DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION

Advisory Committee on 

Immunization Practices (ACIP)

Summary Report

October 22-23, 2008

 Atlanta, Georgia
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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C O N T E N T S 

Acronyms...................................................................................................................................4

Agenda.......................................................................................................................................5

Wednesday, October 22

Welcome & Introductions..........................................................................................................8

Pneumococcal Vaccines

Pneumococcal Vaccines Workgroup Update.................................................................11

Proposed Recommendations for use of PPSV23 among 

Adult Cigarette Smokers.................................................................................................12

Revised Recommendations for use of PPSV23 among

American Indians and Alaska Natives.............................................................................19

Revised Recommendations for use of PPSV23 in High 

Risk Children Aged < 10 Years.......................................................................................30

VFC Vote.........................................................................................................................33

Update on Investigational 13-Valent Pneumococcal Conjugate Vaccine........................34

General Recommendations......................................................................................................38

Human Papillomavirus (HPV) Vaccines 

HPV Vaccines Workgroup Update and Session Overview..............................................45

National Provider Survey.................................................................................................45

Vaccine Safety Update: VAERS.....................................................................................49

Vaccine Safety Update: CISA.........................................................................................51

Vaccine Safety Update: VSD Rapid Cycle Analysis Summary.......................................53

Vaccine Safety Update: Summary of Findings for HPV Post-Licensure Safety.............57

Vaccine Safety Update: Vaccine Pregnancy Registry....................................................59

2009 Adult Immunization Schedule.........................................................................................61

2009 Immunization Schedule for Children 0-18 Years of Age...............................................67

Japanese Encephalitis Vaccine

Revised Recommendations for the Use of JE Vaccines for US Travelers......................77

Hepatitis Vaccines

Convening of Hepatitis Vaccine Workgroup...................................................................85

Anthrax Vaccines

Introduction......................................................................................................................86

Data in Support of Biologics License Application............................................................87

Immunogenicity Analyses...............................................................................................90

Recommendations of the Anthrax Vaccine Work Group.................................................92

AVA Use in Pregnant Women.......................................................................................112

Recommendations for the Use of AVA in Pregnant / Breastfeeding Women................115
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Public Comment......................................................................................................................119

Thursday, October 23

Agency Updates

CDC / CCID / NCIRD....................................................................................................121

Center for Medicare and Medicaid Services (CMS)......................................................122

Department of Defense (DoD).......................................................................................122

Department of Veteran Affairs (DVA) ...........................................................................122

Food and Drug Administration (FDA)............................................................................122 

Heath Resources and Services Administration (HRSA)................................................123

Indian Health Services (IHS).........................................................................................124

National Institutes of Health (NIH).................................................................................124 

National Vaccine Program Office (NVPO).....................................................................124

National Vaccine Advisory Committee (NVAC).............................................................125

Rotavirus Vaccines 

National Trends in Rotavirus Detections, 2007-2008....................................................127

Effectiveness of Pentavalent Rotavirus Vaccine in US Clinical Practice.......................129

Trends in Diarrhea and Rotavirus Hospitalizations in New York State..........................132

Immunization Safety Office Update.......................................................................................136

MMRV Vaccine Safety

MMRV Vaccine Safety Workgroup Update....................................................................137

Vaccine Safety Datalink (VSD) Project Safety Study of MMRV Vaccine.......................138

Merck Safety Study of ProQuad® MMRV Vaccine........................................................140

MMRV Vaccine Safety Workgroup: Interim Synthesis of 

Evidence for Febrile Seizure Risk After MMRV Vaccination 

and Considerations for Future Activities........................................................................143

MMRV Vaccine Supply..................................................................................................150

National Immunization Survey: Teen Results.....................................................................152

Influenza Vaccines 

Update on Influenza Surveillance.................................................................................155

Interim Vaccine Effectiveness Studies, Adult Vaccinations, and

Influenza Efficacy in the Elderly....................................................................................158

Rabies Vaccines Supply........................................................................................................163

Vaccines Supply.....................................................................................................................165

Tdap (Boostrix®) in Adults....................................................................................................167

Public Comment.....................................................................................................................171

List of Members and Other Participants..............................................................................173
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Acronyms

ACIP Advisory Committee on Immunization Practices

AAFP American Academy of Family Physicians

AAP American Academy of Pediatrics

ACP American College of Physicians

AI / AN American Indian / Alaskan Native children (AI / AN)

BLA Biologics License Application

CAIS Childhood / Adolescent Immunization Schedule

CCID Coordinating Center for Infectious Diseases

CDC Centers for Disease Control and Prevention

CIN Cervical Intraephithelial Neoplasia

C. jejuni Campylobacter jejuni

CMS Centers for Medicare and Medicaid Services

CSTE Council of State and Territorial Epidemiologists 

DBD Division of Bacterial Diseases (of NCIRD)

DoD Department of Defense

DSMBs Data Safety Monitoring Boards

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

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 

IC Immunocompromised

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

IPD Invasive pneumococcal disease 

ISD Immunization Services Division (of NCIRD)

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

MCO Managed Care Organization 

MCV4 Meningococcal Conjugate Vaccine

MMRV Measles, Mumps, Rubella, Varicella

MMWR Morbidity and Mortality Weekly Report

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

NCIRD National Center for Immunization and Respiratory Diseases (of CDC/CCID)
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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

Diseases

NCVIA National Childhood Vaccine Injury Act

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

CDC/CCID)

NFID National Foundation for Infectious Diseases 

NIACCHO National Immunization Council and Child Health Program, Mexico 

NIH National Institutes of Health

NIS National Immunization Survey

NVAC National Vaccine Advisory Committee 

NVPO National Vaccine Program Office

OD Office of the Director (of CDC)

OMB Office of Management and Budget 

P&I Pneumonia and Influenza

PCECV Purified Chick Embryo Cell Vaccine

PCV Pneumococcal Conjugate Vaccine

PEP Postexposure Prophylaxis

PhRMA Pharmaceutical Research Manufacturers of America

PPSV23 pneumococcal polysaccharide 23-valent vaccine 

PSC Protein Sciences Corporation

QALMs Quality-Adjusted Life Months

QALYs Quality-Adjusted Life Years

RCA Rapid Cycle Analysis

sBLA Supplemental Biologics License Application

SMEs Subject Matter Experts

VAERS Vaccine Adverse Event Reporting System

VFC Vaccines for Children

VICP National Vaccine Injury Compensation Program

VSD Vaccine Safety Datalink

VZV Varicella-Zoster Virus

WHA World Health Assembly

WHO World Health Organization

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

October 22-23, 2008

AGENDA ITEM PURPOSE PRESIDER/PRESENTER(s)

Wednesday, October 22

8:00 Welcome & Introductions Dr. Dale Morse (Chair, ACIP)

Dr. Larry Pickering (Executive Secretary, 

ACIP; CDC)

8:30 Pneumococcal Vaccines

• Update on Work Group (WG) activities

• Proposed recommendation for use of PPSV23 

among adult cigarette smokers

• Revised recommendation for use of PPSV23

among American Indians and Alaska Natives 

• Revised recommendation for use of PPSV23 in 

high risk children age < 10 years 

Information

Discussion

Vote

Discussion

Vote

Discussion

Vote

Dr. Mike Marcy (ACIP, WG Chair)

Dr. Pekka Nuorti (CDC/CCID/NCIRD/DBD)

Dr. Kate O’Brien (Johns Hopkins University)

Dr. Pekka Nuorti (CDC/CCID/NCIRD/DBD)
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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• VFC vote

• Update on investigational 13-valent 

pneumococcal conjugate vaccine 

VFC Vote

Information

Dr. Jeanne Santoli (CDC/CCID/NCIRD/ISD)

Dr. Peter Paradiso (Wyeth Vaccines)

9:55 General Recommendations Information

Discussion

Vote

Dr. Ciro Sumaya (ACIP, WG Chair)

Dr. Andrew Kroger (CDC/CCID/NCIRD/ISD)

10:45 Break

11:15 Human Papillomavirus (HPV) Vaccines

• Introduction and update 

• National Provider Survey

• Vaccine safety update 

 - VAERS

 - CISA

 - VSD rapid cycle analysis summary

 - Vaccine pregnancy registry 

Information

and

Discussion

Dr. Janet Englund (ACIP, WG Chair)

Dr. Lauri Markowitz (CDC/NCHHSTP/DSTDP)

Dr. Matt Daley (University of Colorado)

Dr. Angela Calugar (CDC/ISO)

Dr. Barbara Slade (CDC/ISO)

Dr. Julianne Gee (CDC/ISO)

Dr. Adrian Dana (Merck)

12:30 Lunch

1:30 2009 Adult Immunization Schedule Information

Discussion

Vote

Dr. Paul Cieslak 

 (ACIP, WG Chair)

Dr. Gina Mootrey (CDC/CCID/NCIRD/ISD)

2:05 2009 Immunization Schedules for Children 0-18 

Years of Age

Information

Discussion

Vote

Dr. Cody Meissner (ACIP, WG Chair)

Dr. William Atkinson (CDC/CCID/NCIRD/ISD)

2:50 Japanese Encephalitis Vaccine

• Update from the Japanese Encephalitis (JE) WG

• Revised recommendations for the use of JE 

vaccines for U.S. travelers

Information

Discussion

Dr. Paul Cieslak (ACIP, WG Chair)

Dr. Marc Fischer 

(CDC/CCID/NCZVED/DVBID)

3:40 Break

3:55 Hepatitis Vaccines

• Convening of Hepatitis Vaccines Work Group Information Dr. Mark Sawyer (ACIP, WG Chair)

4:00 Anthrax Vaccine (Anthrax Vaccine Adsorbed, AVA)

• Introduction 

• Safety/immunogenicity data from AVA clinical 

trial 

• Recommendations of Anthrax Vaccine WG 

• AVA use in pregnant women 

• Recommendations for the use of AVA in 

pregnant/breastfeeding women 

Information

Information

Discussion

Vote

Information

Discussion

Vote

Dr. Dale Morse (ACIP, WG Chair)

Ms. Stacey Martin, Dr. Conrad Quinn (CDC/ 

CCID/NCIRD/DBD)

Dr. Jennifer Wright (CDC/CCID/NCIRD/DBD)

CAPT Margaret Ryan (DOD)

Dr. Jennifer Wright (CDC/CCID/NCIRD/DBD)

6:00 Public Comment

6:15 Adjourn
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Thursday, October 23

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

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

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

Information

8:45 Rotavirus Vaccines

• National trends in rotavirus detections, 2007-

2008 

• Effectiveness of pentavalent rotavirus vaccine 

in US clinical practice 

• Trends in diarrhea and rotavirus hospitalizations 

in New York State 

Information

Information

Discussion

Information

Discussion

Dr. Jacqueline Tate (CDC/CCID/NCIRD)

Dr. Julie Boom (Texas Children’s Hospital)

Dr. Hwa-Gan Chang (New York State 

Department of Health)

9:15 Immunization Safety Office Update Information Dr. John Iskander (CDC/ISO)

9:20 MMRV Vaccine Safety

• Measles, Mumps, Rubella, and Varicella (MMRV)

Vaccine Safety WG Update 

• Vaccine Safety Datalink (VSD) Project safety 

study of MMRV Vaccine 

• Merck safety study of ProQuad ® (MMRV vaccine) 

• MMRV Vaccine Safety WG: interim synthesis of 

evidence for febrile seizure risk after MMRV 

vaccination and considerations for future 

activities 

• Discussion 

Information

Information

Information

Information

Discussion

Dr. Jonathan Temte 

 (ACIP, WG Chair)

Mr. Eric Weintraub (CDC/ISO)

Dr. Patricia Saddier (Merck)

Dr. Karen Broder (CDC/ISO)

Dr. Jonathan Temte 

 (ACIP, WG Chair)

10:20 Break

10:45 National Immunization Survey - Teen Results Information Dr. Nidhi Jain (CDC/CCID/NCIRD/ISD)

11:00 Influenza Vaccines

• Influenza surveillance 

• Update on vaccine effectiveness studies 

• Adult vaccination 

Information

Information

Information

Dr. Anthony Fiore (CDC/CCID/NCIRD/ID)

Dr. Kathy Neuzil (ACIP, WG Chair)

11:45 Rabies Vaccine Supply Information

Discussion

Dr. Charles Rupprecht 

(CDC/CCID/NCZVED/DVRD)

12:15 Vaccine Supply Information

Discussion

Dr. Jeanne Santoli (CDC/CCID/NCIRD/ISD)

12:30 Tdap (Boostrix) in Adults

Information Dr. Jennifer Liang (CDC/CCID/NCIRD/DBD)

Dr. Wayde Weston (GSK)

12:45 Public Comment

1:00 Adjourn
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

CENTERS FOR DISEASE CONTROL AND PREVENTION 

ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES 

October 22-23, 2008 

Atlanta, Georgia 

Summary Report 

The Department of Health and Human Services (HHS), Centers for Disease Control and 

Prevention (CDC), National Center for Immunization and Respiratory Diseases (NCIRD) 

convened a meeting of the Advisory Committee on Immunization Practices (ACIP) on October 

22-23, 2008 at CDC’s Global Communications Center in Atlanta, Georgia. The following 

represents a summary of the proceedings.

Wednesday, October 22

Dr. Dale Morse (Chair, ACIP)

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

Dr. Dale Morse, 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. 

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

meeting functions (Antonette Hill, Committee Management Specialist for ACIP; 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 Curtis Allen to arrange those 

interviews. 

Regarding new ACIP Liaison Organizations, Dr. Pickering pointed out that for more than five 

decades, the Council of State and Territorial Epidemiologists (CSTE) and CDC have worked in 

partnership to support a shared mission. CSTE is an organization of member states and 

territories and represents the perspective of epidemiologists working in state and local 

governments in matters related to the practice of public health. CSTE is a professional 

association of over 1,150 public health epidemiologists working in federal, state, local, and tribal 

health agencies, and U.S. territories.

Welcome & Introductions
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Dr. Christine Hahn, State Epidemiologist Division of Health, Idaho Department of Health and 

Welfare will serve as the representative for CSTE.

Unable to attend this meeting were the following: Ex Officio Members: Dr. James Cheek, 

Indian Health Services (IHS), with Ms. Amy Groom attending on his behalf; Dr. George Curlin, 

National Institutes of Health (NIH), with Ms. Carolyn Deal attending on his behalf; and Dr. Bruce 

Gellin, National Vaccine Program Office (NVPO), with Dr. Dan Salmon attending on his behalf. 

Liaison Representatives: Dr. Joseph Bocchini, American Academy of Pediatrics (AAP), with Dr. 

Lorry Rubin attending on his behalf; Dr. Stephan Foster, American Pharmacists Association 

(APhA), with Dr. Jeff Goad attending on his behalf; Dr. Greg Poland, American College of 

Physicians (ACP), with Dr. Sandra Fryhofer attending on his behalf; Dr. Steven Gordon, 

Healthcare Infection Control Practices Advisory Committee (HICPAC); Dr. Vesta Richardson, 

National Immunization Council and Child Health Program, Mexico (NIACCHO); and Dr. William 

Schaffner, National Foundation for Infectious Diseases (NFID).

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. Dr. Pickering stressed the importance of all members remaining throughout the 

meeting in order to maintain a quorum, requesting that appointed members return from breaks 

and lunch in a timely manner to participate in the meeting in order 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.

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 your 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.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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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 

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, Dr. Morse indicated that 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, which begins in July 2009, are due no later than November 16, 2008. 

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

announced the appointment of the following new ACIP members:

Kristen Ehresmann, R.N., M.P.H., is the Section Chief, Immunization, Tuberculosis, and 

International Health Section, Infectious Disease, Epidemiology Prevention and Control Division, 

Minnesota Department of Health, Minneapolis, Minnesota. Ms. Ehresmann has extensive experience 

in public health, nursing, and epidemiology. As manager of the Minnesota immunization program, Ms. 

