP regarding whether it was 

worth using the existing licensed vaccine in attempt to prevent it. 

Dr. Morse requested that Dr. Moore articulate the context in which the two questions were being 

posed to the ACIP and the timetable in which they were planning to bring this back to the group 

for a recommendation and vote.

Dr. Moore responded that the working group knew that this would be a lot of information to 

present in one session. It was not being brought to the ACIP during this meeting for a vote. At 

this point, the group merely wanted to determine whether the type of information presented 

would be beneficial to the ACIP in making recommendation decisions. If so, there would be a 

series of additional questions to address, such as: Should the vaccine be stockpiled? When 

should it be stockpiled, in what form, and at what cost? At this time, the group was merely 

seeking input from the full committee regarding what type of additional information they might be 

interested in receiving to have enough information to vote on the question. 

Dr. Judson thought there were far too many unknowns, and too many current assumptions that 

were likely to change depending upon when the group anticipated a pandemic influenza 

occurring. In his 30 years in infectious diseases, the proportion of bacterial pneumonia that is 

pneumococcal from outside the hospitals as well as inside the hospitals where it has often 

become secondary to pulmonary edema, he would not be able to answer this question. He also 

wondered what was used for the assumption for the cross-protection from existing N1-

containing vaccines. 

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Dr. Moore responded that the assumption made for pre-pandemic vaccine effectiveness was 

75% to a high of 85% and a minimum of zero. This range was chosen based on discussions 

with colleagues from the Influenza Division. The problem is that no one knows, nor will anyone 

ever know, what the vaccine effectiveness of pre-pandemic vaccine is until the pandemic 

actually occurs. The question the group is struggling with is whether to wait until the pandemic 

actually occurs to decide whether and how to use pneumococcal polysaccharide vaccine, or 

given this broad range of assumptions and a pretty favorable case for using this vaccine due to 

the relatively low numbers needed to vaccinate and the quite favorable cost-effectiveness 

analysis, to make a recommendation. He invited members to offer input regarding other critical 

information that the ACIP might need to make a decision. 

Dr. Judson thought it was contradictory for society and ACIP to label pandemic influenza as 

somehow different from what the world experiences every year. Billions are being spent 

preparing for a hypothetical epidemic under circumstances that cannot be foreseen, although 

36,000 deaths per year are accepted on normal pandemics that occur every year.

Harry F. Hull, MD (H.F. Hull & Associates, LLC) noted that there is a $600,000 cost for a 

stockpile of vaccine to prevent 35,000 cases. Although not all of the cases are going to be 

susceptible to antibiotics, it seemed important to know the comparison of stockpiling vaccine to 

that of stockpiling antibiotics, some of which will already be stockpiled. As a former ACIP 

member, he would want to see a comparison with antibiotic treatment. 

Dr. Meissner requested information regarding the time factor. His understanding was that it 

would be a matter of months between the appearance of a pandemic strain, peak of activity, 

and winding down of pandemic influenza. He wondered if it was practical to administer 20 

million doses to individuals within a relatively short period of time.

Dr. Gellin (NVPO) responded that a pandemic was very different from a seasonal epidemic. 

Part of the problem is that it is unknown what it would look like, and part of the planning is to 

deal with worst case scenarios. The mantra is “leave no stone unturned” in an effort to 

determine what is feasible to mitigate the otherwise unmitigated outcome of a pandemic. The 

question on the table is: Pneumococcal disease is a co-traveler with influenza. What if 

anything should the US do to try to prevent as much pneumococcal disease as possible in the 

setting of a pandemic? There is the issue of stockpiling and it is fair to consider how operational 

it is to conduct a “just in time” vaccination program. Another issue regards the pros and cons of 

whether people should be vaccinated now to create population immunity. This is not an 

academic exercise. It must lead to some decision by the government with respect to what to do. 

ACIP was silent on the matter in the last round of guidelines. 

Rick Zimmerman (University of Pittsburgh) thought this was an exercise worth pursuing, 

particularly given the biologic tendency of influenza vaccine to predispose individuals to 

secondary bacterial infections, which may be even more common in pandemic. This is not yet 

well-understood. With respect to antibiotic speculation, he cautioned that there was no way to 

know what the resistance patterns would be to antibiotics in a pandemic, nor could they know 

how much would be available supply-wise.

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Update on PCV13 Pediatric Phase 3 Trial Results

Peter R. Paradiso, MD

Vice President, New Business and Scientific Affairs

 

Dr. Paradiso presented an update on investigational 13-valent pneumococcal conjugate vaccine 

(PCV13). Prevnar® and PCV13 have 7 common serotype components (4, 6B, 9V, 14, 18C, 

19F, 23F). Each of these 7 polysaccharides is conjugated to the same carrier protein, CRM197. 

The amount of conjugate per dose (2.2ug for each serotype except 4.4ug for serotype 6B) is 

identical for Prevnar® and PCV13. The 6 new serotypes include: 1, 3, 5, 6A, 7F, 19A. Each of 

these polysaccharides is also conjugated to CRM197 and the amount of each in a dose is 

2.2ug. The conjugation chemistry used for the preparation of all 13 conjugates is the same. So, 

PCV13 uses a technology that has worked successfully with Prevnar®. The use of the CRM197 

carrier protein in both Prevnar® and PCV13 will allow for the ability to transition between the two 

vaccines at any point in the vaccination schedule, as the 13-valent vaccine becomes available.

With regard to invasive pneumococcal disease (IPD) caused by PCV13 serotypes in the US in 

2006, in children under 2 years of age, the 13-valent vaccine will cover approximately 64% of 

the disease and approximately 73% of the remaining disease in children 2 to 4 years of age. 

The types causes by the 7-valent are very low at 2% in children under the age of 2 and 4% in 

children 2 to 4 years of age after 7 years of use of that vaccine in the US. The rate of disease is 

21 per 100,000 in children under 2 years of age and approximately 7.5 per 100,000 in 2 to 4 

year olds [Matt Moore, Personal Communication, ABC Surveillance System]. Over 50% of IPD 

cases in children under the age of 5 are caused by serotype 19A. Serotype 19A has been 

increasing every year for the past several years, and becomes an increasing proportion of the 

total. It is also most likely to be antibiotic-resistant. 

In terms of licensing a new vaccine that is actually a replacement for a currently available 

vaccine, given that Prevnar® is available, it is not possible to conduct placebo controlled 

efficacy trials. Thus, the basis of licensure for a new conjugate vaccine is a comparison to 

Prevnar®. Therefore, the pivotal trials compared PCV13 immune response to Prevnar®

immune response, looking for non-inferiority by pre-established conditions of the immune 

response for the 7 common serotypes. For the 6 new serotypes, it was necessary to 

demonstrate that the immune response was comparable to the response of the original 7. This 

is done in a number of ways. The primary endpoints are the percentage of subjects who 

achieve a level of antibody of > 0.35 ug/ml, established by the WHO as a threshold to measure 

protection after 3 doses in infants; geometric mean antibody concentration (GMC) after 3 doses 

as well as after the booster; functionality of the antibody (opsonophagocytic activity); boostability

in the second year of life; compatibility with concomitant vaccines; and safety. 

Wyeth conducted a number of studies throughout the world that fall into a variety of categories. 

Numerous schedules were tested, given that various schedules are used around the world. 

Tests were conducted in infants as well as older children, and with a fairly broad variety of 

concomitant vaccines, to demonstrate that the 13-valent vaccine can be given as part of a 

routine immunization program with any schedule and almost every concomitant vaccine 

(Infanrix hexa, Pentavac, Pentaxim, Pediacel, DTwP, Priorix, Proquad, Meningitec, Neissvac C, 

Vaqta, Engerix B, and OPV). All of these programs provide information for the safety database.

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The pivotal non-inferiority trials were designed in a way to compare the 7-valent and 13-valent 

vaccines. To illustrate, Dr. Paradiso reported on a trial in Germany in which infants were

randomized blindly to receive either PCV7 or PCV13 (n=603). Vaccinations were administered

at 2, 3, and 4 months of age in the primary series, with serology one month later. Booster 

doses were administered at 11-12 months of age, with serology one month later. The endpoints

included: Non-inferiority of %>0.35 ug/ml after 3 doses for each serotype (within 10% of the 

95% confidence interval of the difference)l; non-inferiority of the GMCs for each serotype (within 

50% of the 95% confidence interval of the ratio PCV13/PCV7); and for new serotypes, the 

comparison was to the lowest Prevnar® type. 

In the pivotal study, non-inferiority was achieved for every serotype except 6B. For 6B, the 

response was about 10% less but the lower bound of the confidence interval was around 16, so 

it failed. However, secondary outcomes that were agreed to with the regulatory agencies 

passed. These included passing the 2-fold non-inferiority test for GMC and demonstration of 

functional antibody response. In the US study, using the same lot at 2, 4, and 6 months of age, 

there was a better overall response to 6B as expected and the lower confidence of the 

difference was around 11%, barely failing. Another important point to focus on is the high 

percentage of responders for all of the new serotypes. The cross-reaction with serotype 19A in 

Prevnar® was non-functional in nature. With regard to GMC levels post-primary, each of the 

serotypes passed on inferiority that was preset for endpoints for these trials for regulatory 

purposes. All of the new serotypes were compared for non-inferiority against the lowest 

serotype in the Prevnar® types, and all of those passed as well. 

For each of these groups in each serotype, functional antibody was measured, with good 

functional antibody demonstrated not only for the 7 serotypes that are common between 

Prevnar® and 13-valent, but also for the 6 new serotypes. For 19A, the GMT for Prevnar® was 

6.70 compared to 442.48 in the PCV13 arm. While cross-reactive antibody is made from 

Prevnar® against 19A, that antibody does not have any functional activity. Ratios of OPA 

GMTs (PCV13 / PCV7) ranged from 0.64 to 1.02 for the 7 common serotypes, showing 

comparable functional activity. For the additional 6 serotypes, much higher PCV13 / PCV7 

ratios of OPA GMTs were noted, ranging from 10 to 100. PCV7 recipients do have a significant 

OPA response to serotype 6A, but the GMT in the PCV13 recipients is 10-fold greater, 

suggesting the PCV13 might have increased efficacy against 6A. It is important to remember 

that the ELISA has been externally standardized, so comparisons can be made across 

serotypes. For the OPA, it is not standardized; therefore, comparison can be made only within 

a serotype, but not across serotypes.

Another way to look at this is to examine the correlation between the total antibody response 

and the functional antibody response. For common serotype 4, there is a good correlation for 

the total antibody to the functional antibody for both the 7-valent and 13-valent vaccines. PCV7 

elicits binding antibody to the PS capsule of 19A; however, there is no functional activity to 19A 

in PCV7 recipients. There is no correlation between binding and functional antibody to 19A in 

PCV7 recipients. In contrast, there is a good correlation between binding and functional 

antibody in PCV13 recipients. This supports what has been observed in post-marketing 

surveillance for PCV7, where no protection was observed against 19A disease. Unlike PCV7, 

PCV13 has a substantial degree of PS binding antibody and also functional activity against 19A; 

thus, the expectation is that inclusion of 19A in PCV13 may have substantial clinical benefit. All 

of these considerations go into the assessment of the comparison between Prevnar® and 13-

valent vaccines, and particularly the assessment of the value of 13-valent for the new serotypes, 

including 19A. 

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Following the booster dose in children, there is a very high response of subjects achieving a 

pneumococcal IgG antibody concentration of greater than 0.35 μg/mL after the booster dose. 

Each one of those responses is functional as well. 

With regard to the consistency lot trial conducted in the US, children were immunized at 2, 4, 

and 6 months of age. The antibody response and percent responders to each of the serotypes 

across the three lots of vaccine (Pilot Lot 1, Pilot Lot 2, Full Scale Manufacturing Lot) were 

examined. Each of the serotypes passed preset non-inferiority criteria to demonstrate 

consistency of manufacture.

These were the type of data that formed the basis for the immune correlate of protection and the 

non-inferiority of the immune response between Prevnar® and the 13-valent vaccine. There are 

more data from various studies, including non-inferiority trials in the US that have not yet been 

presented publicly. All of these support the conclusion that the 13-valent vaccine induces a 

response to all 13 types and can be expected to be non-inferior to Prevnar® for the 7 types and 

expand coverage for the new types. The trials included: Phase 1–2 (003) US; Pivotal Noninferiority (006) Germany; Pivotal Non-inferiority (004) US; Safety, immuno & Convax (501) 

Spain; Safety, immuno & Convax (3007) Spain; Safety, immuno & Convax (008) France; Safety, 

immuno & Convax (500) Italy; Safety, immuno & Convax (007) UK; Safety, immuno & Convax 

(011) India; Polysorbate 80 Non-inferiority (009) Poland; Manufacturing scale trial (3000) 

Poland; and Clinical consistency (3005) US. 

With regard to the safety database for the EU filing, the total number of infants in the database 

is over 7,000 with safety being assessed in all trials, in infants, toddlers, and after 6 months of 

follow-up. The total safety database includes data from 12 infant studies in which the safety and 

immunogenicity of PCV13 co-administered with other pediatric vaccines were evaluated. Most 

(9) of these studies included PCV7 as an active comparator. In the 3 remaining studies, 

different formulations or lots of PCV13 were assessed. Each of the 12 studies was conducted 

in a single country, and vaccination schedules varied across the studies, according to national 

recommendations. Various countries were selected to allow a thorough evaluation of different 

schedules.

Given the similarity of PCV13 to Prevnar®, the clinical development of PCV13 builds upon the 

record of safety that has been established for Prevnar®. The safety profile of Prevnar® is welldefined on the basis of the vaccine’s pre-licensure clinical evaluation and extensive postlicensure experience, with more than 200 million doses having been distributed worldwide. 

Most of the clinical trials of PCV13 include Prevnar®, allowing a direct safety comparison 

between the two vaccines. The safety of PCV13 was evaluated on the basis of prompted 

(questions in an electronic diary relating to pre-specified symptoms or signs) adverse events 

(AEs), including local reactions and systemic events, as well as spontaneously reported AEs. 

Data on prompted AEs were recorded daily by the parent or legal guardian for a minimum of 4 

days after each dose. Comparisons between PCV13 and PCV7 groups were made using a 

meta-analysis statistical procedure that could detect significant numeric differences between the 

two groups. This approach is a sensitive screening tool designed to identify any small 

differences that would not otherwise be detected in a single trial. Any such differences were 

then evaluated for potential clinical importance.

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The rates of local adverse events were comparable between PCV7 and PCV13. No clinically 

significant differences in spontaneous adverse events were seen during the infant series, 

between infant and toddler dose, or after the toddler dose. Serious adverse events (SAEs) 

incidence was comparable between the PCV7 and PCV13 groups during the vaccination period 

and follow-up. Overall, the safety profile of PCV13 was comparable to PCV7 Compatibility of 

PCV13 with concomitant vaccines was demonstrated many vaccine antigens including 

diphtheria, tetanus, pertussis, IPV, Hib, hep B, and MMR. Only the safety of concomitant 

administration of rotavirus vaccine and hepatitis A vaccines were tested and were found to be 

comparable between the PCV7 and PCV13 groups.. 

In terms of the transition from PCV7 to PCV13, the vaccination schedule for unvaccinated 

Children ≥7 Months of Age for Prevnar® is as follows:

Age at First Dose Total Number of 0.5 mL Doses

7-11 months of age 3*

12-23 months of age 2†

≥24 months through 5 years of age 

(prior to the 6th birthday)

1

*2 doses at least 4 weeks apart; third dose after the one-year birthday, separated from the second 

dose by at least 2 months.

 † 2 doses at least 2 months apart.

A trial was conducted in Poland where children have not had Prevnar®, conducting the same 

experiment with the 13-valent vaccine. The conclusion was that the schedule in unvaccinated 

children will be the same for the 13-valent vaccine as it is for Prevnar®. This is not really an 

issue in the US where the vast majority of children have received or are in the process of 

receiving Prevnar®. However, in many countries where Prevnar® introduction has not yet 

occurred, this is important information to have. Indications being sought from the FDA for the 

transition from Prevnar® to PCV13 include the same age-appropriate schedules for 

unvaccinated children as Prevnar®; PCV13 can be substituted for PCV7 at any point in the 

immunization schedule (rationale: the seven Prevnar® types are common in the two vaccines; 

CRM is the carrier protein in the two vaccines); and a single dose of PCV13 in children >12 

months olds will induce a response to the 6 new serotypes in over 90% of the children that is 

comparable to the response observed following the infant dosing. These were the criteria used 

to establish the catch-up schedule in unvaccinated children, and are the criteria that are now 

being applied to 13-valent vaccine.

The following chart helps to illustrate all of the possibilities that may be faced when Prevnar13® 

is introduced. For example, the top line is a child who receives a dose of 7-valent and 

subsequently receives two doses of 13-valent and booster dose of 13, and so forth:

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Transition from PCV7 to PCV13

Infant

 2 mo 4 mo 6mo > 12 months

7v 13v 13v 13v --

7v 7v 13v 13v --

7v 7v 7v 13v --

7v 7v 7v 7v 13v

The data to support this is really derived from several studies, but importantly the study 

conducted in France in which children were examined who received three doses of Prevnar® 

and one dose of Prevnar13®, found that for the 6 new serotypes there was a good response to 

one dose of the Prevnar13®, which was comparable to the response in infants following 3 

doses. Based on those criteria, the goal for children who are previously immunized with 

Prevnar® is to recommend that they only need to have 1 dose of Prevnar13® if they are over 12 

months of age.

Another very interesting trial underway is the Alaska Safety and Effectiveness Study with the 

13-valent vaccine, which is being conducted in the YK Delta Region of Alaska. This study was 

initiated in January 2009. This region has experienced a great deal of disease caused by nonPrevnar® serotypes, particularly of 19A and 7F. In this study, the 13-valent vaccine has been 

introduced into the YK Delta Region population. This is the first location in which the vaccine is 

being introduced broadly into the population, with the Transition from PCV7 to PCV13 Schedule 

being applied. All children <5 years of age will receive PCV13. All children will be transitioned

from PCV7 to PCV13. Those children who are fully immunized with PCV7 will receive an ageappropriate dosing of PCV13. In addition, the study will examine whether the disease occurring 

in this population can be reduced with the new serotypes in the PCV13. 

The current status of PCV13 in the US is that the FDA has granted fast-track status for the 

pediatric indication based on unmet medical need. This means that Wyeth has been able to 

start the submission of the package in a phased manner. Rolling submission was initiated in 

September 2008, and Wyeth plans to complete the submission by the end of March 2009. The 

FDA will then decide whether they will conduct a priority review of that application. Key ACIP / 

AAP / AAFP considerations at the launch of PCV13 in the US include planning for the transition 

from PCV7 to PCV13 and catch-up recommendations. The first indication will be for children up 

to 5 years of age, but at the same time Wyeth has a Phase 3 trial on-going in adults over 50 

years of age. That program is moving forward in the US and throughout the world, with trials 

based on immunogenicity, as well as a Phase 3 efficacy trial that is on-going in the Netherlands 

examining all-cause and pneumococcal pneumonia. The ultimate goal is to make this vaccine 

available for all ages.

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Discussion 

 

Dr. Morse noted that this presentation was part of continuing education as the ACIP moved 

closer to a vote.

Referring to the last line of the schedule to transition from PCV7 to PCV13 (e.g., 4 doses of

Prevnar® and one of 13-valent), Dr. Baker inquired as to what the durability of a single 

conjugate dose would be and whether it would take a child through 5 years of age. She 

expressed concern that based on the bottom two lines, with a single dose of 13-valent, it was 

not clear that children would be protected through the period of risk for the 6 new serotypes. 

She wanted reassurance that these individuals lasted at least through 2 years, but stressed that 

they should last through 5 years. 

Dr. Paradiso responded that they did not know the answer to this question, given that the 

durability of that dose has not been measured in over 12-month olds. At this point, only one 

month has been measured to show that it is as high as achieved in infants. The criteria used 

were the same as those used to determine the catch-up dosing schedule for Prevnar®. They 

found that, particularly in 12 to 18 months of age, certain serotypes of the original 7 after 1 dose 

of the 13-valent did not achieve a good response or a response that was comparable to the 

post-infant response. It took 2 doses in that age group. Since all 7 did not respond that way, 

they went to 2 doses. Above 24 months of age, the response was comparable to the response 

post-infant so the recommendation was for 1 dose. The response to the 6 new serotypes looks 

more like the response to the 7 types in above 24-month olds. Wyeth also has data with 2 

doses in that age group. 

Regarding the response to 6B, Dr. Meissner noted that in terms of the ELISA the IgG was 10% 

lower. However, in the functional assay, the GMT was still lower at 750 versus 1150. He 

wondered whether that was significant and whether this changed after a fourth dose.

Dr. Paradiso responded that following the booster dose, the responses were all comparable. 

Thus, they both boost very well. For all of the 7 types in the 13-valent, GMC is somewhat lower 

but not enough to fail non-inferiority for percent responders or even by GMC. These were the 

data in 2-, 3-, and 4-month olds. In 2-, 4-, 6-month olds (the way the US vaccinates) the 

response is somewhat better. In the consistency lot trial, the percent responders to serotype 6B 

were between 90% and 95% in that schedule compared to 77% in the 2-, 3-, 4-month old 

schedule. That difference becomes less with the 2-, 4-, 6-month old schedule. Wyeth does not 

believe that based on the reduction in percent responders that this will be clinically significant. 

With respect to future ACIP recommendations, Joel Ward (UCLA) inquired as to whether Wyeth 

anticipated an increase in price of the 13-valent vaccine, whether they would continue to 

produce the 7-valent vaccine in addition to the 13-valent, and whether they would lower the 

price of the 7-valent vaccine. In addition, he thought there were interesting immune responses 

to some of the new antigens in the control group who did not receive 19A as if there was some 

cross-immunity from some of those antigens. 

Dr. Paradiso replied that the global goal is for the 13-valent vaccine to replace the 7-valent 

vaccine. While at this time he did not have pricing information, this information would be 

presented as they moved closer to approval. With regard to the cross-reaction of the ELISA 

titers were most dramatically observed with 19A and were clearly vaccine-induced. Some of the 

other responses were perhaps due to some cross-reactivity, but also some natural immune 

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responses occurred in some of the older children. Oftentimes, however, that was not mirrored 

in the functional response. It was more of an ELISA cross-reactivity without functionality. 

Use of Pneumococcal Vaccines: VFC Vote 

Dr. Jeanne Santoli

CDC / CCID / NCIRD, ISD

 

Dr. Santoli presented an update on the VFC resolution for pneumococcal vaccines, which was 

last discussed during the October 2008 ACIP meeting. She reminded everyone that CDC 

wanted to simplify the VFC resolution by streamlining the text. Currently, VFC resolutions 

provide information about eligible groups, recommended schedule, dosage intervals, 

recommended dosage, and contraindications/precautions. Much of this information is detailed 

in the ACIP recommendations. CDC is working to identify ways to streamline the VFC 

resolutions, pointing to the ACIP recommendations and avoiding rewriting those 

recommendations to the extent possible. Whenever there are repetitions, there is potential for 

error. CDC would like to move to referring to published documents where these exist, and it is 

appropriate to do so.

When the update was made to the resolution in October 2008, the focus was on the 

pneumococcal polysaccharide component because that was where the changes in the 

recommendations were. What was posted had an updated pneumococcal polysaccharide 

component of the resolution. However, shortly after it was posted, a number of astute 

individuals submitted emails to point out at least two errors that were in the pneumococcal 

conjugate component of the VFC resolution. This underscores the need to avoid repetition of 

wording in more than one place.

With that in mind, she reviewed the places in which CDC wanted to streamline the resolution 

either because there was wording that did not add to the wording already there or because 

published documents could be referred to. With respect to the pneumoccocal conjugate 

component of the resolution that defines the eligible groups, Dr. Santoli explained that the VFC 

resolutions have five components: eligible groups, recommended schedule, dosage intervals, 

recommended dosage, contraindications and precautions. For the eligible group section, CDC 

found that one bullet is very inclusive, “All infants and children at least 6 weeks of age through 

59 months of age . . .” Because of the time this recommendation was first made, there was 

discussion regarding high risk groups, those high risk groups are also listed. However, the first 

bullet is inclusive of all children who are eligible for the VFC resolution, so the proposal was to 

eliminate the second bullet because everyone in the second bullet was included in the first 

bullet. Looking at the other components, there are published documents that can be referred to 

regarding the vaccine schedule, the dosage interval, and the contraindications and precautions. 

These published documents include three ACIP recommendations. The first is the 2000 

recommendations that detail out the schedule, dosage intervals, and contraindications and 

precautions. The second is the 2003 updated brief recommendation that covered children who 

were either indicated to have a cochlear transplant or who were cochlear transplant recipients. 

The third is another update to the recommendations published in 2008 regarding vaccinating 

older children for catch-up. By reference, the wording from the recommendations that the ACIP 

has made are incorporated. 

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At this point, while there is a recommendation that is in the process of being published regarding 

the pneumococcal polysaccharide component, there is not a published document to which to 

refer, so the eligible groups would look exactly as they look in the statement. In fact, there was 

a decision to make the eligible groups for VFC somewhat broader than the recommendations. 

Therefore, this component would not change. However, the language for the vaccination 

schedule and the dosage intervals will soon be published in the ACIP statement. 

Because CDC would like to be able to refer to the URL once it is available and to update the 

older URLs when they become available, there is a statement at the bottom of the resolutions 

that indicates that, “If an ACIP recommendation regarding the pnuemococcal vaccination is 

published within 12 months following this resolution, the relevant language above except for the 

eligible groups sections (which was specifically for the VFC resolution and not for the 

recommendation) will be replaced with language in the recommendations and incorporated by 

reference to the publication URL.” The reason that this statement says “within the next 12 

months” is that is not intended to cover all updates for future ACIP recommendations. CDC 

would want to bring those to ACIP to update the resolutions as the recommendations change. 

Motion: VFC Resolution

Dr. Sawyer moved to approve the recommendations as presented. Dr. Cieslak seconded the 

motion. The motion carried with 15 affirmative votes, 0 abstentions, and 0 negative votes. 

Introduction

Dr. Jane Seward

CDC / CCID / NCIRD / DVD / OD 

Dr. Seward indicated that this session would address a proposed change in policy for 

vaccination of healthcare workers with measles, mumps, and rubella (MMR) vaccine. The 

context is the revision of the “HICPAC / ACIP Immunization Recommendations for Healthcare 

Workers” from 1997. This is a compilation of ACIP statements for specific vaccines that are 

endorsed by the Healthcare Infection Control Practices Advisory Committee (HICPAC). This 

work is being done in the context of the Adult Vaccine Working Group chaired by Dr. 

Ehresmann. Most of the vaccines being included in this statement were recently revised, such 

as varicella, Dtap, and yearly influenza. The “evidence of immunity” requirements for healthcare 

personnel are typically lifted and put into the statement. The MMR vaccine recommendations, 

in contrast, are a decade old. While the schedule is to be revised and updated across the 

board, the first topic under consideration is vaccination of healthcare workers. 

The recommendations for healthcare workers for MMR vaccine are quite complicated, covering 

routine vaccination recommendations as well as vaccination during outbreaks. They are 

complicated by different language, footnotes, different strengths of recommendations for the 

routine and outbreaks, et cetera. CDC has received feedback that it would be beneficial to 

simplify these complicated recommendations. This is a new era of measles and rubella, having 

eliminated both of these diseases in the US since the general MMR recommendations were 

published in 1998. That might require a higher bar of immunity for the US population. The 

Measles, Mumps, & Rubella Vaccine

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Division of Viral Diseases (DVD) has worked very closely with the Division of Healthcare Quality 

Promotion (DHQP) on the suggested recommendations.

Proposed Changes in MMR Vaccine “Evidence of 

Immunity” Requirements for Healthcare Personnel

Amy Parker, MSN, MPH, LCDR USPHS

CDC/CCID/NCIRD/DVD/EB 

LCDR Parker provided background on current MMR vaccine recommendations for healthcare 

personnel (HCP) routine vaccination and vaccination during outbreaks; and discussed the 

proposed changes and rationales. 

The current MMR recommendations for healthcare personnel (HCP) that are being updated are 

from 1997 and 1998. During the national mumps outbreak in 2006, vaccine policy 

recommendations for children in high risk groups in the population, including HCP, were revised 

from 1 to 2 doses of mumps or MMR vaccine. At that time, the changes currently being 

proposed were raised in relationship to mumps prevention by some state and city public health 

officials. The decisions on these issues were deferred until the issues could be addressed for 

all three vaccines (e.g., measles, mumps, and rubella) simultaneously. Current ACIP MMR 

vaccine recommendations for HCP state that HCP without other evidence of immunity should 

receive 2 doses of MMR vaccine for measles and mumps and 1 dose of MMR vaccine for 

rubella. The recommendations stress the importance of vaccination to protect HCP and the 

responsibility HCP have to avoid transmitting these diseases and thereby causing harm to 

patients. The ACIP MMR vaccine recommendations include a permissive recommendation for 

1 or 2 doses of MMR vaccine for unvaccinated workers born before 1957. 

Currently, HCP are considered to have presumptive evidence of immunity if they have met one 

or more of the following four conditions:

1. Documentation of administration of appropriate vaccination against measles, mumps, and 

rubella (e.g., administration on or after the first birthday of 2 doses of live measles and 

mumps vaccine separated by greater than or equal to 28 days and one dose of live rubella 

vaccine); 

2. Laboratory evidence of immunity; 

3. Documentation of physician diagnosed disease (measles and mumps); or

4. Born before 1957, which may vary depending on current state or local requirements. That 

is, state or local areas may choose not to use this evidence of immunity criterion. 

Healthcare facilities should consider recommending a dose of MMR vaccine for 

unvaccinated workers born before 1957 who are at risk for occupational exposure to 

measles and who do not have a history of measles disease or laboratory evidence of 

measles immunity. 

During outbreaks of measles and rubella, ACIP recommends that health-care facilities should 

strongly consider vaccinating HCP born before 1957 with a dose of MMR vaccine unless they 

have other evidence of immunity, such as serologic evidence of measles or rubella immunity or 

a history of measles disease [CDC. MMWR 1998;47{RR-8}:1-57]. During a mumps outbreak, 

healthcare facilities should strongly consider recommending 2 doses of a live mumps virus 

vaccine to unvaccinated workers born before 1957 who do not have evidence of mumps 

immunity [CDC. MMWR Notice to Readers. 2006;55(22):629-630].

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Since the last revision of the ACIP / HICPAC vaccine recommendations for HCP, the 

epidemiology of measles has changed considerably. The US declared elimination, meaning 

interruption of endemic disease transmission of measles, in 2000. However, there is an ongoing risk of measles importation and indigenously acquired cases in the US. A single measles 

case anywhere in the US now results in an extensive response by local and state health 

departments to contain transmission. There is now a much higher expectation of maintaining 

high population immunity to measles and minimizing risk of transmission than a decade ago. 

Between 2001 and 2007, there was an average of 60 total reported measles cases per year. 