Ehresmann has developed expertise in programmatic issues related to implementation of vaccine 

recommendations and strategies to assure high immunization coverage rates. Ms. Ehresmann currently 

serves as chair of the Association of Immunization Managers and is an active member of the CSTE. 

Her understanding of the programmatic perspective on vaccine recommendations will be of great 

benefit to the committee.

Stephan Michael Marcy, M.D., is a Clinical Professor of Pediatrics, University of California, Los 

Angeles School of Medicine, Torrance, California. Dr. Marcy has served on numerous local, national, 

and international committees, including the Committee on Infectious Diseases of the American Academy 

of Pediatrics (IDAAP), and the California State Immunization Committee (CSIC). Both organizations 

are recognized for developing national vaccine recommendations. Dr. Marcy is a nationally recognized 

speaker on pediatric infectious diseases and has been honored in “Best Doctors in America” for several 

years. His tireless efforts to advance immunization practices will contribute greatly to the committee 

objectives.

H. Cody Meissner, M.D., is Chief, Pediatric Infectious Disease Service, Tufts-New England Medical 

Center, Boston, Massachusetts. Dr. Meissner serves as a consultant to the American Academy of 

Pediatrics (AAP) Committee on Infectious Diseases. He has participated in sponsored research on 

respiratory syncytial virus, human-bovine rotavirus, measles-mumps-rubella vaccine, and parainfluenza. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Dr. Meissner has been the lead author for many publications, book chapters, and peer-reviewed articles, 

and is lead author for many AAP policy statements. His extensive background and training in pediatric 

infectious diseases and his broad knowledge of immunization policy issues will be of great benefit to the 

committee.

Prior to beginning the first session, Dr. Morse requested that ACIP members state any conflicts 

of interest. Dr. Janet Englund indicated that she has research support from sanofi pasteur and 

MedImmune. Dr. H. Cody Meissner indicated that Tufts University receives support from Wyeth 

and MedImmune for clinical trials. All other ACIP members present declared that they had no 

conflicts of interest. 

 

Update on Work Group (WG) Activities

Dr. S. Michael Marcy

ACIP Work Group Chair 

Dr. Marcy reported that the Pneumococcal Vaccines Work Group convened several 

teleconferences to discuss policies that had been deferred from prior ACIP meetings and came 

to some conclusions, which Dr. Nuorti planned to discuss. The topics currently under review by 

this group include the following:

 Expand the pneumococcal polysaccharide 23-valent vaccine (PPSV23) target groups to 

include persons 19 through 64 years of age who are cigarette smokers 

 Use of PPSV23 after pneumococcal conjugate 7-valent vaccine (PCV7) for American Indian 

/ Alaskan Native (AI / AN) children 24 through 59 months of age

 Use of PPSV23 for AI / AN persons younger than 65 years of age, for which the Work 

Group received assistance from the following AI / AN consultants:

 Indian Health Service: Amy Groom, MPH, Immunization Program Manager; and Steve 

Holve, MD, Chief Clinical Consultant, Pediatrics

 Alaska Native Tribal Health Consortium: Ross Singleton, MD, MPH, Immunization 

Consultant

 Johns Hopkins Center for American Indian Health: Kate O’Brien, MD, MPH, Associate 

Professor

 CDC Arctic Investigations Program: Tom Hennessy, MD, MPH, Director; and Jay 

Wenger, MD, Associate Director for Science

Pneumococcal Vaccines
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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 Discuss intervals for revaccination with PPSV23 for persons >2 years of age who are 

immunocompromised, who have sickle cell disease, anatomic or functional asplenia

Major considerations in reviewing these proposed recommendations included the burden of 

disease; short-term and long-term vaccine effectiveness; vaccine safety (e.g., adverse events; 

hypo-responsiveness (PPSV23)); feasibility of implementation, particularly in cigarette smokers 

and AI / AN population; cost-effectiveness; and the status of PCV13 on the horizon, which may 

alter use for serotypes not used in the conjugate 7-valent vaccine and perhaps mitigate to some 

extent the use of the polysaccharide 23-valent vaccine.

Proposed Recommendations for Use of 

PPSV23 among Adult Cigarette Smokers

Pekka Nuorti, MD, DSc

CDC / CCID / NCIRD / DBD

Dr. Nuorti reported on the summary of evidence documenting the association of cigarette 

smoking with invasive pneumococcal disease (IPD) before and after routine childhood PCV7 

use; the prevalence of cigarette smoking, current PPSV23 indications and vaccine uptake 

among IPD cases and the U.S. population; the work group’s considerations of pros and cons 

regarding use of PPSV23 in smokers; and the proposed recommendation.

With respect to background, current ACIP recommendations for use of PPSV23 in adults do not 

address the association of cigarette smoking with invasive pneumococcal disease (IPD), given 

that those data were not available when this recommendation was made in 1997. In June 2008, 

information was presented to the ACIP on two new risk factors (e.g., asthma and cigarette 

smoking). At that time, ACIP recommended adding asthma to the list of chronic lung diseases 

that are PPSV23 indications, and that the work group evaluate whether a specific 

recommendation is needed for use of PPSV23 among cigarette smokers.

Before routine use of childhood PCV7, population-base surveillance studies consistently 

reported that smokers accounted for approximately half of otherwise healthy adults with IPD 

[Plouffe JAMA 1996;275:194-8; and Pastor CID 1998;26:590-5]. That observation led to a CDC 

population-based case-control study of cigarette smoking and IPD among immunocompetent 

adults aged 18-64 years of age [Nuorti et al. N Engl J Med 2000;342:681-9]. The key findings 

from that study showed that cigarette smoking was the strongest independent risk factor among 

this group, with an adjusted odds ratio of 4.1. Also in this study, about half of the disease 

burden in this group could be statistically attributed to cigarette smoking in the multi-variable 

model. This study also found numerous dose response relations. Subsequently, the 

association of smoking and pneumococcal disease was also confirmed in the U.S. and 

European studies among immunocompromised groups [Breiman Arch Int Med 2000; and Grau 

Arch Int Med 2005].

With regard to dose response relationship Intensity of cigarette smoking and risk of IPD

[N Engl J Med 2000;342:681-9], the adjusted odds ratio increased from 2.3 to 5.5 when the 

number of cigarettes smoked daily increased. In terms of cumulative exposure to smoking, or 

pack-years of smoking and risk of IPD, there is a highly significant dose response relation with

increasing pack-years of smoking [N Engl J Med 2000;342:681-9].
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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In a comparison of estimated IPD rates among asthmatics and smokers with rates among 

persons with current PPSV23 indications in persons ages 18 to 64 years of age, three quarters 

(74%) of IPD cases with asthma were high risk (e.g., hospitalization / ER visit, use of rescue 

corticosteroids, or 3+ beta agonists) in the Talbot study. There are caveats for calculating these 

rates in that they are from different data sources and the asthma data are from a different age 

group, from 2 to 49 years of age [Talbot NEJM 2005, ages 2-49 years; Kyaw JID 2005, ages 

18-64 years; Nuorti NEJM 2000, ages 18-64 years]. In addition, some of the alcohol use data 

may be unreliable in the National Health Interview Survey (NHIS) that was used for the 

denominator data. Nevertheless, this was the best data available in terms of approximate rates 

of disease in different groups with underlying conditions. 

The pneumococcal conjugate vaccine in children has resulted in dramatic changes in the 

epidemiology of IPD in non-vaccinated groups as well. The CDC preventability study [CDC. 

Active Bacterial Core surveillance (ABCs), unpublished], some of which was presented to the 

ACIP in another meeting, was reanalyzed with regard to smoking information. Most of these 

data were collected in the early conjugate vaccine era in 2002. Among the cases of 

pneumococcal disease, the prevalence of smoking is high from early age on and continues to 

be very high until approximately the mid-50s, after which the prevalence of smoking decreases 

rapidly; whereas, the prevalence of former smokers increases. During the PCV7 era, 2001-

2003, over half (53.4%) of adult cases aged 18 to 64 years identified by CDC’s ABCs 

surveillance were current and 17.4% were former cigarette smokers. Among the current 

smokers, three quarters had another indication for the PPSV. Only approximately 25% to 27% 

of current smokers reported ever receiving the vaccine. One of the work group members, Dr. 

Schaffner, had pointed out that while smokers have other indications, these are not working 

very well. 

In terms of the prevalence of current and proposed PPSV23 indications in adults aged 19 to 64 

years of age in the U.S. population in 2007, the following precentages had current PPSV 

indication (excluding asthma): 10.9% among ages 19 to 49 and 28.9% among ages 50 to 64, 

and 16.1% for all ages. Some 2.0% among ages 19 to 49 and 1.2% among ages 50 to 64, and

1.8% all ages had asthma and no other condition. Some 19.1% among ages 19 to 49 and 

12.8% among ages 50 to 64, and 17.3% in all ages were current smokers with no other 

indication. Those with asthma or smoking and a current PPSV indication include 32.6% among 

ages 19 to 49 and 43.2% among ages 50 to 64, and 35.7% for all ages in the U.S. population 

[National Health Interview Survey, 2007].

Regarding the size of the current and proposed PPSV23 target groups and self-reported 

coverage in adults ages 19 through 64 years in the U.S. in 2007, 32.3 million have a current 

PPSV indication (e.g., diabetes, heart diseases, bronchitis, emphysema, kidney disease, liver 

diseases, and cancer) [National Health Interview Survey, 2007]. Among those, there is 24.5% 

PPSV23 coverage. For those with asthma only (3.9 million), coverage is 13.6%. For the 31.6 

million who have only the proposed a cigarette smoking indication, there was 6.0% vaccine 

uptake. The estimated total number of adults with a PPSV23 indication including age 65 years 

is about 71 million, although individuals may have multiple conditions. An estimated 16.7 million 

(30.3%) of persons aged 50 through 64 years of age have high risk conditions that are PPV 

indications. Again, the caveats for using the NHIS as denominator data are that the information 

for e.g., HIV and alcoholism are not very good, so the proportion of smokers with other 

indications may be somewhat underestimated in the general population. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

14

To address a question raised during the June 2008 ACIP meeting regarding the number of 

individuals who would need to be vaccinated in order to prevent one case of invasive 

pneumococcal disease, either among asthmatics or cigarette smokers, CDC ‘s ABCs 

surveillance data were used to determine a projected number of pneumococcal cases among 

smokers and asthmatics in the U.S. NHIS data were then used to determine the denominator 

for those groups, and the number needed to vaccinate per year were calculated using a vaccine 

effectiveness estimate of 60% as the base case, and then ranging that from 50% to 70% 

effectiveness. In the older age group for cigarette smokers, the number needed to vaccinate to 

prevent one case is approximately 4000 (3992) per year, ranging from 3422-4791. In the older 

age group for asthma, the number needed to vaccinate to prevent one case is approximately 

5600 (5598), ranging from 4798-6718. Again, there are uncertainties in terms of the different 

data sources and the accuracy of the denominator data. Therefore, these should be considered 

to be approximate estimates.

In terms of the percent of invasive pneumococcal cases caused by serotypes in different 

vaccine formulations, assuming no cross-protection against 19A, about 40% of invasive disease 

in adults aged 50 through 64 years is caused by the 6 serotypes included in PCV13 but not

PCV7, 22% is caused by the 11 serotypes included in PPSV23 but not in PCV13. About 84% of 

disease in smokers is caused by PPSV23 types among persons aged 18 through 64 years.

During the work group’s conference calls, a number of considerations were debated. The group 

came to the conclusion that there are consistent data on increased risk of IPD among smokers 

in both immunocompetent and immunocompromised groups; increased risk and NNV among 

smokers is similar to other high risk conditions (e.g., asthma); and many non-elderly adult IPD 

cases among cigarette smokers already have another condition for which PPSV23 is currently 

recommended, although vaccine uptake is low. Cigarette smoking is a risk behavior that is easy 

to identify in clinical practice. Smoking cessation should be part of the therapeutic plan for 

persons hospitalized or treated for severe pneumococcal disease regardless of immunization 

recommendations. Although many smokers have other indications, the “other” indication is not 

working. 

Smoking cessation should be recommended regardless of immunization recommendations. 

Data from a case-control study show the reversibility of disease risk since quitting smoking [N 

Engl J Med 2000;342:681-9]. Although the association of former smoking and IPD was not 

significant, the risk was reduced 14 % per year since quitting and returned to baseline (e.g., that 

of never smokers) in approximately 13 years. This supports the recommendation that other 

professional organizations have made regarding smoking. The Infectious Diseases Society of 

America (IDSA) / American Thoracic Society guidelines on the management of communityacquired pneumonia in adults state that, “Smoking cessation should be a goal for persons 

hospitalized with CAP who smoke.” (Moderate recommendation; level III evidence) and 

“Smokers who will not quit should also be vaccinated for both pneumococcus and influenza.” 

(Weak recommendation; level III evidence) [Mandell LA, et al. Infectious Diseases Society of 

America / American Thoracic Society Guidelines on the Management of Community-Acquired 

Pneumonia in Adults. CID 2007;44:S27–S72].

The uncertainties with regard to this recommendation are that about one-fifth of U.S. adults 

smoke cigarettes (approximately 39.8 million people in the 19 to 64 year old age group). 

Although most smokers have another PPSV23 indication, targeting this group may substantially 

increase the number of vaccines required. As with other risk-based indications, determining the 

optimal timing of vaccination with PPSV23 is challenging, given the unknown and likely limited 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

15

duration of protection during an extended period of risk. It is known from the data that most 

smokers begin in adolescence or early adulthood, but the risk of IPD increases with increasing 

pack-years. Among IPD cases, smoking prevalence is high beginning in early adulthood. The 

work group believed that using indicators such as pack-years smoked may not be feasible in 

clinical practice. Studies in older adults suggest that PPSV may result in lower antibody 

responses to subsequent PCV [de Roux CID 2008;46:1015-23; and Musher JID 2008;198:1019-

27], although the implications for potential future adult conjugate vaccine use are currently 

unknown. 

The proposed recommendation for vote (1) was as follows:

 “Persons at increased risk for invasive pneumococcal disease include those who smoke 

cigarettes.

 The work group recommends adding cigarette smoking to the list of conditions that are 

indications for PPSV23 in adults aged 19 through 64 years

 Proposed wording: “Persons aged 19 through 64 years who smoke cigarettes should 

receive PPSV23.” 

 Smoking cessation should be part of the therapeutic plan for persons hospitalized or 

treated for severe pneumococcal disease.

The proposed recommendation for vote (2) was as follows:

 Due to a request from the Harmonized Schedule Work Group, the workgroup also 

recommends revising the previously approved asthma recommendation to begin at age 

19 years instead of age 18 years to avoid overlap with the adolescent schedule

 The recommendations for both asthma and smoking would then apply to people aged 19 

through 64 years.

 Revised wording: “Persons aged 19 through 64 years who have asthma should receive 

PPSV23.” 

Discussion

Dr. Baker pointed out that 19-64 is misunderstood by many people. Some people believe it is 

“to” 64, but it actually means “through” 64.

Dr. Nuorti responded that it is 19 through 64. Dr. Meissner added that there would be changes 

in terms of dashes, end dashes, and hyphens.

Given that it is not known whether the conjugate will be recommended for adults, and a second 

dose of the 23-valent vaccine is recommended for individuals who remain at highest risk and 

are likely to have falling titers, Dr. Meissner wondered whether an issue would arise in terms of 

whether a second dose of the 23-valent vaccine is recommended for smokers since they remain 

in high risk groups.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

16

Dr. Nuorti replied that he did not recall any data showing a more rapid decline in antibodies 

among smokers. He assumed their antibody response would be fairly similar to other persons 

without underlying chronic illnesses. However, many smokers do have chronic underlying 

conditions (e.g., heart disease, lung disease). He would assume that their immune responses 

would be similar. In terms of a potential recommendation should the adult 13-valent conjugate 

be licensed, there are some data available suggesting that the order the vaccines are given is 

important. An alternative would be a combined scheme with the conjugate vaccine first and the 

polysaccharide vaccine following that, which would be immunologically advantageous and 

potentially increase the serotype coverage. For smokers or other immunocompetent groups, 

there is no current or proposed recommendation to give a second dose of the polysaccharide 

vaccine. Those policy decisions still need to be discussed.

Regarding the number needed to vaccinate to prevent one case raised the question for Dr. 

Chilton concerning whether the proposed recommendation had been subjected to cost-benefit 

analysis. It appeared to him that the cost of preventing a case of IPD is very high.

Dr. Nuorti responded that this was a calculation based on rates of disease and assumed 

vaccine effectiveness. A formal cost-effectiveness analysis was not done for this specific 

proposed indication, nor has such an analysis been done in the past for the existing high risk 

conditions. In terms of the older age group, the number needed to vaccinate is fairly similar to 

what is being reported for persons 65 and older in some Australian data.

Dr. Temte pointed out that for those in practice, it is easy to identify cigarette smokers. 

However, it is very difficult to identify those who have early COPD and nearly impossible to 

identify those who have early cardiovascular disease. Practitioners must often address 

vaccination after the occurrence of an event, which is frequently pneumococcal infection. The 

suggested recommendation provides a very nice preemptive prophylaxis that fits into clinical 

practice, given that often practitioners lack the tools to identify the risk diagnoses, but can easily 

identify the risk habits. 

Dr. Judson agreed that a minimal attempt should be made to determine cost-effectiveness, 

which should probably be based upon recommending it to those smokers who currently do not 

qualify for vaccine. Given that other types of morbidity and mortality from smoking overwhelm 

IPD, any recommendation probably should have the proposed wording, “Persons aged 19 

through 64 who smoke cigarettes should receive the vaccine and smoking cessation.” There 

are teachable and behavior modifying moments when smokers deal with cancer, heart disease, 

COPD, et cetera.

With respect to the number needed to vaccinate and an efficacy duration of a year, Dr. Cieslak 

noted that his “back of the envelope” calculation suggested that it looked pretty good because 

there is likely to be a duration longer than this. Given the high morbidity and mortality of 

invasive pneumococcal disease in adults, he suspected that cost-effectiveness would be good. 

Nevertheless, he would like to see a cost-effectiveness analysis at some point. 

With respect to Dr. Lett’s inquiry regarding why the work group did not consider indications by 

pack years, Dr. Nuorti responded that they considered this but decided it might be difficult to 

determine in clinical practice. The risk increases with pack years. The prevalence of smoking 

among cases is very high from very early on. Among 20 to 30 year olds, it approaches 50%. 

There is no specification for severity for other conditions that are on the list of PPSV23 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

17

indications in the recommendations, either. From a practical and consistency point of view, the 

work group decided not to focus on pack years.

Regarding Dr. Lett’s request for clarification about the use of PCV followed by PPSV23, Dr. 

Nuorti replied that recent studies in older adults have examined the immunological responses 

among persons given either a polysaccharide vaccine or conjugate vaccine followed by another 

dose of polysaccharide or another dose of conjugate. The overall generalization from those 

studies is that it appears that if a polysaccharide vaccine is given before the conjugate vaccine, 

the response to the conjugate will be lower than with primary vaccination; whereas, if the 

conjugate vaccine is given first, there does not seem to be a decreased response with a 

subsequent dose of either vaccine.

Referring to the risk among smokers and asthmatics being similar to that for diabetics and those 

with COPD in similar age groups discussed by Dr. Nuorti, Cynthia Whitney (Respiratory Disease 

Branch) said that if the ACIP wanted CDC to examine cost-effectiveness for smoking, they 

should do so for all of the indications.

In terms of timing of vaccination within the 19 through 64 year old cohort, Dr. Duchin (NACCHO) 

pointed out that because the risk of IPD varies with age, it may also vary with associated 

additional risk factors outside of smoking. With respect to considerations pertaining to the 

pending licensure of PVC13 and issues of hypo-responsiveness whether the ACIP planned to 

issue some more guidance for clinicians. For example, would it be wise to give a 19-year old 

who has been smoking for two years a 23-valent polysaccharide vaccine when they only have a 

few pack years. The risk will rise should this person continue to smoke, at which time it is not 

clear that the same effectiveness would be achieved at that point.

Dr. Nuorti agreed that this is a key challenge with the polysaccharide vaccine not only for the 

smoking recommendation, but also for any of the existing indications on the list. The work 

group agrees that the vaccine has a limited duration of protection, and while the exact duration 

is unknown, it is likely to be relatively short and the person’s risk will increase with age. The 

work group has also reviewed the considerations concerning revaccination and concluded that 

they do not have the data to decide the optimal timing or frequency of re-vaccination.

Dr. Duchin (NACCHO) inquired as to whether there would be any value in examining morbidity 

and mortality over age and trying to time the administration of vaccine to coincide with the 

periods during which morbidity and mortality of invasive pneumococcal disease are highest.

Dr. Nuorti replied that there is some data to suggest that risk increases with age independent of 

the underlying conditions.

Dr. Neuzil agreed with Dr. Duchin, pointing out that as a work group member this was a difficult 

issue that also troubled her personally in terms of the implications in 10 to 15 years of 

vaccinating an increasing number of individuals at younger ages. This pertains to the balance 

of the practical implementation and the limits of data versus that concern. Given that licensure 

of the conjugate vaccine is not clear, the ACIP cannot continue to avoid this topic. They must 

review this issue on a regular basis, and if in three to five years there is not a higher valent 

conjugate, the revaccination issue will have to be readdressed.

David Salisbury (Department of Health, London) expressed concern about the costeffectiveness of the proposed recommendation, certainly in the absence of any evidence of 

cost-effectiveness because it is a very wide ranging recommendation. One of the comparisons 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

18

he would like to have seen was the number needed to treat by counseling to prevent a case 

compared to the number needed to treat by vaccination. The data must be available on the 

number needed to treat by counseling by age and length of smoking experience. Making such 

a recommendation is going to bring far more young people into the category who would be 

recommended for vaccination at a time when their smoking commitment may be relatively short. 

They are not already lifelong committed smokers who have been smoking for 30 years. It is 

known that that data on long-term protection of polysaccharide is very weak. Hence, the young 

people will fall back into the pool of those at risk for a very long period of their lives while they 

are still smoking. Therefore, the value of this intervention has, albeit a very short-term 

intervention, needs to be costed because this will not give young people lifelong protection at a 

time when they may be at lower risk of the complications of IPD. The complications of IPD in 

smokers may be much more powerful at a different time in their lives. 

Dr. Judson concurred. In conclusion, from an overall public health standpoint and thinking in 

terms of opportunity costs, he recommended that any additional resources that might be used to 

comply with this recommendation be diverted to smoking cessation.

Dr. Turner (ACHA) stressed that the conundrum of revaccination would be a major issue for 

those seeing college students. Given that 20% of the students at his school smoke, technically 

he should be giving this vaccine to some 4000 students at the age of 19 or 20 and then 

according to the current recommendations, they should not be revaccinated again until they turn 

age 65. In 25 years of college health he did not believe he had ever seen a case of IPD. 

Hence, he wondered how many young people would truly benefit from vaccinating against this 

disease.

With regard to Dr. Chilton’s request for elaboration on the “back of the envelope” calculation, Dr. 

Cieslak replied that this is an inexpensive vaccine and even it immunization costs are 

considered, there would not be a major expense to vaccinate a single person at a rate of 

prevention of 1 per 10,000 per year, figuring years of potential life lost, wages, et cetera. Based 

on the data presented and what he should make of it, his best guess was that it would not be as 

high as some of the vaccines considered by the ACIP.

Ms. Ehresmann inquired as to whether the recommendation could begin at a later age of 

perhaps 40 through 64, given that 40 to 44 appears to be a peak age. 

Dr. Nuorti replied that the work group discussed whether it would make sense to begin at 

another age, such as 50 years. Based on the data that show the prevalence of smoking among 

cases, this would miss a large number of smokers who develop disease. There are a number of 

former smokers in the 50 and older age group.

With regard to the prevalence of smoking and the ability to reduce it and the comments 

pertaining to effective counseling being an effective method, Dr. Sumaya pointed out that the 

evidence within states with respect to reducing smoking on a long-term basis rest more with 

laws and regulatory mechanisms of age groups, price, and access. They must take the 

vagaries of the political arenas to have an effect on reducing the smoking population at risk.

Dr. Lewis (AHIP) suggested that cost-effectiveness must also be taken into consideration with 

respect to the asthma indication, given that if the number needed to vaccinate in smokers is 

lower than in asthmatics, essentially cost-effectiveness will be better in the smoking population 

than in the asthmatic population. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

19

John Grabenstein (Merck & Company) reported that Merck & Company calculated a number 

needed to vaccinate analysis on a variety of populations. While he did not have smoking data 

and recognized that NNV data had all of the assumption needs of any cost-effectiveness model, 

their assessment was that for 65+ the number needed to vaccinate to prevent an IPD case with 

a 10-year duration of protection is about 1200. If patients with co-morbidities ages 18 through 

64 are added in, this falls to 662. The smokers and asthmatics would be on par with those with 

the co-morbidities recommended.

Stanley Plotkin, sanofi pasteur, thought there may be some virtue in identifying the age of 45 or 

so as the target for vaccination. The data on persistence of antibody protection are not good; 

however, the data are very good on the response to the vaccine with functional antibodies that 

tails off at about age 45. Hence, he thought there would be more benefit in vaccinating at age 

45 just before the incidence of IPD begins to rise and the vaccine would be maximally effective.

Dr. Lett inquired as to whether the vaccine supply was sufficient to accommodate the initial 

uptake for the proposed recommendation.

John Grabenstein (Merck & Company) responded that there is an ample supply of vaccine, with 

stability of 10 years in the freezer.

Reflecting upon the June 2008 ACIP meeting, Dr. Temte pointed out that a request was made 

to look across the data on tobacco smokers using an age cutoff. He took what Jim Turner 

(ACHA) said with a great deal of seriousness, given that there is a large cohort of young 

smokers who are some of the most responsive to intervention for smoking cessation. Hence, 

he went on record to state that he would prefer a combination of smoking and age. With 

respect to the adult immunization schedule, there is currently a 50-year old cutoff for influenza. 

Motion: PPSV23 Pneumococcal Vaccines in Cigarette Smokers

Dr. Baker motioned that the recommendation be approved as written, with the addition of “as 

well as smoking cessation counseling” to the end of “Persons aged 19-64 years who smoke 

cigarettes should receive PPSV23.” Dr. Cieslak seconded the motion. The motion carried with 

11 affirmative votes, 1 abstention, and 3 negative votes. 

Proposed Recommendations for use of PPSV23 

Among American Indians and Alaska Natives

Kate O’Brien, MD, MPH

Center for American Indian Health

Johns Hopkins Bloomberg School of Public Health

Dr. O’Brien acknowledged the following authors of the proposed changes to these 

recommendations: Amy Groom, MPH, Immunization Program Manager, and Steve Holve, MD, 

Chief Clinical Consultant, Pediatrics from Indian Health Services; Ros Singleton, MD, MPH, 

Immunization Consultant, from the Alaska Native Tribal Health Consortium; Tom Hennessy, 

MD, MPH, Director, and Jay Wenger, MD, Associate Director for Science, of CDC’s Arctic 

Investigations Program; and Kate O’Brien, MD, MPH, Associate Professor, from Johns Hopkins 

Center for American Indian Health.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

20

The two recommendations the work group requested that ACIP members discuss included 

PPSV23 after PCV7 for 24 -59 month olds and PPSV23 for adults, which currently reads as 

follows:

Recommendation #1: PPSV23 after PCV7 for 24 -59 month olds

ACIP Recommendation for PPSV23 in AI / AN Children*

Administration of PCV7 Followed by PPSV23 among Children at High Risk for Pneumococcal 

Disease:

 Children who have completed the PCV7 vaccination series before age 2 years and who 

are among risk groups for which PPSV23 is already recommended should receive one 

dose of PPSV23 at age 2 years (>2 months after the last dose of PCV7). 

 These groups at high risk include children with SCD, children with functional or anatomic 

asplenia, children who are HIV-infected, and children who have immunocompromising or 

chronic diseases. Although data regarding the safety of PPSV23 administered after 

PCV7 are limited, the opportunity to provide additional serotype coverage among these 

children at very high risk justifies use of the vaccines sequentially. 

 For children of Alaska Native or American Indian descent, addition of PPSV23 after 

PCV7 can be considered. 

*From: “Preventing Pneumococcal Disease Among Infants and Young Children. Recommendations of the Advisory 

Committee on Immunization Practices (ACIP). MMWR October 06, 2000 / 49(RR09);1-38 

Table 12 in the MMWR (Vol. 49 / No. RR-9; Page 25) shows that for otherwise healthy children, 

no polysaccharide vaccine is recommended. However, there is an asterisk that states that, 

“Health-care providers of Alaska Natives and American Indians should consider whether these 

children would benefit by the additional coverage provided by the expanded serotypes in 

PPSV23 (see recommendations regarding Alaska Natives and American Indians).” 

The strengths the work group members found in the current recommendation is that there is 

permissive language allowing for the option to use PPSV23 in the AI / AN population, which 

includes some groups at high risk. Therefore, the VFC will cover the costs of vaccine if it is 

administered. The weaknesses include the burden of the decision upon individual practitioners. 

Numerous providers have expressed that they do not have sufficient data on risks / benefits to 

make informed decisions. In addition, the language lacks specificity. It is very clear from the 

data and the literature that all AI / AN groups are not at equal risk. In fact, the data on increased 

IPD risk are really limited to Alaska Native, White Mountain Apache, and Navajo populations

rather than all AI / AN groups. In addition, the term “American Indian descent” is not defined.

With respect to why special recommendations should be included for AI / AN children, there are 

high rates of invasive pneumococcal disease in some of these populations, so public health 

authorities and health care practitioners have always considered whether there would be a 

benefit to the use of PPSV23. Considerations of the work group and advisors to the work group

included: age-specific IPD incidence; serotype distribution of IPD; limited data on effectiveness 

of PPSV23 in this age group and population; safety concerns related to immune tolerance / 

hyporesponsiveness and whether that has any clinical ramifications; potential for other 

intervention strategies, such as PCV13; and practical considerations such as cost, 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

21

implementation into an already crowded vaccination schedule, and having to stock multiple 

pneumococcal vaccine products and the possibility of mixing up products.

Regarding incidence rates by age strata among AN and White Mountain Apache and Navaho 

compared with relevant comparison populations, Dr. O’Brien referred to post-PCV7 IPD era in

Alaska Natives and non-Natives from 2004 -2006. For each of the age strata, there continues 

to be a health disparity in terms of IPD rates among Alaska Natives compared with non-Natives. 

This is most prominent in the <2-year old age strata, with 245 per 100,000 in Alaska Natives 

compared with 44 per 100,000 in Alaska non-natives. However, there is still a health disparity in 

these rates in the 2 to 4 year old age strata, with 40 cases per 100,000 in the Alaska Natives 

compared with 15 per 100,000 in Alaska non-Natives.

In post-PCV IPD rates among Navajo (2004-2006), White Mountain Apache (2004-2006), and 

the general US population 2005 data, in the <1 year olds (215 per 100,000 Navajo; 301 per 

100,000 White Mountain Apache; 36 per 100,000 general US population) and the 1 to <2 year 

olds (148 per 100,000 Navajo; 402 per 100,000 White Mountain Apache; 36 per 100,000 

general US population), there continues to be a health disparity in terms of IPD rates. There is 

a health disparity of much small magnitude among those 2 to <5 years of age (27 per 100,000 

Navajo; 0 per 100,000 White Mountain Apache; 12 per 100,000 general US population), but 

only for the Navajo in this era. In fact, the White Mountain Apache had zero cases of IPD in the 

2 to <5 year olds over this three-year period, so their rate has actually fallen below that of the 

general US population. This is the age group being considered for the use of polysaccharide 

vaccine for AI / AN. In terms of the IPD rates over time in 24-59 month old Alaska Natives, 

Navajo, White Mountain Apache, and the general US population the trend is that the rates of 

disease has decreased dramatically between 1995 and the current era. In examining the years 

2004-2006, it is evident that there continues to be some disparity, but the magnitude of that is 

much smaller. 