About half of the cases every year were importations. In 2008, there was a sharp increase in 

total number of cases with 140 and more spread from the imported cases compared to previous 

years. 

Overall, population seroprevalence to measles, mumps, and rubella in the US is high according 

to National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2004. 

Although there is high population seropositivity to each of the three antigens, in persons born 

between 1967-1976 (now 30 to 40 years old), 15% to 20% of these adults do not have 

antibodies to one or more of the three diseases. Among adults born before 1957, approximately 

3% to 8% lack antibodies to at least one of the three MMR antigens. 

Measles is a well-described nosocomial problem. Due to the severity of measles, infected 

persons frequently seek medical care [Atkinson WL, Markowitz LE, Adams NC, Seastrom GR. 

Transmission of measles in medical settings—United States, 1985–1989. Am J Med.

1991;91:320S–4S; Davis R, Orenstein WA, Frank JA, et al. Transmission of measles in medical 

Settings.JAMA1986;255:1295–; and Atkinson WL. Measles and health care workers [editorial]. 

Infect Control Hosp Epidemiol 1994;15:5–7]. During a large US measles outbreak from 1989 to 

1991, transmission of measles in hospitals and emergency departments was enough of a 

problem that triage tents were set up outside of hospitals. According to a 1996 study conducted 

in Washington State, HCP have a 19 times greater risk of being exposed to and acquiring 

measles than adults of similar age (RR 19, 95% CI 7.4, 45.4, p< 0.01). During 1985–1992, 643 

measles cases were reported among healthcare workers (HCW) whose birth year was known, 

of whom 27% were born before 1957 [CDC. MMWR. 1998; 47{RR-8}:1-57].

With the decline in measles cases, fewer cases are occurring in HCP. However, the immunity 

profile for HCP born before 1957 is unlikely to have changed since the measles resurgence, and 

the potential exists for cases in this age group. Although the number of cases in healthcare 

settings is much lower currently than it was in the pre-elimination era, there were still 27 

reported measles cases transmitted in healthcare settings, accounting for 5% of all reported US 

measles cases during 2001- 08 [CDC, unpublished data]. This percent more than doubled in 

2008 when 15 (11%) of the 140 cases were transmitted in a healthcare setting. In the postelimination era, there have been considerable economic costs to contain these cases and 

exposures, ranging from approximately $100,000 to more than $400,000. 

 

In Arizona in 2008, the largest nosocomial US measles outbreak (N = 14 cases) occurred in 20 

years. At hospital A, an adult infected with measles visiting the US from Switzerland was 

hospitalized with measles and pneumonia. This resulted in over 6,000 hospital contact

investigations, including 4,269 hospital contacts and 1,872 HCP contacts. The hospital 

conducted a review of measles documentation of immunity of almost 2,000 HCP and did 

emergency serology and vaccination of 400 persons, many of whom were born before 1957. 

Since the records were not electronic, the review was time-consuming and challenging to 

implement quickly. One HCP with direct contact to one of the measles cases was vaccinated 

following this exposure; however, she developed measles, which resulted in some of the 

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hospital contact exposures and investigations. The total cost to Hospital A was estimated to be 

more than $400,000. 

There are several reasons why changes are being proposed to vaccination and immunity 

requirements for HCP. In the era of measles and rubella elimination, the tolerance for any 

cases or exposures has decreased. To maintain elimination, the goal is to have 100% immunity 

in high risk populations such as HCP. Proposed changes are driven primarily by measles, but 

are also relevant to rubella, another disease that has been eliminated in the US. Measles is 

highly contagious with the chance of spreading in unvaccinated subgroups. Importations into 

the US are continuing. Due to the high exposure risk, it is important to protect HCP 

preemptively. During outbreaks, it is disruptive and time-consuming to determine which staff 

are born before 1957, to find them, and to vaccinate them. This has occurred a number of 

times, as recently as 2008. Current permissive vaccine recommendations that allow healthcare 

facilities to consider vaccinations for HCP born before 1957 are not clear, and many facilities 

are already conducting routine serology screening for vaccination of this group.

Currently, healthcare personnel are considered to have evidence of immunity if they have one 

or more of the following, with the proposed changes underlined or stricken: 

1) Appropriate vaccination against measles, mumps, and rubella (i.e., administration on or after 

the first birthday of two doses of live measles and mumps vaccine separated by greater than 

or equal to 28 days and at least one dose of live rubella vaccine)

2) Laboratory evidence of immunity or laboratory-confirmation of disease

3) Documentation of physician diagnosed disease (measles & mumps)

4) Born before 1957 

The first proposed revision is the addition of laboratory confirmation of disease, as well as 

laboratory evidence of immunity. The second is for the elimination of documentation of 

physician-diagnosed disease for measles and mumps. The third proposed revision is for the 

elimination of birth before 1957 as acceptable evidence of immunity for HCP.

The rationale for including laboratory confirmation of disease in addition to laboratory evidence 

of immunity is for completeness. While cases of measles, mumps, and rubella are currently 

rare in the US, immunity from naturally acquired or wild virus measles, mumps, and rubella is 

considered to be robust and long-lasting. Although laboratory tests are not 100% sensitive and 

specific, for surveillance purposes and counting cases of measles, mumps, and rubella in the 

US, laboratory confirmation of disease is heavily relied upon, especially for measles and rubella. 

It is reasonable to conclude that persons who have laboratory evidence of disease are immune. 

In addition, as measles, mumps, and rubella “evidence of immunity” requirements are 

discussed, it is instructive to examine the updated ACIP recommendations for evidence of 

immunity for varicella published in 2007. Varicella already includes laboratory confirmation of 

disease [CDC. Prevention of Varicella. Recommendations of ACIP. MMWR. 2007;56{RR-4}:1-

37].

There are several rationales for eliminating documentation of physician-diagnosed measles or 

mumps. A number of state health departments and health facilities have concerns that many 

potentially susceptible persons may be working in healthcare settings, because current 

“evidence of immunity” recommendations are not being adhered to as intended. Health 

departments and healthcare facilities report anecdotally that some employees have family or 

friends who are physicians sign off on the forms, even if they have no knowledge of the person’s 

disease history. Thus, health departments do not trust the documentation that the HCP are 

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immune. Additionally, it may not be feasible for persons to contact their childhood physicians to 

obtain verification of documentation of disease history; that is, the childhood physician may be 

retired or deceased. Finally, accuracy of clinical diagnosis has declined and vaccine-modified 

disease may make it especially difficult to determine if a person truly had disease history, 

especially with regard to mumps. 

The rationale for eliminating “born before 1957” is because it is optimal to assure immunity 

through a preemptive vaccine policy. The current routine recommendations are already

permissive and suggest that 1 dose of MMR vaccine “be considered” for this age group. Many 

facilities are already doing this. Current outbreak recommendations to “strongly consider” 

administering 1 dose for measles and rubella or 2 doses for mumps of MMR vaccine to all HCP 

born before 1957 are disruptive and challenging to implement in the midst of an outbreak 

response. The updated ACIP varicella vaccine recommendations do not include birth year as 

presumptive evidence of immunity for HCP. Many facilities already test for immunity of all HCP, 

regardless of birth year. 

A survey of 450 hospitals conducted at the California Department of Health in the beginning of 

January 2009 shows that of the 56 that have responded to date, 95% of hospitals report 

performing serologic screening for vaccine preventable diseases (VPDs), 89% routinely screen

employees born before 1957, and 75% screen new employees. Almost half screen employees 

even if they can provide proof of immunity, almost all (93% to 95%) report screening for 

measles and rubella, and 77% report screening for mumps [K. Harriman, CA Dept Health, 

personal communication].

In another non-randomized sample of occupational health practitioners (N = 38) who responded 

to a listserv survey, 10 (26%) of 38 facilities reported that they conduct serologic screening and / 

or vaccination on all employees regardless of age; that is, they only accepted documented 

vaccine doses and / or previous serologic titers and they did not accept physician diagnosed 

disease or birth before 1957 as adequate evidence of immunity. An additional 8 facilities

reported that they serologically screen and / or vaccinate all new employees. Thus, a total of 18 

(47%) of 38 facilities screen all new employees. Of the 37 facilities who responded to the 

question about whether they accept physician-diagnosed disease, 15 (41%) said they accept 

physician-diagnosed disease as acceptable evidence of immunity. Of the 28 facilities currently 

not screening and / or vaccinating all employees, 19 (68%) estimated how long it would take to 

implement the new policy: 3 (16%) reported that they would be able to implement the changes 

in <1 year; 10 (53%) in 1-2 years; 4 (21%) in 3-4 years; and 2 (11%) in ≥5 years. 

Since 2007, all HCP should be tested for varicella immunity. Testing for measles, mumps, and 

rubella immunity for persons born before 1957 could be conducted concurrently with varicella 

immunity testing. In addition, many larger hospitals are already testing for immunity in all 

employees regardless of birth year. These policies could be implemented as new employees 

join the staff and / or with other annual routine disease-prevention measures (e.g., influenza 

vaccination or TB skin testing). Implementation could be started soon and phased in within a 

few years. The new requirements could be fulfilled either by testing for immunity and 

vaccinating those without serological evidence or by vaccinating with 2 doses of MMR vaccine. 

Whether screening prior to vaccination would be cost saving will depend on the cost of serology 

testing for measles, mumps, and rubella seroprevalence in the healthcare personnel being 

tested. Given that less than 10% are likely to lack antibodies, serology testing is expected to be 

cost-effective. 

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In conclusion, evidence of immunity requirements for HCP for measles and rubella were 

established more than a decade ago. Since then, interruption of endemic transmission of both 

measles and rubella has occurred in the US. In an era of measles and rubella elimination, high 

standards for immunity to measles, mumps, and rubella are appropriate for HCP. HCP have a 

duty to protect themselves and their patients from diseases preventable by vaccination. The 

current permissive recommendations are confusing. It is optimal to have immunity through a 

preemptive vaccination policy prior to an outbreak occurring. From the experiences of state 

health departments during recent outbreaks, it was learned that determining who is presumed 

immune and providing vaccination to hundreds of HCP during a measles outbreak is costly and

disruptive. The epidemiology of measles in 2008 reminds us that despite elimination, measles 

exposures and outbreaks are likely to continue in healthcare facilities. Some facilities are 

already implementing the proposed changes. 

Discussion

Dr. Morse noted that the data on the percent of measles cases for those born before 1957 were 

from 1985-1992. He wondered how much disease there had been in people born before 1957 

since 1992.

Dr. Gallagher added that she did not have data for that entire time period, 2 of the140 cases in 

2008 were born before 1957. It is a small, but not zero percentage. These were US born 

individuals.

Given that someone pays the bills, Dr. Baker raised a question regarding the cost of 

determining immunity in those born before 1957 versus simply vaccination with MMR. 

LCDR Parker responded that she contacted Quest Diagnostics and Focus Diagnostics to 

determine approximate screenings costs. One laboratory indicated that the cost for screening 

tests would range from $56 to $110 depending upon the antigen, while another laboratory could 

screen for measles, mumps, and rubella for approximately $150. The actual cost would depend 

upon whether a facility decided to serologically screen employees first or simply vaccinate, or 

how many employees actually have positive titers if they choose to screen. 

Dr. Meissner agreed with the proposition, thought it made a great deal of sense, and thought it 

would be beneficial for the field to have backing from CDC. He wondered whether lack of 

antibody was a sufficient basis upon which to say a person is susceptible; that is, is there a role 

for cellular immunity in any of these diseases. He also wondered whether the threshold for 

mumps protective immunity was clearly defined and whether this would result in large numbers 

of indeterminate assays in people who do not need it. In addition, it was not clear whether the 

addition of laboratory confirmation of disease referred to the actual isolation of the virus. It is 

pretty infrequently that anyone isolates measles, mumps, or rubella. Therefore, the intention of 

this was not apparent.

LCDR Parker responded that they do not expect laboratory-confirmation of disease to arise very 

often, but because the definition is used for surveillance purposes, they thought this would add 

to completeness in the event that someone had that evidence.

Dr. Sawyer strongly supported the proposal to eliminate physician diagnosis, given continued 

“drive-by” reports of measles from physicians who are absolutely sure that they have observed 

measles, none of which has been confirmed. The current generation of physicians cannot make 

a diagnosis of measles.

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By usual cost-benefit measures, Dr. Judson did not think this would be favorable. As Dr. Baker 

pointed out, someone must pay for this. It appeared that a major change was being proposed 

based upon two small outbreaks. In his 30-year public health career in Denver, he never 

witnessed a case of measles in a healthcare worker from a hospital. He also did not believe 

mumps could reasonably stand the test of being a priority cost-beneficial goal. While measles is 

a bad disease, the issue regards what the recommendation will prevent and what it will cost. He 

did not believe ACIP could make a national recommendation based on a couple of expensive 

anecdotes.

LCDR Parker responded that measles was guiding the proposed recommendations, but many 

of these issues also arose during the 2006 mumps outbreak. Many state health departments 

raised these same issues. This was not addressed at that time because CDC wanted to include 

measles and rubella in any of the “evidence of immunity” requirements for HCW. The time has 

come to update the policy, which led them to raise the proposed changes.

Dr. Seward added that there are some very old studies describing mumps correlate of immunity, 

and there are data from serology studies using neutralizing antibody tests showing that there is 

some susceptibility in the US population. These are not the perfect measure, but it is very 

difficult to use any others. Regarding the cost issue, CDC agrees that on the basis of measles 

cases prevented in HCW, the economics are not favorable. However, when an outbreak occurs 

and it costs a facility $400,000 it would have been cost-effective to have vaccinated. 

Dr. Plotkin said the measles picture is quite clear. There is an antibody level which absolutely 

correlates with protection. For rubella, the issue of B-cell memory may be more important 

because the incubation period is long; therefore there is time for a response.

Dr. Marcy wondered whether any direction should be offered with regard to which test should be 

used to avoid false positives. For example, there is a broad difference in varicella tests in terms 

of specificity and sensitivity.

Harry Keyseling (SHEA) indicated that pediatric facilities have a large volunteer population who 

are quite elderly, and there is rapid turnover (e.g., the Grandmother Program: Feeders and 

Rockers). If screened, there would likely be a large group born before 1920 to 1930 who are 

clearly immune but do not have antibody. He was concerned about safety and this being a 

deterrent to people volunteering. With that in mind, he wondered if there were any data on truly 

naïve people 80 years old who are given the MMR vaccine in terms of safety profiles, and 

whether ACIP would consider having an age implement on implementing the proposed policy.

LCDR Parker responded that she did not believe they had such data. Dr. Seward added that 

she had never seen anybody over 80 years old who did not have measles antibodies. 

Dr. Katz (IDSA) indicated that many people were tested who had no demonstrable antibody but 

who were, indeed, immune to measles. Undoubtedly this was due to T-cells. The absence of 

antibody is not proof positive of susceptibility. Therefore, he tended to agree with Dr. Baker’s 

approach that it is much cheaper for the hospital to vaccinate rather than conduct laboratory 

testing. With respect to giving MMR to adults, there is a significant incidence of arthritis in postmenarchal women who get rubella. The cost-effectiveness issue is a difficult one. If there is a 

case of measles in a community, this would be the time to check immunity. Whether this could / 

should be imposed on all hospitals, clinics, at cetera for all HCW is a difficult question to 

answer.

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Dr. Ehresmann thought a key point was that in an era of measles and rubella elimination, they 

were at a new point. The decisions to be made for the future need to focus on this issue to 

move forward. 

Dr. Lett found the proposed clarifications very helpful from the public health standpoint because 

they harmonize what CDC recommends during cases or outbreaks in routine practice. It is 

difficult when there are cases or outbreaks to ratchet up the criteria, which often results in a 

great deal of disruption. 

With respect to implementation in various settings, Dr. Campos-Outcalt expressed concern 

about how many HCW may have to be re-tested due to the addition of mumps to the proposal. 

In addition, he wondered what was known about the side-effects of mumps antigen in older 

adults.

Dr. Seward responded that evidence of immunity would be serologic evidence or vaccination. 

CDC will take all of the comments and discussion into account, and will discuss this in further 

detail with the Adult Working Group before additional presentations and a vote in either June or 

October. 

Dr. Baker asked whether the wording would be “is recommended.”

Dr. Seward replied that this would depend upon these discussions and further discussions in the 

working group. She thought a range could be considered, although this is complex. For routine 

the language reads “should consider” and for outbreaks it is “should strongly consider.” It would 

be nice to simplify what is currently a complex set of recommendations if possible.

Richard Zimmerman (University of Pittsburgh) requested that opportunity cost issues be 

considered. While everyone is for disease elimination, among occupational health, the 

overwhelmingly predominant concerns pertain to influenza and pertussis. Given this time of 

national economic uncertainties and layoffs, even some of the financially fit hospitals have 

downsized. The question of priority arises in this setting. In his facility, the next $10,000 for 

occupational health would be allocated to influenza and pertussis. While this was not to speak 

against the importance of measles, he found the disease incidence, burden, and risk to patients 

and healthcare workers for influenza and pertussis to be much greater. While not within the 

purview of the ACIP, he thought it would be beneficial if the Occupational Safety and Health 

Administration (OSHA) made pertussis, influenza, and MMR vaccination of HCW mandatory, as 

is Hepatitis B vaccination. 

LCDR Parker responded that CDC recognizes how difficult these decisions are within the 

current economic climate. Consideration has to be given to what the tolerance is for allowing 

potentially susceptible individuals to continue working in healthcare facilities. With respect to 

the global context of what is currently occurring with measles, it is known that it is now endemic 

in the UK and there have been major outbreaks in Switzerland and France. Thus, the US 

continues to get importations of disease and infected individuals will seek healthcare.

Dr. Morse wondered whether the same proposed recommendations were being considered for 

HCW in long-term care facilities. 

LCDR Parker responded that this can be discussed with the Adult Working Group. It would be 

beneficial to have a unified recommendation for state and local health departments, given that 

they are working with various facilities in the context of importations and cases. 

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Dr. Chilton agreed that the ACIP is not in the business of enforcing regulations or even 

recommendations that the committee makes; however, others do. There is a requirement of the 

Joint Commission that hospitals offer influenza vaccine to their HCW. No regulating body is 

feared more in most hospitals than the Joint Commission; however, the success of that effort 

has been only about 45%. He wondered if they thought they could do better than that with 

measles. 

LCDR Parker replied that for this recommendation it would just be a one-time effort. Given the 

fact that facilities could be allowed several years to implement this recommendation, a higher 

success rate could be achieved. 

With regard to attempting to harmonize evidence of immunity for measles with what is already 

being done for varicella, James Turner (ACHA) pointed out that according to the June 2007 

MMWR, physician diagnosed disease is still accepted for varicella as evidence of immunity. 

This appeared to be inconsistent with one of slides that stated that “varicella already includes 

laboratory confirmation of disease.” He wondered whether there was any intent to drop the 

physician diagnosis of varicella from the recommendation. 

 

Dr. Seward responded that the vaccination program for varicella is at a very different stage than 

that for measles and rubella, although it is changing rapidly. The varicella program has only 

been in place for 10 years, so there is a lot more varicella circulation. Perhaps in two to three 

decades varicella history could be dropped. There are already problems with children in terms 

of varicella history. Dropping the recommendation for varicella evidence of immunity has not 

been specifically discussed with the ACIP Working Group; however, it could be raised for 

consideration. She thought they were drawing the analogy that no birth year level of immunity is 

allowed for HCW. A higher bar is required for varicella, so the same should be required for 

measles and rubella. 

Stephen Foster (APhA) thought it would be much easier to find people born before 1957 

compared to trying to find those who knew they had been screened or vaccinated. It was not 

clear how many HCW born before 1957 had been involved in these outbreaks, titers may not 

prove anything, and what the vaccine does to older individuals is unknown as this has not been 

studied. He thought far too many questions needed to be answered before making a general 

recommendation. 

Dr. Katz (IDSA) noted that as discussed in the new MMWR, there were over 3,500 cases of 

measles in Europe in 2008. He wondered what data might be available with regard to 

nosocomial spread among HCW with the outbreaks in Switzerland, France, UK, and Italy. 

Dr. Seward responded that she was not aware of such data. In terms of the experience during 

measles resurgence in 1989 to 1991, California had a lot of measles cases in HCW, including 

many in people born before 1957. She would expect that most people in Europe would have 

sought healthcare and thus they would have experienced a lot of these issues there. She will 

seek further information about this. 

Dr. Cieslak was impressed by how low the numbers were (e.g., 27 reported cases of measles 

over an 8-year period in HCW). He would have a difficult time expanding the recommendation 

for measles vaccination, which this would effectively do, against a disease in which the current 

set of recommendations has resulted in the disease’s elimination.

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Overview

Ciro Sumaya, MD, MPH

Chair, General Recommendations Working Group

Dr. Sumaya reported that the General Recommendations Working Group publishes an MMWR

at approximately 5-year intervals (although they are now working at a 3-year interval due to 

numerous upcoming changes in the general recommendations), addresses immunization issues 

relevant to all vaccines, and addresses topics ad hoc that cannot be attributed to a single 

vaccine. General recommendations on immunization are directed to providers who are giving 

many different vaccines every day. Providers come from variable backgrounds (e.g.,

physicians, nurse-practitioners, nurses, pharmacists, medical assistants). Text is accompanied 

by tables for quick reference. 

Methods for recent general recommendations were to select a group of volunteers to review and 

revise storage and handling of imunobiologics recommendations. The working group has 

convened four teleconferences since the October 2008 ACIP meeting to discuss storage and 

handling and altered immunocompetence. 

General recommendations that were recommended, brought forward, and completed through 

October 2008 included: Introduction, Timing and spacing of immunobiologics, Contraindications 

and precautions, Preventing and Managing Adverse Reactions (Benefit and Risk 

Communication), Reporting adverse events after vaccination, The National Vaccine Injury 

Compensation Program, and Vaccine administration. Added as of the February 2009 ACIP 

meeting were: Storage and handling of immunobiologics and altered immunocompetence. The 

group will continue to move forward on other sections of the document that have not yet been 

completed, and ultimately the entire document will be presented to the ACIP for a final vote, with 

publication projected for December 2009. 

Storage and Handling Immunobiologicals 

Andrew Kroger, MD, MPH

CDC / CCID / NCIRD / ISD / EIPB

Dr. Kroger discussed the revision of a current section in the 2006 General Recommendations. 

The main focus of the 2006 section addresses various topics one of which is maintaining the 

cold chain through the proper selection of storage units, thermometers, and proper 

preparedness for what to do when the temperature deviates. The source material for the 2006

version of the General Recommendations was an MMWR published in 2003 that covered those 

topics [MMWR 2003;52:1023-5]. Information is also included in this section for recommended 

ranges for various vaccines, with its background in discussions which have been documented in 

the General Recommendations chapter of the then 4th Edition of the textbook “Vaccines” by 

Stanley Plotkin and Walter Orenstein. The specific topics in this section are: Introductory 

Statements, Storage Temperature (description and reference to a table that includes the actual 

temperature cutoffs), Storage Units, Temperature Monitoring (staffing considerations, selecting 

appropriate thermometers, et cetera), and Response to Out-of-Temperature-Range Storage. 

Topics considered as “vaccine handling” include: Expiration Dates and Windows and Multidose 

Vials (to state the importance of maintaining sterility and observing the labeled expiration dates).

General Recommendations

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Limited revisions are being made to the storage and handling section. Many of the revisions are 

simply clarifications, the inclusion of new vaccines, and strengthening of the recommendation of 

proper storage units. Because there is an increasing number of vaccines, CDC has made some 

new recommendations, with which this document needs to align. The increasing number of 

vaccines means that financial risk of destroyed vaccine has increased and storage space is a 

concern. Due to these issues, the VFC program has now implemented an action plan to phaseout a particular type of combination unit known as a dorm-style unit. Illustrating with a 

photograph, Dr. Kroger pointed out that in these combination units, the evaporating plate in the 

upper right chamber creates a space that is cooler than the rest of the unit, basically meaning 

there are refrigerator and freezer spaces within the chamber. This type of unit is not sufficient 

for storing vaccines, given that they are typically small and cannot store all of the new vaccines, 

they have an uneven distribution of temperatures specifically in the refrigerator portion, and 

there can be deviations in the refrigerator having to do with the way units self-regulate their 

temperature. The primary problem that exists is that vaccine that should be kept at refrigerating 

temperature is freezing. Dr. Kroger also shared a photograph of a stand alone unit that contains 

only a single chamber. Use of these units is preferable because they are larger and will 

maintain temperature in a more uniform manner. 

With respect to the specific language revisions that will be made to the Storage and Handling of 

Immunobiologics section is to strengthen the section in which the various types of units are 

described, ”Such single-purpose units sold for home use are less expensive alternatives to 

medical specialty equipment (100) and are preferable to combination units “ (Draft Page 2, Line 

10). 

Practical Considerations / Clarifications are also included, which are based on the expert 

opinion of the working group. These include the following statements:

New units may need two or more days of operation to establish a stable operating 

temperature after being set up; vaccine should not be stored in the unit until the unit has 

settled upon an appropriate and stable storage temperature (Draft Page 2, Line 21). 

All office and clinical staff should be aware of vaccine vulnerability and storage 

requirements (Draft Page 3, Line 12). This statement is included in the Temperature 

and Monitoring section that includes accompanying language that still designates one 

person to be the champion of vaccine storage, along with having a back-up. The idea 

was to emphasize that everyone has something to gain from the proper storage of 

vaccine, and that this is a shared responsibility of all office staff.

Some language was changed to qualify or temper some of the absolute language in the 

previous document, with the emphasis on it might be necessary because the working group 

wanted to include qualifying language to emphasize the fact that whereas the previous 

language was very directive with regard to moving vaccine as quickly as possible, they wanted 

to recognize that there are certain occasions (e.g., power outages, fires, et cetera) that may 

make it dangerous for staff to enter the situation:

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It might be necessary to transfer vaccine to a pre-designated alternative emergency 

storage site if a temperature problem cannot be resolved immediately (i.e., unit 

unplugged or door left open) (Draft Page 4, Line 21)







“Weakened” revision reflects recognition that certain environments may 

be dangerous for staff to enter

External temperature monitoring may reduce the need for staff to enter 

the environment and open the door

Vaccine stability is enhanced if the door is NOT opened

Clarification on repeat dosing following administration of expired vaccine was also added, based 

upon expert opinion, ”Inactivated vaccines should be repeated as soon as possible. Live 

vaccines should be repeated after a 28 day interval from the invalid dose. This is to allow 

waning of interfering (i.e., interfere with the replication of the second dose) antibodies that have 

been stimulated by residual antigen from previous doses” (Draft Page 6, Line 4). The point is to 

get across the idea that even if a vaccine has been administered and is considered expired, 

there still may be residual virus within that vaccine that may stimulate an antibody response. 

There was discussion within the working group with respect to what component of the immune 

system is actually responsible, so this language can be further revised. The idea was to 

document the concept of inactivated versus live vaccines in the context of expired vaccine that 

is administered.

 

Table 10, the Vaccine Storage Temperature Recommendations, which lists all of the vaccines in 

use and their storage temperature cutoffs, is straight from the 5th Edition of “Vaccines.” The 

change was to reorder the categories by vaccine types, given the important considerations of 

whether the vaccine contains an aluminum adjuvant (which makes it freeze sensitive), whether 

the vaccine contains a varicella antigen (which makes it heat sensitive), and the route of 

administration. No changes have been made to the temperature range recommendations, with 

the exception of LAIV which now listed at 35o

-46oF. The table will include a list of the vaccines 

within each of the categories of: Non-lyophilized Aluminum Adjuvanted, Non-lyophilized Nonaluminum Adjuvanted, and Lyophilized Reconstituted Vaccine (non-varicella); the storage 

temperatures for the vaccine; the storage temperature for the diluent; and additional comments 

about the vaccine. 

Vaccination of People with Altered Immunocompetence

Andrew Kroger, MD, MPH

CDC / CCID / NCIRD / ISD / EIPB

The other section that the General Recommendations Working Group is revising is “Altered 

Immunocompetence.” The working group does not want to make very many changes from the 

current 2006 General Recommendations. Much of the content in this section comes from the 

1993 Altered Immunocompetence Standalone ACIP statement, which includes a great deal of 

useful information. The general topics in this section include: General Principles, Altered 

Immunocompetence as an Indication to Receive a Vaccine, Vaccination of Contacts of Persons 

with Altered Immunocompetence, Vaccination with Inactivated Vaccines, Vaccination with Liveattenuated Vaccines, Recipients of Hematopoietic Stem Cell Transplants, and Situations in 

Which Some Degree of Immunodeficiency May Be Present. 

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There are safety issues with respect to live zoster vaccine in someone who is 

immunocompromised because it will be a replicating vaccine virus, perhaps not to the same 

degree as other live vaccines. This is a vaccine used in adults, and immunocompromized 

adults typically have antibodies to the vaccine virus due to a previous history of infection with 

varicella zoster virus. Zoster vaccine requires revision to several sections. All changes are 

imports of ACIP Zoster Recommendations (06/08). 

The language for Vaccination with Live-attenuated Vaccines (Draft Page 13, Line 3), which is 

derived primarily from the package insert:

“The incidence of zoster is increased in persons with altered immunocompetence. Adults 

with most types of altered immunocompetence are still expected to maintain residual 

immunity to varicella-zoster virus because of past infection that protects against primary 

varicella but offers incomplete protection against zoster. Zoster vaccine is contraindicated in 

individuals with primary or acquired immunodeficiency states (e.g. lymphoma, leukemia, 

tumors involving the bone marrow and patients receiving chemotherapy) and some AIDS 

patients. In some cases of altered immunocompetence such as AIDS patients with CD4+ 

lymphocyte counts greater than 200 cells/ul, there is no contraindication to zoster vaccine. “ 

Altered Immunocompetence Zos Language reads as follows:

Persons with impaired humoral immunity can also receive zoster vaccine (Draft Page 14, 

Line 18). 

Many candidates for zoster vaccine are treated for other conditions with the drugs 

methotrexate (0.4 mg/kg/week or less) azathioprine (3 mg/kg/day or less or 6-

mercaptopurine (1.5 mg/kg/day). Patients on these medications at these low doses can 

receive zoster vaccine (Draft Page 19, Line 3). 

There are also some revisions to Table 12, Vaccination of Persons with Primary and Secondary 

Immunodeficiencies, which further categorizes primary immunodeficiencies into B-cell and T-cell 

deficiencies. In this table, there were some omissions from the 2006 version, so some 

corrections were made. This section will be harmonized with AAP Red Book. Severe B-cell 

deficiencies will now be included as a contraindication for yellow fever vaccine following 

discussions with yellow fever vaccine SMEs. T-cell deficiencies are also listed as a 

contraindication for yellow fever vaccine. Another correction is a listing of less severe B-cell 

deficiencies as a contraindication for bacterial vaccines. Severe B-cell and T-cell deficiencies 

are also listed as contraindication for bacterial vaccines. The footnote will be revised to indicate 

that OPV is no longer licensed in the US and not routinely recommended. 