With respect to post PCV7 serotype distribution in AI / AN 24-59 months of age, the size of the 

birth cohort, and the actual number of annual cases, there are only 300 annual births among 

White Mountain Apache, 4000 Navajo, and 2600 Alaska Natives. There are zero PCV7 annual 

cases among any of these groups. Non-PCV7 annual cases include 0-1 among White Mountain 

Apache, 1-5 among Navajo, and 3-9 among Alaska Natives. Nevertheless, the proportion of all 

of the IPD in this age strata that are caused by PPSV23 types is >80% in each White Mountain 

Apache and Navajo and 90% in Alaska Natives. Thus, it is true that most of the disease that is 

still occurring is of serotypes in the vaccine. 

In terms of other concerns, it is important to understand the perspective of the practitioners who 

serve these populations. Routine use of PPSV23 has never been implemented in these 

populations, even when rates were significantly higher in the pre-conjugate vaccine era. There 

are no local data on safety or reactogenicity in these populations. The second concern is the 

observation of immune hyporesponsiveness that has been demonstrated following the use of 

PPSV23. This is a relatively complicated topic, but the important point is that while it is quite 

clear that there is a measurable immune hyporesponsiveness, the clinical implications of that

are not known. The third issue is the complexity of a two-product vaccine strategy. In addition, 

little efficacy / effectiveness data exist on PS23 among children in the <5 year old age strata.

The current consensus among practitioners and those who work with these populations is that 

the anticipated benefits of PPSV23 use after PCV7 probably do not outweigh the potential risks 

and practical considerations. In terms of current clinical practice, PPSV23 is not routinely used 

following PCV7 among AI / AN children >2 years by any Indian Health Service or tribal health 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

22

organization serving the populations with documented high rates of IPD. Some individual 

providers have used PPSV23 for individual patients. However, it is very important to recognize 

that PPSV23 is routinely given to those children in these populations who have recognized high 

risk medical conditions, so this is covered elsewhere in the ACIP recommendations and is not 

really the topic of this particular recommendation.

Concerning why the work group would like to preserve a specific statement for AI / AN

populations, the balance of risk / benefit could change in the future. For example, among 

Alaska Native children, there has been an increase in non-PCV7 type IPD rates since the 

introduction of PCV7. There is a plan to use the PCV13 product under compassionate-use IND

in 2009 and it is hoped that there will be licensure for the product soon thereafter. However, if 

PCV13 is not successful, there probably would be reconsideration of PPSV23 use at least in 

some sub-populations in Alaska. The second example is among indigenous children in the

Northern Territories of Australia where PPSV23 is used at 18 months following a 3-dose PCV7 

series. Safety and effectiveness data are anticipated out of that experience, which will 

accumulate over time, so more information may be forthcoming about concerns expressed 

previously.

With regard to IPD in Alaska in those < 2 years old from 1995-2007, although it has been widely 

publicized that there has been considerable replacement disease among Alaska Natives, this is 

completely restricted to children who live in the YK Delta region (a birth cohort of about 600 

children per year). The increase in serious pneumococcal infections has not been observed in 

other Alaska Native children or non-Native children outside those in the YK Delta. With regard 

to the IPD rates in YK Region children < 5 years of age from 1998-2007, replacement disease is 

in < 2 year olds, while PPSV23 in 2-5 year olds is not expected to have much impact on

replacement disease. Replacement disease is actually occurring in children 1 to <2 years of 

age, so the total population size of children <5 is 600 total children and of those, replacement is 

occurring only in a very limited age strata. 

Regarding IPD Rates in the Northern Territories of Australia in indigenous children <5 years, 

there is no change in the non-PCV7 incidence even though they are using PPSV23 vaccine in 

these children at 18 months of age following 3-dose PCV7 priming. In spite of the use of the 

polysaccharide vaccine as the boost, the incidence of the non-7-valent types has not changed 

dramatically over time. Whether they are having any effect of the use of polysaccharide vaccine 

on the non-7-valent serotypes is really to be determined. Obviously, these data would be 

stronger if they showed only the 2-4 year old age strata and looked at the 16-PPV types [Data 

courtesy of Heather Cook and Vicki Krause, Northern Territory CDC, Darwin, Australia].

In terms of what is needed in a recommendation for AI / AN, ACIP needs to indicate clearly to 

practitioners what the routine use of PPSV23 should be. Future use should be allowed if IPD 

epidemiology changes, new data emerge on effectiveness or safety, or if effective higher 

valency conjugate vaccines do not become available. It should be clarified that decisions for 

use should be based on increased risk of IPD rates. Background could include information on 

epidemiologic characteristics to consider (e.g., serotypes, absolute rates, age groups). A 

recommendation should also allow for VFC to purchase vaccine if use is indicated.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

23

The recommendation for the vote pertaining to the use of PPSV23 in AN / AI children read as 

follows: 

“Routine use of PPSV23 after PCV7 is not recommended for Alaska Native or American 

Indian children aged 24 through 59 months. However, in special situations, relevant 

public health authorities may consider addition of PPSV23 after PCV7 for Alaska Native 

or American Indian children aged 24 through 59 months who are living in areas in which 

risk of invasive pneumococcal disease is increased.”

The following table contrasts the current with the proposed recommendations, with those areas 

that differ being underlined:

Current Proposed

 Routine Use: "For children of Alaska 

Native or American Indian descent, 

addition of PPSV23 after PCV7 can be 

considered” (at age 2 years)

 Special Use: "Health care providers of 

Alaska Natives and American Indians 

should consider whether these children 

would benefit by the additional 

coverage provided by the expanded 

serotypes in PPSV23." 

 Routine Use: “Routine use of PPSV23 

after PCV7 is not recommended for 

Alaska Native or American Indian 

children aged 24-59 months.” 

 Special Use: “However, in special 

situations, relevant public health 

authorities may consider addition of 

PPSV23 after PCV7 for Alaska Native 

or American Indian children aged 24 

through 59 months who are living in 

areas in which risk of invasive 

pneumococcal disease is increased.”

With respect to recommendation #2, the ACIP recommendation for use of PPSV23 in AI / AN 

populations [MMWR 1997] currently reads, "Persons aged 2-64 years who are living in 

environments or social settings in which the risk for invasive pneumococcal disease or its 

complications is increased (e.g.., Alaskan Natives and certain American Indian populations) 

should be vaccinated." The strengths of this recommendation are that its permissive language 

allows the option to use PPSV23 in the AI / AN population, and some AI / AN groups are at high 

risk for IPD. The weaknesses are that all AI / AN populations are not at equal risk. Again, 

increased IPD risk data are limited to Alaska Native, White Mountain Apache, and Navajo 

populations. Moreover, risk and health disparity vary by age strata within the very broad age 

range of 2-64 years of age. Also, the language lacks specificity in that there is no definition of

“environments and social settings” at high risk, which leads to a tremendous amount of 

confusion and variable interpretation among practitioners. Furthermore, this language is 

considered to be offensive by some AI / AN groups. In addition, the age group is over-inclusive. 

The 2-5 year old group is already covered by another ACIP recommendation, while the absolute 

risk increases in the remaining age strata are of varying magnitude.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

24

With regard to the post-PCV IPD rates among Navajo and White Mountain Apache populations, 

for each of the age strata (e.g., 5-<18, 18-49, 50- <65, and 65+) there is a health disparity 

compared with the general US population, but the absolute magnitude of the health disparities 

varies according to population and age strata. In terms of IPD rates comparing Alaska Natives 

and non-Natives from 2005-2007, health disparities are observed in the age strata 5 years of 

age and older; however, the absolute magnitude of that risk is not the same across all age 

strata. For example, among children 5-17 years of age there is a difference of 5 cases per 

hundred thousand compared with those 60-64 years of age where there is an absolute rate 

difference of 100 per 100,000. 

The current practice is somewhat more complicated than the pediatric situation. This 

recommendation is not routinely followed among any of the Indian Health Services or tribal 

health organizations who serve populations with high rates of IPD. A few groups do routinely 

use PPSV23 among otherwise healthy adults younger than 65 years. In Alaska, the 

recommendation is to use PPSV23 vaccine beginning at age 55 years. In the White Mountain 

Apache reservation, routine vaccination begins at age 50 years. The Navajo have maintained 

the recommendation for the general US population to start at age 65. Other Indian Health 

Service and tribal health groups follow the recommendation for first use of PPSV23 at 65 years. 

In terms of medical indications, it is important to understand that 70% to 86% of AI / AN adults

aged < 65 years with IPD had an underlying condition that is included in current ACIP 

recommendations for PPSV23. With that in mind, Dr. O’Brien cautioned the group to take into 

consideration that these are not rates among otherwise healthy American Indians or Alaska 

Natives. Most of the cases of IPD are occurring among those people who have other indication 

for getting pneumococcal vaccine. The work group could not provide the rates of disease by 

age strata among otherwise healthy Alaska Natives, Navajo, or White Mountain Apache 

because they could not establish the denominator of people who have no other underlying 

medical condition. 

In terms of what is needed in a new ACIP recommendation, the work group suggested removing

the wording regarding “environments and social settings” at high risk; focusing on at-risk age 

group not already covered by an ACIP recommendation (e.g., > 50 year olds); allowing current 

policies to continue (local decision-making has been evidence-based; there is no firm reason to 

force change in local policies); and adding permissive language to allow PPSV23 use that could 

be used if local IPD epidemiology changes or new data emerges on effectiveness or safety. 

The recommendation for the vote regarding the use of PPSV23 among AN / AI adults read as 

follows:

"Routine use of PPSV23 is not recommended for Alaska Native or American Indian persons 

younger than 65 years old unless they have underlying medical conditions that are PPSV23 

indications. However, relevant public health authorities may consider PPSV23 for Alaska 

Natives and American Indians aged 50 through 64 years who are living in areas in which the 

risk of invasive pneumococcal disease is increased."
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

25

The following table contrasts the current with the proposed recommendations, with those areas 

that differ being underlined:

Current Proposed

 “Persons aged 2-64 years who are 

living in environments or social settings 

in which the risk for invasive 

pneumococcal disease or its 

complications is increased (e.g.., 

Alaskan Natives and certain American 

Indian populations) should be 

vaccinated."

 “Routine use of PPSV23 is not 

recommended for Alaska Native or 

American Indian persons younger than 

65 years old unless they have 

underlying medical conditions that are 

PPSV23 indications.”

 “However, relevant public health 

authorities may consider PPSV23 

for Alaska Natives and American 

Indians aged 50 through 64 years who 

are living in areas in which the risk of 

invasive pneumococcal disease is 

increased."

Discussion

Dr. Judson found the arguments for the proposed changes to be highly compelling. He said that 

throughout his career, he had looked askance at the way the non-defined category of AI / AN 

was lumped together as they are probably one of the most heterogeneous groups 

environmentally, socially, and genetically. He expressed hope that there would come a time in 

which this un-useful grouping would not be singled out for any particular approach and that 

recommendations would apply to them just as they do any other American—based on risk 

factors. 

Dr. O’Brien responded that there is a delicate line. There are some populations which have 

clearly elevated risks for whom they should preserve the opportunity to afford them special 

consideration in times of vaccine shortage or specific products that are needed to take care of 

specific health issues related to these populations, particularly with respect to conjugate 

vaccines and specific HIB products that are needed. She agreed with Dr. Judson, but cautioned 

that they should not go all the way in the other direction so that this group may not be afforded 

what they need.

Dr. Judson responded that he thought this was well covered in the second part. He had written 

down, “in populations where high rates of pneumococcal disease have been documented 

recently,” which would apply to anyone. 

Dr. Sawyer requested clarification regarding how the work group came to the responsiveness 

issue and the age recommendation of 50 and above. He noted that, as pointed out by Dr. 

Plotkin earlier, both the quantity and quality of immune response in older adults is not as good.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

26

Dr. O’Brien replied that the choice of a 50-64 year old age strata was a relatively qualitative one. 

The first consideration was to evaluate the data. Clearly, there is elevated risk of disease in the 

50 to <65 year old age strata in Navajo, White Mountain Apache, and the Alaska Native 

situation. Below this age strata, there would be a potential to vaccinate numerous people 

whose risk of disease is not nearly as elevated as it is thought to be. She emphasized that most 

of the cases of IPD are not among otherwise healthy individuals, but that about 70% to 80% of 

cases have a recognized underlying medical condition. In the lower age strata, the dominant 

underlying medical condition is alcoholism. In all-age IPD, a substantial proportion of the cases 

are related to people who have alcohol-related problems. In the Navajo, approximately 20% of 

the adult population has alcoholism as a medical condition. Thus, the work group did not 

believe that an otherwise healthy population below the age of 50 necessarily would be the place 

to achieve substantial gains in terms of prevention of disease, and it raises the issue of what to 

do about re-vaccination. The lower the age strata at which vaccination begins, the more the 

competing concerns with respect to having to give repeated doses of polysaccharide vaccine 

and what is being done in terms of an immunologic phenomenon and actually protecting them in 

their future years when their risk is higher. Therefore, the work group felt that this was an 

appropriate compromise between programmatic considerations, trying to target the population 

who do likely have the highest risk, and understanding that programs and policies are already in 

place in these settings. No one is using a program or policy in which they go below 50 for 

routine immunization for otherwise healthy individuals.

Dr. Sumaya wondered why the term “relevant public health authorities” was chosen.

Dr. O’Brien said she thought they were trying to indicate public health authorities who would 

have some knowledge of the local situation without being more specific about who those 

authorities are, given that they differ across populations. For the Navajo, the relevant public 

health authorities would likely be a consortium of Indian Health Service practitioners along with 

the Tribal Health Authority, and probably with consultation at the Center for American Indian 

Health at Johns Hopkins which has the data and can provide the evidence with which this would 

be considered. For White Mountain Apache and Alaska Natives, it would be a different group of 

public health authorities. The work group was simply indicating that they wanted it to be the 

most appropriate public health authorities who could guide the local situation.

In terms of “public health authorities” it was not clear to Dr. Cieslak whether they would be 

advising doctors to send these populations to health departments to be vaccinated, or to rely on 

recommendations from public authorities. He was also troubled by areas in which the risk of 

IPD is increased because a doubling of a very small risk may still result in a very small risk. A 

relative risk of 1.1 is an increased risk, so he wondered if the work group had some value in 

mind. 

Dr. O’Brien responded that the intent was a recommendation. There is no public health 

department on the reservations that differs from the Indian Health Service facilities, so perhaps 

the wording could be refined to “public health authorities may consider a recommendation for 

use.” With regard to increased risk of IPD, she indicated that this was why the work group did 

not want to suggest a specific recommendation even for the three populations for which data

exist. Instead they thought it was probably best to let this decision rest in the hands of those 

who could take a very detailed look at the data and the absolute magnitude of the risk as 

opposed to relative risk. It was not intended to mean that any relative risk increase would 

trigger this. The group was trying to exclude calls from people whose grandmother is American 

Indian, but who are living in California or New York, who want to know whether they are at risk. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

27

The idea was to restrict the recommendation to at least those places in which there is an 

elevated risk.

Dr. Baker pointed out that the second sentence had many problem aside from the word 

“relevant.” While she understood that the work group was seeking flexibility based upon the 

particular community, “relevant public health” made it seem as though there are “non-relevant 

public health authorities.” Therefore, she suggested using a less offensive word and using the 

first sentence in order to give flexible / permissive advice, not as part of the summary 

recommendation, but in the language that is published in the MMWR statement.

Dr. Neuzil thought the wording represented an improvement and was much clearer; however, 

she remained troubled by the graph which reflected disparities that the work group found to be 

covered by co-morbidities. Her concern was that this suggests that coverage could be 

improved in these populations among the high risk groups. Depending upon what they decided 

to do with the second part of the recommendation, she suggested that they continue to 

emphasize that people with conditions in these adult populations should be vaccinated with the 

PPSV23. Perhaps they could add, “may extend PPSV23 coverage to include those age 50 to 

64 without medical conditions” to further stress that all of those adult age groups with medical 

conditions need to be vaccinated.

Dr. O’Brien reiterated that approximately 75% to 80% of the cases have an underlying condition. 

Vaccine coverage has been evaluated extensively in the Navajo, White Mountain Apache, and 

Alaska Natives and has been found to be extremely high. In the over 65 year old group, 80% to 

90% have been vaccinated. In the <65 year old group, the proportions are somewhat lower, but 

the one condition that stands out in which vaccination could probably be improved is in the 

alcoholics younger than 65 years of age where only 40% have evidence of vaccination. In the 

other medical conditions, the proportion who are vaccinated, even among those younger than 

64 years of age is 60% to 70% or higher. Hence, there is a significant effort to recognize these 

conditions and get people vaccinated. The work group has also evaluated the effectiveness 

data. This is not a highly effective vaccine against IPD. For example, effectiveness is 

approximately 40% in Navajo in one case-control study.

While the data were compelling for Navajo, White Mountain Apache, and Alaska Natives, Ms. 

Ehresmann pointed out that Minnesota has a number of American Indian populations for whom 

there are no specific data. As a local public health official, she wondered what data they would 

need to begin collecting in order to actively make recommendations. 

Dr. O’Brien responded that there are not population-based, active surveillance data on 

American Indian populations outside of the three populations upon which she reported. The 

question is: Is there an unmeasured, unrecognized, elevated risk among other American Indian 

tribes throughout the United States? The best evidence there is to suggest that this is not 

occurring comes from ICD-9 IHS data. There does not appear to be a signal in these data that 

there is an IHS administrative area that has elevated rates outside of the Southwest and the 

Alaskan area. There are significant limitations to those data, which is why the work group 

wanted to have flexibility within the recommendation so that in the future, if it was recognized 

that there was another population in which there was evidence for increased risk, there would 

be the opportunity to extend the vaccine recommendation to those groups without having to 

vote on a revised recommendation or face issues with respect to reimbursement for use of the 

product.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

28

Dr. Morse recapped that there had been a suggestion to change the wording to “However, 

appropriate public health authorities may consider making recommendations on . . .” 

Dr. Judson suggested using “local public health authorities,” given that they should know what is 

going on. To him, the terms “appropriate” and “relevant” did not seem helpful.

Dr. Englund pointed out that health authorities are not always local. The Hopkins group, for 

example, advises the White Mountain Apache. She thought the word “appropriate” should be 

used.

Dr. Duchin, NACCHO, suggested the wording, “public health authorities using current local 

epidemiological data,” which would negate the concern about whether they were appropriate or 

relevant. Public health authorities using the right data could be sitting anywhere. 

Dr. Englund noted that while this is what they would like, current local epidemiological data is 

not always available.

Dr. Baker stressed that this was why she thought it should be in the narrative rather than as part 

of the recommendation. 

In terms of where language is included, Dr. Neuzil requested clarity with respect to what had to 

be included in the recommendation versus what could be included in the narrative.

Dr. Schuchat responded that the extra sentence was meant to foreshadow a VFC vote or reflect 

what VFC would be allowed to cover. Given that these are separate votes, she indicated that it 

did not matter where the language was included. As long as the language appeared in a 

document somewhere, there could be a VFC vote pertaining to use.

Dr. O’Brien thought it would be relatively important for practitioners and Indian Health Services 

to have something permissive within the recommendation itself as opposed to the text of a 

larger document. He thought practitioners and Indian Health Services would feel somewhat 

uncomfortable if a recommendation was published that said these are not recommended and 

did not allow for permissive use in the recommendation itself.

Dr. Marcy suggested eliminating the word “relevant.”

Dr. Morse clarified with the additional wording of, “public health authorities may consider making 

recommendations on . . . “

Dr. Baker expressed concern that this still did not deal with the problem of what constitutes an 

increase in IPD. 

Dr. Judson indicated his reluctance about being too wordy regarding what local public health 

authorities should do. They will have to do the best they can with whatever resources they 

have. They often will not have fully epidemiologic secular trend data, so the recommendation 

should simply be “local public health authorities” because they are going to have to make the 

decisions and they need to be empowered to do so by these recommendations.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

29

Ms. Ehresmann agreed that local public health would not make a decision if it is not allowed for 

in a permissive manner. She asked for clarification regarding where they stood in terms of the 

language. She wondered if they took out the word “relevant” and addressed increased risk 

being less defined, this would address the issues. 

Dr. Morse replied that he thought based on the discussion there was consensus on the overall 

recommendation.

Dr. Lett indicated that she always found it beneficial for recommendations to state that local 

health authorities should make decisions based on current epidemiologic data, which she 

thought should appear somewhere in the recommendation.

Dr. Pickering pointed out that the recommendations cannot be changed in the VFC vote, so the 

wording should be specific in the motion.

In the absence of a public health recommendation, for example a local health department has 

not data and declines to make a recommendation, Dr. Cieslak wondered if this would permit a 

physician to vaccinate and have it be VFC-covered.

Dr. Santoli responded that it would be a decision of the ACIP. CDC was attempting to update 

the resolution to reflect the recommendations, which meant that at this point the VFC stated, 

“American Indian / Alaska Native children may receive a single dose of polysaccharide vaccine 

following conjugate vaccination when deemed appropriate by public health authorities.” 

Dr. Sawyer expressed confusion with respect to the VFC discussion. He expressed concern 

about the language fundamentally because the provider makes the decision to give the vaccine, 

not public health, on a one-on-one basis. He stressed that he did not want providers to be 

prohibited from the vaccine because it would not be covered by VFC if no public health 

recommendation was in place in a particular locality. 

Dr. Santoli suggested that in order to address this issue, an option would be for the VFC 

resolution to state, “American Indian / Alaska Native children 24 to 59 months old.” Then VFC 

can cover it and the recommendation could include more specific items.

Motion: PPSV23 Pneumococcal Vaccines in American Indian / Alaska Native Children

Dr. Neuzil made a motion to approve the language of the recommendation, with the exclusion of 

the word “relevant,” the addition of “public health authorities may consider recommending 

PPSV23,” and with grammatical and other changes made to improve the recommendation 

based on the intent of the discussion. Dr. Baker seconded the motion. The motion carried with 

14 affirmative votes, 1 abstention, and 0 negative votes.

Motion: PPSV23 Pneumococcal Vaccines in American Indian / Alaska Native Adults

Dr. Neuzil made a motion to approve the language of the recommendation, with the exclusion of 

the word “relevant,” the addition of “public health authorities may consider recommending 

PPSV23,” and with grammatical and other changes made to improve the recommendation 

based on the intent of the discussion. Dr. Baker seconded the motion. The motion carried with 

14 affirmative votes, 1 abstention, and 0 negative votes.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

30

Dr. Nuorti pointed out that a vote was not taken to revise the age range for PPSV23 in those 

with asthma to make it consistent with the cigarette smoker recommendation. Therefore, an 

additional motion was made . 

Motion: PPSV23 Pneumococcal Vaccines in Those with Asthma

Dr. Sawyer made a motion to approve the recommendation to expand the pneumococcal 

polysaccharide 23-valent vaccine (PPSV23) target groups to include persons 19 to 64 years of 

age who have asthma. Dr. Temte seconded the motion. The motion carried with 14 affirmative 

votes, 1 abstention, and 0 negative votes.

Proposed Recommendation for use of PPSV23 

In High Risk Children Ages < 10 Years

Pekka Nuorti, MD, DSc

CDC / CCID / NCIRD / DBD

Dr. Nuorti reminded everyone that the issue of PPSV23 use in high risk children <10 years of 

age was discussed during the June 2008 ACIP meeting. The objective of this session was to 

propose a clarification to the recommended time interval for PPSV23 revaccination in high risk 

children aged <10 years who have previously received PCV7. One of the problems is that there 

are currently two recommendations, one made in 1997 and the other made in 2000. Some 

health care providers have found the 3-5 year revaccination interval to be confusing in the 

section in the 2000 recommendation which states that, “If the patient is aged < 10 years, one 

revaccination 3-5 years after the previous dose should be considered (Sources: CDC. 

Recommendations of the Advisory Committee on Immunization Practices [ACIP]., MMWR 2000; 

49(RR-09)]. 

The original section about revaccination with PPSV23 in high risk children in the MMWR

1997;46 (No RR-8) states the following:

 “Revaccination once is recommended for persons aged >2 years who are at highest risk 

for serious pneumococcal infections and those who are likely to have a rapid decline in 

pneumococcal antibody levels, provided that 5 years have elapsed since receipt of the 

first dose of pneumococcal vaccine.”

 “Revaccination 3 years after the previous dose may be considered for children at highest 

risk for severe pneumococcal infection who would be aged <10 years at the time of 

revaccination.” 

 These children include those with functional or anatomic asplenia (e.g., sickle cell 

disease or splenectomy) and those with conditions associated with rapid antibody 

decline after initial vaccination (e.g., nephrotic syndrome, renal failure, or renal 

transplantation).
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

31

The recommendation for revaccination in high risk children in the 2000 recommendation is as 

follows:

 “Immunocompromised children or children with SCD or functional or anatomic asplenia 

should be revaccinated with PPSV23 as previously recommended” 

 “If the child is aged <10 years, one revaccination should be considered 3-5 years after 

the previous dose of PPSV23”

 “Data are limited regarding adverse events related to second dose of PPSV23

administered after PCV7. Health care providers should not administer a second dose of 

PPSV23 any earlier than 3 years after the initial dose of PPSV23” [MMWR 2000; 49(RR09)]

The rationale for the use of PPSV23 in high risk children who have received PCV7 includes the 

following:

 “Although data regarding safety of PPSV23 administered after PCV7 are limited, the 

opportunity to provide additional serotype coverage among these children at very high 

risk justifies use of the vaccines sequentially” [MMWR 2000; 49(RR-09)]

 PPSV23 provides an excellent booster response in healthy children to the 7 serotypes in 

both PCV7 and PPSV232 [O’Brien Lancet Inf Dis, 2007]

 The intent of the recommendation is to target the 16 serotypes only in PPSV23, although

the effectiveness of this approach is unknown 

In terms of the current rates and serotypes causing IPD in children aged 5-9 years, the overall 

rate is very low at 6 per 100,000. There has practically been no change after PCV7 introduction 

in this group because of increases in non-PCV7 types. The rates of all different serotype 

groupings are <4 cases per 100,000 [Data source: CDC, Active Bacterial Core surveillance, 

unpublished]. The proportion of cases among children aged 5-9 years who had various 

underlying medical conditions as defined in Table 8, MMWR 2000;49(No. RR-9):22 has 

increased after PCV7 introduction. However, the total number of cases is very small. In 2006, 

out of 55 children with IPD, 12 (22%) cases had any high risk condition (PPSV23 indication) 

[Data source: CDC, Active Bacterial Core surveillance, unpublished]. Regarding the proportion 

of invasive pneumococcal disease cases caused by indicated serotypes among children 5-9 

years-old with ACIP indications for PPSV23, in 2006, 12 (22%) of 55 children aged 5-9 years 

had any underlying medical condition that are indications for PPSV23 and all but one were 

conditions for which revaccination is recommended. Of the 12 cases with underlying medical 

conditions, 10 (83%) were caused by serotypes in PPSV23 but not in the conjugate vaccine. 

There were no cases with HIV infection [Data source: CDC, Active Bacterial Core surveillance, 

unpublished].

There are very few data available on multiple doses PPSV23 in children. There are six pediatric 

studies of multiple PPSV23 doses that were conducted from the 1970s and 1980s [Reviewed in: 

O’Brien Lancet Infect Dis 2007;7:597-606]. These were conducted with different vaccine 

formulations (e.g., PPSV8, PPSV12, PPSV14, PPSV23) and most used radioimmunoassay 

(RIA) which predates the development of sensitive and specific assays and lacks specificity for 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

32

serotype specific antibody. Of the six studies, five observed lower antibody concentrations for 

some serotypes with a second PPSV dose.

The work group’s considerations addressed a number of issues. Few studies have evaluated 

the immunogenicity of multiple doses of PPSV23 in children. The clinical effectiveness of 

PPSV23 following PCV7 in children is unknown. No data are available on the effectiveness of 

revaccination with PPSV23 in this age group compared with only a single dose of PPSV23. The 

statement to consider revaccination in high risk children 3 years after the first dose was based 

on immunologic data from the 1980s indicating rapid antibody decline after PPSV23 vaccination 

in certain children at high risk [MMWR 1997; 46 (RR-8)]. However, those studies predated 

development of sensitive and specific antibody assays. Therefore, the interpretation of data is 

hampered by the non-specificity of the assays used to measure the immune response. No data 

are available to determine the relative benefit of a 3- versus 5-year revaccination interval, but 

immunologic responses to PPSV23 may be better in older children [Vernacchio J Infect Dis 

2000; Rao J Pediatr 1995]. There is concern about potential immunologic hyporesponsiveness 

to subsequent exposure to pneumococcal antigens after PPSV23; however, the clinical 

relevance of this observation is unknown. There is a hypothesis that perhaps a longer interval 

between PPSV23 doses may reduce the immunologic hyporesponsiveness. 

Based on the review of the data and these considerations, the work group proposed the 

following recommendation:

 Immunocompromised persons or persons with sickle cell disease or functional or 

anatomic asplenia are at highest risk for serious pneumoccoccal infection and may have 

a rapid decline in pneumococcal antibody levels after PPSV23

 The work group recommends a single revaccination interval for these persons in all age 

groups:

 A second dose of PPSV23 is recommended 5 years after the first dose of PPSV23 for 

persons aged >2 years who are immunocompromised, have sickle cell disease, or 

functional or anatomic asplenia.”

Discussion

Dr. Meissner inquired as to how many of the 16 serotypes that occurred in the small number of 

children would have been included in the 13-valent vaccine. If those are well covered by the 13-

valent conjugated vaccine, he wondered whether this recommendation would still be needed. 

Obviously, they would still be concerned about the 23 minus 13 types.

Dr. Nuorti replied that he did not have this information with him, but he offered to check. These 

are the 16 serotypes that are not in the 7-valent, so there is some overlap with the six additional 

types that are in the 13-valent. He agreed that it was an important point as the serotype 

coverage between the 23-valent and 13-valent became narrower. 

Dr. Judson said he was convinced that they did not have the scientific support for this 

recommendation. If they were going to be arbitrary with recommendations, it would be better 

that they be arbitrarily consistent rather than arbitrarily inconsistent. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

33

Dr. Baker inquired as to whether the intent in the wording was to recommend that if a 2-year 

child with sickle cell disease received a conjugate vaccination series, at 5 years they would 

receive the polysaccharide once for the rest of their lives.

Dr. Nuorti responded that was for the revaccination, so a child with sickle cell disease would still 

receive a vaccine in accordance with the current recommendation at 2 or older.

With respect to not including HIV-infected children, Ms. Seward noted that there were not any in 

the data presented, but there could be in other years. With that in mind, she wondered if they 

needed to be as specific as this.

Dr. Nuorti replied that HIV-infected children are included in the immunocompromised group.

Motion: PPSV23 Pneumococcal Vaccines in High Risk Children <10 Years

Dr. Cieslak made a motion to approve the recommendation as written for PPSV23 in high risk 

children < 10 years of age. Dr. Neuzil seconded the motion. The motion carried with 14

affirmative votes, 1 abstention, and 0 negative votes.