Discussion 

Dr. Marcy strongly emphasized that using a standard fluid-filled thermometer was highly 

outdated. For example, there is no way to know based on this type of thermometer whether a 

power shortage has occurred. There are numerous thermometers on the market for reasonable 

prices that are much cheaper than wasting vaccine. The Fisher Scientific website now states 

that “CDC now recommends using continuous, certified, and calibrated chart recorders for 

vaccine storage monitoring.” He suggested that CDC catch up with what Fisher Scientific says 

the agency does.

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As with many recommendations, Dr. Kroger indicated that the working group wants to use a 

common denominator in terms of the feasibility to be able to purchase these items. They were 

hesitant to make more specific recommendations without cost-effectiveness studies of the 

various products offset against the cost of vaccine losses. These types of studies are 

underway, but in the interim there is other practical guidance in the revised draft that addresses 

issues such as the potential cost-effectiveness of purchasing a new thermometer versus having 

it calibrated. However, no specific preference is stated. 

With respect to corticosteroid, Dr. Marcy indicated that in 1993 the ACIP was asked where they 

acquired the data for 2 mg/kg and 20 mg of prednisone as being safe for live vaccines for less 

than two weeks. At that time, Dr. Orenstein indicated that he got this from the Red Book. The 

Red Book then said they got this from ACIP. With that in mind, Dr. Marcy pointed out that there 

are no data to validate those recommendations and he strongly encouraged someone to review 

this information. 

Neal Halsey indicated that he was coordinating some of this issue, upon which considerable 

effort was spent. Some of the immunologists involved in the care of these children reviewed the 

guidelines. Therefore, while the recommendations were based largely upon expert opinion, it 

was not just the Red Book, but was also based on information from immunologists who use 

these drugs regularly. There is some evidence, although it is not as evidence-based as would 

be preferable. 

Dr. Englund indicated that the Hematopoietic Stem Cell Transplants section needed to be 

updated. She is on the working group that has spent a lot of time on this issue, and reported 

that based on that work, there is good evidence-based medicine to suggest that immunization 

can be started early. This recommendation should be harmonized with the recommendations of 

that working group. Children 6 months of age are routinely immunized in a lot of centers. With 

that in mind, she did not believe ACIP should vote on the Immunocompetence Section at this 

time.

Dr. Sawyer thought the storage and handling recommendations were very good; however, they 

represented changes that would be lost on some practicing physicians who are not very familiar 

with the nuances of the temperature in their refrigerators and less familiar with the general 

recommendations. Thus, some effort to promote this information through CDC, AAP, AAFP, 

and other partners is imperative. 

Dr. Judson indicated that a cheap alternative monitor is the double set back mercury u-tube 

thermometers at a cost of less than $20 that will lock in the high temperature and low 

temperature for a certain period.

Dr. Bell reported that CDC has a pilot project in a number of states in which refrigerators and 

continuous monitoring temperature equipment are being supplied to evaluate feasibility, impact, 

accessibility, et cetera. 

Dr. Morse inquired as to whether there was a process of certifying refrigerators that meet basic 

criteria for vaccine storage. With the amount of funds being spent on vaccines, it seems that 

there should be some industry-wide standard. Recalling and revaccinating patients appears to 

be a major problem and burden that seems to be increasing.

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Dr. Santoli responded that CDC is also partnering with the National Institute for Standards and 

Technology (NIST) to develop a “Consumer Reports” type set of recommendations about 

equipment for storing, monitoring, and calibration.

Dr. Sumaya indicated that the Working Group realized that much remains unknown about how 

best to store and handle vaccines. There is also the reality check that whatever the storage 

unit, it must fit into the various settings where vaccines are kept (e.g., private offices, pharmacy 

areas, et cetera). All of this must be addressed.

Sandra Jo Hammer (Department of Public Health, California) pointed out that offices have a 

tendency to underestimate the value of the vaccines in their refrigerators. The California 

Department of Public Health has already sent out a letter indicating that facilities having more 

than 5000 doses a year must have a refrigerator only unit. The major problem is that many 

offices have equipment that has been recycled from elsewhere (e.g., the latest remodeling of a 

physician’s home kitchen). There is no control over the temperature in such units. They receive 

calls asking them whether slush means that vaccine is frozen. Their VFC representatives have 

been equipped with temperature guns, who report different temperatures for different shelves 

within the same unit, yet vaccine get rearranged. To address this issue, perhaps ACIP could 

convene a special working group as Australia did to consider this complex problem.

Motion: Storage and Handling Revisions 

Dr. Chilton moved to approve the Storage and Handling Section revisions. Dr. Baker seconded 

the motion. The motion carried with 14 affirmative votes, 0 abstentions, and 1 negative vote.

Introduction

Janet Englund, MD

Chair, ACIP HPV Vaccine Workgroup 

As discussed during the last few meetings, upcoming issues for ACIP consideration for HPV 

vaccine include: Bivalent HPV vaccine in females; quadrivalent HPV vaccine use in males; and 

quadrivalent HPV vaccine use in females greater than 26 years of age. Dr. Englund briefly 

reviewed the status of each of these topics. 

As discussed during previous ACIP meetings, a supplementary Biologic License Application 

(BLA) with data for the quadrivalent HPV vaccine for females greater than 26 years of age was 

submitted to the FDA. This included data from the interim analysis of the efficacy trial in women 

26 to 45 years. The workgroup considered and proposed some options to ACIP concerning 

possible recommendations for this age group. However, in December 2008 the FDA requested 

48 month data from the trial. These data will be submitted in late 2009, so it is likely that this 

issue will not be considered by ACIP until 2010.

A supplementary BLA with data on the quadrivalent HPV vaccine in males was submitted to the 

FDA in December 2008. FDA action is expected to take up to 10 months. The workgroup is 

preparing for a potential ACIP vote in October 2009. 

HPV Vaccines

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For bivalent HPV vaccine in females, the BLA based on interim data from the Phase III trial was 

submitted to the FDA in 2007. Following feedback from the FDA, GSK decided to wait for endof-study data. These data will be submitted during the first half of 2009. FDA action is expected 

to take up to 6 months. The ACIP workgroup is preparing for a vote in October 2009 or 

February 2010. 

Based on the expected time frame for the upcoming decisions, the workgroup hopes to present 

data for these two decisions (e.g., quadrivalent HPV vaccine in males and bivalent HPV vaccine 

in females) over the next few ACIP meetings. The potential schedule for the HPV sessions 

during the ACIP meetings is as follows:

Dates Quadrivalent HPV 

Vaccine: Males

Bivalent HPV 

Vaccine: Females

February 

2009 

Burden of disease in males

Phase III efficacy data

ASO4 adjuvant and meta-analysis 

June 

2009 

Cost effectiveness

Acceptability studies

Recommendation options

Phase III efficacy data

Cost effectiveness

Recommendation options

October 

2009

If FDA approval, vote If FDA approval, vote

The workgroup hopes to present cost-effectiveness analyses relevant to both of these 

decisions, as well as potential recommendation options during the June 2009 meeting. It is 

possible that there could be a vote on both of these decisions in October 2009. 

The workgroup has continued to convene conference calls at least monthly, and has been 

reviewing data related to both of these decisions. For the bivalent vaccine, the workgroup has

heard data on comparative bivalent / quadrivalent immunogenicity, ASO4 adjuvant mechanism 

of action, and meta-analysis of adverse events in Monophosphoryl Lipid A® (MPL®)-containing 

vaccines. The workgroup has also started to consider issues related to the quadrivalent HPV 

vaccine in males, reviewing efficacy data in males that were to be presented during this meeting

and an overview of cost-effectiveness models published to date. Workgroup members have 

also reviewed data on HPV vaccine in pregnancy and vaccine safety. 

Update on Bivalent HPV Vaccine: AS04 Adjuvant

Mechanisms of Action and Safety Meta-Analysis 

Thomas Verstraeten, MD, MSc

Head of Safety, GSK Biologicals

Dr. Verstraeten explained that the reason for introducing the AS04 adjuvant was to have a 

better and more prolonged immune response, which is expected to lead to longer protection. 

During this presentation, he discussed the safety aspects of this novel adjuvant. Dr. 

Verstraeten reported on the mechanism of action of the adjuvant system AS04, the metaanalysis of the risk of Auto Immune Disease (AID) following AS04 adjuvanted vaccines, and the 

post-marketing experience. GSK does not believe this mechanism of action supports biological 

plausibility for induction of autoimmune disease. 

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The novel adjuvant AS04 consists of two components: Alum and MPL®. MPL® is derived from 

lipopolysaccharide LPS (Salmonella Minnesota). MPL® basically has similar but reduced 

immune activity as LPS in that it acts via a TLR4 signaling pathway, and induces cytokines with 

a key role in the induction of humoral responses (IL-6 and TNFα); and does not induce IFNα, a 

cytokine associated with the precipitation of some autoimmune diseases [Baccala R et al,Nature 

medicine,vol13, N5, 543-551]. AS04 effect requires a temporal and spatial co-localization with 

antigen to function. AS04 acts at the earliest step of the immune response on antigen 

presenting cells (APC) only through TLR4 pathway and has no direct, non-specific activation of 

T and B effector cells. 

To evidence that the AS04 effect requires temporal and spatial co-localization with the antigen, 

GSK investigators injected a group of mice first on one side with AS04 by itself and later with 

the VLP separately. This was done at several time intervals. The immune response decreased 

with the longer interval between the two administrations. From co-administration to one hour, 

there is little difference and it is not significant. However, after one day there is already a 

significant decrease in the response, and after three days the response has further decreased. 

A second experiment involved administering the AS04 on one side and then later administering 

the VLP on a different site. It made little difference whether this was done simultaneously or at 

different time intervals. The immune response was always highly inferior compared to the colocalization in time and space. This means that the adjuvant needs to be injected at the same 

place as the antigen, and needs to be injected simultaneously or at least within one day. This 

supports previous observations that the adjuvant is only present for about one day at the 

injection site. With respect to the relevance to autoimmune disease, in general the concern 

about this new adjuvant’s relationship to autoimmune disease is that many people have a 

perception that these adjuvants are extremely potent and have prolonged and generalized 

stimulus of the immune system. This experiment shows that this is actually not the case. 

Instead, the immune stimulation is quite localized, it is targeted to a specific antigen, and there 

is limited time and space for the stimulation even though the actual immune response is quite 

long-lasting. 

With regard to the clinical data, GSK performed a meta-analysis to examine the risk of 

autoimmune disease following the HPV vaccine and other AS04 adjuvanted vaccines. This 

safety evaluation was done in support of the HPV BLA in the US at CBER’s request. Although 

there have been more updates of these analyses with more recent data, Dr. Verstraeten 

focused on that data that has been published. This evaluation included over 68,000 subjects 

from 42 studies, including on-going studies. All except two of these studies were completely 

sponsored by GSK. Two studies were co-implemented by GSK and other institutions. The data 

presented during this meeting were the analyses and interpretation of GSK only. The 

methodology for this analysis was pre-specified and agreed to with CBER [Analysis of adverse

events of potential autoimmune aetiology in a large integrated safety database of AS04 

adjuvanted vaccines. Verstraeten et al, Vaccine 2008, 26: 6630–6638].

This analysis was conducted at two different levels. The first level was the HPV vaccine alone,

which is AS04 adjuvanted. This analysis included over 39,000 subjects in clinical trials. The 

second level is that added to this first group were the Herpes Simplex 2 Virus vaccine (HSV) 

clinical development program and a Hepatitis B Adjuvanted vaccine (licensed in Europe under 

the name FendrixTM) development program. The second level of analysis added an additional 

30,000 subjects for a total of more than 68,000 subjects in this analysis.

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The list of events included in this analysis were: Neuroinflammatory (e.g., optic neuritis, multiple 

sclerosis, demyelinating disease, myasthenia gravis, transverse myelitis, myelitis, encephalitis, 

and Guillain-Barre syndrome); Musculoskeletal (e.g., systemic lupus erythematosus, Sjogren’s 

syndrome, rheumatoid arthritis, juvenile rheumatoid arthritis, arthritis, reactive arthritis, and 

scleroderma); Gastrointestinal (e.g., inflammatory bowel disease, Crohn’s disease, ulcerative 

colitis, ulcerative proctitis, and Coeliac disease); Thyroid (e.g., Graves’ disease, thyroiditis, 

hyperthyroidism, hypothyroidism, and goiter); Skin (e.g., cutaneous lupus, dermatomyositis, 

vitiligo, erythema nodosum, psoriasis, psoriatic arthropathy, Stevens-Johnson syndrome, and 

Raynaud's phenomenon); and Others (e.g., autoimmune haemolytic anaemia, antiphospholipid 

syndrome, IDDM, idiopathic thrombocytopenic purpura (ITP), autoimmune hepatitis, nephritis, 

autoimmune glomerulonephritis, uveitis, sarcoidosis, Addison’s disease, and vasculitis).

Regarding the primary results of the AS04 safety meta-analysis of autoimmune disorders, Dr. 

Verstraeten described the relative risks observed when comparing the subsets who received 

AS04-containing vaccines compared to the group that received control vaccine without AS04. 

In the comparison of subjects who experienced any events, there were 96 diagnoses in the 

AS04 group compared to 104 in the control group, with a relative risk of 0.92 and relatively 

narrow confidence intervals of 0.70 to 1.22. The relative risks for systems (e.g., gastrointestinal, 

musculoskeletal, neuroinflammatory, skin disorders, thyroid disease, and others) do not differ 

much from 1.0 and the confidence intervals, as would be expected, are dependent upon the 

number of cases that go into the analysis. The majority of the cases came from the group of 

thyroid diseases, as would be expected in this female age group. Much fewer events were 

observed in the group of neuroimflammatory disorders. In terms of the second level of analysis 

(e.g., HPV vaccines combined with HSV-adjuvanted and Hepatitis B vaccines) overall the 

relative risk is not very much different, the confidence intervals become somewhat more narrow, 

and the relative risks change very little from category to category (all are fairly close to 1.00). 

None of the confidence intervals exclude 1.00. 

 

In a comparison of observed and expected incidence rates (per 100,000 person years) for 

neuroinflammatory events among the subjects in the meta-analysis (e.g., Level 2, pooled 

controlled and uncontrolled studies), investigators estimated the incidence rates in the AS04 

group and compared that to rates expected given the background rates and rates as they were 

observed in Northern California Kaiser in a similar gender and age group. The observed 

incidence rates fall pretty well within the expected incidence rates, which is reassuring in two 

ways: there does not seem to be an increase; and it supports that GSK did capture these cases 

in their clinical trials:

Observed Rate

In the MPL Group (+ 95 % CIs)

Range of background 

rates

Guillain-Barré Sy 1.3 (0.0, 7.4) 0.4 – 3.5

Multiple sclerosis 5.3 (1.4, 13.6) 3.1 – 15.9

Myasthenia gravis 1.3 (0.0, 7.4) 0.1 – 2.0

Optic neuritis 4.0 (0.8, 11.7) 5.7 – 8.2

Transverse Myelitis 0.0 (0.0, 6.4) 0.1 – 3.2

There are some limitations to these analyses. The first is that there is a lack of validation of the 

diagnoses. The analyses as shown are based on the diagnosis as reported to GSK by the 

investigators. Given that these are randomized trials, there is no reason to expect that the 

validity of the diagnoses would differ between the AS04 and control groups. Further subanalyses are on-going, including adjudication of selected events of interest. Another limitation is 

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the variability between studies in the collection of adverse event data. The HPV studies 

collected more extensive and complete safety information, including non-serious adverse events 

throughout the study periods. The results are consistent between HPV only and extended 

analyses. 

Regarding the post-marketing experience to date, GSK’s vaccine is now licensed in 93 

countries. The largest use of the vaccine currently is in the UK, given that this vaccine has been 

chosen to be used for universal mass vaccination of females 12 years of age. This universal 

program began in September 2008. At this time, Over 80% have received at least one dose 

[www.immunisation.nhs.uk/vaccines/hpv]. Catch-up vaccination in those up to 18 years of age 

using GSK’s vaccine has begun. Intense safety monitoring is being conducted by the Medicines 

and Healthcare products Regulatory Agency (MHRA) and GSK. No safety concerns have 

arisen thus far. 

In conclusion, the MPL® mode of action does not suggest a biologically plausible mechanism 

for induction or exacerbation of AID. A meta-analysis of clinical studies showed no indications 

of any causal association between GSK’s HPV or other AS04 adjuvanted vaccines and the 

development of autoimmune disease, given that the proportion of subjects in whom autoimmune 

diseases occurred was comparable between the AS04 and control groups, and that the 

distribution of the autoimmune diseases reported corresponds to the distribution expected. The 

observed incidence rates for neuroinflammatory events are within the expected ranges. Postmarketing surveillance has indicated no safety concerns on GSK’s HPV vaccine thus far. 

Burden of HPV Related Disease in Males

Mona Saraiya, MD, MPH

CDC / NCCDPHP / DCPC

Dr. Saraiya discussed HPV and its causal role in various male diseases, and the burden of 

HPV-associated male disease with respect to anal cancer, penile cancer, oropharyngeal cancer, 

and genital warts. For the sake of comparison, she provided disease burden information about 

women as well.

The International Agency for Research on Cancer (IARC) released a second report in 2007

assessing the causal role that HPV plays in cancers. They found that 13 HPV types, including 

HPV 16 and 18, cause cervical cancer. In addition, they concluded that HPV 16 causes several 

other anogenital and oropharyngeal cancers. However, the report concluded that there was 

insufficient evidence that HPV 16 definitely causes laryngeal or that HPV 18 causes other 

anogenital or oral cancers [International Agency for Research on Cancer (IARC) Monographs 

on the Evaluation of Carcinogenic Risks to Humans. Volume 90 (2007) Human 

Papillomaviruses].

With regard to HPV-associated cancers and the attributable fraction due to HPV, 90% of anal 

cancers are thought to be due to HPV. Of those, approximately 92% are thought to be due to 

HPV 16 or 18. That is, approximately 80% are due to HPV 16 and 18. This percentage is fairly 

conservative for some cancers and it is important to know that this percentage can vary 

depending on when the study took place, type of HPV assay used, where and when the study 

was conducted, how the anatomic site was sampled, and what kind of histology the study was 

limited to. More recent studies do show that the percentage of HPV prevalence may be higher 

in vaginal and oral cavity and oropharynx cancers.

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The status of US registries today is such that 100% of the US population is covered. Having 

such a large amount of coverage is ideal for monitoring rare cancers and having the ability to 

look at specific histology or racial / ethnic groups for a shorter period of time. Cancer registries 

collect data on all types of invasive cancers and all in situ cancers, except cervical carcinoma in

situ. Generally, the Surveillance, Epidemiology and End Results (SEER) cancer registries have 

been in existence much longer; therefore, they are able to provide trend data. Traditionally, 

cases are diagnosed by providers in hospital-based registries. Registries have expanded over 

the years to also register cases diagnosed in non-hospital settings (e.g., physician offices, nonhospital based pathology labs, radiation treatment centers, and surgery centers). All cases are 

registered by certified tumor registrars and reported to state-based central cancer registries, 

also known as population-based registries, either through direct reporting or via regional 

registries. These data are transmitted to federal agencies to compile a national database of 

cancer incidence and mortality. Throughout the remainder of her presentation, Dr. Saraiya used 

SEER data to described trends because they go back to the 1970s, and she used the combined 

cancer registries to illustrate the current burden of disease.

With regard to the average annual counts and rates of HPV-associated cancers among women 

and men from 1998-2003, 39 cancer registries met the criteria for high quality data so the 

coverage is limited to 83% of the US population. Since cancer registries do not collect data on 

HPV positivity, the way HPV-associated was defined was by limiting cancers to the epithelial 

types, and in certain instances limiting it to certain anatomic sites that are considered to have 

higher HPV DNA prevalence. Not taken into consideration was the fraction of those cancers 

attributed to HPV, given the caveats described earlier. Among women, cervical cancers 

represent the largest proportion of all HPV-associated female cancers for a total of 17,350 

HPV–associated cancers in women compared to 7,568 in men. Of those 7,568 in men, the 

number of oropharyngeal cancers are by far the larger proportion of all HPV-associated cancers

(n=5,658).

Trends for anal cancer have been increasing over the past 30 years, with approximately 1000 

cases a year, the rate being 1.0 per 100,000. Females have higher rates than men. Risk 

factors in men include lifetime number of sexual partners, receptive anal intercourse, and 

immunosuppression. High risk populations include men who have sex with men (MSM), those 

who are HIV+, and African Americans. Routine screening using anal cytology is not 

recommended, although certain experts do advocate screening in high risk populations, such as 

MSM and HIV+ populations. 

The incidence of invasive anal cancers has been increasing over the past 30 years, from 0.6 in 

1973 to 1.3 in 2003. The increase occurred in both males and females, but the gap between 

women and men persisted over time [Data source: SEER 9 Regs Limited-Use, Nov 2005 Sub 

(1973-2003), covering 9% of US population]. The incidence increases with age and peaks 

somewhat earlier for males than females. The median age of diagnosis for males is 57 versus

62 for females [Adapted from Joseph D et al. Understanding the Burden of Human 

Papillomavirus-associated Anal Cancers in the US, Cancer 2008. Data Source: National 

Program of Cancer Registries and SEER, covering 83% of US population]. 

Penile cancer rates have also been decreasing in the US for the past 30 years. It accounts for 

less than 1% of all cancers in men, with 829 cases of invasive cancer per year, withy a rate of 

0.8 per 100,000. Risk factors include lack of circumcision, chronic penile inflammation, 

immunosuppression, and cigarette smoking. High risk populations include Hispanic men

partially due to lower circumcision rates. Routine screening is not recommended. The 

incidence of penile caner actually has declined over the past 30 years from 1.0 per 100,000 in 

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1973 to 0.6 per 100,000 in 2003 [SEER 9 Regs Limited-Use, Nov 2005 Sub (1973-2003), 

covering 9% of US population]. Like most cancers, penile cancers increase with age. The 

median age of diagnoses is 68 [Adapted from Hernandez B et al. Burden of Invasive Squamous 

Cell Carcinoma of the Penis in the United States, 1998-2003. Cancer 2008. Data source: 

National Program of Cancer Registries and SEER covering 83% of US population]. 

Twenty to 35% of oropharyngeal and oral cavity cancers have had HPV DNA presence. 

However, even with that group, a certain subset has higher HPV positivity. Anatomic sites used 

as surrogates of potentially HPV-associated cancers include the base of the tongue, Waldeyer 

Ring, lingual and palatine tonsil, and oropharynx. The rest of the head and neck cancers are 

considered less HPV-associated, are grouped together for comparison, and are called HPVunrelated sites. The trend for oropharyngeal and oral cavity cancers has been increasing

specifically in men. There are approximately 5,658 cases per year, with a rate of 5.2 per 

100,000. Risk factors include tobacco use, alcohol use, and lifetime number of sexual partners. 

High risk populations include African American. Routine screening not recommended by the 

USPSTF as screening has not been shown to reduce mortality, but certain experts do 

recommend screening as part of a routine checkup.

From 1973-2003, the incidence of invasive HPV-associated oropharyngeal and oral cavity

cancers increased from 3.2 to 4.9 among men, with an annual percent change of 0.8 per year. 

The rate for women went down every year [SEER 9 Regs Limited-Use, Nov 2005 Sub (1973-

2003), covering 9% of US population]. The trend has decreased for non-HPV-associated 

oropharyngeal and oral cavity cancers in both men and women. The age-specific incidence 

curves show that the peak for men is curvilinear and rises steeper compared to women. The 

median age of diagnosis for men is 58 versus 64 for women [Adapted from Ryerson B, et al. 

Burden of Potentially Human-Papillomavirus-associated Cancers of the Oropharynx and Oral 

Cavity in the US, 1998-2003. Cancer 2008; Data source: National Program of Cancer 

Registries and SEER covering 83% of US population]. 

An important HPV disease in men is genital, with HPV 6 and 11 causing 90% of genital warts. 

The incidence is estimated at 250,000 cases per year, although these are imprecise estimates

given that there is no systematic surveillance of genital warts. The prevalence is higher in men 

than women in most studies. Risk factors include lifetime numbers of sexual partners and being 

immunocompromised. Genital warts impact quality of life, are often recurrent, and can require 

extensive treatment. Administrative claims data on the prevalence of genital warts show that 

the rate peaks earlier by five years for women in their early 20s compared to men in their late 

20s to early 30s [Insigna R et al. The health and economic burden of genital warts in a set of 

private health plans in the United States; Clin Infect Dis 2003. Data Source: Medstat]. In

contrast to other studies that show prevalence is higher in men and women, in an NHANES 

nationally representative sample of 18-59 year olds from 1999-2004, sexually active men and 

women were asked, “Has a doctor or health care provider ever told you that you had genital 

warts?” Based on this survey, the cumulative prevalence of genital wart diagnosis in women 

was 7.2% and in men was 4% [Dinh TH et al. Genital warts among 18- to 59-year-olds in the 

United States, National Health and Nutrition Examination Survey, 1999-2004; Sex Trans Dis 

2008]. 

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In summary, there is a higher burden of HPV-associated cancers in females compared with 

males. Oral cavity / oropharyngeal cancers are the largest proportion of HPV-associated 

cancers among males and the incidence is increasing. There is a low incidence of anogenital 

cancers in men, although anal cancers are increasing and certain populations are at higher risk. 

No screening is recommended for anal, penile, or oral cavity / oropharyngeal cancers. Genital 

warts are common. 

Update on Quadrivalent HPV Vaccine: Efficacy Data in Males

Richard M. Haupt, MD, MPH

Clinical Research

Infectious Diseases & Vaccines

Merck Research Laboratories

Dr. Haupt reported on Merck’s male efficacy and safety study, known as Protocol 020, in 16 to 

26 year old males (N = ~4000 men). Merck conceptualizes the benefit of male vaccinations is in 

terms of the benefit of GARDASIL® in two populations: (1) boys and men themselves, and (2) 

in addition, the broader population, including females. There is an intrinsic benefit to boys and 

men, given the overall disease burden of cancers and genital warts in men. There is also an 

overall public health benefit in that vaccine coverage in girls is likely to be incomplete. 

Vaccinating men offers the opportunity for herd immunity. Transmission of HPV occurs 

efficiently between sexual partners. The value of a gender-neutral vaccination is that it extends 

vaccination coverage, eliminates gender inequities, reduces viral transmission, decreases 

circulation of virus in the population, and broadens the population and public health benefit. 

With respect to background, Protocols 16 and 18 were immunogenicity and safety studies in 

adolescent males and females between 9 and 15 years of age. These studies were conducted 

several years ago, have already been published, and were submitted to the FDA with the 

original Biologic License Application (BLA) in Fall 2005. In December 2008, the data from 

Protocol 020 (male safety and efficacy study) were submitted to the FDA.

As with all of Merck’s GARDASIL® efficacy trials, Protocol 020 is a randomized (1:1), doubleblind, placebo-controlled trial. Males received GARDASIL® or placebo at 0, 2, and 6 months. 

Anyone who received three doses within a year would have been counted in the per-protocol 

efficacy analysis. This study is designed to be 36 months in total follow-up, while the women’s 

studies were designed to be 48 months. The data to date in the men’s study are based on 

approximately 30 months of follow-up and is based largely on the heterosexual male component 

of the study. Enrolled subjects include heterosexual men (HM) 16-23 years old (N = 3463) and 

men having sex with men (MSM) 16-26 years old (N = 602). The enrollment for MSM lagged 

behind enrollment for HM; therefore, the majority of the HM population is completing this study 

while the MSM are approximately a year and half behind. This is important because it affected 

the endpoints Dr. Haupt was able to review during this presentation. 

The primary endpoints in Protocol 020 included safety and efficacy. The primary efficacy 

endpoint is the combined incidence of HPV 6/11/16/18-related external genital lesions. Both the 

HM and MSM study participants contribute to that endpoint. External genital lesions includes 

external genital warts; penile / perianal / perineal intraepithelial neoplasia (PIN); and penile, 

perianal, or perineal cancer. There is also a sub-study in the MSM in which anal intraepithelial 

neoplasia (AIN) and anal cancer are the primary endpoints; however, because the MSM 

population is behind in enrollment, the pre-specified event cases have not been reached to 

conduct the formal analysis for this endpoint. Therefore, Dr. Haupt presented no data on the 

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AIN sub-study at this time. Also examined was immunogenicity in terms of GMTs and 

seroconversion rates. The secondary efficacy endpoints included incidence of persistent HPV 

6/11/16/18 infection, and incidence of HPV 6/11/16/18 DNA detection at one or more visits. 

Persistent infection is defined as two consecutive swabs or biopsies (defined as six months 

apart) positive for a vaccine type. The any type DNA means that they were looking for efficacy 

against any type of DNA detection, one time or more, of a vaccine HPV type in a swab or 

biopsy. 

Baseline demographics, are as follows:

GARDASILTM

(N = 2,032)

Placebo 

(N = 2,033)

Total 

(N = 4,065)

n (%) n (%) n (%) 

Age (years) 

 Mean +/- SD 20.5 +/- 2.0 20.5 +/- 2.0 20.5 +/- 2.0 

 Median (range) 20 (15-26) 20 (16-27) 20 (15-27) 

Race/Ethnicity 

 Asian 201 (10) 205 (10) 406 (10) 

 Black 412 (20) 393 (19) 805 (20) 

 Hispanic American 388 (19) 447 (22) 835 (21) 

 Native American 2 (0.1) 1 (0.0) 3 (0.1) 

 White 734 (36) 697 (34) 1,431 (35) 

 Other 292 (14) 293 (14) 585 (14) 

Circumcision 

 Yes 794 (39) 749 (37) 1,543 (38) 

 No 1,232 (61) 1,286 (63) 2,518 (62) 

 Missing or Unknown 3 (0.1) 1 (0.0) 4 (0.1) 

There was a greater participation of black males in Protocol 020 than in the studies with women, 

given that one of the sites was in South Africa. The circumcision rates were also captured, 

although these are more typical of rates observed globally than in the US alone.

While he did not have AIN efficacy data for MSM, Dr. Haupt was able to share Day 1 baseline 

PCR and serology information that includes both MSM and heterosexual males. 14 HPV types 

were tested for on Day 1, the four types in the vaccine (6, 11, 16, and 18) and 10 other high risk 

types. 25.2% of men were positive for one or more of the tested types. The day 1 HPV DNA 

positivity rate for one or more of the 14 tested HPV types was 20.9% in the HM population and 

48.1% in the MSM population. The exclusion criteria were the same for heterosexual men and 

MSM, in that both groups were supposed to have had five or fewer lifetime sexual partners. 

This represents a relatively lower risk MSM population. 12.2% of the subjects were HPV DNA 

positive by PCR to at least 1 of the 4 vaccine types. The day 1 HPV DNA positivity rate for one 

or more vaccine HPV types was 8.8% in the HM population and 30.5% in the MSM population. 