VFC Resolution Update: Pneumococcal Vaccines

Dr. Jeanne M. Santoli

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Dr. Santoli indicated that the purpose of this presentation was to consider changes to the 

current VFC resolution based on the discussion over the course of the morning with respect to 

polysaccharide vaccine in terms of eligible groups and the recommended schedule, and 

pneumococcal vaccine in terms of the recommended schedule. While there were several areas 

in the resolution in which it was thought changes would need to be made, this would not be 

necessary. She provided the language to illustrate the current language, with changes 

underlined:

For Polysaccharide Vaccine, Eligible Groups:

Eligible Groups: Children and adolescents aged 2-18 years who have functional or anatomical 

asplenia, immunocompromising illness or medications, chronic illness (as specified above), 

who are American Indian or Alaska Native (when deemed appropriate by relevant public health 

authorities based on local circumstances), or who have received a bone marrow transplant. 

For Polysaccharide Vaccine, Recommended Schedule:

For children who are immunocompromised or who have functional or anatomical asplenia: a 

single revaccination is recommended if 5 or more years have elapsed since the previous dose.

For Conjugate Vaccine, Recommended Schedule:

American Indian and Alaska Native children, 24-59 months, who have received the 

pneumococcal conjugate vaccine, may receive a single dose of polysaccharide vaccine after 

conjugate vaccination when deemed appropriate by relevant public health authorities based on 

local circumstances.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

34

With respect to simplification of VFC resolutions, Dr. Santoli stressed that currently the 

resolutions contain information according to the statute with regard to eligible groups, 

recommended schedules, dosage intervals, recommended dosage, and contraindications and 

precautions. All of this information is included 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, in order to avoid repeating 

language that will need to be changed in more than one place when changes are made. There 

are some challenges, but improvement is underway.

Motion: VFC Vote

Dr. Baker made a motion to approve the suggested additions to the VFC resolution for

polysaccharide vaccine (eligible groups; recommended schedule), and pneumococcal vaccine

(recommended schedule). Dr. Meissner seconded the motion. The motion carried with 14

affirmative votes, 1 abstention, and 0 negative votes.

Update on Investigational 13-Valent

Pneumococcal Conjugate Vaccine

Dr. Peter Paradiso

Wyeth Vaccines

Dr. Paradiso presented an update on investigational 13-valent pneumococcal conjugate 

vaccine. The current 7-valent vaccine, PREVNAR®, contains the serotypes that were the most 

prevalent in the US at the time this vaccine was launched (e.g., 4, 6B, 9V, 14,18C, 19F, and 

23F). The 13-valent vaccine, PCV13, includes those seven serotypes and an additional six new 

conjugate vaccines covering serotypes 1, 3, 5, 6A, 7F, and 19A. The seven components that 

are common within the vaccine are essentially identical in dosage and form to those found in 

PREVNAR® (e.g., 2 μg of each of those serotypes, except for 6B which is 4 μg). The six new 

serotypes are all conjugates of the same carrier protein as the original seven types in 

PREVNAR® (e.g., CRM197), using the same chemistry of reductive amination to the 

polysaccharide and in a dosage of 2 μg of each of those serotypes. Thus, the 13-valent vaccine 

essentially takes the PREVNAR® vaccine in its dosage form and adds the six new serotypes 

that make 13 all together. It is important to point this out, particularly as it relates to the seven 

original types, because the transition anticipated from 7-valent to 13-valent will be facilitated by 

the fact that those seven types are common and it should be possible to switch to the 13-valent 

at any point in the immunization program. 

When considering the assessment of a new conjugate vaccine, the situation is different from 

that of developing PREVNAR®, given that PREVNAR® is now on the market. Thus 

immunogenicity must be considered as the correlate or the way to assess the new vaccine. 

Wyeth has had some assistance in that consideration from many groups, particularly the World 

Health Organization, who have reviewed the data regarding efficacy and immune response for 

PREVNAR® and established criteria by which they can consider comparing a new vaccine to an 

old vaccine. Weyth’s clinical trials are set up to compare the 13-valent vaccine to the standard 

of care, the 7-valent vaccine. The serological criteria used to assess PCV13 immunogenicity for 

the common serotypes in PREVNAR® and PCV13 are to examine non-inferiority to PCV7 in the 

percentage of children achieving > 0.35 ug/ml anticapsular antibody, and the non-inferiority to 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

35

PCV7 types in geometric mean antibody concentration. For the six additional serotypes in 

PCV13, a comparison is made to the original types to examine non-inferiority in the percentage 

of children achieving 0.35 ug/ml anticapsular antibody compared to the lowest responses in 

PCV7, and non-inferiority in geometric mean anticapsular antibody concentration compared to 

the lowest responses in PCV7. In considering the entire immune response, good functional 

antibody that correlates with overall immunogenicity is an important parameter, given that it is 

essential to show that a functional response is induced with the six new types and that this 

response correlates with the overall antibody response. For the immunization program and 

long-term immunity, boostability in the second year of life is also examined within a schedule 

that has been used for many conjugate vaccines over the years. There are additional predetermined analyses that may be examined should the primary criteria not be met.

Wyeth is currently completing their Phase 3 Clinical Pediatric Program, which is extensive and 

global. Some of the types of studies include: 

 Non-inferiority studies, which are the pivotal studies that directly compare the immune 

response between PREVNAR® and the13-valent vaccine in Europe and the US using 

different schedule

 Evaluation of different dosing schedules (e.g., 2, 3, 4,& 12-15 months; 2, 4, 6, & 12-15 

months; 2, 4, & 12 months; 3, 5, & 11 months)

 Evaluation of older children who have never been vaccinated to determine what the ageappropriate vaccination should be for children who are >7 months and >12 months (1, 2 

or 3 doses)

 New serotype catch-up in children completely immunized with PREVNAR® in order to 

understand the safety and immunogencity to protect them against the six new serotypes

(1 or 2 doses)

 Immune response to concomitantly administered vaccines (e.g., Infanrix hexa, Pentavac, 

Pentaxim, Pediacel, DTwP, Priorix, Proquad, Meningitec, Neissvac C, Vaqta, Engerix B, 

OPV)

 Safety evaluation in all studies

 Safety and immunogenicity evaluation in different countries 

With respect to the data that led Wyeth to move forward with this program, Dr. Paradiso 

reported on the Phase 2 Study. In terms of the percentage of subjects achieving antibody 

concentration of ≥ 0.35 μg/ml post-primary series, the percentage of responders to the seven 

types in PREVNAR® are quite high compared to the six additional types:
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

36

Phase 2 Study: Percentage of Subjects Achieving Antibody 

Concentration of ≥0.35 μg /ml Post-Primary Series

0

10

20

30

40

50

60

70

80

90

100

4 6B 9V 14 18C 19F 23F 1 3 5 6A 7F 19A

 PCV7 Serotypes Additional Serotypes

PCV7 PCV-13 

Percentage of Subjects

In a study conducted in the US in children 2, 4, and 6 months of age, in a post-primary series 

there is quite comparable immune response of PCV13 to PREVNAR®: 

6

Opsonophagocytic Assay (OPA) – Post-Primary Series

1

10

100

1000

10000

Geometric Mean Titer

4

6B

9V

14

18C

19F23F

135

6A

7F

19A

Serotypes PCV7 Additional Serotypes 

PCV7

PCV13

Therefore, it appears that Wyeth was able to add six new serotypes without negatively 

impacting the response to the original seven, while still inducing a good response to the six new 

types. Dr. Paradiso pointed out that serotype 19A illustrates one of the reasons that it is 

important to examine the entire immune response when evaluating a new conjugate vaccine for 

pneumococcous. There is quite a lot of cross reactivity, probably from the 19F component to 

19A in the PREVNAR® recipients. It is known that PREVNAR® is not protective against 19A, 

so this cross reactive antibody is not functional. Therefore, it is important to consider this only 

for components that are in the vaccine and be careful about cross protection because clearly, 

cross protection is not observed. It is also important to consider other parameters. There is a 

comparable response between PREVNAR® and the 13-valent for the common types, and there 

is a good response to the new serotypes. With respect to 19A, there is quite a difference to the 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

37

response between PREVNAR® and PREVNAR-13, which probably explains the lack of efficacy 

against 19A in PREVNAR®. In addition, with respect to the response following the booster 

dose at 12-15 months of age, there is a high percentage of responders to all of the serotypes.

There are a number of considerations that must be made with respect to catch-up. PCV13 is 

designed to provide direct coverage against six additional serotypes. It should be possible to 

incorporate that vaccine into the schedule regardless of where a child is in the program. There 

is a significant burden of disease of PCV13 serotypes in children aged 1-5 years (e.g., 1,700 

cases of IPD; 4,000 cases of hospitalized pneumonia; 20,000 of ambulatory pneumonia; 

>100,000 cases of otitis media). Surveillance studies post PCV7 suggest indirect effects may 

be accelerated with inclusion of a catch-up program. A catch-up immunization program may 

accelerate the indirect effect of PCV13 in populations > 5 years of age.

Some clinical trials have been completed to help further assess the safety and immunogenicity 

of PCV13 in children aged 1- 5 years and will be part of the package. Safety and

immunogenicity trials are being conducted in children who are either naïve or fully immunized 

with PCV7 (e.g., 2 doses in 12 - 23 month olds; 1 dose in 2 - 18 year olds). Importantly, a 

demonstration project will be initiated by the end of 2008 in the YK Delta of Alaska where a 

significant amount of disease is caused by serotypes that are in PCV13 and not in PCV7, 

particularly serotype 7F and 19A in that group. The plan is to incorporate 13-valent into the 

immunization program in the YK Delta region by the end of 2008, transitioning all children who 

are receiving PCV7 to PCV13. Children up to 5 years of age who are fully immunized with 

PCV7 will be immunized with PCV13. This will offer an opportunity to have an important public 

health impact in a region that is experiencing significant increases in certain serotypes, as well

as to collect safety, immunogenicity, and perhaps effectiveness data in that population. 

Wyeth is also in a Phase 3 program examining PCV13 for adults with the goals of studying the 

indication for the prevention of pneumococcal disease in adults; induction of a functional 

immune response in individuals >18 yrs of age that is non-inferior / superior to the 

polysaccharide; induction of immunological memory that allows periodic boosting of immunity; 

demonstration of no hyporesponsiveness; and ability to overcome hyporesponsiveness induced 

by the polysaccharide. Unfortunately, the preliminary data show that those who have had the 

polysaccharide vaccine are hyporesponsive not only to another polysaccharide vaccine, but 

also to a conjugate vaccine. Therefore, a component of the program will be to examine whether 

that hyporesponsiveness can be overcome with a dose of the conjugate vaccine and be set up 

for a future booster of that response. This study is particularly focused on adults 58 years of 

age and older, but will go down to 18 years of age. This study will also include a large-scale 

effectiveness trial that just began in the Netherlands. 

With respect to the current status of PCV13 in the US, the FDA has granted fast-track status for 

the pediatric indication for the 13-valent vaccine based upon the unmet medical need of the six 

new serotypes. That means that Wyeth will be using a rolling submission, which is anticipated 

in 2008. The file will be complete in the first quarter of 2009, at which time the FDA will decide 

about priority review. Key ACIP / AAP / AAFP considerations include transition from PCV7 to 

PCV13 and catch-up immunizations for children who are older. The adult indication will be filed 

as a supplement after licensure of the pediatric indication, given that it will be the same vaccine.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

38

Ciro Sumaya, MD, MPH, Chair

Andrew Kroger, MD, MPH, CDC / EIPB

Dr. Sumaya indicated that the intent of this presentation was to offer a current update of the first 

half of the General Recommendations document for the ACIP’s review, comments, and an 

indication that the General Recommendations Work Group could move forward on the second 

half of the recommendations knowing that a vote on the entire document would be taken at a 

later date. In addition, this session was intended to address needle length considerations, 

recommendations, and a vote on options relevant to choosing needle length for administration 

of vaccines.

 

The General Recommendations Work Group develops a document that is publishes in an

MMWR at approximately five-year intervals. However, the interval will be approximately three 

years for the next publication, in part because of the emergence of new data. The general 

recommendations document addresses immunization issues relevant to all vaccines, as well as 

topics ad hoc that cannot be attributed to a single vaccine. The general recommendations 

document is directed to providers who are administering a multitude of vaccines every day. 

Providers come from variable backgrounds (e.g., physicians, nurse-practitioners, nurses, 

pharmacists, medical assistants). The text is accompanied by significant use of tables for quick 

reference to the text.

With regard to the preliminary results of the document, a new outline has been developed and a 

revised draft has been written for roughly the first half of the document. Modifications, 

consolidations, and rearrangements have been to the sections that seem more suitable. The 

outline is as follows, with a focus on the first half contained in the box: 

 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

 Vaccine administration

 Storage and handling of immunobiologics

 Altered immunocompetence

 Special situations

 Vaccination records

 Vaccination programs (Adolescent and Adult Vaccination Topics)

 Vaccine information sources

Some of the changes made deal with the risk / benefit communications, which has now been 

placed earlier in the document under “Preventing and Managing Adverse Reactions” section. 

Adverse events have been grouped in a better form with better sequencing and some 

consolidation. In the last version (2006) contraindications and precautions were handled 

differently in that the table included three columns: Vaccines, True Contraindications and 

General Recommendations 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

39

Precautions, and Untrue (vaccines can be administered) [MMWR; December 2006; Table 5]. 

The work group believed there should be more clarity in the way in which this information was 

formatted and presented. Therefore, they recommended having two tables, one which 

combines the vaccine and true contraindications and precautions, and one which addresses

common misconceptions.

Significant additions have been made to syncope with respect to updating the statistics and the 

language (Page 19, Line 16). There has been an increase in syncope, probably reflecting the 

increase in vaccines being given to adolescents and young adults. Adolescents seem to be at 

higher risk of syncope-related head injury [VAERS data]. The need to anticipate injury from this 

reaction is addressed with the following statement, “Adolescents and adults should be seated 

during vaccination and the observation period to decrease the risk of injury should they faint.” A 

number of other revisions and updates have been made, which the work group should take into 

consideration.

Dr. Sumaya concluded that the anticipated timeline is for the General Recommendations Work 

Group to present the second half of the document to the ACIP in February 2009. The second 

half of the document will incorporate combination vaccines, storage and handling, and 

programmatic issues (adolescent vaccination; adult vaccination). A final vote on the entire 

document is also anticipated at that time, followed by the clearance process and a predicted 

publication date of December 2009.

Dr. Kroger then indicated that one major revision in the draft provided to ACIP members 

pertained to the provider choice of needle length for intramuscular injection (IM). This begins on 

approximately page 23 of the draft document in the “Vaccine Administration” section. The 

choice of needle length is dependent upon technique (e.g., bunching versus flattening), site, 

age, and weight and gender for adults only. In the 2006 document, this was found in Table 7. 

The General Recommendations Work Group struggled with how to display recent revisions that 

they believe need to be made to this document. Much of this is reflected in a new paper that 

was published in Pediatrics in 2008 by William Lippert, which suggests that the needle lengths 

reflected in this table may be too long and could lead to over-penetration and the striking of 

bone and periosteum.

It is important that IM vaccines are administered intramuscularly. If IM vaccines are 

administered into the subcutaneous space, the risk for local reactions is higher. Risk of injection 

into subcutaneous space is increased if the needle is too short. This is thought to be due to 

vaccine components (e.g., adjuvant or other components meant to increase the efficacy of the 

vaccine by slowing absorption), so it may be specific to certain vaccines. Studies of infants 

using 5/8 inch versus 1 inch needles clearly indicated that risk for tenderness or swelling higher

with the 5/8 inch than with 1 inch needles. The risk of redness and swelling is 1.5 to 3 times 

higher with use of the short needle. While this is counterintuitive, it is what these data 

demonstrate. The vaccines used included DTP, Hib, and Group C meningococcal conjugate 

vaccines [Diggle J, Deeks J, 2000; Diggle, L, Deeks JJ, Pollard A. BMJ 2006]. These studies 

were conducted in 100 to 200 infants in 2000, and in 600 to 700 infants in 2006. Other studies 

examined intramuscular needle length (e.g., 5/8 inch versus 1 inch) used in toddlers and young 

children, which also demonstrated that shorter needles were associated with increased risk of 

erythema, swelling, and pain. The vaccines used included DTaP, DTP, and Polio [Ipp MM, et. 