87.8% of all subjects were naïve to all 4 types. In terms of seropositivity on day 1 to vaccine

HPV types, 7.6% of all study participants were seropositive to at least 1 of the 4 vaccine HPV

types. Stratified results based on sexual orientation showed that 5.0% of the HM population 

were seropositive to one or more vaccine HPV types at day 1 while 22.8% of the MSM 

population were seropositive. Overall, 82.7% of male subjects in the Protocol 020 male efficacy 

study were naïve by PCR and serology to all 4 HPV vaccine types. Most men who were 

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infected were infected to only one vaccine type, which is very similar to the women’s study. 

Hence, the vast majority of men would benefit from protection to at least 3, if not 4, of the 

vaccine types from vaccination with Gardasil. 

There was a very high vaccine efficacy of approximately 90% against external genital lesions, 

with 3 cases in the GARDASIL® group (n = 1,397), all of which were genital warts. There were 

31 cases in the Placebo Group (n = 1,408). Persistent infection efficacy was approximately 

86%, with 45% efficacy against any type DNA detection over the course of the study. The 

efficacy across the different types is very similar. The differences in efficacy depend more on 

the number of endpoints. Some of these infections are more common for types 6 or 16. 

Generally, there is high efficacy across all 4 of the vaccine types. In terms of GMTs and 

seroconversion in males, very similar to what was observed in women, virtually all men 

seroconverted to this vaccine who were naïve to the relevant type at baseline. The GMTs are 

high across all 4 types. The GMTs in men, compared to women, are somewhat lower, although 

it is not clear what this means at this point. Adverse events in men were similar to those in 

women, with the most common adverse event being local injection site reaction. Very few 

serious adverse events occurred, and there was no imbalance in any of the adverse events 

across the placebo or GARDASIL® groups. In the women’s trials, the injection site reactions 

were in the 80% range, while these are in the 60% range in the men’s trial. Merck is in the 

process of conducting more analyses from the placebo arm of the trial assessing natural history. 

Early analyses of the placebo subjects demonstrates a high rate of infection with vaccine HPV 

types in sexually active men who were previously uninfected.

In summary, sexually active men are at high risk for acquiring genital HPV infections. Genital 

HPV infections lead to a significant burden of disease in men. HPV 16 and 18 are important 

cancer-causing HPV types in men, responsible for the majority of HPV-related penile, anal, and 

oropharyngeal cancers and their associated pre-cancers. HPV types 6 and 11 cause over 90% 

of genital warts and RRP. GARDASIL® is highly efficacious against HPV 6/11/16/18-related 

persistent infections and genital warts in men. This efficacy may also translate to reduced 

transmission of vaccine type HPV strains between sexual partners. GARDASIL® was generally 

well-tolerated in 9-26 year-old boys and men. The value of vaccination of boys and men is the 

direct impact in preventing HPV 6/11/16/18-related diseases in boys and men, as well as the 

contribution to an additional public health benefit of GARDASIL®. 

Discussion

Dr. Ehresmann noted that in his summary Dr. Haupt mentioned that GARDASIL® is generally 

well-tolerated in males 9-26 years old; however, the study design was in 16 to 26 year olds.

Dr. Haupt responded that for the sake of time, he did not present data from the 9- to 15-year old 

population. Studies were conducted in the younger age groups several years ago and those 

data were presented to the ACIP in the past. The adverse event profile is very similar across 

the age groups between 9 and 26.

Recalling that in the immunogenicity studies, the group the younger women had higher immune 

responses Dr. Neuzil inquired as to whether the same was true for males. It appeared as if the 

younger ages of both genders have better immune responses than the older age groups.

Dr. Haupt responded that the 9 to 15 year old boys had higher GMTs than the 9 to 15 year old 

girls. In the adult population (16-26 year-olds), women are somewhat higher than men. It is 

known that there are gender differences in immune responses, and reports with other vaccines 

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and other immune response to natural infection have demonstrated that. That may explain the 

difference in adult women 16 to 26 years of age. Merck believes that the difference in the 9- to 

15-year old age group in terms of GMTs is that many of the 9- to 15-year old adolescent girls 

have gone through puberty versus the boys in that age group (who are predominantly prepubertal). It is known that there is developmental impact that is related to immune response. 

Without question the younger ages of both genders have better immune responses than the 

older age groups.

 

Dr. Neuzil’s recollection of prior presentations was that a high level is achieved, which quickly 

comes down to baseline, and then the baseline is fairly consistent. She wondered if there was 

an additional time point in Protocol 020 (e.g., blood draws between 7-months and 12-months). 

Based on the antibody kinetics observed with women, Dr. Haupt indicated that that they did not 

believe the 12-month antibody level to be very valuable. Thus, they do not do a blood draw 

between 7-months and 12-months for the males. Indeed a peak response has been observed, 

followed by a tapering of antibody level, and a what appears to be a plateau by about 24 months 

where they have stayed five years out. The Protocol 020 men will have another blood draw at 

month 36. 

Referring to the 9- to -15-year olds, Dr. Meissner noted that this is very analogous to what was 

done with females; that is, rather than efficacy data, these are bridging studies and presumably 

approximately the same number of males (25%) are sexually active by 15 or 16 years of age. 

Dr. Haupt responded that the 9- to 15-year old immunogenicity data bridging data was used in 

the original application for approval or 9- to 15-year old girls in the original bridge. Protocol 18 is 

an adolescent study that was extended up to month 36, which is now being extended as an 

effectiveness study for boys and girls for the next 10 years to evaluate vaccine effectiveness 

over time if, and when, the study participants become sexually active. 

Dr. Meissner pointed out that Dr. Haupt was very careful in the way he phrased the effect of 

immunization on transmission. He wondered whether there were any data or Dr. Haupt could 

address this question at all; that is, is a vaccinated male less like to transmit HPV to his contacts 

than an unvaccinated male. Thinking of the inactivated polio vaccine, for example, such a 

vaccinee can still transmit polio virus.

Dr. Haupt responded that while they do not have data to support this, Merck has had internal 

discussions about conducting formal studies to examine the interruption of transmission. It 

certainly makes sense that if men and women are not becoming infected, especially 

persistently, and especially if they are not getting disease, transmission is very likely to be 

reduced. Merck is aware of data are being generated in Australia where the coverage rates are 

very high (80% to 90%) in which they are examining disease outcomes to determine whether 

there is already a reduction. In addition, they are looking at disease reductions in males to 

determine whether there is an impact on transmission.

An audience member inquired as to whether Dr. Saraiya had any estimates on the impact of 

vaccinating women according to the current vaccination recommendations on the burden of 

disease. 

 

Dr. Saraiya replied that at this time, such information was not available. 

Dr. Katz (IDSA) was under the impression that dentist screened for oropharyngeal cancers. 

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Dr. Saraiya responded that she was going by the recommendations of the US Preventive 

Services Task Force, which does not recommend routine screening in general. While screening 

is conducted for oral cavity cancers, the kinds of cancers she addressed occur further back, so 

there is no recommended screening.

It was not clear to Dr. Chilton that all of the oropharyngeal and oral cavity cancers are caused 

by HPV 16 and 18. He wondered if there was an attributable risk for those. 

Dr. Saraiya responded that the way that CDC defined the sub-set of oropharyngeal and oral 

cavity cancers that were HPV-associated for cancer registry purposes was to look at the 

anatomic sites that have been shown by studies to have high HPV prevalence (e.g., base of 

tongue, Waldeyer Ring, lingual and palatine tonsil). Systematic studies have been conducted

that show that approximately 25% of oral cavity cancers have HPV identified in them, as do 

35% of all oropharyngeal cancers.

With that in mind, Dr. Chilton wondered what percentage would be used to calculate the riskbenefit ratio and the cost-benefit ratio of GARDASIL®. 

Dr. Saraiya replied that the modeling studies will take into consideration the percentage that are 

HPV associated. She did not present any in situ cancers, but these will also be of significant 

burden, especially in anal and penile cancers and these should be taken into account as well. 

Dr. Plotkin asked Dr. Haupt to compare and contrast the male efficacy data with what was 

achieved in females, given the difference by gender that was observed in the herpes simplex 

virus (HSV) vaccine efficacy results. His impression was that there was somewhat less efficacy 

in men than women with respect to genital warts.

Dr. Haupt indicated that the efficacy observed for genital warts in the young adult women was 

approximately 99%. There were 2 cases in the GARDASIL® group and approximately 156 

cases at the end of study. The point estimate was 99% and the confidence intervals were very 

narrow (96% to 100%). There may be a slight difference between efficacy in women and men, 

but certainly it is very high in men as well, and very different from what was observed with the 

HSV vaccine. Perhaps the size of the study and the robustness of the data is driving the point 

estimate somewhat lower on the male side. The any kind DNA detection was not a prespecified analysis in the women’s trial.

Georges Peter (Brookline, Massachusetts) understood that the value of the AS04 adjuvant is 

that it leads to more prolonged antibody responses. He wondered if Dr. Verstraeten had data to 

demonstrate this particular point with GSK’s HPV vaccine, and wondered whether it would lead 

to an argument for a 2-dose schedule for this vaccine versus a 3-dose schedule. 

 

Gary Dubin (GSK) responded that all of the efficacy data have been generated with vaccine 

given on a 3-dose schedule. They have observed efficacy that has now been demonstrated for 

up to 6.4 years, which is the longest follow-up to date. They have shown that antibody titers 

plateau at approximately 18 months and are sustained for that entire period of time. Modeling 

has been done to show that the plateau level of antibodies is likely to be sustained for at least 

20 years from the time of vaccination. Given that they do not have efficacy data beyond 6.4 

years, the question about 2-dose vaccination is difficult to answer. In theory a 2-dose regimen 

might be possible, but the studies have not been conducted to evaluate a 2-dose schedule. 

Studies conducted to evaluate 3 doses have shown a significant boost (approximately 5-fold) in 

antibody response upon receiving the third dose. Therefore, it may be the three doses are 

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required for long-term protection. Dr. Haupt agreed, adding that it is not known what minimum 

level of antibody is needed for protection. A 2-dose vaccine study may demonstrate 

comparable GMTs at month 7 to a 3-dose schedule. However, it is unknown what this 

translates to in terms of long-term protection. The prime boost is probably very important for 

this vaccine in terms of its durability of immune response. 

Georges Peter (Brookline, Massachusetts) inquired of Dr. Haupt whether there were differences 

in the incidence of genital disease geographically. 

Dr. Haupt responded that while many countries are involved and surveillance is limited in some 

countries in terms of their disease states, there are some rate differences in terms of genital 

wart development across the various countries. The efficacy did not different no differ by 

country. Efficacy was high across all populations, all racial / ethnic groups, and all countries in 

which the studies were conducted. 

Regarding genital warts, Dr. Judson wondered whether there was any good evidence for same 

type re-infection or relapse. 

Dr. Haupt replied that this is a difficult question to answer. The concept of whether one has 

long-term natural immunity versus whether there is a latent stage with HPV that can reactivate 

over time is a question that has yet to be answered. There are varying expert opinions in the 

field with respect to this issue.

Martin Cetron, MD, Division Director

CDC / CCID / NCPDCOD / DGMQ

Dr. Cetron noted that the purpose of this session was to give ACIP an informational update on 

the topic of vaccination of immigrants and refugees, and to set forth the proposed language. 

With respect to background, in 1996 the Immunization and Nationality Act was amended by 

Congress to require “Proof of vaccination against at least mumps, measles, rubella, polio, 

tetanus and diphtheria toxoids, pertussis, Haemophilus influenzae type B and hepatitis B, and

any other vaccinations against vaccine-preventable diseases recommended by ACIP.” 

Given that 13 years have passed since this amendment, there has been some discussion with 

respect to whether the original intent is still in place or whether it needs to be revised—not as 

vaccines recommended for public health purposes, but vaccines specifically that would be 

required in time and place as a pre-requisite for immigration. 

With that in mind, an internal committee at CDC has been convened with representation across 

the agency to consider proposing some criteria by which the original amendment would be 

interpreted in a more contemporary context. Clearly, the portfolio of vaccines that are available 

and the purposes for which vaccines are being used have evolved significantly over time. The 

proposed criteria for identifying ACIP-recommended vaccines as immunization requirements for 

immigrants: “The vaccine must be an age-appropriate vaccine as recommended by ACIP for 

the general U.S. population and at least one or more of the following: 1) The vaccine must 

protect against a disease that has the potential to cause an outbreak; and 2) The vaccine must 

protect against a disease that has been eliminated in the United States, or is in the process for 

Vaccination of Immigrants & Refugees

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elimination in the United States.” An outbreak is defined as the occurrence of more cases of 

disease than expected in a given area or among a specific group of people over a particular 

period of time. 

This is language believed to reflect more clearly the Congressional intent of having an 

immunization requirement for the purposes of immigration. The proposed language more 

directly addresses the sub-set of vaccines for diseases that have epidemic potential and for 

which introduction of those diseases through importation may cause significant propagation, 

versus the broader pallet of vaccines that ACIP actively considers. Another important 

consideration is that from a regulatory framework, vaccine mandates in the U.S. are in the 

jurisdiction of the states. The federal oversight for vaccine mandates for immigrants is part of 

the regulatory framework in the Division of Global Migration and Quarantine (DGMQ). ACIP 

serves as an advisory board for vaccine recommendations. DGMQ is proposing a set of criteria 

that would be used (in consultation with the respective disease/vaccine experts at CDC) to 

determine which vaccines would be required at the time and place of the medical exam for 

immigration. The application of the criteria with the required list of vaccines would be put forth in 

“Technical Instructions” for panel physicians and civil surgeons performing the medical exam. 

The Technical Instructions generally outline recommendations within the regulatory framework 

and are submitted to the Department of Homeland Security, the Department of State, and the 

implementing partners that conduct medical assessments for immigration applicants. The 

process DGMQ was proposing would include ACIP’s weigh in on the criteria, provisions for 

public comments, and potential annual revision of the Technical Instructions based on the 

criteria ultimately determined.

Discussion 

Drs. Baker, Beck, and Judson expressed their support for the language shown on the slide, 

particularly with respect to its simplicity in cutting across a number of complex issues.

Indicating that she had been following this issue since 1996, Sandra Jo Hammer (California) 

suggested that yearly requirement changes were too often. This is an adjudication process, so 

people may have been in the United States for 4, 10, to 15 years. This is when they actually 

receive their Green Card, not when they enter the United States. The Civil Surgeon makes the 

assessment of the vaccines, which are then submitted to the Adjudication Officer who ensures 

that the form is filled in correctly. Given that changes in requirements every year will involve 

numerous processes, she suggested a two- to three-year change. With regard to vaccines 

being required to protect against diseases with potential for outbreak, ZOSTAVAXTM is currently 

recommended for people over the age of 60, which includes adjudicated aliens who are 60 

years of age and older. This means that a grandmother who has been in the United States for 

20 years must suddenly obtain ZOSTAVAXTM and influenza vaccines before she can acquire 

her Green Card. Varicella is an outbreak type of disease, so perhaps the language should be 

revised with the idea that ZOSTAVAXTM may not be appropriate as a requirement.

Dr. Cetron clarified that the application process for lawful permanent residence applies overseas 

to incoming applicants (approximately n=400,000 per year) through Panel Physicians of whom 

there are approximately 600, and the Civil Surgeons of whom there are approximately 3,000 in 

the United States for applicants for adjustment of status (approximately n=600,000 per year). 

The Vaccine Technical instructions apply in both frameworks. 

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No public comments were offered during the first day of the meeting.

February 26, 2009

Invasive Haemophilus Influenzae Type B (Hib) Disease Minnesota 2008

Kristen Ehresmann, RN, MPH

Minnesota Department of Health 

During this session, Ms. Ehresmann reported on Minnesota’s experience with five cases of 

Haemophilus Influenzae b (Hib) that occurred in 2008 and how they responded to this outbreak. 

To frame this in the current context of Hib vaccine, she reminded everyone that in December 

2007, Merck announced a voluntary recall of 10 lots of Hib vaccines and the suspension of Hib 

vaccine production. In October 2008, Merck announced a continued delay. At this point, the 

return of the Merck product is expected no earlier than mid-2009, leaving a single manufacturer 

of Hib vaccine. The interim Hib recommendations during this vaccine shortage have been that 

the Hib vaccine supply is sufficient to ensure completion of primary series for all children. 

Providers have been instructed to continue the primary series; temporarily defer the booster 

dose except for children at high risk; and to prioritize polysaccharide polyribosomal phosphate 

outer membrane protein (PRP-OMP)-containing Hib vaccines for American Indian / Alaska 

Native (AI / AN) children. 

The Minnesota Department of Health (MDH) conducts surveillance for invasive H. influenzae as 

part of the Active Bacterial Core surveillance system of CDC’s Emerging Infections Program. A 

case of Hib is defined as isolation of H. influenzae type b from a normally sterile site. There was 

a Hib cluster in Minnesota in 2008. During that time five Hib cases were reported, which is the 

highest number observed there since 1992. The cases were in children ages 5 months to 3 

years old. There was one death in a 7-month-old, prior to which the last death due to Hib 

reported in Minnesota was in 1991. Clearly, this was a departure from surveillance in recent 

years. In 1983, Minnesota had approximately 250 cases of Hib. With the licensure and 

introduction of the polysaccharide vaccine, the cases decreased to approximately 200. Upon 

licensure of the conjugate vaccine >18 month olds the number of cases dropped below 200. 

With the licensure of the conjugate vaccine for infants the number of cases declined to 

approximately 120 and steadily declined from there until 2008.

With respect to the characteristics of 2008 Hib cases in Minnesota, three of the five children

were unvaccinated due to parent refusal. All of the children were from different counties, 

although they were clustered in a central band across the state. Pulsed-field gel electrophoresis 

(PFGE) data results showed that there were three different strains, so there was no 

commonality in terms of the fingerprinting. The cases had no known relationship with each 

other, and none of children were enrolled in group child care: 

Pediatric Haemophilus

Public Comments Day 1 

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Illness 

onset Age

Clinical

syndrome Outcome

Hib vaccination

status

January 15 mos Meningitis Survived 2 doses, 2 and 5 

mos

February 3 yrs Pneumonia Survived 0 doses

November 7 mos Meningitis Died 0 doses

November 5 mos Meningitis Survived 2 doses, 2 and 4 

mos

December 20 mos Epiglottis Survived 0 doses

 

The 15-month old had received the Merck product and was up to date in terms of the two doses 

of their primary series. At age 15 months when diagnosed, further medical work-up indicated 

that this child had an immune deficiency that was unrecognized prior to that time. Therefore, it 

is likely that the child may not have had a good response to the vaccine. The 5-month old was 

on schedule for the three-dose series, but contracted the disease.

Based on Minnesota Immunization Information Connection (MIIC) registry data, MDH evaluated 

immunization data for children born between November 2007 and March 2008 to include 

children who would have been receiving vaccine after the shortage had begun. Due to limitation 

in the data, they were unable to determine whether use of the Merck product was a factor in 

reduced coverage rates. There was a difference in coverage rates by dose and antigen. Other 

states have reported similar data. As 2008 progressed, the number of doses attributable to 

Merck was reduced considerably.

In a comparison of the three-dose series, MDH studied PCV7 and Hib. For the first dose these 

two vaccines are given at 2 months and they very much correlated. The second dose and 

PCV7 is very close. However, a very large difference was observed with the third dose. 

Therefore, it appeared that children were being taken to clinics but were not receiving the third 

dose of vaccine [Administration of Hib Vaccines by Brand and Month of Vaccination, Minnesota, 

2008]. Data presented in the MMWR article highlight that difference. Children were receiving 

DTaP and PCV by age 7 months, but the third Hib dose was much lower than would have been 

expected for the other two antigens [Centers for Disease Control and Prevention. Invasive

Haemophilus influenzae Type B Disease in Five Young Children — Minnesota, 2008. MMWR

2009;58:58-60].

Rates for 2007 were compared with rates for 2008. It does not appear that there was a 

difference in terms of the third dose of the Hib vaccine. However, in examining the data MDH 

discovered that the coding for Hib is very complicated due to different schedules for different 

products and because coding is probably not a providers’ highest priority. It appears that many 

providers are still coding for use of the Merck product, although it was not the product they were 

actually using. While it appears that there has been a reduction of the third dose of Hib, the 

registry data and coding need further scrutiny.

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Regarding Minnesota’s public health response, MDH has engaged in a considerable amount of 

communications. The MMWR article was published in conjunction with CDC. MDH also 

engaged in a joint press conference with CDC. In advance of the publication of the MMWR and 

the press conference, conference calls were convened with state AAP and AAFP affiliates and

local public health representatives. A statewide HAN was also issued. In addition, MDH 

collaborated with CDC on coordination of the allocation of more Hib vaccine to Minnesota so 

that there were adequate doses once providers became aware of the situation. MDH is 

planning to expedite resumption of the booster dose once the vaccine supply resolves. 

Significantly, an extensive evaluation is underway to determine Hib carriage and understand 

reasons why some children are not vaccinated. The plan is to swab 2000 children across the 

state and conduct surveys with their parents to examine Hib carriage in Minnesota. 

In terms of some of the challenges, with the vaccine shortage Pentacel® has become available; 

however, there has been a provider reluctance to switch inventory and schedules. There are 

also concerns about proper use of vaccine (e.g., mixing liquid and powder). In addition, there 

are catch-up issues in terms of determining differences between primary and booster doses, as 

well as over-vaccination. Providers and parents have expressed concerns about overvaccination when a third dose is needed and Pentacel® is the only vaccine available. It has 

been wonderful to receive the CDC guidance that will now be included in all of the packages for 

providers that re-emphasizes that using Pentacel® is appropriate, even if it may result in 

additional antigens for the children. 

Ms. Ehresmann concluded that Minnesota had reached a “Perfect Storm” situation due to

parental refusal, the vaccine shortage, and reduced herd immunity. A very important message

out of this situation was that three of the five children’s parents had refused vaccine. This 

included the child who died. In addition, it is clear that heightened disease surveillance during 

vaccine shortages is highly important. Moreover, parental concerns about vaccine safety must 

be addressed to reassure parents.

CDC’s Response

Dr. Jeanne Santoli

CDC / CCID / NCIRD / ISD

Dr. Santoli reported on CDC’s response with respect to the Minnesota issue, as well as issues 

pertaining to the nation. Regarding the third dose, CDC examined registry data from CDC 

sentinel site projects which have well-populated registries with very good data to determine 

whether the phenomenon was occurring in states other than Minnesota. At this point, CDC 

continues to struggle with analyzing Hib coverage due to the complexities (e.g., different 

products with different schedules, coding issues in terms of what product was actually used, et 

cetera). CDC conducted a re-analysis to study product type and did find that across all of the 

sites there appear to be some limitations with regard to the third dose coverage. This is of great 

concern and needs to be better understood to protect children with at least the primary series at 

this point. CDC is also working with states that do not have registries and are not sentinel sites, 

but may have other registries and want to use similar analyses to study the coverage of children 

within their jurisdictions. For the states that do not have the registries needed to conduct their 

own analyses, CDC is providing tools such as sampling strategies for use with provider 

practices, sometimes through their vaccine coverage assessment data, to get a sense of 

whether a problem is occurring in their jurisdictions.

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CDC has a number of other activities underway as well. Work is being done to enhance Hib 

surveillance nationally, disease modeling is being done to help understand how the shortage 

might impact what could be expected in terms of the incidence of this disease, and carriage 

studies are begin conducted as well. A provider survey was conducted in 2008, which identified 

very high awareness of the recommendations. However, there was some reported noncompliance with the recommendations that led to increased messaging at that time. CDC is 

considering conducting another survey to better understand if providers are unable to comply 

with the recommendations, why that is and what the barriers are. Consideration is being given 

to whether such a survey should be conducted nationally or targeted to areas where third dose 

coverage appears to be lower. Communications are very important. CDC has made an effort to 

reach providers directly through provider organizations. In addition, due to a centralized 

distributor in the VFC program, CDC has the opportunity to include a letter in every box of 

vaccine shipment that goes out to providers. The letter emphasizes that there is sufficient Hibcontaining product to vaccinate children with the primary series, and that the issue of giving 

children antigens that they do not need is an important consideration, but when not 

contraindicated for other reasons, it is recommended that the combination Pentacel® vaccine 

be used so that children have Hib protection even if they repeat some of their antigens.

Based on all Hib-containing products available, the current vaccine supply is sufficient to 

support a three-dose schedule for non-high risk children and a full schedule for children who are 

at increased risk of Hib disease. In 2008, sanofi pasteur distributed approximately 13.5 million 

doses of this vaccine. From the stockpile for AI / AN children in residential settings, CDC 

distributed approximately 250,000 doses in addition to the 13.5 million. The distribution of 

anything is not 100% efficient, so CDC recognizes that there are challenges and that sometimes 

provider experiences in their offices may differ from what is observed at the national level. 

However, CDC feels assured with the current distribution scheme that there is a sufficient 

number of doses to meet the recommendation currently in place. Merck communicated to CDC 

that their return to market which had been predicted for mid-2009 may be further delayed until 

later in 2009. At the same time, sanofi pasteur has developed a supply plan that supports 

reinstatement of the booster dose in the US in summer 2009 using both ActHIB® and 

Pentacel®. CDC is working closely with sanofi pasteur to understand supply more precisely so 

that options regarding catch-up can be defined. 

Discussion 

Dr. Leonard Friedland (GSK) reported that GSK had been working closely with CDC and FDA 

for the past several months on a plan to assist during the shortage and to ensure adequate 

supply of a monovalent Hib vaccine for the booster dose. GSK has engaged in several 

meetings with the FDA to discuss a licensing application for Hiberix®, a monovalent Hib vaccine 

currently registered in nearly 100 countries. GSK has submitted the initial data to the FDA, and 

is currently preparing a BLA. In addition, GSK has deployed resources to begin manufacturing 

for the supply of Hiberix® in the US. Although the timing is not currently known, GSK is 

committed to continued collaboration with CDC and FDA to bring an additional Hib vaccine to 

the market in the US to help protect children. 

Dr. Sawyer wondered whether providers were confused about the difference between the twodose and three-dose schedule such that if they were in the habit of using the two-dose vaccine 

and had now shifted to the three-dose vaccine, some of their staff are not remembering that the 

third dose is required. 

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Ms. Ehresmann replied that this is a possibility; however, providers have also indicated that they 

are concerned about not receiving an adequate supply of vaccine for the third dose. 

Joel Ward (UCLA) found this to be an onerous report, given that this is such a preventable 

disease. There were as many as 20,000 to 40,000 cases per year in the US as late as 1989. 

To return to that by any means is not necessary. With respect to the three of the five cases that 

refused, he thought an investigation was to illustrate the health risk of refusing to immunize for 

any vaccine in terms of impact so that this part of the story is told. There was a preventable, 

fatal outcome. Carriage is typically at an older age between 18 months and 5 years (e.g., 

daycare center range). Therefore, a markedly increased carriage rate could be observed in that 

age group as compared to what it would have likely been when immunizations are low. When 

there is a shortage and people are not receiving their booster doses at 18 months, there may be 

a carriage rate increase in that pool, which is where the younger children are being exposed. 

With that in mind, he suggested investigating the five Minnesota cases to determine how much 

contact they had with daycare or other siblings in the household who were in the age range 

between 18 to 20 months. H. influenzae conjugate vaccine is now available almost globally, so 

the US should not be experiencing shortages. Those involved in the causes of the shortage 

should question the consequences of doses not meeting perfect expiration dates, not having a 

back-up supply, switching manufacturers, et cetera. 

Dr. Ehresmann clarified that these children were not in childcare settings. As mentioned in her 

presentation, Minnesota is conducting a carriage study of H. influenzae in 2000 children under 

the age of 5 years in Minnesota. In addition, parents will be surveyed regarding vaccination and 

their views on vaccination. 

Dr. Paul Offit (Children’s Hospital, Philadelphia) wondered whether there had been a 

concomitant increased incidence of invasive Hib disease across the US, and if not, he 

wondered why. If they were arguing that absent a booster dose, carriage was being increased 

in older children and thereby increasing risk for parents choosing not to vaccinate or those with 

compromised immune systems, a national increase would be expected. If a national increase 

was not observed, then they must take into consideration whether there was something unique 

about Minnesota. 

CDC’s active bacterial core surveillance, for which CDC receives every isolate and is able to 

confirm the serotype for 10% of the population, detected no national increase reflected in Hib 

disease in any age group. No increase has been noted transnationally either. Modeling 

suggests that for a while after deferring the booster dose, there is a cushion of protection that 

protects everyone which, over time, begins to wane. As the booster is increasingly deferred and 

as third-dose coverage is imperfect, the cushion of protection may not be waning universally 

across the US. It is early and this is all occurring rapidly. Thus far, Minnesota’s clustering 

experience has not been observed elsewhere in the nation.

It was not clear to Dr. Offit why there would be pockets of waning immunity, assuming that the 

shortage occurred for all areas of the US simultaneously. 

It was noted by CDC that this does not pertain to pockets of waning immunity, but to pockets of 

introduction of Hib. Even if immunity is similar nationally, perhaps Minnesota had the 

unfortunate luck to experience introduction of Hib strains at the wrong moment in time, resulting 

in localized increased transmission in Minnesota. Unfortunately, perhaps these five cases were 

simply at higher risk for disease because of underlying illness or lower immunization, it was 

simply a conglomeration of those events. 

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With regard to timing, Dr. Ehresmann noted that if they had not had the cases in November

(n=1) and December (n=2), the year was relatively normal. 

Phil Hosbach (sanofi pasteur) reported that of the 13.5 million doses of Hib-containing vaccine 

supplied by sanofi pasteur in 2008, approximately 62% of that went into the VFC program. 

Given that this was higher than would normally have gone into that program from this resource, 

there was adequate vaccine from sanofi pasteur’s perspective. If immunizing 100% of the 

cohort with three doses, only 12 million doses total should be required. Knowing that 100% of 

the cohort is not immunized, it was not clear to him where the doses were. Whilst there were 

distribution issues, there were other confounding factors that were not mentioned. For example, 

not only did providers hesitate to utilize Pentacel® to supplement their Hib usage, but also 

there was hesitancy on the state and local levels to allow it to be made available to their 

providers. In fact, a couple of states are still doing this. There was a communication from CDC 

about how to code for Pentacel®, which may also have confused providers and resulted in 

incorrect coding. Thus, the number of children who did not receive a third dose may be 

overestimated. 

Dr. Ehresmann responded that Minnesota began promoting Pentacel® in August 2008 before 

they even had the ability to order it.

While a great deal of discussion had centered around supply, shortage, and forumations, Dr. 

Schuchat stressed that three of the five cases refused vaccines. CDC observes clusterings of 

hesitant parents or vaccine refusals due to social, cultural, and other factors. Perhaps it is 

similar to the measles situation in which there is fairly good measles coverage throughout the 

country, but there are areas (e.g., communities, states, towns) in which many people are 

unvaccinated. Hence, Minnesota has rightly focused on the issue that three of five cases 

occurred that were not vaccinated despite the availability of vaccine. It is known that 

approximately 400,000 deaths from Hib occur every year throughout the world despite 

increasing Hib coverage. One action item is to remind people that this is a tragic, preventable 

disease. Parents must understand that vaccine for this disease is truly lifesaving. 

Ms. Stinchfield (Children’s Hospital and Clinics in Minnesota) commented that a great deal of 

information is expected to result from the carriage study with respect to the age group of 5 years 

and under in terms of whether they are in childcare, what their parents vaccine beliefs are, what 

their antibiotic use has been, et cetera. She has been highly impressed with the state health 

department’s rapid response due to their excellent surveillance capabilities. Moreover, parents 

have been extremely willing to offer up their children’s throats and have been very concerned 

about this. Kindergarten surveys do reflect that the number of conscientious objectors has 

increased throughout the years from 1% to 3%. The 15-month old with immune deficiency was 

cared for at Children’s Hospital and Clinics in Minnesota and this mother is very interested in 

telling her story, explaining what it was like to wait for her child fighting for her life with 

meningitis when she had had all of the precautions possible. Ms. Stinchfield also underscored 

that Pentacel® is causing confusion amongst practitioners.

Dr. Baker reminded everyone that children 6 to 24 months of age who have disease do not 

make a protective immune response and should be immunized following their illness.

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Centers for Disease Control and Prevention

Dr. Bell reported that in December 2008, the Measles Initiative using an updated estimation 

procedure reported a 74% drop in measles mortality globally since 2000. That represents 

197,000 deaths in 2007. The Measles Initiative is a partnership that includes American Red 

Cross, CDC, UN Foundation, WHO, and UNICEF. The goal is 90% reduction in measles 

mortality globally by 2010. She also noted that the final version of the stimulus package 

includes $300,000 million to CDC for the 317 Immunization Program as part of the $1 billion 

Wellness Initiative. CDC is working in the context of an HHS process to determine how these 

funds will be allocated. The vast majority of these funds will be utilized to purchase vaccines for 

states through the 317 program. Dr. Bell also mentioned that the National Immunization 

Conference will be convened in Dallas, Texas March 30 through April 2, 2009.

Center for Medicare and Medicaid Services (CMS)

Dr. Linda Murphy indicated that the items that will be published in the new Federal Register

notice have been agreed upon. The previous Acting Director approved the notice to begin the 

regulatory process. The anticipated date to have this published is July 2009 so that it can be 

completed and acted upon before school is back in session.

Department of Defense (DoD)

Wayne Hatchey indicated that the DoD was looking forward to the FDA licensure of the new 

Japanese encephalitis (JE) vaccine and adenovirus vaccine, both of which represent 

components of the DoD’s overall protection portfolio. With regard to influenza vaccines, the 

2009 DoD influenza policy included the expanded pediatric age groups without the “if feasible” 

clause and universal recommendations, with mandatory immunization for all those in uniform. 

Current DoD immunization rates exceed 95% of all uniformed personnel. DoD also has a policy 

making it mandatory for all healthcare workers providing direct patient care with the services 

being required to report immunization compliance beginning with the next influenza season. 

DoD is also in the process of improving its immunization tracking system to begin capturing 

dependents and retirees across all services. Some of the services do capture that data 

currently; however, others do not. The goal is to have one system that meets the services 

needs in terms of readiness, but also includes an accurate account of what is occurring 

throughout the entire beneficiary population. CDC issued their guidance pertaining to antiviral 

resistance, DoD issued a policy making it mandatory for DoD installations and the policy was 

placed on DoD’s influenza website as an information piece in the medical health system blog, 

and was disseminated through DoD’s listserv, a flash email, and DoD pharmacies and 

immunization clinics as a flash alert. 

Agency Updates

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Department of Veterans Affairs (DVA)

Linda Kinsinger indicated that while they were not yet mandating influenza vaccine for all 

employees who engage in direct patient care, DVA does track this. In 2008, they had a 65% 

vaccination rate of all employees in the Veteran’s Health Administration (VHA). That was up 

from 55% in 2007. The target set for 2009 is 70% and facilities are required to track and 

monitor this. A feature of their electronic medical record (EMR) system is a clinical reminder 

window that pops up for each patient that reflects their recommended services due. DVA 

recently revised a comprehensive list of all ICD-9 and CPT codes that would trigger a clinical 

reminder for patients with any codes for influenza and pnuemococcal vaccines. Everyone over 

50 years of age would be targeted, but having a list of high risk patients helps facilities 

determine which patients with high risk codes have not been immunized to be able to engage in 

an outreach effort to get to them. This represents another way of increasing the targeting of 

influenza and pnuemococcal vaccine delivery to those patients. In addition, DVA is in the 

process of developing a set of clinical preventive services guidance statements that would cover 

all recommended preventive services for all eligible patients. Immunizations will be included in 

this guidance statement that will follow ACIP guidelines.

Food and Drug Administration (FDA) 

Dr. Norman Baylor indicated that the FDA convened a Vaccines and Related Biological 

Products Advisory Committee (VRBPAC) meeting the week prior to the ACIP meeting, which 

included three parts related to influenza. The first part was deciding the strains for the 2009-

2010 influenza season. The strains agreed upon are 1) A/Brisbane/59/2007 (H1N1)-like virus 

(same as 2008-2009); 2) A/Brisbane/10/2007 (H3N2)-like virus (same as 2008-2009); and 3) 

B/Brisbane/60/2008-like virus (new; this is the Victoria lineage virus which is different from the 

Yamagata virus that is currently in the vaccine). Also discussed was the feasibility of a 

quadrivalent influenza vaccine. CDC presented data during this meeting on the modeling of 

epidemiology and discussed whether there was a public health need for adding a second B 

strain to the current TIV. Although discussions are in the early stages, the FDA will be revisiting

this issue. Based on the outcome of the meeting, FDA believes they should move forward to 

work with the manufacturers to develop a regulator pathway for the possibility of developing a 

quadrivalent influenza vaccine. How that will be implemented into the routine schedule, how it 

will be licensed, et cetera is yet to be determined. FDA will also engage in discussions with 

WHO, given that they are involved in the process of reviewing surveillance data to make 

recommendations to national regulatory authorities. Also discussed during the VRBPAC

meeting was whether there is a need to continue pediatric studies for pandemic influenza 

vaccine candidates. Although the committee members were not asked to vote, it was clear that 

that the committee overwhelmingly agreed that such studies should continue to move forward. 

This issue is somewhat complicated due to regulation of Subpart D, which addresses specific 

pediatric trials and the prospect of the benefits. FDA will move forward to develop a regulatory 

pathway for the requirements for clinical studies in pediatric populations with pandemic 

influenza vaccine candidates other than H5N1. 

Heath Resources and Services Administration (HRSA)

Dr. Geoffrey Evans indicated that he had distributed the 20-year history of the program statistics 

versus just the vaccines. Overall, nearly 13,000 claims have been filed of which 5,500 are 

autism claims. Of the 5,500 claims over5,100 are pending. Awards are just over $1.8 billion 

total and the trust fund currently stands at $3 billion with annual revenues against outlays of 

approximately $180 million per year. Interest alone is over a third of that annually. That is, the 

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trust fund stands in very good stead. Another handout he provided regarded the omnibus 

autism proceeding. To the US Court of Claims credit, it did a very nice job of outlining the 

procedural history, the current status, what is expected in terms of the appeals schedule, et 

cetera. This is available on the court’s website as well. The decisions that received so much 

publicity on February 12, 2009 reflected the outcomes in three test cases that originally were 

supposed to have been the combination theory of MMR and thimerosol. However, because 

there was no separate MMR vaccine only proceedings, it is covering both theories: combination 

of MMR and thimerosal as well as MMR vaccine alone. The 670 pages of decisions are 

daunting to read, but include a great deal of scientific information. The remaining theory 

(thimerosal-only) is still being briefed. The briefing period is expected to end in summer 2009. 

These were based on hearings in 2008. It is unknown when the court will issue decisions in 

those three test cases. There has been publicity on a case that was decided by the US Court of 

Federal Claims that was tried individually and was defended by HHS. The specifics of the 

ruling, procedural history, et cetera can be accessed on the court’s website. He will forward the 

URL to Dr. Jean Smith. As reported during the last ACIP meeting, HRSA has contracted with 

the Institute of Medicine (IOM) to conduct a two-year evaluation of the medical and scientific 

literature on four vaccines: Hepatitis B, influenza, varicella, and HPV. The first organization 

meeting is expected to take place in April 2009. 

Immunization Safety Office (ISO)

Melinda Wharton announced that ISO has been working very closely with NVPO and with all of 

the other HHS operating divisions to update the National Vaccine Plan. The IOM is hosting a 

stakeholders meeting on the vaccine safety goal of the National Vaccine Plan on April 14, 2009 

in Washington, DC. This is part of an on-going review of the priorities of the National Vaccine 

Plan. 

National Institutes of Health (NIH)

Barbara Mulach noted that the question she had been receiving the most often regarded what 

NIH planned to do with the stimulus money it would be receiving. NIH has been engaged in 

numerous discussions pertaining to the best way to move forward with this in the most effective, 

transparent, and quick use of the funds. The agency has taken to heart the true goal of the 

funds which is to stimulate the economy and what can be done within NIH’s purview to allocate 

the funds to do so. They have a couple of things in mind, the first being an NIH accelerated 

program known as the Challenge Grants Program, which would request applications in focus 

areas that would be reviewed and funded in a very short turnaround. R01s are also being 

considered that are highly meritorious but could not have been funded normally, which are for 

basic research grants. Some of the funding is allotted for construction, alterations, and repairs. 

The Director’s page of the NIH website has a short summary and updates will be provided, and 

updates will also be reported on www.recovery.gov. 

National Vaccine Program Office (NVPO) / National Vaccine Advisory Committee (NVAC)

Given that Dr. Gus Birkhead was unable to attend, Dr. Bruce Gellin presented updates for both 

NVPO and NVAC. During the February 2009 NVAC meeting, there was a discussion of a 

document that was developed by NVAC titled, “State of the National Vaccine Program.” This 

was developed to be put forth to the Assistant Secretary for Health and the new administration 

as a transition document. A major activity was the late November 2008 release of the updated 

draft of the National Vaccine Plan. The previous National Vaccine Plan was written and 

released in 1994. The plan includes five broad goals: 1) new and improved vaccines, 2) 

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vaccine safety, 3) education, communication, and informed decision-making, 4) supply and use 

of current vaccines, and 5) global vaccination. The comment period was scheduled to be open 

through the end of March 2009. NVAC welcomed comments from non-federal stakeholders on 

their views of what should be included in the plan, particularly with respect to the state goals, 

objectives, and indicators and the role of non-federal stakeholders in the development of a 

national and not just a federal plan. They have struggled with whether such a national plan 

should be achievable or aspirational. 

The Vaccine Safety Working Group is currently addressing two charges that were made for 

them, which are to: 1) review the ISO’s research agenda to determine gaps and help prioritize 

the research the ISO conducts; and 2) examine the broader vaccine safety infrastructure. The 

working group has been engaged in the process of collecting input from a variety of 

stakeholders. A stakeholders meeting was planned for March 16, 2009 during which they 

hoped to hear from the broader community with an interest in this area. Documents were to be 

available approximately a week prior to that meeting to help focus the discussions. This 

meeting is designed to address the specific task currently before the working group to examine 

CDC’s ISO research agenda. Safety is one of the goals of the National Vaccine Plan, which is 

where NVAC expects to have synergy with IOM’s activities. The IOM’s April 2009 meeting is 

being convened regarding the National Vaccine Safety Plan, and will address safety more 

broadly. Due to many discussions regarding vaccine financing, several years ago NVAC 

established a Vaccine Financing Working Group that Dr. Birkhead leads. A series of 

recommendations pertaining to vaccine financing were voted upon that are now working their 

way through the system. 

Beyond NVPO and NVAC, the National Biodefense Science Board (NBSB) was created under 

the authority of the Pandemic and All-Hazards Preparedness Act signed into law on December 

19, 2006 to provide expert advice and guidance to the Secretary of the HHS. This group is 

examining the current policy pertaining to the use of stockpiled H5N1 vaccine with respect to: 

1) timing and whether it should be used before a pandemic is eminent, which is the current 

policy; 2) broader population use; the current policy is 20 million people made up primarily of 

first responders, but new adjuvants allow the potential for a greatly expanded stockpile if 

adjuvants are applied to the existing antigen. The Office of the Biomedical Advance Research 

and Development Authority (BARDA), an authority within HHS, is tasked with developing 

products that essentially do not have commercial use. Dr. Gellin suggested that ACIP hear a 

briefing on what BARDA has in the Emergency Use Authorization (EUA) pathway pipeline to 

have some awareness of what vaccines are in development for use in emergencies. 

Indian Health Services (IHS) 

James Cheek indicated that over the last few months IHS has been working on the Assistant 

Secretary’s Initiative to Improve Vaccine Coverage of Healthcare Workers. During the first year, 

IHS managed to reach 71% influenza vaccination coverage among IHS healthcare workers 

throughout the country. 

Discussion

Noting that the rates of vaccines being given to pregnant women are increasing, Dr. Baker 

asked Dr. Baylor what FDA’s plans were for studies during pregnancy and in infants. Dr. Baylor 

responded that these discussions are occurring with respect to pandemic influenza vaccine, 

although no firm decisions had been made thus far. There is also a paucity of data for seasonal 

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influenza vaccine in pregnant women. The question does need to be addressed across the 

board.

Dr. Neuzil requested that Dr. Gellin clarify the role of ACIP in addressing the two pandemic 

vaccine questions. She thought they would have to be very careful to coordinate this issue, 

reminding everyone that during the first day of the February ACIP meeting they heard a 

discussion about ACIP weighing in on using PPV23 in a pre-pandemic. ACIP has an Influenza 

Work Group that routinely makes recommendations for seasonal influenza vaccine, but it 

seemed to her that these recommendations should be made together and not by separate 

committees.

Dr. Gellin responded that part of the reason that this evolved as it did was that ACIP’s purview is 

to deal with licensed vaccines. The vaccines under consideration by NBSB may not be licensed 

and may be used under an EUA, which falls under its purview as a broad policy question. 

NBSB will wrestle primarily with the question: Should the vaccine be used prior to a pandemic 

and if so, for what reasons? Given that the current policy was created before there was 

enhanced production capacity and adjuvants, it was set at 20 million people who would keep 

society going while a pandemic vaccine is being developed. Given that there is a potential for 

that number to now be expanded beyond 20 million people, NBSB is reviewing this policy. Who 

in the population should receive it would certainly fall under the purview of ACIP. He concurred 

that the two committees should ensure that their recommendations are congruous to avoid 

having cross purposes or finding themselves in conflict. NBSB will receive input from a range of 

other existing federal advisory committees, not just those pertaining to vaccines, but also those 

that have access to this in other places. For example, DHS has a Critical Infrastructure 

Advisory Committee (CIAC) which will also be a liaison. Without having to convene this meeting 

in a stadium, the idea was to have the appropriate components of the government and external 

advisory committees be included as part of these discussions, which regard broad policy versus 

specific individual use.

Dr. Neuzil suggested that an ACIP member should serve as an ex officio member of the NBSB 

committee to facilitate clear communication between the two committees.

Dr. Bell indicated that CDC will be addressing this issue further to ensure that ACIP does not 

take up an issue which may be duplicative.

Update: Meningococcal Work Group

Carol J. Baker, MD 

Chair, Meningococcal Work Group

Dr. Baker reported on recent and future activities of the Meningococcal Work Group, as well as 

adolescent vaccine considerations with respect to new vaccines on the horizon in addition to 

MCV4. With regard to meningococcal disease incidence from 1970-2007, importantly there 

have been cycles of meningococcal vaccine incidence every five to seven years until recently. 

The downturn is for all serogroups, including B which is not included in the adolescent vaccine 

program. Unfortunately, what accounts for the downturn is unclear [1970-1996 uses National 

Meningococcal Vaccines

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Notifiable Diseases Surveillance System (NNDSS) data; 1997-2007 uses ABCs data projected 

to US population].

In terms of recommendations from 2005 to the present, in May 2005 following the ACIP vote an 

MMWR was published regarding the prevention and control of meningococcal disease. Shortly 

after the summer use of this vaccine, the first Guillain-Barré Syndrome (GBS) report was 

published. In 2006, a second report was published. There was then the problem of reduced 

supply, along with the problem of inadvertent administration in that the polysaccharide was to be 

administered subcutaneously and the conjugate intramuscularly. This was followed by a third 

GBS update approximately midway into 2006. Improved supply by the end of 2006 was 

followed by a recommendation of MCV4 for all adolescents 11 through 18 years of age. 

Recommendations were then made for MCV4 for children 2 through 10 years of age at highrisk, but routine vaccination was recommended with MCV4 for children 2 through 10 years of 

age based on disease burden, et cetera.

With regard to the projected licensure of new meningococcal vaccines (2009-2012), it is difficult 

to project precisely for a variety of reasons. However, the manufacturers have worked with the 

group to determine a projected timeline. There is now a second conjugate vaccine for ACYW135 (MenACYW-CRM) anticipated to be licensed in 2009 for 11 to 55 year olds, the same age 

group for the first conjugate. A revision of the 2005 ACIP statement is anticipated that would 

include all of the interval recommendations. The first statement was for three cohorts of 

adolescents, so this statement needs to be brought more up to date. At the beginning of 2010, 

licensure is anticipated for a conjugate for 9 to 12 month olds and infants. 

In terms of considerations for adolescent MCV4 meningococcal vaccination, vaccine 

effectiveness and duration of protection are very important. Safety and reactogenicity continue 

to be under surveillance, with updated data that are very reassuring. As noted, the new 

meningococcal conjugate vaccines, MenACYW-CRM, is anticipated to be licensed for 11 

through 55 year-olds in 2009.

Regarding the estimated number of cases of meningococcal disease per year in 10 to 21 year 

olds due to vaccine-containing strains (A,C,Y,W-135), Dr. Baker reminded everyone that the 

reason for the three cohorts for the adolescent platform to be utilized was to immunize those 

entering high school or 15-year olds (whichever came first) was due to the peak between 15-18 

year olds and the special risk group of college freshman who would be living in dormitories. The 

2005 meningococcal vaccination recommendations focused on two age cohorts in the setting of

the limited vaccine supply: 11-12 year-olds, 14-15 year-olds (high school entry), and others at 

increased risk for disease (college freshmen) based on the amount of supply available. The 

assumption was that the vaccine would protect for 10 years. The hope was that those 

immunized at 11-12 years of age would be protected through age 21. The 2007 revised 

recommendation stated that there should be “Routine vaccination of all persons aged 11-18 

years with 1 dose of MCV4 at the earliest opportunity” and that “The ACIP goal is routine 

vaccination of all adolescents with MCV4 beginning at age 11 years. ACIP and partner 

organizations . . . recommend a health-care visit for children aged 11-12 years to receive 

recommended vaccinations and indicated preventive services. This visit is the optimal time for 

adolescents to receive MCV4.” Thus, a strong statement was made in the 2007 

recommendations to strengthen the adolescent platform.

In terms of MCV4 coverage among 13-17 year-olds based on NIS-Teen data for 2006 and 

2007, there were fairly low coverage rates across the age groups in 2006 and approximately 

30% coverage across the age groups in 2007. In 2009, four years after the initial MCV4 

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recommendation, 11-12 year-olds are now 15-16 years-old and 14-15 year-olds are now 

entering college. The work group has been discussing whether there should be a 

recommendation for revaccination with the conjugate. The prior recommendations for 

revaccination with meningococcal polysaccharide vaccine (MPSV4) was 3 to 5 years. More 

recently, there was a five-year interval recommended. The most recent Red Book will 

recommend a three-year interval. 

With respect to the duration of protection, the correlate of protection is serum bactericidal 

activity (SBA). SBA diminishes over time with the conjugate and the polysaccharide, and this 

correlate alone may underestimate protection. Immunologic memory alone may not be 

sufficient to protect against meningococcal disease. Not all conjugate vaccines are created the 

same. Meningococcal conjugate vaccines are unlikely to provide life-long protection. Dr. 

Baker’s own opinion of why the Hib conjugate vaccines are so effective is because there was a 

routine immunization for all infants, so there was an incredible herd effect. This is also a limited 

disease in terms of invasive disease versus a 10-year period of risk for healthy children. 

In terms of monitoring the safety of MCV4, in place are the VAERS and VSD systems as well as 

a post-licensure case-control study of Guillian-Barré Syndrome (GBS) after MCV4. The goal of 

the post-licensure case control study for monitoring of GBS after immunization with MCV4, 

funded by sanofi pasteur, was to design and conduct a study with adequate power to answer

the question of increased risk of GBS following MCV4 vaccination. The challenges are the low 

prevalence of GBS (1/100,000 PY), and the MCV4 vaccination within specific 6-week time 

windows (0.614% estimate). The study requires the combined efforts of several large health 

plans with active health research divisions. This is a multi-site retrospective cohort study. It is a 

nested case-control study examining the period from March 2005 through August 2008. This is 

a collaboration between Harvard Coordinating Center and the research arms of five US health 

plans. Cases are being identified through claims data, confirmed through medical chart review, 

and adjudicated by neurologist panel [Registered at ClinicalTrials.gov (NCT00575653)]. 

Pertaining to the interim GBS study results, 4.5 million 11 to 18 year-olds were identified for the

primary study population (5.9 million total, over 7 million person years). The MCV4 

immunization level overall was 7.6% through May 2007, with 20% among 17 to 18 year olds 

(n=387,491 total vaccinations). Of the 240 potential GBS cases identified in claims, 100 had

sufficient information to determine case status, 29 met the primary study endpoint definition, 26 

during study period (21 from primary / 5 secondary), and 0 cases were exposed to MCV4 or 

other vaccinations within 42 days of an interval. This is very encouraging data that suggest that 

GBS is not occurring in any greater a frequency in vaccinated versus unvaccinated adolescents.

The new vaccine, MenACWY-CRM, is being reviewed for licensure in 11 to 55 year-olds. The 

expected licensure in summer 2009. Immunogenicity data will be presented by the company to 

ACIP in June 2009. There will be no VFC or ACIP vote required because this is another 

conjugate vaccine just like the Hib conjugate. MenACWY-CRM will protect against the same 

groups as the first meningococcal conjugate (serogroups A, C, Y, W-135). Conjugation is 

somewhat different in that there is sizing of oligosaccharides before conjugation with CRM-197. 

In summary of the adolescent meningococcal immunization considerations, early adolescent 

immunization may not maximize protection through late adolescence. The work group is 

evaluating all available data. MCV4 safety continues to be monitored, and safety to date 

appears very good. With the MCV4 conjugate vaccine on the market, no changes are expected 

to the recommendations. 

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With regard to revision of the 2005 ACIP meningococcal vaccine statement, the work group 

plans to update the full ACIP in Fall 2009 with new data and recommendations for the current 2

to 10 year-olds and 11 to 18 year- old adolescent recommendations. Safety data to be 

presented will include GBS monitoring. MenACYW-CRM vaccine information will be added, and 

hopefully data will be presented regarding the duration of protection. A new statement for infant 

vaccination recommendations will need to be made for 2010 to 2011, for which data 

presentations to ACIP are not expected to begin until in October 2009. 

Discussion

Dr. Katz requested further information about the potential for a group B vaccine. It seemed to 

him that if ACIP was going to move forward with an infant and toddler program, it would be 

beneficial if the vaccine was pentavalent rather than quadrivalent.

Dr. Baker indicated that when the work group asked this question, they were told about the 

ACYW-135 vaccine.

Dr. Decker (sanofi pasteur) responded that sanofi pasteur is hard at work on a group B vaccine, 

but that ACIP recommendations should not be held up and the ACYW vaccine based on this.

Dr. Friedland (GSK) indicated that GSK also continues to work on the development of 

meningococcal serogroup B vaccine, and that they hoped to report to ACIP in the future on the 

results of these development plans. 

Dr. Stoddard (Novartis Vaccines) replied that Novartis is also actively engaged in serogroup B

meningococcal vaccine development. They too hope to update the panel in the near future.

Laura York (Wyeth Vaccines) reported that Wyeth has a bivalent recombinant conserved protein 

program that, based on preclinical work, appears to have broad coverage in some early work 

with clinical sera. This program is currently in Phase II. 

Guillain-Barré Syndrome (GBS) Among Recipients of 

Meningococcal Conjugate Vaccine (MCV4, Menactra®) 

Angela Calugar, MD, MPH

CDC / OD / OCSO

MCV4 was licensed on January 17, 2005. Over 22,181,400 doses were distributed in the US 

through December 31, 2008. Data about doses administered nationwide is not available, 

however. As noted, the ACIP recommendations in June 2007 are for “...routine vaccination of 

all persons aged 11-18 years with 1 dose of MCV4 at the earliest opportunity,” and “...routine 

vaccination for persons aged 19-55 years who are at increased risk for meningococcal 

disease...including college freshmen living in dormitories.”

Several updates were made by ACIP regarding GBS following MCV4. In an MMWR update in

October 2006, it was indicated that, “Data suggest a small increased risk for GBS after MCV4 

vaccination, the inherent limitations of VAERS and the uncertainty regarding background 

incidence rates for GBS require that these findings be viewed with caution . . . Because of the 

risk for meningococcal disease and the associated morbidity and mortality, CDC continues to 

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recommend routine vaccination with MCV4 for adolescents, college freshmen living in 

dormitories, and other populations...” An update in the MMWR in December 2007 read, 

“Persons with a history of GBS might be at increased risk for GBS after MCV4 vaccination; 

therefore, a history of GBS is a precaution to administering MCV4.” 

Based on post-licensure findings, changes were incorporated into the package insert in its 

contraindications and warnings sections. Product approval information for Menactra® states 

under Contraindication: “known history of GBS is a contraindication to vaccine administration”

and under Warnings: “GBS has been reported in temporal relationship following administration 

of Menactra vaccine. An evaluation of post-marketing events suggests a potential for an 

increased risk of GBS following Menactra vaccination.” 

GBS is an immune-mediated rapidly evolving polyradiculoneuropathy generally manifested as a 

symmetric motor paralysis. Certain infections may cause this condition. Some cases are 

vaccine-associated. A study of GBS following A/NJ/1976 “swine flu” vaccine confirmed a risk 

window within six weeks following vaccination, or 42 days. That is, attributable risk was within 

six weeks after vaccination with 4.9 to 11.7 cases per million in the 42-day risk window. This is 

a rare condition. The estimated incidence rate of GBS is 1 to 2 cases per 100,000 person

years. 

Methods used for post-licensure surveillance of GBS after MCV4 vaccination include VAERS, 

which is a national post-licensure passive surveillance system. MedDRA coding may capture all 

possible cases, and this system allows for the generation of hypotheses for further studies, but 

does not show causality. The VSD is a collaboration between CDC and eight managed care 

organizations. Data from 8.8 million members is captured annually, which represents 2.9% of 

the US population. The Clinical Immunization Safety Assessment (CISA) Network includes six 

medical research centers and individual consultants. 

In terms of the VAERS data, all reports of GBS and with symptoms of suspected GBS were 

carefully reviewed using the Brighton case definition. Additional medical information was 

obtained during the follow-up process, when possible. Of the total of 61 reports to VAERS, 

there were 37 confirmed cases for all ages, which had onset within 42 days following 

immunization. Of the 37 confirmed cases, 33 were in the age group of interest, 11 to 19 year 

olds. Dr. Calugar focused the remainder of her presentation on the 33 confirmed cases. 

Importantly, there were no cases with onset on day 0. Some cases were excluded from the final 

count for various reasons. The reports broken down by age group are as follows:

0

2

4

6

8

10

11 12 13 14 15 16 17 18 19

1 1 2 3 3

2

5

9

7

Number of 

reports Age, years

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The onset interval from MCV4 administration to the adverse event ranged between 2 to 37 

days, with a mean of 19.2 days, a median of 15–days, and temporal scan cluster of 10 to 15 

days (p=.002). To better understand VAERS data, the background rate is of interest. To that 

end, a comparison was made of observed GBS cases in VAERS to the background rates in the 

Healthcare Cost and Utilization Project (HCUP) data from 2000 to 2004 (prior to the licensure of 

the vaccine). Based on VSD data, investigators assumed that 45% of doses were administered 

in the sub-group of 15 to 19 years. In the 11 to 19 year old age group, the 33 reports is a lower 

number than the expected rate of 36.17% in HCUP. Of the 33 total reports, 26 occurred in the 

15 to 19 year old age range, which is a higher number than the expected 19.78% in HCUP data. 

However, the confidence interval of .87 to 1.90 indicates that there is no statistically significant 

difference between the observed and expected number of cases of GBS reports based on the 

background rate calculation using HCUP data. Dr. Calugar acknowledged that background 

rates in VSD were similar to HCUP background rates. 

Regarding monitoring GBS following MCV4 through the VSD Rapid Cycle Analysis (RCA) Study

is an on-going project from April 2006 through February 2009. The case definition for GBS for 

signal detection is an ICD 9 code 357.0 (acute infective polyneuritis). An exposure window of 1 

to 42 days was used. Hospitalization, outpatient, and emergency department visit records were 

used to find diagnoses of GBS. The first event of GBS had to be within the 42-day risk window. 

Diagnosis is confirmed with chart review. RCA results reflect that 642,493 doses were 

administered at eight study sites. Five GBS cases < 42 days after MCV4 were found in the

automated data. Three GBS cases received a chart review. Of the three cases, one was preexisting GBS, one had a related diagnosis that was not GBS, and one had “rule out GBS” and a 

different subsequent diagnosis. A fourth case had onset of symptoms on day 0, which is not 

within the formal risk window. A fifth case is pending medical record review. For comparison, if 

the fifth case proves to be GBS, this will mean that there is one observed case.

In summery, more than 22 million doses were distributed in the US from January 2005 through 

December 2008, including 642,493 doses administered in the VSD population. Reported GBS 

within 42 days of vaccination among MCV4 recipients continues to be of concern. VAERS data

identified 33 confirmed cases of GBS identified following MCV4. Current data do not suggest 

an overall increased risk for GBS in ages 11 to 19 years; however, there is a possible risk in the 

subgroup of 15-19 year olds. VSD RCA data identified five cases following MCV4, of which four 

were ruled out from the final count after chart review, and one is pending review. There is no 

safety signal.

Surveillance data limitations for surveillance of GBS following MCV4 vaccination are that the 

completeness of reporting to VAERS is unknown. Thus, there is a risk of underreporting or 

stimulated reporting. The system includes incomplete data, lacks a direct and unbiased 

comparison group, and lack of data for doses administered. VSD has limited capability to detect 

very rare AE following immunization (1 per 100,000) in minimal time periods for minimal risk 

ratios. VAERS and VSD continue to monitor for GBS reports following MCV4 vaccine. Harvard 

Medical School / Harvard Pilgrim Health Care are conducting a consortium study to assess the 

relationship between immunization with MCV4 and GBS. 

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Discussion

Dr. Temte noted that over time there had been a consistent pattern than under the age of 14, 

little activity is observed. With that in mind, he wondered whether any analyses had been 

conducted for just the subgroup of 17 to 19 year olds.

Dr. Weintraub replied that they had not done so, partly due to the limited power. Somewhat 

ironic with regard to the five automated cases that have been found from computerized records 

in VSD, only one was in the 15 to 19 year old age range. 