Al. Pediatrics 2003; Jackson LA, et. Al. Pediatrics 2008]. The Ipp MM article examined 18-

month olds, finding increased risk of pain in the thigh when compared to the arm (p < .001). 

This study used a 5/8 inch needle. CDC recommends deltoid administration for children older 

than 2 years, and has traditionally recommended erring on the side of using longer needles. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

40

Other data suggest that another important reason for erring on the side of needle which may be 

somewhat long in adults is that there is evidence of reduced immunogenicity (e.g., a 17-fold 

decrease) when Hepatitis B vaccine is injected into the gluteus as opposed to the deltoid [Shaw 

FE Jr., et Al. Vaccine 1989]. While many conclusions can be drawn from the results of this 

study, this is likely to be related to superficial placement of vaccine.

As noted, the new study by Lippert and Wall suggests that needle lengths recommended by 

CDC risk over-penetration and striking of bone and periosteum. With that in mind, they make 

the following recommendations based on diagnostic imaging (e.g., CT and MRI scans):

Younger than 6 y 7/8 – 1 inch (thigh)

Male ≤ 70 kg 1⁄2 inch (deltoid)

Female ≤ 75 kg 1⁄2 inch

Female 70 – 115 kg 5/8 inch

Male 70 – 140 kg 5/8 inch

Female ≥ 115 kg 7/8 – 1 inch 

Male ≥ 140 kg 7/8 – 1 inch

The recommendations do vary dramatically from what is already published in the general 

recommendations. Nevertheless, the Lippert study has a number of strengths in that it

recommends flexibility to providers for the choice of needle length, which the work group 

supports. It demonstrates, using diagnostic imaging, that in patients 3–18 years of age that in 

74 of 137 the distance would be short enough for a 1 inch needle to reach the measured level of 

bone using these technologies. In addition, it is known that providers are concerned generally 

about hitting underlying structures when they vaccinate (e.g., sciatic nerve in some situations). 

The limitations of this study are that unlike the previous studies mentioned, the method of 

ascertaining the appropriate needle length does not involve actual administration, yet technique 

is a very important aspect of this issue. The work group believes that the risk can be reduced

by giving clear guidance in this area, and risk is reduced with careful site selection. There 

should be site flexibility as well in terms of the recommendation. For children younger than 3 

years of age, this study also showed that in 6 of 38 individuals, the needle would hit the level of 

subcutaneous fat with a 5/8 inch needle.

In the new general recommendations, the needle length table now appears as Table 9 at the 

end of the document. The table is currently divided by age group, with the top row addressing 

children from birth through 18 years old and the bottom row addressing adults. The work group 

took into consideration various option regarding how to go about revising this table, and 

regardless of the option chosen, the text will be harmonized with the table. 

With respect to the top section (e.g., children from birth through 18 years old) Option 1 would be 

to leave the table exactly as it appears in the 2006 document, in which the footnotes discuss 

techniques to some degree: 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

41

Option 1

Birth–18 years

Age Needle length Injection site

Newborn* 5/8” (16mm)† Anterolateral thigh

Infant 1–12 months 1” (25mm) Anterolateral thigh

Toddler 1 – 2 years 1”–1 1/4” (25-32mm) Anterolateral thigh§

5/8”†–1” (16-25mm) Deltoid muscle of the arm

5/8”† Children 3–18 years –1” (16-25mm) Deltoid muscle of the arm§

1”–1 1/4” (25-32mm) Anterolateral thigh

• *Newborn = First 28 days of life.

• †If skin stretched tight, subcutaneous tissues not 

bunched.

• §Preferred site.

In terms of the pros and cons of Option 1, it does reflect maintenance of the current 

recommendation, which is already published. Using these needles lengths can reduce local 

reactions caused by IM injections being given subcutaneously. This table emphasizes age and

site as important parameters. The table is simplified to the extent that children from birth 

through 18 are listed as one cluster, and there is really no reference to using weight as a factor 

in choosing needle length. In addition, it accounts for needle size availability. However, the 

table does not emphasize technique, although the text does.

Option 2 appeared to be the option most members of the General Recommendations Work 

Group seemed to support:

Option 2

• *Newborn = First 28 days of life.

• †If skin stretched tight, subcutaneous tissues not 

bunched.

• §Preferred site.

• ¶ assumes needle is fully inserted

• **Some experts recommend a needle shorter than 1 inch 

(25 mm) for children/adolescents 3 years through 18 

years who weigh less than 140 kg (males) or less than 

115 kg (females)

Birth–18 years

Age Needle length Injection site

Newborn* 5/8” (16mm)† Anterolateral thigh

Infant 1–12 months 1” (25mm) Anterolateral thigh

Toddler 1 – 2 years 1”–1 1/4” (25-32mm) Anterolateral thigh§

5/8”†–1” (16-25mm) Deltoid muscle of the arm

5/8”¶** Children 3–18 years –1” (16-25mm) Deltoid muscle of the arm§

1”–1 1/4” (25-32mm) Anterolateral thigh

With respect to the pros and cons of Option 2, it involves leaving the grid the same, but 

including some additional footnotes (e.g., the fourth and fifth footnotes). In addition, it 

emphasizes age and site as important parameters; emphasizes technique with an additional 

footnote about insertion of the needle; includes weight-based criteria in the footnote [Lippert 

study]; and accounts for needle-size availability. However, this approach involves a partial 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

42

adoption of new data. It is restricted to 3-18 year olds, and the weight cutoffs do not harmonize 

with previous adult based cutoffs (adult data would reside in the same table).

Option 3 would be as follows:

Option 3 Birth–18 years

Age Needle length Injection site

Newborn* 5/8” (16mm)† Anterolateral thigh

Child ≤ 6 years 7/8” - 1” (25mm) Anterolateral thigh

Children 7 – 18 years

Female ≤ 70 kg

Male ≤ 75 kg

1/2 “ Deltoid muscle

Female 70 – 115 kg

Male 75 – 140 kg

5/8 “ Deltoid muscle

Female ≥ 115 kg

Male ≥ 140 kg 

7/8” – 1” Deltoid muscle

*Newborn = First 28 days of life.

†If skin stretched tight, subcutaneous tissues not 

bunched.

The pros are that it involves greater incorporation of data from the Lippert study, and includes 

weight classification for children 7-18 years of age and the corresponding needle lengths that 

are recommended. However, the cons are that there may be an increased risk of local adverse 

reactions due to IM injections subcutaneously; reduced flexibility as to site choice; lack of 

harmonization with the published adult data about weight cutoffs; and the recommended needle 

lengths may not be available.

Option 4 involves removing contents that are included in the 2006 document. The plan is to be 

all-inclusive with the age groups in this table, and there is an adult table that uses weight-based 

cutoffs based upon Greg Poland’s study published in 1997 in JAMA using ultrasound data: 

Option 4: Entire Table
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

43

The Poland weight-based cutoffs would be included, which are different from the Lippert data. 

The same footnote would be kept as well. The option that is really proposed with respect to 

Option 4 is to remove weight-based content as a result of the fact that it is not harmonized. If 

this seems to be an option, all consideration of weight could be removed for the purposes of 

choosing a needle length for all age groups, which would result in an option appearing as 

follows:

The pros of Option 4 is that it equalizes and somewhat diminishes the emphasis on weight for 

children, adolescents, and adults. This seems to be an option, given the available data. 

Granted, the Poland study uses ultrasound to determine distance, while the Lippert study uses 

CTs and MRIs, but perhaps this is justified. The cons are that it removes current weight 

parameters for adults is that this would be a discontinuity from previous recommendations and 

information already placed in the document.

In conclusion, Dr. Kroger reiterated that the work group appeared to be divided between Option 

1 and Option 2. Option 2 seemed to be supported by more people within the work group, but 

they wanted to ensure that ACIP had an opportunity to weigh in on these options as well. 

Discussion

Dr. Marcy indicated that he had been practicing pediatrics for 44 years and had never seen a 

problem with osteo-periostitis or any difficulty. The only paper he has ever been able to find 

describing any complications was by Russell S. Asnes, MD in 1966 discussing four cases of 

septic arthritis of the hip in neonates, which were believed to be valid examples of a 

complication arising from femoral venipuncture [Pediatrics; Vol. 38 No. 5 November 1966, pp. 

837-841]. Therefore, the Lippert study is interesting but is perhaps irrelevant. In addition, the 

current recommendation is permissive for 1 inch needles for infancy up to 200 pounds, which 

makes if very simple. He watches the people with whom he works very closely, but not 

everyone is watched closely at every institution. By making a recommendation that includes 

5/8, 7/8, 1, 1.5 inch needles, it is unlikely that this will be done properly. To Dr. Marcy, the risk 

of hyporesponsiveness as a result of administering a vaccine subcutaneously rather than 

intramuscularly far transcended the risk of any consequences. Obesity is an increasing problem 

in the US. To use a shorter needle when the whole world is becoming more obese does not 

make sense. The need for weight which is then brought into this is a barrier to immunization, 

given that many locations in which immunizations are being administered do not have a scale. 

Overall, Dr. Marcy thought that any change would be unworkable. The Diggle paper [BMJ 

2006] found that that a 23 gauge needle has a far lower reactogencity rate than the 25 gauge 

needle, perhaps because with a narrow diameter product comes out faster, so the jet is less 

with a 23 than with a 25 gauge needle. With that in mind, he thought perhaps they should 

revisit this issue and consider 23 versus 25 gauge needles.

Dr. Englund concurred with Dr. Marcy, stressing that simple recommendations that can easily 

be carried out are needed in the practice setting. She thought that such recommendations 

should be based on clinical practice and clinical evidence, not on a potentially theoretical basis. 

Based on the clinical evidence from the Jackson and Diggle papers, it is clear that 1 inch is 

better. There are problems with the CT and ultrasound guided evidence because a squiggling, 

19 Years and Older 1-1 1⁄4 “ (25-32 mm) Deltoid muscle of the arm
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

44

squirming child may not be injected at a 90 degree angle. Instead, practitioners are doing the 

best they can. With that in mind, she personally preferred Option 1.

Dr. Judson thought that introducing layers upon layers of complexity without compelling 

outcome advantages would not be in anyone’s best interest. 

Dr. Halsey (Johns Hopkins) agreed with Drs. Marcy and Englund, adding that increasingly 

vaccines are coming as unit dose vials with needles included. People in practice typically get a 

single size needle. All vaccines can be done with a 7/8 or 1 inch needle. What was missing 

was the need to simplify this from everybody’s standpoint, which could be done by changing the 

technique for different sized individuals. In working with nurses who do this hundreds of times, 

he has observed that they change the technique to either bunch, flatten, or do nothing based 

upon their perception of the depth they must reach.

Dr. Sawyer pointed out that the compelling data which they were seeking was that too deep an 

injection causes a clinical problem. He agreed with Dr. Marcy that there did not seem to be data 

to illustrate this.

Dr. Duchin (NACCHO) inquired as to whether the current recommendations would allow 

flexibility for a health care provider to administer hepatitis B vaccine in the anterolateral thigh 

with less than a 1 inch needle. NACCHO recently discussed a case with ACIP in which a 

healthcare provider did that in children over 1 year of age. The recommendation was that those 

children needed to be recalled. If a health care provider decided to use a less than 1 inch 

needle, Dr. Duchin wondered whether it would be a violation of the ACIP guidance.

Dr. Kroger responded that the current recommendations are not specific about this point. They 

address hepatitis B vaccination in sites other than the deltoid. There are data in adults, but not 

in infants. Some indirect analyses must be done based on the literature available. However, 

the data available argue pretty strongly that a 5/8 inch needle should not generally be used. 

The recommendation will depend upon which option is selected, but there is language specific 

to this point on hepatitis B vaccine in terms of site selection. Perhaps information about needle 

length could be added to that, although it had not yet been included.

Patsy Stinchfield (NAPNAP) as the only nursing organization in the room, she wished to go on 

record to concur with Dr. Marcy. Nurses with experience know what to do with children in terms 

of bunching, flattening, and administering properly. Keeping the recommendation simple will be 

more beneficial.

Dr. Morse pointed out that there appeared to be consensus to keep Option 1, which would not 

require a vote as there would be no changes.

Dr. Pickering stressed the importance for members to read all of the background materials 

provided to them, and to submit any comments regarding the general recommendations 

document to Dr. Kroger as soon as possible so that these may be incorporated. Any changes 

can be dealt with during the next ACIP meeting. He pointed out that part of the ACIP’s process 

every three to five years is to renew, reaffirm, or retire all documents from the ACIP.

Dr. Marcy quipped that it was a tribute to the advances of modern obstetrics and to their 

colleagues in ACOG that it was felt necessary to list pregnancy as a contraindication to the use 

of zoster vaccine—a vaccine limited to persons 60 years of age and older.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

45

Introduction and Update

Introduction and Update

Lauri Markowitz, MD

NCHHSTP, CDC

Dr. Markowitz reported that three upcoming HPV vaccine policy issues the ACIP would address 

in the next, and potential voting dates, would be as follows:

Policy Issue Earliest Vote Date

Quadrivalent vaccine in females >26 yrs February 2009

Bivalent vaccine in females June / October 2009

Quadrivalent vaccine in males October 2009 

During the June 2008 ACIP meeting, quadrivalent vaccine in females >26 years was discussed. 

Clinical trial data interim results were presented, along with an overview of the epidemiology

and cost effectiveness (CE) models. The work group presented a proposed permissive 

recommendation, but no extension of catch-up over age 26 years. The current plan is to await

FDA review, review CE models, and re-discuss recommendations with ACIP in 2009. 

With respect to HPV vaccine implementation, > 20 million doses of quadrivalent HPV vaccine

have been distributed in the US through September 2008. There are now national data on 

coverage in teens from the Teen National Immunization Survey, which were published in the 

MMWR in 2008. Coverage with at least one dose of HPV vaccine in the fourth quarter of 2007

was approximately 25% among 13-17 year-old females. Coverage was similar across all age 

groups surveyed in the Teen National Immunization Survey. 

National Provider Survey

Matthew F. Daley, MD

Associate Professor, Pediatrics

University of Colorado Denver

Dr. Daley began by disclosing that the authors had no relevant financial relationships with any

commercial interests to report, and that no reference would be made to the use of medications 

in manners not licensed by the FDA. 

He then explained that the study objectives of the National Provider Survey were to assess, in a 

nationally representative sample of family medicine physicians (FM) and pediatricians (Peds): 

1) knowledge, attitudes, and current practices regarding HPV vaccination; 2) perceived barriers 

to HPV vaccination; and 3) factors associated with strongly recommending HPV vaccine to 11-

12 year old female patients. The investigation was conducted in an existing sentinel physician 

network recruited from random samples of AAP and AAFP. Quota sampling was done to 

Human Papillomavirus (HPV) Vaccines
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

46

ensure that the networks were similar to overall AAP and AAFP memberships. The 

representativeness of this network has been examined closely. Network participants generally 

similar to physicians were randomly sampled from AMA with regard to demographic 

characteristics, practice attributes, and range of vaccine-related attitudes [Ref: Crane LA, Eval & 

Health Prof, 2008]. The survey period was from January through March 2008.

There was an 80% response rate overall: 79% FM (331 of 419) and 81% Peds (349 of 431). 

Respondents were not significantly different from non-respondents with respect to a variety of 

characteristics (e.g., gender, graduation year, urban / rural location, or practice type). For family 

medicine practitioners, respondents were less likely to be from the South and more likely to be

from the West. 