Dr. Baker reminded everyone that former ACIP member Dr. Allos used to point out that the 

disease peak is between 15 to 19 years of age for GBS incidence. Individuals 18 to 19 years of 

age going to college had the highest uptake in the first year of immunization, with a summertime 

predominance. Campylobacter is the most common preceding event before GBS, yet data 

have not been able to be teased out due to insufficient numbers to determine whether this is the 

same season association-wise with the peak incidence of Campylobacter and GBS. 

Referring to the ACIP recommendations and the package insert, Dr. Chilton noted that there 

was a discrepancy regarding whether MCV4 was a precaution or contraindicated in previous 

GBS sufferers, and wondered where ACIP stood on this currently. 

Dr. Calugar replied that the manufacturers decided that a known history of GBS was a 

contraindication to vaccine administration. However, based on MMWR updates, this is a 

precaution. With respect to the ACIP recommendations, it was left up to providers to address 

specific patient situations.

Dr. Iskander reminded everyone that the data point used in support of listing prior GBS as a 

precaution rather than a contraindication was that among the initial case series of five reports, 

one young woman had experienced three episodes of post-vaccination GBS all following 

diphtheria toxoid-containing vaccines. 

Sandra Jo Hammer reported that when she took her two nephews for their camp physicals, 

amongst the eight forms to be completed, several required meningococcal vaccine for overnight 

camps. Of those, two had the incorrect meningococcal vaccine requirement (e.g., the 

polysaccharide vaccine). She assumed that this was because they were using an old form that 

was duplicated; however, if there was a case of GBS in a camp setting, this could delay 

investigation of the disease, a determination of who might be susceptible, et cetera. With that in 

mind, she suggested some type of communication to camp associations, Boy Scouts, Girl 

Scouts, et cetera to update their forms. 

Dr. Baker responded that some states and some camps have overnight requirements; however, 

that was never an ACIP recommendation for the polysaccharide vaccine or the quadrivalent 

conjugate vaccine except in someone who was not immunized between 11 and 18 years of age. 

There are no data to suggest that there is sufficient risk in a camp situation. 

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Update: Herpes Zoster Shingles Vaccine

Rafael Harpaz, MD MPH

CDC / CCID / NCIRD / CDC

Dr. Harpaz noted that it had been approximately two years since ACIP voted to recommend the 

herpes zoster vaccine (HZV). Thus, CDC thought it would be beneficial at the beginning of this 

session to present an update on the status of the vaccine program.

With regard to the background of herpes zoster (HZ) and post-herpetic neuralgia (PHN), there 

are approximately 1 million cases of HZ annually. The primary known risk factors include age

and immunosuppression. The risk of HZ increases with age and the risk of PHN increases even 

more dramatically with age. Approximately 30% of all persons develop HZ in the course of a 

lifetime. Immunosuppression explains only a small portion of that 30%. It is not clear what 

other risk factors may exist or what distinguishes the 30% who get HZ from the 70% who do not. 

HZV is 51% effective at preventing HZ. However, efficacy declines with age and varies from 

youngest to oldest vaccinees by a factor of 3 to 4. Other than age, risk factors for vaccine 

failure are plausible but have not been well-characterized. The vaccine is 67% efficacious at

preventing PHN. 

With respect to HZV cost and reimbursement, this is an expensive vaccine. The catalogue price

of the vaccine is approximately $150, while in 2008 the average wholesale price was $194 and 

the retail price was variable. At Dr. Harpaz’s pharmacy the price was $250. The vaccine is 

covered by Medicare Part D primarily for persons ages 65 and over. For persons aged 60-64, 

commercial insurance is the typical coverage. Other payor mechanisms include VA, Medigap 

Medicare supplemental insurance, Medicare Advantage, Medicaid, and health departments. 

With regard to Medicare Part D reimbursement, the relationship of drug plans is with 

pharmacies rather than physicians. Therefore, vaccination by physicians usually entails filing a 

claim (e.g., paying full price up front), referring the patient to a pharmacy for vaccination, or

referring the patient to the pharmacy to purchase HZV for transport and vaccination at the 

doctor’s office. This practice is known as “brown-bagging.” Given that this is a freezer-required 

vaccine, this is not a good practice. Non-reimbursable costs include deductibles, co-pays, and 

the coverage gap / “donut hole.” Co-pays alone are approximately $20 to $60. For commercial 

insurance for persons 60-64 years old, deductibles and co-pays also apply. 

With regard to the HZV target population, there is marked heterogeneity in the senior population 

as compared to pediatric or adolescent populations. Dr. Harpaz would argue that the 

heterogeneity is many times greater. This has an important bearing on the unknown risk factors 

in terms of vaccine uptake, immunogenicity, risk of zoster itself, vaccine efficacy, vaccine safety, 

et cetera. All of those unknown risk factors can translate to unmeasured confounding, and 

make it very difficult to interpret data regarding the impact of the vaccine program . 

The challenges to enabling vaccinations is that there have been HZV supply shortages, 

although these have been largely resolved. Provider barriers include awareness, up front cost, 

complexity of reimbursement, and storage / handling issues. Patient barriers include

awareness, financial burden, and finding HZV. A shared barrier is that the system does not 

accommodate adult vaccines very well. Activities and plans through NCIRD to enable 

vaccinations include promotional and informational activities; provider training and education; a 

Herpes Zoster Vaccine

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provider survey on practices and barriers (completed), and a patient survey that is being 

developed to characterize barriers from their perspective.

 

Given the barriers to HZV vaccination, timely and thorough monitoring of uptake is needed to 

determine whether corrective measures are necessary. Due to the heterogeneity in the target 

population, it is important to know who is / is not being vaccinated to be able to interpret vaccine

performance. No routine state-level data are available on HZV uptake such as those which 

exists for pediatric vaccines (e.g., NIS). With regard to NCIRD activities and plans regarding 

these issues, an adult National Immunization Survey (NIS) module was conducted in the 

summer of 2007. That survey found that uptake in the target population was just under 2%. 

There are no plans to repeat that survey. Instead, NCIRD is working with the University of 

Michigan on the Health & Retirement Study, which is a biennial survey of 22,000 adults ≥50 

years on a variety of issues (e.g., health, insurance, et cetera. Results are expected in July 

2009 on HZ rates and HZV uptake. NCIRD is also working with the National Health 

Immunization Survey (NHIS), which is an annual survey, from which data are expected in July 

2009 on HZV uptake from approximately 6,200 adults ≥60 years. The Behavioral Risk Factor 

Surveillance System (BRFSS) annual survey would typically provide state-level data on HZV 

uptake; however, it is not clear whether any states are going to adopt the HZV module. Biologic 

surveillance data are collected semiannually from the manufacturer on the number of doses 

distributed. Medicare Part D claims data provides a theoretical mechanisms to acquire data on 

uptake, but that will be delayed. State registries also provide a theoretical source of information; 

however, to date only one state collects comprehensive information on HZV vaccination.

There are considerable challenges with respect to safety. This is the first live (i.e. not inactive) 

vaccine targeted for seniors. Distinguishing cause and coincidence among the elderly who 

have high rates of medical events will be very challenging. Safety may vary by co-morbidities, 

medications, and frailty in this heterogeneous population. Adult providers may be less 

experienced at reporting to VAERS. The ISO and FDA are conducting VAERS surveillance, 

with the two-year review currently in preparation. A Vaccine Safety Datalink (VSD) protocol is in 

development to assess safety.

The challenges are also considerable with respect to impact. It is difficult to make HZ 

reportable; therefore, accordingly, CSTE did not express an interest in such measures. It is 

difficult to monitor the outcomes of greatest interest (e.g., severity and duration of pain). Agespecific HZ rates appear to be increasing over time without any recognized cause. Thus, it is

challenging to interpret HZV impact when it is not clear how rates would change in its absence. 

The unique risk factors in most of the 30% of persons who develop HZ are unknown. It is

challenging to interpret HZV impact without knowing the risk factors. Studies are underway to 

better define long-term HZ trends (e.g., Olmsted County, Medstat, Medicare, Harvard). Studies

are also underway to better define HZ risk factors (e.g., Medstat, Marshfield, Medicare). NCIRD 

and its partners at Harvard are developing and validating methods to conduct HZ and PHN case 

findings using claims data. Prospective HZ and PHN surveillance has also been established

(e.g., Medicare, Medstat, HRS, Varicella Active Surveillance Project). 

In terms of challenges to monitoring performance of the HZ vaccine program, no surrogates 

exist for vaccine protection. Greater understanding of baseline HZ trends, risk factors for HZ, 

characteristics of elderly who receive HZV is critical for designing studies to monitor HZV 

performance and duration of protection. Current and planned HZ studies should provide data 

needed to inform the design of studies to measure HZV performance. 

Provider Attitudes and Practices Regarding 

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Herpes Zoster Vaccine and Perceived Barriers

Allison Kempe, MD, MPH

Professor, Pediatrics

University of Colorado Denver

Dr. Kempe noted that she viewed her job as representing the interests of the primary care 

providers who were kind enough to share their attitudes and thoughts with the University of 

Colorado and to assist ACIP with its deliberations. With that in mind, she reported on provider 

attitudes and practices regarding HZV and perceived barriers to its use.

HZV is the first vaccine to be reimbursed through Medicare Part D. It is the most expensive 

vaccine recommended for older adults (≥ 60). The vaccine requires freezer storage at an 

average temperature of <5°F (<-15°C). The NIS 2007 found a low rate of uptake at 1.9% six 

months after recommendations [Lu et al. Vaccine 2009 (in press)], although these data did 

proceed the MMWR publication. Nevertheless, this low uptake number raised concerns about 

why use was so low.

The objectives of the study were to assess, in a nationally representative sample of family 

medicine physicians (FM) and general internists (GIM), current vaccination practices, barriers to 

vaccination, knowledge and practice regarding reimbursement for vaccine, and characteristics 

associated with stocking and administering HZV. This study was conducted just over two years 

after HZV was licensed in the US in an existing sentinel physician network recruited from 

random samples of AAFP and ACP. Quota sampling was done to ensure that networks were 

similar to overall AAFP and ACP memberships. A previous study demonstrated this method 

produced comparable results to the most commonly used method of randomly sampling the 

AMA membership with respect to physician demographics, practice characteristics, and 

responses on surveys regarding vaccine-related issues [Crane LA, Eval & Health Prof, 2008]. 

The survey period was from July through September of 2008 (26 months post-licensure, 21 

months post-provisional recommendations, and 1 month post-publication of the

recommendations). Providers were surveyed by internet or mail based on their preference. 

The internet group received a pre-letter and up to 8 e-mail reminders with links to the survey, 

while the mail group received pre-letter and up to 3 surveys. 

Dr. Kempe noted that she would be presenting FM and GIM results together with any 

differences highlighted, given that the results were generally similar. She presented separate 

multivariate models predicting routinely stocking and administering zoster vaccine for each 

specialty, given that these differed somewhat. There was an overall 72% response rate: FM: 

72% (301 / 417) and GIM: 72% (297 / 411). Respondents were not significantly different from 

non-respondents with respect to region, practice location, and practice setting. With regard to 

the most common vaccine delivery methods for this vaccine, 51% of physicians stock and 

administer vaccine in their offices; 39% refer patients to the pharmacy to purchase vaccine and 

administer the vaccine in the office (e.g., brown bagging); 33% refer patients to the pharmacy to 

purchase and have the vaccine administered at the pharmacy; 23% refer patients to the public 

health department to purchase and have vaccine administered at the public health department; 

and 9% refer patients to another clinic or office to purchase vaccine and the vaccine is 

administered at that clinic or office. Some physicians use more than one delivery method. 

Among both FM and GIM physicians, 93% reported using at least one delivery method. Of 

these physicians, 62% used one delivery method, while 38% used two or more delivery 

methods.

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With respect to the estimated number of patients to whom providers administered HZ vaccine in

the past year, 49% of FMs and 47% of GIMs reported delivering the vaccine to less than 10 

patients in a year; 45% of FMs and 35% of GIMs to 10 to 49 patients; and 6% of FMs and 16% 

of GIMs to over 50 patients. 

In terms of the strength of the recommendation for HZV compared with other vaccines, rates of 

strongly recommending pnuemococcal (94%) and influenza vaccine (96%) are almost universal, 

and 76% strongly recommend tetanus and diphtheria. However, only 41% are strongly 

recommending HZV. It is important to note that when the strongly recommend and recommend 

categories are added, 88% are doing either. Thus, there is a shift rather than a real difference 

in direction. With regard to the reported percentage of time patients decline HZV after provider 

recommendation, approximately 50% of providers in both specialties report that the vaccine is 

declined less than a quarter of the time; 25% of FM and 29% of GIM report that the vaccine is 

declined a quarter to half of the time; and 25% of Fm and 17% of GIM report that the vaccine is 

declined more than half of the times they recommend it. 

Regarding the perceived barriers to delivery of HZV, of the combined FM / GIM (n= 598), 53% 

said that cost concerns for patients was a major barrier, while 30% said cost was somewhat of a 

barrier. Reimbursement problems for physicians’ practices were a major barrier for 52% of 

providers and somewhat of a barrier for 25% of providers. Up-front cost to purchase the 

vaccine was a major barrier for 43% of practitioners, while this was somewhat of a barrier for 

30% of practitioners. The need to pick up zoster vaccine at a pharmacy was a major barrier to 

23% and somewhat of a barrier to 25% of providers, while the need to store the vaccine in the 

freezer was a major barrier to 16% and somewhat of a barrier to 20% of providers. More 

pressing medical issues taking precedence was a major barrier to 12% and somewhat of a 

barrier to 23% of providers, with difficulty obtaining vaccine posing a major barrier to 12% and 

somewhat of a barrier to 14% of providers. Barriers reported as major less than 10% of the time

include provider / patient concerns about safety of the vaccine; provider / patient concerns 

about effectiveness of the vaccine; perceived low incidence of HZ and PHN; perceived lack of 

serious sequelae of HZ and PHN; provider feeling the vaccine is not important; patients feeling 

the vaccine is not important; provider discomfort with administering vaccine that the patient 

brought back from a pharmacy; and provider concern that he / she will inadvertently administer 

vaccine to an immunocompromised patient. 

Pertaining to knowledge of HZV reimbursement of the combined FM / GIM (n= 598), only 45% 

knew that this vaccine is reimbursed through Medicare Part D, 3% thought it was through 

Medicare Part B,13% thought it was not covered by Medicare, and 39% did not know or were 

not sure. In terms of knowledge of HZV administration reimbursement, only 13% knew this was 

reimbursed through Medicare Part D, 31% thought it was reimbursed through Medicare Part B, 

9% thought administration was not covered by Medicare, and 48% did not know or were not 

sure. The eDispenseTM Vaccine Manager is a web portal through which physicians can 

electronically submit claims for reimbursement for HZV. This was launched in August 2007 in 

the hope that this would simplify the process for physicians. Unfortunately, only 7% of 

respondents were aware of eDispense and only 1% reported being members. 

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In terms of strategies to evaluate coverage for HZV. The most commonly used strategies were 

generally similar for the two insurance types (e.g., Medicare Part D; Private Insurance), with the 

exception of the most common reported strategy of asking the patient to check with their plan 

regarding coverage. This strategy was more commonly used for private insurance (69%) than 

with Medicare Part D (57%). Asking the patient to pay for vaccine and pursue reimbursement

on his / her own was done 27% of the time for those with private insurance and 33% of the time 

with Medicare Part D. Office staff contacted the patient’s plan to identify coverage 24% of the 

time for private insurance and 20% of the time for Medicare Part D. Practitioners later billed the 

patient if administration of the vaccine was subsequently not covered 19% for private insurance 

and 18% for Medicare Part D. The strategy of assuming the vaccine would be reimbursed by 

the patient’s plan was used 15% of the time with private insurances and 20% of the time with 

Medicare Part D. Responses were not mutually exclusive. 

Focusing down specifically on major barriers to reimbursement for HZV when dealing with 

Medicare Part D or private insurance, 43% reported that the level of complexity of the 

reimbursement process was a major barrier for Medicare Part D, while 33% reported complexity 

as a major barrier for private insurance. Other major barriers were similar for the two insurance 

types and included the time and effort required to assess insurance coverage (44%, 39%), lack 

of inadequate reimbursement for purchasing the vaccine (40%, 37%), and the lack of or 

inadequate reimbursement for administering the vaccine (24%, 23%). 

Multivariate associations with not stocking and administering HZV, included perceiving the upfront cost of vaccine as major barrier with an odds ratio of 5 for FM and almost 14 for GIM; 

perceiving freezer storage as a major barrier with an odds ratio of 4.3 for FM and 49 for GIM 

(although the confidence intervals are very wide for that estimate); perceiving reimbursement as 

a major barrier with and odds ratio of 2 for FM; having a low volume of patients with private 

insurance; and being in a rural location. The only factor that was associate with stocking and 

administering the vaccine among the items checked were having knowledge of the claims 

submission and reimbursement process with an odds ratio of 2 for both specialties, which is 

likely to be a circular issue as they are likely to know about if they are doing it. Also tested but 

not found to be significant in these models were a variety physician demographic issues (e.g., 

age, gender, demographic issues, graduation year) and practice characteristics (e.g., region, 

type, urbanicity). In terms of the likelihood that physicians would provide HZV if covered under 

Medicare Part B, 49% of practitioners said they would be much more likely to provide the 

vaccine, 27% said they would be somewhat more likely to provide it, and 24% said it would not 

change their practice.

There are some important strengths and limitations to these studies. With regard to the 

strengths of this study, this represented the first survey to assess physician perceptions of the 

HZV post-licensure and the response rate was high. However, the limitations are that 

respondents may have differed from non-respondents, sentinel physicians may differ from 

physicians overall (although previous data do not suggest that these differences are significant), 

analytic associations do not imply causality, and probably most importantly the survey results 

represent reported practice—actual practice was not observed in this study.

In terms of the summary of findings, although roughly half of physicians report stocking and 

administering the vaccine, the number of patients to whom they administer is generally small. 

Multiple delivery methods are being used, some of which may jeopardize the integrity of the 

vaccine and compromise vaccine delivery in the medical home. Although most physicians felt 

that the vaccine was safe, effective, and important, the reported strength of recommendation 

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compared to other routine adult vaccines thus far is low. Only 45% of providers knew that HZV 

is reimbursed through Medicare Part D. Providers appear to be turning to their patients to 

determine coverage and rarely report taking responsibility for that aspect, and reported that the

reimbursement process for Medicare Part D was more complicated than for private insurance. 

The most frequently reported barriers to vaccination were financial. However, in multivariate 

analyses controlling for physician and practice characteristics, those who identified the need for 

freezer storage and the up-front costs of the vaccine as major barriers were the least likely to 

stock and administer the vaccine. 

Thus, barriers to optimal adoption of HZV may include lack of uniform support from physicians; 

lack of knowledge regarding reimbursement; perception that the reimbursement process 

through Medicare Part D is complicated; reliance on patients to determine coverage; and 

physicians’ concerns regarding upfront cost, reimbursement problems, and freezer storage. 

Approaches to optimizing HZ vaccine delivery should include education regarding appropriate 

delivery methods and a focus on solutions to financial and billing problems, such as the 

inclusion of HZV coverage under Medicare Part B; promotion of provider use of eDispenseTM, 

simplification of the claims process under Medicare Part D; and increased reimbursement for 

vaccine and administration. 

Discussion

Given the previous day’s discussion pertaining to refrigeration and freezers in pediatrician and 

family medicine practices, Dr. Morse wondered what kind of obstacles this posed for internists 

with respect to storage and types of freezers used. 

Dr. Kempe responded that the survey basically shows that internists are more concerned than 

family medicine doctors about the freezer issue. It is a major barrier. However, the survey did 

not specifically inquire about the type of storage the practices have.

Dr. Marcy asked whether the investigators examined what was occurring at Kaiser in Denver 

and Northern and Southern California where there are no financial barriers to speak of, freezers 

are not an issue, and claims are not of concern. 

Dr. Kempe responded that they had not, although she supported the idea. Their particular 

database does not include a large number of HMOs because it is sampled in the same way as 

the organizations. While they could certainly examine the HMO population, it would probably be 

better to go directly to the HMOs.

Dr. Temte was struck within his own patient population of the knowledge of seniors about this 

vaccine. Overwhelmingly, most of his patients have heard about it and want it. However, he 

had to create a phrase in his EMR that can be entered easily for this vaccine, which is 

“economic deferral.” This is a vaccine that he is not providing to patients because they cannot 

afford it. Increasing numbers of his patients lack the resources to afford this vaccine. This is a 

crucial issue because this is the one vaccine of those he provides that he provides in a very 

inequitable manner. 

Dr. Neuzil stressed that this is a horrible disease for which there is a safe and effective vaccine. 

This illustrates that the adult immunization system is broken. The Shingles Prevention Study 

was conducted as a VA cooperative study. The VA has an electronic medical record and cost is 

removed as a financial barrier, so it would be a wonderful place to also examine some of these 

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same attitudes. She expressed her hope that the results presented by Dr. Kempe would be 

published and in the public domain very quickly.

Dr. Hahn had heard from providers that they are aware that efficacy declines with age; 

therefore, the comfort level is greater for a strong recommendation for someone 60 years old 

than 80 years old. She wondered whether this was considered. 

Dr. Kempe responded that they did consider strength of recommendation for certain subgroups, but did not find any major differences for the perception of effectiveness for those over 

80 years of age.

Dr. Harpaz highlighted how important it is to vaccinate the oldest of the old because not only are 

they are the ones who disproportionately bear the longer duration and more severe disease, but 

also they have less resources, are more frail, are less able to tolerate the disease, are less able 

to tolerate the medications used to treat post-herpetic neuralgia, et cetera. 

With regard to the efficacy of the vaccine, Dr. Plotkin pointed out that the CD-4 T-cell response 

is a probable surrogate as shown in the VA study. In addition, a good deal is known about 

immunosenescence and the immune response profile; that is, distinguishing the elderly who can 

or cannot respond immunologically. This is crucial with respect to the economics, given that if it 

makes no sense to vaccinate a frail elderly individual at 75, this should be known. Therefore, it 

is very important to conduct studies regarding the response in different classes of elderly using 

the immunologic tests that are known to correlate with immune response in the elderly so that 

response to the HZV can be predicted to tailor the recommendations more carefully. While not 

against the vaccination itself, when making a choice about who should be vaccinated, a 

correlation should be made with immune status. 

Dr. Harpaz responded that of the different correlates studied, none really performed very well. 

Although the efficacy against zoster per se in persons 80 years and older was not very good 

(18%), considering the very high burden of post-herpetic neuralgia amongst that 18% and the 

fact that they are not able to tolerate disease or perhaps seek medical attention or tolerate the 

medications as easily, in terms of population and the burden of disease, in the broadest sense, 

prevented, he would argue that those 80 and over should be the first ones targeted. 

Florian Schodel (Merck) agreed that the efficacy against the severe consequences of zoster is 

fairly high in the elderly; whereas, the efficacy against herpes zoster is less high in terms of the 

simple incidence of herpes zoster. Given that proportionally the severe cases increase with 

age, the net effect is still pretty good. It is true that there is a correlation of immune response, 

but it is better for antibodies than for T-cell responses. While that may be a function of T-cell 

response, it is easier to measure which may be the reason it is easier to find. That is true for 

placebo and vaccine recipients. That is, if someone has a high antibody titer initially, they will 

have a lower likelihood of becoming a case than if they do not have a high titer. Unfortunately, 

there is not a cutoff so there is no test that could be administered to people to determine 

whether they would benefit from the vaccine.

Dr. Schmader indicated that his own institution decided not to stock this vaccine for all of the 

reasons Dr. Kempe mentioned and are referring people to a local community pharmacy. The 

Medicare Improvements for Patients and Providers Act (MIPPA) has extended benefits for a 

number of items, potentially vaccines. He wondered if that would perhaps provide a mechanism 

for adding HZV to Medicare Part B. 

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Dr. Harpaz responded that CDC is aware of the MIPPA legislation and is in the process of 

exploring the implications and whether it would change the payment for the HZV from Medicare 

Part D to Part B.

Dr. Foster reported that one of the greatest problems was the “donut hole” in co-pays because 

not only with vaccines in this particular case, but also with all prescription medication, 

prescription volume in most pharmacies is decreasing significantly because patients are not 

taking their medications due to the payments they are having to make. Pharmacists who go 

through this program probably have as much if not more training in giving vaccines and 

vaccinology than probably any other healthcare professionals. In 49 states, pharmacists are 

approved to administer vaccines, and are required to take approximately 20 additional hours of 

CE credit before they can qualify to do so. Pharmacists also do not experience too many 

difficulties with supply or storage issues. The cost is not an issue because there are far more 

prescriptions that cost much more. Their greatest problem is getting the physicians to 

understand that pharmacies are working with them rather than in competition. There are areas 

in the country in which physicians will not sign standing orders for pharmacists to administer 

vaccines. Pharmacists do not administer vaccines without a prescription or standing orders. 

Another mechanism that can be used is for physicians to write a prescription for their patients to 

have their vaccine administered by the pharmacist. As an organization and in teaching, APhA 

highly discourages “brown bagging.” Their pharmacists are told that it is appropriate if they 

have a delivery system through which they can deliver a frozen prescription to the physician’s 

office; however, they discourage giving a vaccine to a patient to take to a physician to be 

administered. He agreed with Dr. Temte that patients do want this vaccine, but when they 

realize the barriers, they defer. 

While Dr. Harpaz agreed that while most pharmacists were likely opposed to the practice of 

“brown bagging,” this was not universal. 

Dr. Kempe added that most of the physicians referring to a pharmacy were generally writing 

prescriptions. Based on what physicians were telling the investigators, “brown bagging” is 

occurring frequently. 

Dr. Lett thought what was presented was an accurate representation of what was being 

observed at the state level when visiting providers’ offices. Massachusetts has a strong 

partnership with pharmacists and has several pilot programs. She stressed that pharmacists 

are excellent partners for administering this vaccine because they have the knowledge and 

skills to do so. One thing she thought would facilitate vaccination outside the medical home in 

pharmacies, public health clinics, and mass vaccination settings would be standardized 

protocols for screening patients (e.g., to determine who may be immunocomprised, et cetera). 

Perhaps some standing orders and screening forms would be beneficial with respect to 

operationalizing the administration of this vaccine. 

Dr. Judson thought it was fair to present this to older patients as them having approximately a 1 

in 6 chance of benefiting from the vaccine, with 50% efficacy and 30% risk. As others had 

implied, the greatest challenge in using this expensive vaccine with maximum cost-benefit 

impact was to learn more about why 30% obtain it and 70% do not. He declined to take the 

vaccine, which was offered to him free through Kaiser, because the 30 people in his family who 

made it into their 80s never had zoster. While he did not know what that meant genetically or 

immunologically, he typically looked to his ancestors to get some idea of what is in store for him. 

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With regard to the economic issue, John Grabenstein (Merck) reported that Zostavax® is one 

component of Merck Vaccine’s patient assistance program. That has been rolled out to private 

practices first, and have several projects in place using public clinics as well. Merck is at the 

point of shipping its 4 millionth dose, which when administered would bring the coverage of the 

indicated populations to approximately the 9% level. Merck is currently filling orders from the 

second half of January and should be caught up by summer. He agreed that “brown bagging” 

was not appropriate, and Merck councils against this practice. He encouraged everyone else to 

do the same. 

Dr. Neuzil clarified that 50% efficacy was against the rash, which was not what they were trying 

to prevent. Instead, they were trying to prevent post-herpetic neuralgia, which is closer to 70% 

efficacy, which is better maintained with age. 

Dr. Jeanne Santoli

CDC / CCID / NCIRD / ISD

Dr. Santoli presented vaccine updates for hepatitis B vaccines (pediatric and adult); hepatitis A 

vaccines; varicella-containing vaccines; and measles, mumps, and rubella vaccines. 

In February 2009, both US manufacturers experienced an inability to fill orders for pediatric 

hepatitis B vaccine, resulting in backorders. CDC has released doses from its monovalent 

pediatric hepatitis B vaccine stockpiles to each manufacturer to support private and public 

sector vaccine usage through March 2009. Merck expects supplies of pediatric 

RecombivaxHB® to be limited during 2009 and does not expect to return to full supply until 

some time in 2010. Additional vaccine may be available in the second quarter of 2009. GSK 

expects to be able to meet the US market demand for monovalent hepatitis B vaccine through 

the end of May 2009, and is working closely with CDC to determine how much additional 

monovalent hepatitis B product can be supplied for the US market for the second half of the 

year should the shortage persist. Their combination product that contains hepatitis B, 

PediarixTM, is another option for hepatitis B vaccination. Based on current supply projections, 

there is no change in the recommendations for the use of pediatric hepatitis B vaccine at this 

time. Obviously, it will be imperative to work closely with the vaccine manufacturers, the ACIP, 

and other stakeholders should the situation change.

In December 2008, Merck communicated with CDC that it expected to deplete available 

supplies of the adult and dialysis formulations of RECOMBIVAX HB® in the first quarter of 2009. 

Merck does not expect to return to full supply of the adult and dialysis formulations of 

RECOMBIVAX HB® until some time in 2010. The supply of GSK’s adult hepatitis B vaccine 

(Adult Engerix-B®) and adult hepatitis A/hepatitis B combination vaccine (Twinrix®) is sufficient 

to meet US market demand for usage of this vaccine, including routine use and CDC's on-going 

High Risk Adult Hepatitis B Initiative in state and local health departments. Based on current 

supply projections, there is no change in the recommendations for the use of adult hepatitis B 

vaccine. 

With respect to hepatitis A vaccines, Merck’s pediatric formulation of Vaqta® became available 

again in December of 2008. Merck’s adult formulation is currently not being distributed, but may 

be available in the second half of 2009. GSK’s production and supply of adult hepatitis A 

vaccines (Adult Havrix®) and adult hepatitis A / hepatitis B combination vaccine (Twinrix®) are 

Vaccine Supply

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currently in good supply to meet demand. Based on current supply projections, there is no 

change in the recommendations for the use of hepatitis A vaccine. 

The current and projected supply of single antigen varicella vaccine is sufficient for anticipated 

demand in 2009, including the second dose catch-up. Distribution delays for zoster vaccine 

have become shorter, and Merck expects to clear backorders during the first quarter of 2009 

and return to normal shipping times in mid-2009. MMR-V vaccine will not be available during 

2009.

In December 2008, Merck communicated with CDC that it would not be producing or taking 

orders for its monovalent measles, mumps, or rubella vaccines. Merck is currently prioritizing 

the production of M-M-R® II over the monovalent components of the vaccine, and has not yet 

made a decision about the future availability of these monovalent vaccines. 

Discussion

Dr. Pickering pointed out that CDC’s vaccine shortage link is updated in real-time. When there 

is knowledge about a shortage, it is immediately entered. This section also includes links to any 

interim recommendations that have been made while shortages are in effect. The URL for the 

shortage page is http://www.cdc.gov/vaccines/vac-gen/shortages/default.htm. 

Dr. Moore (Tennessee Department of Health) pointed out that the issue with the single antigen 

hepatitis B vaccine for children is being exacerbated by the need to use Pentacel® due to the 

Hib shortage. That is, the use of single antigen hepatitis B is having to be increased to pair that 

with Pentacel®, so PediarixTM does not work due to having to deal with Hib. This is a practical 

issue faced at the local and state level.

Dr. Santoli agreed that the use of combination products changes the use of single antigens, and 

sometimes not completely in sync as providers are determining exactly how much they need of 

each of the components. CDC realizes that the situation is confusing, especially when there are 

multiple combinations that have some overlap. This is why they have been focusing on the 

monovalent supply and doing what they can to release doses of CDC’s stockpile to make 

monovalent vaccines available. GSK is explicating considering the issue of monovalent vaccine 

because they know that this is what CDC has requested, given that the agency believes this 

would minimize the confusion that already exists.

Dr. Whitley-Williams requested that Dr. Santoli comment on the use of monovalent mumps and 

rubella, particularly given that some parents are choosing not to have their children immunized 

with measles vaccine. She wondered if requests for monovalent antigens by some parents 

were affecting the supply. 

Dr. Santoli responded CDC has engaged in discussions with Merck about the use of 

monovalents, which is fairly modest. The issue around that decision is not that demand has 

increased dramatically for those products, but rather is that it is much more efficient to make the 

combination. Even making a small amount of monovalent impacts how much combination 

product can be made. Her sense was that this was the reason the focus was on the 

combination. 

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Dr. Feinberg (Merck) replied that use of monovalent products is very limited, and these have 

gone in and out of stock over the past few years. Therefore, it has not been a reliably available 

product on the market. Indeed, production of monovalents mitigates against the maximized 

production of the combination M-M-R® II vaccine. Given the importance of ensuring the supply 

of M-M-R® II in the US as well as the growing global demand for combination M-M-R® II

vaccines, Merck prioritized M-M-R® II. A final decision about bringing monovalent vaccines 

back to the market has not yet been made. Merck is in the process of seeking extensive 

stakeholder feedback about that. To the best of Merck’s understanding, there is no independent 

public health rationale for use of monovalents; however, it remains an important question to 

address. 

Dr. Morse wondered whether CDC was easily able to replenish the stockpile financially when it 

is tapped, and whether consideration was being given to expanding the stockpile with stimulus 

funding. 

Dr. Santoli replied that typically the stockpile loans the doses to the manufacturers so they can 

use them to fill orders—CDC’s orders as well as private sector orders. Manufacturers repay the 

doses when they are able to do so. It does not mean that additional doses must be purchased. 

For short-term problems, CDC receives the vaccine back quickly. For the Hib shortage, the 

stockpile will not be rebuilt until there is enough vaccine on the market to meet the demands for 

vaccination. With regard to the stimulus funding, CDC’s stockpile funding is a VFC-supported 

program, while stimulus funding is a different source of funding. At this point, consideration for 

the stimulus funds is directed more toward routine use. The stockpile does have other options 

within the VFC program, which supports the building up of stockpiles. 

Dr. Marcy pointed out that the shortage appeared to be primarily related to shortages of Merck 

products.

Dr. Feinberg (Merck) responded that Merck sincerely regretted any supply issues for which they 

were responsible. The issues being cited are all valid concerns, although they each were 

independent episodes with independent issues. Merck is making significant investments to 

ensure the capacity and stability of its vaccine manufacturing processes. They take this very 

seriously and regret any public health issues and inconveniences that have accrued as a result 

of these shortages. They are doing their best to bring all of these vaccines back to the market 

in a stable and reliable manner.

Dr. Lett expressed concern about issues occurring with not giving hepatitis B and people not 

being able to switch back to PediarixTM. Of Massachusetts providers, 80% are using Pentacel®

and 20% are using PediarixTM. Their vaccine unit said that it was like “turning a battleship on a 

dime” to prevent any Hib shortage in the state. To ask providers to switch back will be difficult. 

She anticipated children not receiving doses of hepatitis B just like children are currently not 

receiving Hib doses.

Dr. Santoli responded that this is why CDC has requested that manufacturers look at the 

monovalent supply that could be brought in. Given the situation, that is probably the vaccine 

needed to ensure that children are fully protected moving forward. She said she mentioned 

PediarixTM because it does contain hepatitis B, but manufacturers are currently considering how 

much monovalent they can bring to the market. 

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Introduction

Jonathan Temte, MD, PhD

University of Wisconsin

Chair, MMRV ACIP Vaccine Safety Working Group

Dr. Temte introduced the ACIP Vaccine Safety session. Since forming last summer, the MMRV 

ACIP Vaccine Safety Working Group has been meeting on an every two week basis. This 

working group has had a very ambitious schedule, and has received a great deal of excellent 

input from numerous consultants. The group hopes by June 2009 to have a comprehensive 

product to present to the full ACIP with regard to policy options for MMRV vaccine use. 

Update on Work Group Activities for 

Developing Policy Options for MMRV Vaccine Use

Mona Marin, MD

CDC / CCID / NCIRD / DVD

Dr. Marin provided a brief background regarding the MMRV Vaccine Safety Working Group. 

Pre-licensure MMRV data indicated significantly more fever after MMRV vaccine than after 

MMR and varicella vaccine administered at the same visit–0-42 days post-vaccination (22% 

versus 15%) usually within 5-12 days post-vaccination. Two post-licensure studies were 

initiated to assess the risk for febrile seizures, which included a Vaccine Safety Datalink (VSD) 

study and a Merck-sponsored study. In February 2008, preliminary information from both 

studies suggested an increased risk for febrile seizures during the first through second weeks 

after the first dose of MMRV vaccine among children aged 12 to 23 months. Based on these 

findings, ACIP recommended removing the preference for MMRV vaccine over separate 

administration of MMR and varicella vaccines, and forming an ACIP MMRV Vaccine Safety 

Working Group.

The MMRV Vaccine Safety Working Group terms of reference were to conduct a risk 

assessment, on which CDC / ISO is the lead, to evaluate post-licensure safety data on risk for 

febrile seizures after MMRV vaccine, identify data gaps, and propose additional analyses or 

studies; to review encephalitis cases reported after MMRV vaccine; and to communicate 

vaccine safety findings related to MMRV vaccine with ACIP and the public in a clear and 

transparent manner. The activities for this term of reference are in progress. An interim 

synthesis of evidence for febrile seizure risk after MMRV vaccine was presented during the 

October 2008 ACIP meeting. The working group was also tasked with addressing risk 

management, on which CDC / DVD is taking the lead, to formulate policy options for use of 

MMRV vaccine for ACIP, considering benefit of vaccination and risks of vaccine adverse events; 

and identify and reconcile potential inconsistencies in ACIP statements related to measles, 

mumps, rubella, and varicella vaccination and febrile seizure prevention. Activities for this term 

of reference have begun in November 2008. MMRV vaccine is not currently being distributed in 

the US and is not expected to be available in 2009. 

MMRV Vaccine Safety

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As presented during the ACIP meeting in October 2008, for the first term of reference to assess 

the evidence for febrile seizure risk, the working group developed an evidence framework that 

incorporated criteria using other frameworks, and which considers three separate lines of 

evidence for risk: clinical importance of the event (febrile seizures), population-based risk, and 

biological plausibility. The clinical importance of the event was to be assessed after the October 

2008 ACIP meeting; requires consideration of medical impact and perceived severity of adverse

event following immunization (AEFI). To address the population-based risk, the epidemiologic 

evidence was assessed regarding a possible causal relationship between vaccine exposure and 

the AEFI. The biological plausibility of the association between the immunization and the AEFI

should be explicable biologically according to known facts in the natural history and biology of 

the disease, antigen, and / or host response [This framework was adapted from criteria used by 

the IOM, WHO, and draft guidance from the ACIP Evidence Based Recommendations Working 

Group].

The table summarizing the core epidemiologic data presented as part of the interim synthesis at 

the October ACIP meeting was discussed. VSD and Merck-sponsored studies compared the 

rates for confirmed febrile seizures after Dose 1 of MMRV versus rates after separate MMR and 

varicella vaccines administered simultaneously (MMR+V). VSD found a statistical significant 

increased risk for febrile seizures within 7 to 10 days post-vaccination with an odds ratio of 2.3 

and attributable risk of 5.2 per 10,000 doses. VSD did not conduct chart reviews to confirm 

febrile seizures during the later period after vaccination (weeks 3-4). The Merck-sponsored 

study had similar findings for 5 to 12 days post-vaccination, with a statistically significant 

increased risk for febrile seizure with a relative risk of 2.2 and an attributable risk of 3.8 per 

10,000 vaccinations. Merck did confirm febrile seizures in the later period, and found nonsignificant decreased risk during the 13 to 30 days following vaccination in the MMRV group 

compared to the MMR+V group, and found no statistically significant difference in the risk for 

the overall 0 to 30 post-vaccination between the two groups. 

After reviewing the epidemiologic evidence, as well as the biological plausibility line of evidence, 

the working group made two interim conclusions regarding the risk for febrile seizure after Dose 

1 of MMRV vaccine. Compared with separate Dose 1 injections of MMR and varicella vaccines

administered at the same visit, the evidence supports a causal relationship between receipt of 

Dose 1 MMRV vaccine and increased risk for febrile seizures during the 5 to 12 days after 

vaccination. The magnitude of the risk is approximately two-fold. During the 5 to 12 days after 

MMRV vaccine, 1 additional febrile seizure is expected to occur per approximately 1,900 to 

2,600 children vaccinated. Compared with separate Dose 1 injections of MMR and varicella 

vaccines administered at the same visit, the evidence is insufficient to accept or reject a

conclusion that Dose 1 MMRV vaccine is associated with a decreased risk for febrile seizures 

during the 13 to 30 days after vaccination. Therefore, the evidence is also insufficient to accept 

or reject a conclusion that children receiving Dose 1 MMRV vaccine have no overall increased 

risk for febrile seizures during the 0 to 30 days after vaccination. 

With respect to activities performed following the October 2008 ACIP meeting, VSD has 

expanded its study to conduct a cohort study to assess risk for confirmed febrile seizures after 

Dose 1 MMRV vaccine in the 0-42 day post-vaccination period. The initial VSD study only 

confirmed febrile seizures during the 7-10 day post-vaccination period. The study population 

includes the more recently vaccinated children aged 12–23 months who received MMRV or 

MMR+V during the same visit. MMRV is a contemporary cohort of children vaccinated between 

January 2006 and October 2008, while the MMR+V group continues to be a largely historical 

cohort with children vaccinated from January 2000 to October 2008. The study is for Dose 1 

only [Information provided by Dr. N. Klein, Principal Investigator VSD study].

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The methods for the VSD expanded MMRV epidemiologic study are identical to what was 

previously presented to the committee. Febrile seizure identification will be made by using 

seizure codes in automated data during the 42 days after MMRV or MMR+V. The ICD-9 codes

include: 345.* (epilepsy) and 780.3* (convulsions, febrile convulsions, other convulsions). The 

study is limited to an emergency department or a hospital visit, and to children with no seizure 

diagnosis of any etiology in any setting in the previous 42 days. The case definition for the 

study is a diagnosis of febrile seizure in the chart. For confirmation of febrile seizures, chart 

review will be performed for all seizures occurring 0 to 42 days following MMRV, all seizures

occurring 7 to 10 days following MMR+V, and a random sample of seizures occurring 0 to 6 and 

11 to 42 days following MMR+V. Analyses will compare the risk for febrile seizures after MMRV

with that after MMR+V during different post-vaccination time windows comparable to the Mercksponsored study to allow for comparison of data. The post-vaccination windows include: 7-10, 

13-30, 0-30, and 0-42 days. [Information provided by Dr. N. Klein, Principal Investigator VSD 

study]. The working group plans to present the results of this study during the June 2009 ACIP 

meeting. 

Another update on risk assessment refers to assessing the risk for febrile seizures after Dose 2 

of MMRV versus MMR+V vaccines. The risk after Dose 2 was not an initial objective of either 

VSD or Merck-sponsored studies, and only automated data were available. They include codes 

for seizure and epilepsy. Very few seizures were reported in either study. As presented during 

the October 2008 ACIP meeting, the rates between the MMRV and MMR+V groups were not 

statistically different. In addition, febrile seizures are less common in children 4 to 6 years of 

age compared with children aged 12 to 23 months. The working group is currently assessing 

the risk for febrile seizure after Dose 2 MMRV, with several updates since October 2008. There 

are now data from 7 VSD sites as of October 2008. During the 7-10 days after dose 2 

vaccination, the following was observed: 4 seizures were identified among 84,653 MMRV 

recipients; the same number of seizures as previously reported but with an increase of 

approximately 50% in the number of doses administered; and 0 seizures were identified among 

61,489 MMR+V recipients, an increase of approximately 40% in the number of doses 

administered. Of the 4 seizures reported after MMRV, a review of charts showed that three 

were not febrile seizures [Information provided by Dr. N. Klein, Principal Investigator VSD 

study].

The working group has several other safety activities underway to finalize the safety 

assessment according to the evidence framework, including discussions of the clinical 

importance of febrile seizure in consultation with experts, with medical and psychosocial impact 

considered; assessing the population-based risk for each relevant age group and the biological 

plausibility of febrile seizure patterns after MMRV and MMR+V. A review of the two encephalitis 

cases reported in VSD after MMRV vaccine is underway and is being performed by two 

independent pediatric neurologists using the Brighton Collaboration case definition [SejvarJJ et 

al. Vaccine. 2007].

Regarding the working group’s second term of reference, risk management, the group 

developed an analytic framework for policy discussions that includes: 1) vaccine safety (febrile 

seizures and other important events); 2) burden of disease to prevent, including influence of 

vaccine coverage for measles, mumps, rubella, and varicella burden of disease; 3) efficacy / 

effectiveness and immunogenicity; 4) program implementation (e.g., storage conditions, number 

of injections); 5) social expectations / perceptions (current context of parent and provider 

perceptions regarding general safety issues and febrile seizure, which has some overlap with 

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risk assessment); 6) equity in access to vaccine and use of public funds; and 7) 

recommendations of other groups (e.g., AAP, AAFP). The working group welcomed 

suggestions from the committee for additional elements to consider for the analytic framework.

In terms of the process for arriving at a working group decision, the first priority will be to discuss 

policy options separately for MMRV vaccine for Dose 1 and Dose 2 at routinely recommended 

ages because both the data available and the epidemiology of febrile seizures is different at the 

routinely recommended ages for Dose 1 and Dose 2. The recommended age for Dose 1 is 12

to15 months and for Dose 2 is 4 to 6 years. The working group will formulate policy options for 

the general population of children. The second priority will be to discuss policy options for 

MMRV vaccine for Dose 1 and Dose 2 separately, but at ages other than those routinely 

recommended, and to discuss special considerations for MMRV vaccine use for children at 

higher risk for febrile seizures (e.g., those who have had previous seizures, family history of 

seizures, and other situations identified by the working group). For each of these scenarios, the 

working group will assess the evidence for each element of the framework, discussing the 

evidence for MMRV and for separate MMR and varicella vaccines. The working group will 

attempt to assess the quality of evidence for each element, the difference in benefit or risk of 

MMRV versus separate MMR and varicella vaccines [Assessment based on guidelines of the 

ACIP Evidence-Based Recommendations Working Group and US Preventive Services Task 

Force], and assess and synthesize the evidence across the entire analytic framework. The 

conclusion will be a value judgment of the working group rather than a sum of each element 

assessment. Based on that, the working group will make recommendations for policy options 

for MMRV vaccine use to be considered by ACIP for a vote. 

The policy options currently under consideration by the working group are separate policy 

options for Dose 1 and Dose 2 MMRV vaccine include (presented in no particular order): 1) No 

preference for MMRV versus separate injections of MMR and varicella vaccines (the current 

recommendation [CDC. Update: Recommendations from the Advisory Committee on 

Immunization Practices (ACIP) Regarding Administration of Combination MMRV Vaccine. 

MMWR. 57(10);258-260]; 2) Preference for MMRV versus separate injections of MMR and 

varicella vaccines; 3) Preference for separate injections of MMR and varicella vaccines versus

MMRV use; and 4) MMRV not recommended; separate injections of MMR and varicella

vaccines recommended. 

The current ACIP recommendations for MMRV vaccine use voted on in February 2008 state, 

"Combination MMRV vaccine is approved for use among healthy children aged 12 months-12 

years. MMRV vaccine is indicated for simultaneous vaccination against measles, mumps, 

rubella, and varicella. ACIP does not express a preference for use of MMRV vaccine over 

separate injections of equivalent component vaccines (i.e., MMR vaccine and varicella vaccine)" 

[Update: Recommendations from the Advisory Committee on Immunization Practices (ACIP) 

Regarding Administration of Combination MMRV Vaccine. MMWR. 57(10);258-260].

In regard to the proposed timeline for working group activities, during the June 2009 ACIP 

meeting, the group expects to present the following: results from the VSD Dose 1 expanded 

epidemiologic study; a final safety evidence assessment; a synthesis of evidence for the policy 

framework; and the working group’s recommendations for policy options for MMRV vaccine use 

for a proposed ACIP vote. 

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Discussion

Having been in private practice during at least two brief shortages of varicella-zoster viruscontaining vaccine within the past year (varicella vaccine and zoster vaccine), and realizing how 

difficult shortages are in a practice that is required to recall patients, Dr. Chilton wondered 

whether it was justifiable to put more varicella virus into an MMRV vaccine when there is a 

shortage of varicella-zoster virus-containing vaccines. 

Mark Feinberg (Merck) responded that to be clear, there is not a shortage of the monovalent 

varicella vaccine. There is an adequate supply to meet the current ACIP recommendations for 

Doses 1, 2, and catch-up immunization. The reason that Merck has made certain decisions to 

prioritize the monovalent varicella at the expense of ProQuad® (MMRV) or Zostavax® (zoster 

vaccine) was due to the public health priority for varicella prevention. The issues regarding how 

to proceed will be determined by what the best public health recommendations that arise from 

the ACIP and the best way for Merck to allocate the supply of varicella-zoster virus-containing 

products are to ensure that the range of medical needs that are addressed by these vaccines is 

met. Merck has made significant efforts to ensure the availability of varicella-zoster viruscontaining vaccines to meet the childhood immunization recommendations. 

Regarding the framework for policy decisions, Dr. Englund pointed out that public relations and 

publicity were not included, although these are important activities. Many outbreaks are due to 

parental refusal rather than shortage issues.

Dr. Temte thought under social expectations and perceptions this was very clear. From the 

outset, safety and risk have been elevated in this working group by the very nature of the group. 

Formulation of policy should be done in a clear and transparent manner not only to help 

partners in clinics, but also to provide reassurance to the population. An internal AAFP survey 

found that one leading barrier for appropriate immunization was the concern that patients and 

parents have for the safety of the vaccine.

Dr. Marin added that the discussions regarding social expectations and perceptions pertained to 

better understanding of trends in vaccine exemptors and reasons for choosing exemption from 

vaccination. 

Dr. Seward indicated that for the first dose the risk was an extra febrile seizure for every 2000 

doses MMRV administered compared with MMR+V. For the second dose, there is likely no 

risk.. 

Tamara Lewis (AHIP) noted that in the current recommendations, according to the footnote, 

providers are allowed to give Dose 2 three months following Dose 1. The providers in her area 

have elected that choice with the increase in measles and varicella circulation to cover children 

earlier and achieve higher rates. Consideration is being given to giving Dose 2 along with 

hepatitis A at its Dose 2 visit, which would be 18 to 24 months. With that in mind, she requested 

that the working group take this age group into consideration as well for Dose 1 and 2.

Dr. Marin responded that they would consider this, but the three-month interval for Dose 2 

MMRV is driven by the interval between the two varicella doses. In the varicella statement, the 

emphasis is to give the second varicella dose at 4 to 6 months with a permissive language to 

give it three months after the first dose. The recommendations will reflect that. The age 

routinely recommended will not be changed. 

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Dr. Temte added that this would be a consideration, but not an evidence-based one given that 

there is not sufficient data that would inform the working group either way in terms of the risk for 

a second dose at an earlier interval.

Dr. Marin indicated that there may be some data from clinical trials on febrile seizures from 

Dose 2 given at 15 to 26 months of age, but the numbers will be small. 

Florian Schodel (Merck) reported that Merck has extensive second dose data for fever, which 

are available and some of which are published. If not published, Merck can supply these data. 

If this is at all linked to fever, the second dose should not pose the same risk because there is 

no risk of fever. 

Dr. Temte indicated that along that line, the working group had the privilege of reviewing data 

also from the VSD with regard to fever specifically following a second dose. The working group 

found that to be very reassuring as well.

Dr. Broder indicated that she was not aware of data that would specifically address the issue of 

second dose use in the younger age group under age 2. 

It appeared to Dr. Judson that there was no difference. The numerators are obviously small to 

be slicing them into 5- or 7-day or other intervals. In the 0- to 30-day period, there is no 

difference. Thus, it could be speculated that if there really is a difference in the first 5 to 12 

days, the few people who are prone or susceptible to febrile seizures might have been triggered 

early in the period and therefore were not available later in the period for other causes of febrile 

seizure. Perhaps one could argue for a compensatory decrease during the second two or three 

weeks. At any rate, the differences are trivial over a 30-day period. 

Dr. Marin clarified that they have data from only one study examining 0 to 30 days. The working 

group is waiting for results from the VSD study to make a final conclusion about 0 to 30 days in 

general.

Dr. Katz (IDSA) disagreed with Dr. Judson, pointing out that during the 5 to 12 days after MMRV 

vaccine, 1 additional febrile seizure is expected to occur per approximately 1,900 to 2,600 

children vaccinated. If 3 million children are receiving this vaccine, this translates to 1,500 

children having febrile seizures nationally. That is significant, not miniscule. 

Dr. Judson noted that with the Merck side, there was a statistically significant underrepresentation with regard to the 30-day period. 

Dr. Temte interjected that the Merck study was not significant, and the conclusion of the working 

group was that there was not sufficient evidence for or against making a statement of a 

compensatory decline.

To keep this in some perspective, Dr. Marcy pointed out that the incidence of febrile seizures in 

children is 3% to 5%; that is, 3 to 5 out of every 100 children will at some time in the first five to 

six years of life have a febrile seizure. While he was not questioning that there is a relationship 

temporally, he thought they should keep this in mind. 

Dr. Judson stressed that his point was that the background is high.

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Florian Schodel (Merck) indicated that in clinical studies more febrile seizures are observed than 

in observational studies. In the randomized blinded studies they did not have enough power to 

exclude an increase in febrile seizures, but they saw equal distribution between MMRV and 

MMR+V.

Provider Survey Regarding Opinions on the Use Of MMRV Vaccine 

Allison Kempe, MD, MPH 

Professor, Pediatrics

University of Colorado Denver

Dr. Kempe explained that the study objectives for the survey regarding provider opinions 

pertaining to MMRV vaccine were to determine, in nationally representative samples of family 

medicine (FM) and pediatric (Peds) physicians, 1) knowledge regarding increased risk of febrile 

seizures with use of MMRV vaccine and ACIP’s removal of preference for administering MMRV 

over separate MMR and Varicella (MMR+V) vaccines; 2) perceptions regarding severity of 

febrile seizures; 3) intended practice regarding recommending MMRV versus separate MMR+V 

vaccines in light of data regarding post-vaccination seizures; and 4) barriers and important 

factors in the decision to use MMRV vs. MMR+V vaccines. 

The study population included family medicine and pediatric physicians who were part of 

existing sentinel networks, recruited from random samples from AAFP and AAP. Quota 

sampling was done to ensure that the networks were similar to overall AAFP and AAP 

memberships. A previous study compared the sentinel networks to randomly selected 

physicians sampled from AMA (most commonly used survey method) and found results 

comparable with respect to physician demographics, practice characteristics, and responses on 

surveys regarding vaccine-related issues [Crane LA, Eval& Health Prof, 2008]. Respondents 

practicing less than 50% in primary care practice were excluded. The survey was pilot-tested in 

a community advisory panel including 6 pediatricians and 6 family medicine physicians from 

throughout the US. The survey period was from October 2008 to January 2009. 

With regard to survey administration, physicians were sent a survey based on their preferred 

method (e.g., mail or internet-based). Those who preferred mail received an initial mailing and 

up to two mail reminders, while those who preferred internet-based received an initial e-mail and 

up to eight e-mail reminders, with a final mailing to non-respondents by e-mail. In the survey 

instrument, physicians were provided with informational paragraphs about the post-licensure 

studies showing an increased risk of febrile seizures 5 to 12 days after MMRV compared to 

MMR+V in 12- to 15-month old children; ACIP’s removal of the preference for MMRV 

combination vaccine because of these data; and the fact that no data were available regarding 

risk of seizures following MMRV in 4- to 6-year old children. Physicians were first asked their 

baseline knowledge of risk of febrile seizures related to MMRV or MMR+V and of ACIP’s 

removal of preferences for MMRV prior to reading the provided information. Physicians were 

then asked to respond to all questions regarding vaccination practices with the assumption of 

adequate supply of MMRV, MMR, and varicella vaccines. 

There was a 73% response rate overall, with 71% for FM (299 of 424) and 76% for pediatricians 

(321 of 425). The pediatrician respondents were not significantly different from nonrespondents with respect to gender, birth year, urban / rural location, region, and type. 

Compared to non-respondents, FM respondents were more likely to be female, more likely to be

from rural locations, and less likely to be from the South. Of the respondents, 43% of FM and 

74% of pediatricians reported offering the MMRV vaccine in the past two years. With regard to 

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the awareness of increased febrile seizure risk after MMRV, 26% of FM and 71% of 

pediatricians among all MDs and 30% of FM and 74% of pediatricians among MDs who offered 

MMRV were aware of the increased risk. Among all MDs, 18% of FM and 65% of pediatricians 

were aware of ACIP’s removal of the preference for MMRV, while 26% of FM and 67% of 

pediatricians among MDs who offered MMRV were aware of this removal.

In terms of intended practice in healthy 12 to 15 month old children, given the data provided to 

them regarding risk for febrile seizures, of FMs 43% reported that they would definitely 

recommend separate MMR+V, 24% reported that they would probably recommended separate 

injections; together 67% of FM indicated that they either probably or definitely would 

recommend separate injections given this data. Another 24% would allow the parents to 

decide, while 9% would either definitely or probably recommend the MMRV vaccine. Among 

pediatricians, 35% reported that they would definitely recommend a separate MMR+V, and 24% 

would probably recommend separate MMR+V. Together 59% would definitely or probably 

recommend MMR+V, 20% would let parents decide, and 21% would either definitely or probably 

recommend MMRV. 

Regarding intended practice in 12 to 15 month old children with a history of febrile seizures, 

much higher percentages among FM and pediatricians would definitely recommend MMR+V 

separately (79% of FM, 71% of pediatricians); 15% of FM and 20% of pediatricians would 

probably recommend separate injections. In terms of intended practice in 12 to 15 month old 

children with known or suspected seizure disorder, 83% of FM and 72% of pediatricians would 

definitely recommend MMR+V. With respect to intended practice in healthy 4 to 6 year old 

children, given the lack of data, among FM 36% would definitely recommend MMR+V 

separately, 19% probably would, together 55% would definitely or probably use MMR+V, 25% 

would let parents decide, and 20% would definitely or probably recommend MMRV. Among 

pediatricians, 23% would definitely recommend MMR+V, 18% would probably recommend 

separate injections for a total of 41% in these categories, 21% would let parents decide, and 

38% would definitely or probably recommend MMRV. 

With respect to physician perceptions about the severity of febrile seizures, there are fairly 

notable distinctions between the specialties. Among FM physicians, 22% perceive febrile 

seizure to be a moderately serious event, 1% find it to be a very serious invent. In contrast, only 

8% of pediatricians consider a febrile seizure to be a moderate or serious event. A little over 

half of both specialties (57% of FM and 53% of pediatricians) consider febrile seizure to be 

mildly serious, while 20% of FM versus 39% of pediatricians consider this event to be not at all 

serious. Regarding physicians’ perception of parent attitudes of severity of febrile seizures, 

there is substantial agreement between the specialties that the vast majority of parents view a 

febrile seizure to be a very serious event (76% of FM, 56% of pediatricians). The 

preponderance of people who do not think it’s very serious think it is moderately serious (22% of 

FM, 36% of pediatricians). In terms of factors reported as very important to physicians in their 

decision to give MMRV versus MMR+V in 12 to 15 month old children, the percentages are 

substantially similar between the specialties, with only one significant difference between the 

two. The top most important factor was ACIP, AAFP, and AAP recommendations regarding this 

issue. Second were parental concerns for the risk of febrile seizures. Third was the amount of 

reimbursement for vaccine administration, which did differ between the specialties with 45% of 

pediatricians compared to 36% of family medicine physicians ranking this as a very important 

factor. These were followed by the cost of the vaccine to the practice, physician concerns for 

risk of febrile seizures, parent preference for fewer injections, the potential to improve varicella 

up-to-date rates, and the time spent discussing with parents safety issues related to MMRcontaining vaccines. 

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Regarding the results of a multivariate analysis the factors associated with recommending the 

MMRV vaccine to healthy 12-15 month olds were: potential to improve varicella up-to-date rates

with an odds ratio of 4.46 (95% CI 2.41-8.28); parent preference for fewer injections, odds ratio 

of 3.75 (95% CI 2.02-6.97); and physician specialty of pediatrics, odds ratio of 3.33 (95% CI 

1.70-6.55); variables tested and found not significant included: physician gender and age, 

practice setting and location, physician and parent perception of febrile seizures, vaccine cost, 

and amount of vaccine administration reimbursement. Factors associated with recommending 

separate MMR+V to healthy 12 to 15 month old children included physician concern for febrile 

seizures associated with an odds ratio of 8.73 (95% CI 5.07-15.04); and the importance of AAP

/ AAFP / ACIP recommendations in decision-making regarding MMRV versus MMR+V was 

associated with an odds ratio of 1.93 (95% CI 1.19-3.14). Variables tested and not significant

included: physician gender and age, practice setting, location, and region, physician and parent 

perception of febrile seizures, vaccine cost, and amount of vaccine administration 

reimbursement. 

In summary, most FM physicians were unaware of the increased risk of febrile seizures 

associated with MMRV and the change in ACIP recommendations. Most pediatricians were 

aware of both of these. FM physicians were more likely than pediatricians to feel that febrile 

seizures are very or moderately serious medical events (23% versus 8%). However, the 

majority (>90%) of both FM and pediatricians thought that parents perceive febrile seizures as 

either very or moderately serious events. Given the data provided regarding febrile seizures

risk after MMRV, only 9% of FM and 21% of pediatricians reported that they would give MMRV 

to healthy 12 to 15 month olds. Despite the lack of data, only 20% of FM and 38% of 

pediatricians would give MMRV to healthy 4 to 6 year olds. Factors correlated with the intended 

use of MMRV vaccine in healthy 12 to15 month olds included the potential to improve varicella

up-to-date rates and parent preference for fewer injections. Factors correlated with intended 

use of separate MMR+V vaccines in 12 to 15 month olds included increased physician concern 

for febrile seizures and the importance of AAP / AAFP / ACIP recommendations. 

There are important limitations to these data. No MMRV vaccine was available at the time of

the survey; therefore, some responses are theoretical. Information provided in the survey may 

have resulted in reporting bias, although reported rates of not being aware were quite high, so it 

is not clear that this case can be made. Respondents may have differed from non-respondents, 

although the response rate is high. Sentinel physicians may differ from physicians overall, 

although previous data do not suggest this. Most important, these survey results represent 

intended practice, some of which was based on new information, so actual practice may differ. 

Actual practice was not observed. 

In conclusion with respect to Dose 1 for children 12 to 15 months old, the majority of physicians 

report they would recommend MMR+V separately in this age group even if adequate supplies of 

MMRV were available. Concern about febrile seizure risk was the most important predictor of 

this behavior. With regard to Dose 2 for children 4 to 6 years of age, despite having no data on 

febrile seizure risk for this age group, more physicians would recommend MMR+V separately 

than MMRV vaccine. 

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Discussion

Dr. Seward noted that data on the second dose had become available since this survey was 

conducted and are reassuring with regard to there being no detectable risk of febrile seizure due 

to Dose 2. The risk of febrile seizures in that age group is much lower as well. 

Regarding the intended use, given that more than half of FM and about a quarter of the 

pediatricians had not used this vaccine at all in the previous two years, Dr. Sawyer pointed out 

that it appeared they had already decided not to recommend it presumably for a variety of 

reasons not just febrile seizure, since it is a more recently identified problem. With that in mind, 

he wondered if the investigators had examined the sub-set who had previously used the vaccine 

and if so whether they observed the same distribution of intended use.

Dr. Kempe’s guess was that many physicians who had not used the vaccine simply did not have 

any supply of it. It was not necessarily a conscious choice not to use it. They have not broken 

the results down by those who previously used the vaccine versus those who had not.

Dr. Sumaya noted that a single febrile seizure has a great deal of impact on physicians and 

families. It could cause a major disruption in seeking additional immunizations on the part of 

those who have been afflicted with this. Therefore, it is important to amass as much 

quantitative information as possible.

Dr. Marcy pointed out that one of the take-home messages may be that family physicians are 

simply not well-informed regarding vaccine problems such as this.

Dr. Temte replied that on the flipside, the spectrum of care is very different. For example, within 

the context of febrile seizures in children, it is a rare event since most of the children seen by 

family physicians are healthy. Parents are also being seen by family practitioners in the 

aftermath for sleep problems. The dynamic of the family may change for months following a 

febrile seizure. These things weigh into this as well.

Harry Keyseling (SHEA) observed that it would be interesting to distinguish why physicians 

choose not to give the second dose. Two possible reasons would be increased inventory 

control and the possibility of making a mistake. Even if there is no increased safety risk for the 

second dose, there are other consideration that might be worthwhile to understand.

Dr. Temte indicated that the working group had the opportunity to hear the results of a provider 

survey conducted by Merck.

Update on the Global Polio Eradication Initiative 

Steven Wassilak, MD

CDC / CCID / NCIRD / GID

During this session, Dr. Wassilak reported on the current status of progress toward polio 

eradication to inform the ACIP discussion on polio vaccination policy in the US, and discussed 

the challenges and the way forward. 

Polio Vaccine

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The Global Polio Eradication Initiative was established in 1988, after the Global Health 

Assembly voted to eradicate polio from the globe. The Global Polio Eradication Initiative

employs four key strategies, which include routine immunization, Supplemental Immunization 

Activities (SIAs), surveillance, and mop-ups in areas of high risk. Fecal specimens are collected 

from children who have paralysis and are tested in the laboratory. The Acute Flaccid Paralysis 

Surveillance is the system used. If a virus is found, it can be characterized and sequenced. 

Among the many families of viruses circulating in Nigeria from 2007 and 2008, three were 

selected to illustrate to ACIP where these are. Basically, families can be tracked to determine 

whether they are newly moving into an area, or if they have been in an area before, and how 

well they are promulgating. In 1988, there were 350,000 cases of paralytic polio in more than 

125 endemic countries. In 2008, there were 1655 laboratory-confirmed cases. Four endemic 

countries remain, including India, which borders Bangladesh. 

Since the resolution in 1988, there has been great progress with only four countries in which 

transmission has not been interrupted for Type 1and Type 3 poliovirus. Type 2 was interrupted 

successfully in 1999. From these four countries, however, there have been re-seedings into 

countries that had previously stopped transmission. There have been problems in up to 14 

countries in 2008, some of which have had very persistent transmission. In common for all 

countries with persistent transmission is weak health infrastructure and therefore poor routine 

immunization and limited other health structures to support supplementary immunization. With 

respect to a reduction in the number of polio-affected districts relative to the prior year, at the 

end of 2007, there was an overall reduction of 24%. The number of districts worldwide affected 

with Type 1 poliovirus dropped 59%. The status at the end of 2008 was an overall increase of 

36%. The number of districts worldwide affected with type 1 poliovirus increased 112%. 

Regarding the level of immunity against polio among children aged 6-35 months in affected 

districts, the status by the end of 2007 was that 2 of the 4 endemic countries achieved or are 

close to achieving at least the level in polio-free districts. By the end of 2008, 2 of the 4 

endemic countries had achieved or were close to achieving at least the level in polio-free 

districts. By the end of 2007, outbreaks were stopped in 10 of 13 countries (31 of 35 separate 

importations stopped), but new outbreak countries and previously undetected circulation were

identified. At the end of 2008, there were 32 importation events in 13 countries.

With regard to current areas of active transmission, polio is endemic with transmission never

having been interrupted in India, Nigeria, Pakistan and Afghanistan. Outbreaks following 

importations in previously polio-free areas have included Angola / DRC, Chad / Central African 

Republic, and Sudan / Ethiopia. Recently, with the seedings from the four endemic countries 

into other countries, there have been large outbreaks and the number of cases has been 

substantial relative to these seedings. The good news is that even with continued seedings, it 

has been better and more quickly recognized due to laboratory advances and better control. 

Therefore, the number of cases tends to be lower. In the last six months (August 11, 2008 

through February 10, 2009), the number of cases and number of districts affected have gone 

up.

In terms of the background on how CDC considers progress, Dr. Wassilak introduced the tool of 

looking at a surrogate of population immunity through the AFP surveillance system. The 

immunization histories in children who present with acute flaccid paralysis at 6 to 35 months of 

age who were not found to have polio virus in their stools are used as a surrogate of the history 

for the background community. Referring to data regarding the OPV status of children from

2003 to 2008, Dr. Wassilak indicated that by the time a child is 6 months of age, he or she 

should have reached seven doses. In reality, this is found to be true in India. Even in high risk 

states, the immunization history of the background population is high. The problem is that the 

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cases also have the same type of immunization history. The vaccine is failing to protect in the 

Indian environment for reasons of virus load, malnutrition, diarrheal disease, et cetera. 

Somewhat of the same problem is occurring in Pakistan because there are still pockets in which 

immunization efforts are not as strong. Within Afghanistan, there is a specific problem within an 

area of the country where there are security issues, which have been increasing. In Nigeria, 

there is a massive failure to reach children with vaccine.

The cases within India are located within Uttar Pardesh and Bhar historically. Over time, in 

2005 there was an introduction of monovalent vaccine which is basically more effective against 

Type 1 polio than the trivalent dose for dose—about three times more effect. Despite that 

introduction, there was a recrudescence of disease. Basically, by increasing the number of 

rounds, there was better control of Type 1. With the emphasis on Type 1, because it is found 

throughout the world more frequently, there has been an increase in Type 3. However, even 

that is complicated because it is based on how the vaccines were used and where they were 

used. The pocket of all disease was Western Uttar Pardesh. That is the location where Type 3 

had been at the beginning of the time period from January 2006 to September 2007. They were 

focusing on Type 3 vaccine use intermittently with the other vaccines in that area. Bihar was 

poorly covered by Type 3 vaccines and in the process of the virus marching across from 

Western Uttar Pardesh, to Eastern Uttar Pardesh, to Bihar a massive outbreak occurred long 

before there could be a response. After three effective rounds, there was better control, at least 

before the high season began.

In 2006 the focus was still in Western Uttar Pardesh. At the beginning of 2007, over time, very 

few of these genetic families are found. Basically, by the end of 2007, there were no more 

cases occurring in Uttar Pradesh; however, the virus that had been circulating in Uttar Pradesh 

moved to Bihar, and then returned to Delhi and to the high risk area again, leading to expansion 

of disease. The good news is that polio transmission can be stopped. The bad news is this has 

not been possible everywhere at the same time in India. 

With regard to Nigeria, the disease is centered in the Northern states where routine 

immunization has been the worst and where there also was a problem in trust of vaccine. In 

2003-2004, for various reasons vaccine was being considered a sterilizing agent and some 

leaders of the communities voiced opinions against vaccination, and four states stopped 

vaccinations. Even with a restart of the program because of a continual effort of community and 

leader education, uptake remained weak and health workers were complacent and were not 

necessarily delivering the vaccine they said they were. Beginning in 2006, the monovalent type 

1 vaccine was introduced, which was thought to be more effective. They also introduced an 

integrated program, adding multiple antigens plus other health interventions such as antipyretics 

or de-worming. There was improved uptake and immunity levels improved, but the program 

was never implemented the way it should have been. Health interventions have been poorly 

delivered and with the continued birth cohort, there was a build-up of a susceptible population in 

the outbreak of 2008. Routine immunization in particular has been weak, and seems to have 

worsened between 2007 and 2008. In addition, the data over-represent the truth. Coverage is 

actually lower than what is reported. There are some halos of good news within Nigeria. 

Certain states have actually understood the message and have attempted to supply the 

logistics, supervision, and political will to improve the supplementary campaigns. 

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In terms of Pakistan and Afghanistan, there have been two zones of circulation primarily 

compounded by the fact that security and access are major problems on the borders both in the 

Northern Zone that includes the Northwest Frontier Province and in the Southern Zone that 

includes high risk areas on both sides. This also included a zone where immunization should 

not have been a problem as there are no security issues in most of Balochistan and Sindh. 

However, in 2008 increases in these two zones led to an outbreak in Punjab State where 

routine coverage is not strong and supplementary immunization has been weak. Fortunately, 

since this has occurred, the highest levels of health authorities and politicians have become 

involved such that there has been some effort shown to improve delivery in Sindh and Punjab. 

In fact, there have been no Type 1 cases in Sindh since August 2008. However, security issues 

cannot be ignored. Between 2005 and 2008 children could not be reached. The UN staff could 

not go in to supervise and the local staff have been hindered in their movement. Even when 

there have been agreements with anti-government forces, those agreements have not always 

been honored, so coverage and security have deteriorated. 

Seeding is traced with molecular epidemiology and the sources for multiple outbreaks have 

been India and Nigeria. From 2003 to 2005 when there was suspension of vaccination in 

Nigeria, there were movements East and West of the polio virus. Much of this movement is 

frequent, with many viruses moving around. From Northern India to Angola, there have been 

three importations—two Type 1 and one Type 3 that have not been abated. With regard to the 

immunization histories among those children, basically the immunity level was poor when these 

problems first occurred from 2003 to 2005. Due to additional supplementary immunization, the 

overall immunity of surrounding countries has improved. 

In conclusion, the threat of long-distance importations of wild poliovirus in the US continues into 

2009. In India, Type 1 wild poliovirus transmission is at its lowest level, with potential for 

interruption in 2009. Type 3 interruption is to follow. Conflict and security issues continue to 

plague polio eradication operations in Afghanistan and Pakistan. There are potential signs of 

improvement in the non-secure areas of Pakistan with better implementation. Poor vaccine 

delivery and inadequate political commitment impede success in Nigeria, with uncertain 

outcome from recent political “commitments.” Chronic problems remain to be mitigated in 

reaching children in Angola, Chad, Sudan (less so in the Democratic Republic of Congo), albeit 

with low level of transmission. The worst situation is that this is compounded by weak 

surveillance, so in addition to having persistent transmission, there are times when virus is not 

found in a given area, but it is a false negative. In fact, for approximately three years virus was 

not found to be circulating in Sudan when, in fact, it was. There have been recent importations 

traveling further into Uganda and Kenya from Sudan. These are relatively low transmission 

issues, but they are chronic. Other options are being considered for other vaccinations, 

including inactivated polio vaccine and other ways of using oral polio vaccine. If successful, the 

focus will be placed back on eliminating polio entirely, which means interrupting Type 3 as well 

with the monovalent Type 3 vaccine. For the other problem countries, there are areas of 

promise. 

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Discussion

William Schaffner (NFID) inquired as to where consideration was being given to using 

inactivated polio vaccine rather than the continued reliance on oral polio vaccine in the 

problematic areas.

Dr. Wassilak responded that among the people who worry about polio eradication, there has 

been a great deal of discussion. It has only been discussed in seriousness for India because 

that is where vaccine delivery is not the problem. In the other countries the issue is more a 

failure to vaccinate. While discussions have been serious for the last two years, beyond a very 

small clinical trial, there is no testing planned at this time. Realistically, none of these 

contingencies will be considered until later in the year due to elections. IPV is not off the table, 

but the Indian government is not leaning in that direction. They are trying to make a link to their 

strengthening of routine immunization in general and would like to use a combination vaccine 

with IPV, which would complicate how to deliver the vaccine and how to follow up. 

Neal Halsey stated that he had a conflict of interest in this arena in that he had conducted 

studies for many years with IPV and OPV, some of which was supported by sanofi pasteur. He 

also participated in the workshop held by NIH that was published in The Lancet recently, which 

comes down strong on the need to use IPV much more extensively not just for India, but also for 

some of the other areas as well and in the transition to sometimes stopping OPV. Most people 

who have been involved in this arena believe that this will be necessary. No doubt there are 

major cost and delivery issues, but there should be a much more open discussion of this issue 

in the WHO presentations. Also not mentioned was the very problematic issue of the continuing 

outbreak in Nigeria of the vaccine-derived polio and the multiple outbreaks that have occurred 

and continue to occur. That should be a part of the presentation on the elimination of paralytic 

disease due to polio viruses. 

Dr. Wassilak agreed that those two issues were incredibly important. With respect to vaccinederived polio virus, at least 12 outbreaks have been recognized, with 150 cases in Nigeria that 

is on-going despite four rounds of Type 2-containing vaccine over several years. Many are in 

agreement that to stop oral polio vaccination is absolute, but to do it without some reliance on 

IPV is perhaps reckless. Even among WHO colleagues, there is an understanding that IPV will 

provide an important role if not in interrupting wild polio virus perhaps in transitioning to the 

cessation of oral polio vaccine use. While this point is valid, he did not address it during this 

session due to time constraints. The other aspect is that despite the non-immediate intention of 

the use of IPV within the next several months, an incredible amount of research is underway to 

examine how to make it affordable for the vast part of the world. That includes dose reduction, 

intradermal vaccination, less expensive and safer production, et cetera. 

Stanley Grogg (AOA) was recently in Afghanistan where he inquired as to what the problem 

was with getting the polio and rotavirus vaccines to refugee areas, outside of security issues. 

The response was that they do not have refrigeration. 

Dr. Wassilak noted that OPV can be used even without a cold box in some situations because it 

has temperature thermal indicators on it to see how well the vaccine is holding up to heat stress. 

There can be barriers to doing the right thing, but given the right preparation it can be done 

correctly. The funding for the program is 85% secure for the next two years thanks to the 

generosity of the Gates Foundation, Rotary International, the German and UK governments 

most recently, and others. The US government also provides a substantial amount of money for 

the program.

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Domestic Poliovirus Vaccine Issues

Gregory S Wallace, MD, MS, MPH

CDC / CCID / NCIRD / DVD

Dr. Wallace presented on the history of poliovirus and poliovirus vaccine in the US and 

inactivated poliovirus vaccine (IPV) schedule issues including minimum intervals and 

accelerated schedules, and optimal schedules including timing of boosters. 

With regard to the history of poliovirus vaccine in the US, IPV was introduced in 1955 and OPV

was introduced from 1961 to 1964. Enhanced Potency eIPV was licensed in 1987. The 

Americas were certified polio free as a region in 1994, with the last indigenous case in the US 

occurring in 1979. With the transition from routine OPV, to sequential IPV-OPV schedule, to an

all-IPV schedule came the elimination of VAPP cases with the exception of an imported case in 

a young adult who had traveled to Central and South America. No OPV has been distributed 

since 2000. More recently, there has been a transition to a use of more IPV-containing 

combination vaccines with DTaP-HepB-IPV licensed in 2003 and DTaP-IPV/Hib and DTaP-IPV 

licensed in 2008. 

In terms of the evolution of IPV schedule in US, when the enhanced potency IPV was licensed 

in 1987, while it was not the routine vaccine at the time, it was indicated for certain high risk 

groups. The ACIP recommendation for eIPV for Dose 1-2 to have a preferred 8 week interval, 

but a 4-week interval was acceptable. Dose 2-3 had a minimum interval of 6 months, with 12 

months being preferred. A booster dose was to be administered after the 4th birthday. This is 

really two priming doses, a booster dose, and an additional booster dose prior to school. With 

the transition from IPV to a routine OPV schedule there were priming doses of IPV at 2 and 4 

months of age, with OPV being given in the second year of life, and at age 4 or over. There 

was some language about accelerated schedules if starting late. At that point, the package 

insert for eIPV was amended to allow the third dose to be administered as early as 6 months of 

age. Prior to that, the minimum age for the third dose was 12 months of age. 

With the evolution to an all-IPV schedule in the US in 1997, the ACIP recommendation for

transition to IPV was IPV at age 2 and 4 months, OPV at 12-18 months and 4-6 years, and an 

accelerated schedule for IPV if starting at >6 months of age. The minimum interval was 4 

weeks between doses 1 and 2 and 6 months preferred between Doses 2 and 3, and a 4th dose 

at age 4-6 years. IPV PI was amended to allow a 3rd IPV dose as early as age 6 months in an 

all-IPV schedule. With the evolution of the IPV schedule in the US in 1999 / 2000, the ACIP 

recommendation for routine use of IPV was at 2, 4, 6-18 months and 4-6 years, with a minimum 

interval of 4 weeks between doses, and 2 months preferred between Doses 2 and 3. 

The 2009 recommended routine schedule is 2, 4, the window of 6-18 months, and 4 to 6 years. 

With the other routine schedules and the use of combination vaccines, a lot of IPV is being 

given at 6 months of age. The catch-up schedule for those who are late, for those under 7 

years of age, is 4 weeks between all doses and is the same for older children as well.

Studies have shown that a 2, 4, 6 month priming schedule induces higher GMTs than a 2, 3, 4 

months or a 6, 10, 14 weeks schedule. Starting later and / or having longer intervals does 

induce higher GMTs. Maternal antibodies can have an impact on the first dose, especially if 

given early. However, this does not affect subsequent responses to doses administered later. 

Longer intervals are optimal for memory response for GMT and duration of immunity. At least 

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4-6 month intervals prior to the dose in the second year of life are optimal for memory cell 

maturation. Essentially everybody, regardless of their priming schedule, will have detectable 

antibodies in a booster given in the second year of life. With respect to how long that lasts, 

there are some data but it is incomplete. There are also anecdotal reasons to think that this is 

long-lasting, but there are no specific data to show exactly how long the duration of immunity 

would persist.

The current minimum intervals and minimum age are 4 weeks between each IPV dose, starting 

at least at 6 weeks of age for the first dose. The statements from package inserts, depending 

upon the vaccine preparation is used may include a “preferred” interval of 6 or 8 weeks, with a 

longer interval “preferred” between the 2nd and 3rd dose and / or the 3rd and 4th dose. For routine 

scheduling, current ACIP recommendations include a booster dose at age 4 to 6 years, but with 

the advent of Pentacel®, the package insert allows a 2, 4, 6, and 15-18 month schedule with all 

doses counting as valid. Accelerated schedules with minimum intervals can result in shorter 

intervals and younger ages, with technically 4 doses in the first year of life.

Examples of IPV Schedules in Various Countries

COUNTRY DOSE 1 DOSE 2 DOSE 3 DOSE 4 DOSE 5

USA 2 mos 4 mos 6-18 mos 4-6 yrs ---

Canada 2 mos 4 mos 6 mos 18 mos 4-6 yrs

Sweden 3 mos 5 mos 12 mos 5-6 yrs ---

United 

Kingdom

2 mos 3 mos 4 mos 3.3-5 yrs 13-18 yrs

Spain 2 mos 4 mos 6 mos 15-18 mos ---

In summary of the different IPV schedules used worldwide, the variations are either 2 or 3 doses 

in the first year of life followed by later booster doses. The vast majority of recommended IPV 

schedules include 1 or more doses after the 2nd year of life. Spain has utilized a 2, 4, 6, 18 

month schedule using IPV-containing combination vaccines since 2004. 

Potential policy questions include the following:

1. Minimum Intervals and Accelerated Schedules: 

• Are Minimum Intervals with lower GMTs okay in the first year of life?

• Should Minimum Intervals be extended for boosters?

• Is more specific guidance on accelerated and catch-up schedules needed?

2. Timing of IPV-containing Vaccine Doses for Routine Schedule: 

• What are the optimal intervals for each dose?

• Should the current schedule for the 3rd and 4th dose be changed?

• Should a booster dose at ≥4 years of age be maintained? (which may require one 

additional IPV-containing dose in some circumstances)

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Discussion

Dr. Morse requested information about forming the group and submitting recommendations to 

the full ACIP.

Dr. Wallace responded that they anticipated the general recommendations possibly being 

approved in June 2009, with a publication possibly later in the year. Ideally they would like to 

take on the minimum interval issue by the June 2009 meeting, and certainly by the October 

2009 meeting.

It appeared to Dr. Marcy that the UK had one-month intervals between doses and to his 

knowledge were not having a problem. It seemed that ACIP was being asked to fix something 

that was perhaps not broken. 

Dr. Wallace responded that it was only broken because people were confused and there are 

recommendations that could be interpreted as being in conflict with each other. There are two 

issues, the timing of the booster dose and the accelerated schedule issue. They probably do 

not have the same types of problems with that in the UK. 

Dr. Seward added that CDC has data that show a minimal interval on the catch-up schedule 

produces inferior immune response. That is fairly new data from a study CDC conducted. The 

first question regards whether it is acceptable to have an accelerated 6, 10, 14 week schedule 

or whether those minimum intervals need to be changed. Combination vaccines are being used 

increasingly on an accelerated schedule, which is pushing that to become routine. There must 

be clear guidance. The UK is starting later, and they have an accelerated schedule within a 

schedule of five overall doses. 

Dr. Wallace interjected that 4 months to 3.3 years raised his eyebrow to some extent, but the 

US schedule compared to others is somewhat of a hybrid. Even if not accelerated, the 

schedule could be 2, 4, 6 and nothing until 4 to 6 years. However, that is not the way the 

studies have been conducted. There are two issues. The minimum interval issue informs the 

routine issue to some extent, but the minimum interval issue needs to be communicated more 

clearly. Spain and Slovenia are the only countries known to be routinely stopping with a booster 

in the second year of life. UK is the outlier waiting a while to give their booster. There have 

been some discussions about whether that is ideal or not. Also at issue is how clinically 

relevant a higher GMT is to a lower one with a vaccine that protects everybody eventually. 

Dr. Sawyer noted that in his short tenure with ACIP, this was not the first time he had heard 

questions raised about minimum intervals in general. He encouraged the effort to examine the 

minimum intervals carefully as stated to ensure that they are appropriate. If they are, then they 

need to be minimum intervals and it needs to be acceptable to give the vaccine at those 

minimum intervals.

Dr. Wallace added the caveat that the appropriateness of a minimum interval can change 

depending upon how old someone is at the time, the disease, and the vaccine. For an adult 

who has never been vaccinated, who is going to go to Afghanistan, a 4-week interval for the first 

two doses and a slightly longer interval to the third dose is all they really need for optimum 

protection. 

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139 

Carol J. Baker, MD, Chair

ACIP Yellow Fever Working Group

Dr. Baker indicated that the ACIP Yellow Fever Working Group’s charge was to update and 

revise the 2002 ACIP Yellow Fever Vaccine Recommendations, as necessary, based on new

information. 

Yellow Fever Working Group meetings have included the following:

































September 16, 2008

Welcome and Group Introduction

Background of yellow fever disease and vaccine

November 10, 2008

Vaccine presentation, dose and booster

Simultaneous administration of other vaccines

December 9, 2008

General Safety

Requirements for vaccination before international travel

Upcoming changes to yellow fever risk areas

January 12, 2009

Hypersensitivity

Yellow fever vaccine-associated viscerotropic disease

February 9, 2009

Thymic disease and use of vaccine

Yellow fever vaccine-associated neurotropic disease

Regarding the proposed timeline, monthly meetings are planned from February to May 2009 to 

review topics pertinent to yellow fever vaccine use. Draft recommendations are expected to be 

developed to present to ACIP to obtain feedback before the final recommendations are 

presented. Final recommendations are expected to be presented for an ACIP vote in October 

2009. The final document will be submitted to the MMWR in November 2009.

Anticipated revisions to the 2009 document include updating the epidemiology of yellow fever 

disease, including an updated risk map and recent epizootic activity (South America); including 

information on updated International Health Regulations (2005); updating vaccine safety

information, including new incidence rates and additional information on serious adverse events

(e.g., viscerotropic disease, neurotropic disease); strengthening the wording related to vaccine 

precautions and contraindications based on new data; and outlining research priorities.

Yellow Fever Vaccine

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No public comments were offered during the second day of the meeting.

I hereby certify that to the best of my 

knowledge, the foregoing Minutes of the 

February 27-28, 2008 ACIP Meeting are 

accurate and complete. 

_____________________

________________________________

 

 Date 

Dale Morse, M.D., M.S. Chair,

Advisory Committee on 

Immunization Practices (ACIP)

Public Comments Day 2

Certification

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Abraham Brian

Abramson Allison

ALLAVOINE Thierry

Allred Stephen

Ambrose Karita

ANI GEORGE

Arnhart Tom

Ault Kevin

Bahta Lynn

Baker Carol J.

Banach Stephanie

Bandell Allyn

Baylor Norman

Beck Robert L.

Benning Eric Benning

Benning Eric

Billings Pamela

Blazek Nicole

Bocchini, Jr. Joseph

Bowman Pepe

Brooks Dennis

Buehler James

Calhoun Eve

CamposOutcalt Doug

Cary Donna

Chamberlain Allison

Chaney Mike

Cheek James

Chilton Lance

Cieslak Paul

Cipriano Michael

Colwell Chris

Conner Penny

Counard Catherine

Curlin George

Cyrus Jobin

Dalrymple Donald "Dack"

Deal Carolyn

DeBlois 

Buchanan Anna

Decker Michael

Denovchek Bradley

Dhankhar Praveen

Dinovitz Richard

Dosanjh Jag

Dougherty Kelley

List of Attendees

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9

142 

Douglas John

Dubin Gary

Dubischar-

Kastner Katrin Luise

Duchin Jeffrey

Duffy Colleen

Dzubin Shannon

EBULE 

SAMMEH ELVIS

Ehresmann Kristen

Englund Janet

Evans Geoffrey

Feinberg Mark

Feng Zijian

Feng Luzhao

Fitzgerald Bernadette

Florez Jorge

Foster Stephan

Friedland Leonard

Frutos Sylvina

fryhofer sandra

Gaffoglio Diane

Gall Stanley A

Garrett William Matthew

Gaskins Diana

Geddes Cathy

Gellin Bruce

Gershon Barry

Gonda Mike

Grabenstein John

Greenberg David

Grogg Stanley

Grogg Barbara

Gurunathan Sanjay

Hachey Wayne

Hahn Christine

Halsey Neal

HALSTROM ERIK

Hammer Sandra

Hammes Mary

Haupt Richard

Hosbach Philip

Huber Helen

Hull Harry

Humphrey-

Franklin Donelle

Iacuzio Dominick

Ismail (nee 

Virani) Shainoor

Jackson Melonie

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JAMES 

ANUEKATOA PETER

Johnson David

Joice Melodie

Judson Frank

Kaplan Susan

Katz Samuel

Kempe Allison

Keyserling Harry

Kimberlin David

Kinsinger Linda

Koinis Thomas

Kroger Andrew

Krull Andrea

Kruzikas Denise

Kuter Barbara

L OKESADE

Laird Susan

Lake Tom

Lammers Peter

Lane Barbara

Langley Joane

Lease Christian

Lee Lucia

Leger Marie-Michele

Lett Susan

Lewin Clement

Lewis Tamara

Lievano Fabio

Lovell Ethan

Lukus Lori

Malik Manzoor

Malone Jill

Malone Robert

Mansoura Monique

Manzoor Malik

Marcellous 

Agendia Nkengacha

MARCY S(tephan) Michael

Martinez Laura

Mascarenas Cesar

Mason Dean

Mazur Marie

McGriff-Lee Nayahmka

McLoughlin Sean

McMullin David

Meigs Wendy

Meissner Cody

Middleman Amy

Miller Elaine

Milley Frankie

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Mina Vivian

Moore Kelly

Morse Dale

Mulach Barbara

Murphy linda

Naumoff Nicole

Neuzil Kathleen

Obara Timothy

Offit Paul

Omer Saad

omer hamza

O''Neill Kevin

Oriol Valérie

Otoo Drew

Papa Thomas

Paradiso Peter

Parikh Shefali

Pei Xuesong

Penrod Deborah

Peter Georges

Peters Martin

Peterson Diane

Pisani Amy

Plotkin Stanley

Poland Gregory

PQIDJohn PQIDJohn

Pugh Pearl

Quinn Jane

Rall Kristen

Randall Lisa

Ransom James

RANTI OKESADE

Ray Jill

Rennels Margaret

Richards Steve

Richardson Vesta

Ross David J.

Rousculp Matthew

Saddier Patricia

Sammons David

Saslow Debbie

Sawyer Mark

Schaffner William

Schechter David

Schmader Kenneth

Schodel Florian

Schott Chris

Schutt Robert

SEARFOORCE AMY

Sever Perica

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Sherner James

Shin Tom

Shindman Judith

SIEVERT ALAN

Silverstein Leonard

Skjeveland Eric

Smith Parker

Smith Stephen

Southall Jennifer

Spencer Yvonne

Stinchfield Patsy

Stobbe Mike

Strutton David

Stuerke Stacy

Sumaya Ciro

Swain Christopher

Sylvester Gregg

Tan Litjen

Temte Jonathan

Thomas Lonnie

Tucker Miriam E.

Turner James

Tursi James

Uduman Sayenna

Verstraeten Thomas

Ward Joel

Wassil James

Waytes Tom

Wexler Deborah

Wheatley Lisa

WhitleyWillimas Patricia

Wible Sharon

Wighton Timothy

Wiskind Robert

Wood Laurel

Yamauchi Terry

York Laura

Zimmerman Richard

Zink Thomas

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