Respondents were asked a variety of true false questions with regard to knowledge about HPV. 

Their knowledge was generally pretty good, although roughly half of the individuals, both family 

medicine practitioners and pediatricians,did not know that “genital warts are caused by the 

same HPV types as cervical cancer” is a false statement. 

Knowledge about HPV

Statements (Correct response) % Correct, 

FM

% Correct, 

Peds

Most genital HPV infections symptomatic 

(False)

86 85

Almost all cervical cancers caused by HPV 

(True)

95 85

Genital warts caused by same HPV types as 

cervical cancer (False)

58 43

Respondents were also asked their knowledge about HPV vaccines through a series of true / 

false questions, with their knowledge about HPV vaccination being generally pretty good. 

However, there was some misunderstanding about what to do with women who had been 

previously diagnosed with HPV and whether a pregnancy test should be performed prior to 

administering HPV vaccine:

 Knowledge about HPV Vaccines

Statements (Correct response) % Correct, 

FM

% Correct, 

Peds

Sexually active women should be tested for 

HPV before starting HPV vaccination (False)

85 91

Women diagnosed with HPV should not be 

given HPV vaccine (False)

81 77

Pregnancy test should be performed prior to 

giving HPV vaccine (False)

69 86

Respondents were also asked about their attitudes about HPV vaccination on a 4-point Likert 

scale. In this case, roughly half of the respondents agreed with the statement that it is 

“necessary to discuss sexuality prior to recommending HPV vaccine.” Roughly half believed 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

47

that parents were going to be “concerned that vaccination against STI may encourage earlier or 

riskier sexual behavior,” although the physicians themselves were not concerned about this. 

 Attitudes about HPV Vaccination

% Strongly / 

Somewhat Agree

FM Peds

Necessary to discuss sexuality prior to 

recommending HPV vaccine

54 42

Parents concerned that vaccination against STI 

may encourage earlier or riskier sexual behavior

49 42

Physician concerned that vaccination against STI 

may encourage earlier or riskier sexual behavior

6 4

With respect to overall HPV vaccination practices, 88% of family medicine practitioners and 

98% of pediatricians were administering HPV vaccine to female patients in practice at the time 

of the survey from January through March of 2008. 

In terms of the strength of the respondents’ recommendations by age, overall high rates were 

recommending HPV vaccine to female patients. However, 49% of family medicine practitioners

strongly recommended the vaccine to 11 to 12 year olds compared with 87% who strongly 

recommended it at 16 to 18 years of age. The trends from pediatricians were quite similar, with 

56% of Peds strongly recommending the vaccine to 11 to 12 year olds and 94% who strongly 

recommended it at 16 to 18 years of age. Perceptions about HPV vaccine safety were also 

examined, with 13% of family medicine practitioners and 33% of pediatricians expressing 

concern that syncope is more likely to occur following HPV vaccine than other vaccines, and 9% 

of family medicine practitioners and 8% of pediatricians being concerned that Guillain-Barré 

syndrome may occur after HPV vaccination.

Family medicine practitioners and pediatricians were also asked the extent to which they see 

refusal and deferral of HPV vaccination, which were explicitly defined in the survey as follows: 

1) Refusal was defined as outright refusal with no consideration of vaccination later; and 2) 

Deferral was defined as postponing vaccination, but the parent will consider later. There was 

more reported parent / patient deferral than refusal of HPV vaccine among both specialties. 

There was more reported refusal at 11 to 12 years than at 13 to 15 years. Of the specialties, 

29% of family medicine practitioners and 18% of pediatricians reported that at least 25% of 

parents of 11 to 12 year olds refused HPV vaccine when offered. 

For both specialties, the most common reported reasons for vaccine refusal / deferral among

was that parents felt as though the vaccine was too new and had not been around (28% FM; 

47% Peds). The second most common reason for family medicine physicians was that parents 

reported that insurance did not cover HPV vaccine for the patient and that the parent could not 

afford it (19% FM; 7% Peds). Respondents were all asked about reported barriers to HPV 

vaccination. The three most prominent barrier both specialties were financially related: 1) 

Vaccine is not covered by insurance (64% FM; 47% Peds); 2) Lack of adequate reimbursement 

(52% FM; 38% Peds); and 3) “Up front” costs to purchase the vaccine (44% FM; 35% Peds). 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

48

Parent opposition was a moderate barrier (30% FM; 23% Peds). Provider concern about 

vaccine safety was a less prominent barrier (8% FM; 3% Peds). 

In the multivariate analysis of factors associated with not strongly recommending HPV vaccine 

to 11 to 12 year old female patients, controlling for specialty and region of the country, the 

findings were as follows:

Adjusted 

ORs

(95% CIs)

Considering it necessary to discuss sexuality prior to 

recommending HPV vaccine

1.6

(1.1-2.4)

Reporting that parents of 11-12 y.o. have been more likely 

to refuse than parents of 16-18 y.o.

4.0

(2.5-6.4)

Believing that the time it takes to discuss HPV vaccination is 

definitely/somewhat a barrier

1.9

(1.1-3.4)

25% or more of respondent’s patients have public health 

insurance

0.4

(0.3-0.6)

Limitations of the survey results are that respondents may have differed from non-respondents, 

but there was a high survey response rate. Sentinel physicians may differ from physicians 

overall, although prior work suggests that they do not. Survey results represent reported 

practice. Actual practice was not observed. Results may not be generalizable to all settings. 

Nevertheless, there are several important findings to put into context. With respect to 

knowledge, most family medicine practitioners and pediatricians were aware of several key 

aspects of HPV epidemiology. However, there are some knowledge gaps regarding HPV 

vaccination. With respect to vaccination practice, there is quite high adoption overall (88% of 

FM, 98% of Peds administering HPV vaccine in practice). More physicians were strongly 

recommending the HPV vaccine to patients 13 years and older versus 11 to 12 years old. In 

terms of reported parent refusal, the most prominent reason was that the parents said the 

vaccine is too new. Other issues were raised with regard to the adolescent being too young or 

not being sexually active, and concerning insurance not covering the vaccine. With respect to 

perceived barriers to HPV vaccination, for both specialties, the top three barriers were financial. 

Parent opposition to the vaccine was more of a moderate barrier. In terms of responses about 

vaccine safety, parent vaccine refusals were not explicitly safety-related, although the statement 

about the vaccine being too new may in part be safety-related. There was moderate provider 

concern about syncope, especially among pediatricians.

These findings have a number of implications. Regarding the financial implications at the level 

of the patient, it is possible that these findings suggest that there are more underinsured insured 

patients. If so, this could lead to increased referrals to public health clinics. The financial 

concerns were more prevalent among family medicine physicians than among pediatricians. 

Therefore, it is important to ask: How much do financial considerations factor in when family 

medicine physicians decide not to offer HPV vaccine at all? Further studies are needed 

regarding vaccine cost and reimbursement issues in family medicine. These findings also have 

some implications in terms of missed opportunities: Risk for missed HPV vaccination 

opportunities; physicians are not strongly recommending the vaccine at 11 to 12 years old; 

parents are deferring at 11 to 12 years old; and there are knowledge gaps that could lead to 

missed opportunities. The important question regards whether these missed opportunities will 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

49

stay “missed.” Consideration should be given to interventions to reduce missed HPV 

vaccination opportunities.

Vaccine Safety Update: VAERS

Angela Calugar, MD, MPH

Immunization Safety Office

Division of Healthcare Quality Promotion

National Center for Preparedness, Detection, and Control of Infectious Diseases, CDC

Dr. Calugar reported on the Vaccine Adverse Events Reporting System (VAERS) with respect 

to its background; HPV4 data in VAERS (e.g., methods, adverse events [AEs] following HPV4; 

and general data); and selected serious conditions of clinical interest (e.g., syncope, venous

thromboembolism [VTE], Gillain-Barre Syndrome [GBS]; transverse melitis (TM), and deaths).

VAERS is a national post-licensure passive surveillance system for vaccine adverse events 

operated by CDC and FDA. The advantages of VAERS is that it covers the US population, 

permits monitoring for known AEs, detects signals for previously unrecognized / rare AEs, and 

is designed to generate hypotheses for further testing. Its limitations include risk of 

underreporting, stimulated reporting due to media attention and other factors, incomplete data, 

and lack of availability of denominator data on the number of doses administered. However, the 

number of doses distributed is available. 

The primary methodological aspects of VAERS reports following HPV4 vaccine included all 

primary US reports received between 06-30-06 and 8-31-08, which were reviewed on 10-03-08. 

The Medical Dictionary for Regulatory Activities (MedDRA) is used. More than one MedDRA 

code may be assigned to a single event and one VAERS report may include more than one 

symptom. Brighton case definitions are used for AEs. “Confirmed” case means that a report 

met the case definition, but was not necessarily causally associated with the vaccination. 

Serious AEs are defined by the Code of Federal Regulations as hospitalization, death, 

permanent disability, life threatening illness, or certain other medical important conditions.

From June 30, 2006 through August 31, 2008, there were 10,326 total VAERS reports following 

HPV4. Of those, 619 reports were serious across all years. This translates to 4% in 2006, 5% 

in 2007, and 7% in 2008. As of August 31, 2008, more than 20 million doses (20,383,145) of 

HPV4 vaccine have been distributed in the US [Biologics Surveillance Data, unpublished, CDC]. 

Based on these numbers, VAERS received almost 51 reports for every 100,000 doses 

distributed, including three serious reports per 100,000 doses. With regard to AEs by age, it is 

obvious that the numbers are highest in the recommended age groups. Ages 11-18 years 

comprise 50.4% of all reports (n=5,202), while ages 19-26 years of age comprise 24.5% of all 

reports (n=2,535). This is most likely proportional with the doses administered in these age 

groups. 

The most frequent AEs following HPV4, including all serious and non-serious events combined, 

were: syncope (n=1,564 / 15%), dizziness (n=1,469 / 14%), nausea (n=959 / 9%), injection site 

pain (n=818 / 8%), headache (n=731 / 7%), pyrexia (n =680 / 7%), and rash (n=580 / 6%). Dr. 

Calugar reminded everyone that one VAERS report may include more than one symptom. For 

example, the same patient could develop syncope, dizziness, and nausea. The individual would 

count as one case with one VAERS identification number; however, they would be listed in 

three different adverse events with their same VAERS identification number. Specific attention 

is paid to the following selected conditions of clinical interest: syncope (n=70), VTE (n=41), 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

50

deaths (n=27), GBS (n=52), and TM (n=10). Of the 1,564 reports of syncope there were 119 

serious SEs. Of those, 70 were US reports. Of the total US reports of syncope, 5% were

serious. These were coded as “syncope” or “syncope vasovagal.” Of these, 38 occurred on the 

same day as the vaccination, with 37 requiring hospitalization. The most commonly associated 

symptoms included loss of consciousness, dizziness, headache, nausea, vomiting, fall, and

head injury In addition, Dr. Calugar mentioned that there was a recent 2008 MMWR publication 

on Syncope. [CDC. Syncope after Vaccination: United States, January 2005–July 2007; 

MMWR 2008; 57(17);457-460]. 

There were 65 total reports of VTE following HPV4, of which there were 41 US reports

reviewed. Of these, 6 are pending evaluation. There were 17 reports upon which CDC was 

unable to follow-up or for which there was “no case.” For 8 of the 17, CDC was unable to obtain 

critical data for further evaluation and 9 reports were determined not to be cases. Of the 18 

confirmed cases, 14 were currently using hormonal contraception. Of these, 12 cases were 

using oral contraceptive pills and 2 cases were on Nuvaring, which increases the risk of clots. 

Some cases had additional risk factors. Among 4 cases who were reported as using no 

hormonal contraception, there was 1 case of pregnancy; 1 case of combination risk factors 

(e.g., obesity, smoking, truck driver); 1 case in which the VTE onset preceded a long bus ride; 

and 1 case with no reported risk factors. 

Of the 31 reported deaths, 27 were US reports. CDC was unable to follow-up on 7 cases, 3 

cases are pending, and there were 17 confirmed cases. Of those, 4 were 12 to 14 year olds, 6 

were 15 to 18 year olds, 4 were 19-21 year olds, and 3 were 22 to 26 year olds. With respect to 

the number of doses, 7 had 1 dose, 6 had 2 doses, 3 had 3 doses, and the number of doses 

was unknown for 1 case. Of the 17 confirmed cases, the time to death from vaccination is 6 

cases at 2 to 7 days, 5 cases at 13 to 21 days, 2 cases at 22 to 62 days, 2 cases at 62 to 117 

days, and 1 case at 288 days. Among the 27 US deaths, only those among the categories 

“pending evaluation” (n=3) and “confirmed cases” (n=17) were considered for the summary of 

clinical events. The list of clinical conditions which preceded or caused deaths, some of which 

developed following HPV4 vaccination and others which were reported in the medical histories 

for these cases, follow:

 Viral illnesses (n=3): acute myocarditis, meningoencephalitis, influenza B viral sepsis 

 Pulmonary embolism (n=2)

 Cardiac events (n=2): arrythmia due to cardiomyopathy, probable cardiac arrythmia –

patient had a history of

 Diabetic ketoacidosis (n=1)

 Idiopathic seizure disorder and history of seizures (n=1)

 Atypical GBS vs Juvenile ALS (n=1)

 Drug overdose (n=2)

 Unknown cause (n=3) and limited information for further evaluation (n=4) 

In summary, more than 20 million doses of HPV4 have been distributed. There have been 

10,326 overall HPV4 reports to VAERS, of which 6% across all years were serious AEs. This is 

similar to what is observed with other adolescent vaccines. Syncope following vaccination could 

lead to serious outcomes and preventive measures are critical. Predisposing factors in cases of 

VTE include hormonal contraception use (n=14), co-morbidities, and life-style risks. Further 

monitoring and elaborated studies are warranted for these conditions, since prevalence of 

hormonal contraception use is high in females in the recommended HPV4 vaccine age groups. 

In terms of deaths, there is no clustering observed by age groups, onset intervals, or dose 

number. No trends have been observed in clinical conditions which preceded or caused death. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

51

It is important to keep in mind that VAERS is not designed to assess the biological or 

epidemiological plausibility of AEs following vaccination.

The VAERS team is committed to working further on HPV4. Future VAERS / ISO activities will 

be to continue monitoring and evaluating all serious AEs following HPV4; evaluate VAERS 

reports of inadvertent vaccination during pregnancy; communicate to the public and partners; 

update the ACIP HPV working group on a regular basis; and collaborate with the VSD, CISA, 

NCHHSTP / CDC, FDA, and others. References and related links include the following:

 Reports of Adverse Events Following Gardasil ® on the CDC Vaccine safety web site: 

http://www.cdc.gov/vaccinesafety/vaers/gardasil.htm

 VAERS information: http://vaers.hhs.gov/info.htm

 VAERS public search tool: http://wonder.cdc.gov/vaers.html

 Brighton Collaboration: http://www.cdc.gov/vaccinesafety/brighton/

 Gardasil ® Package Insert: http://www.fda.gov/cber/label/gardasilLB.pdf

 CDC. General Recommendations on Immunization; MMWR 2006; 55(RR15);1-48

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5515a1.htm

Vaccine Safety Update: CISA

Barbara A. Slade, MD

Team Lead, CISA

Immunization Safety Office

Centers for Disease Control and Prevention

Dr. Barbara Slade presented the specific clinical assessments that were conducted by the 

Clinical Immunization Safety Assessment Network (CISA). CISA is a network of six academic 

centers with vaccine safety subject matter experts located at Boston Medical Center, Columbia 

University Medical Center, Johns Hopkins University, Northern California Kaiser Permanente, 

Stanford University Medical Center, and Vanderbilt University Medical Center. CISA was 

established in 2001 to investigate the pathophysiologic mechanisms and biological basis of 

adverse events following immunization (AEFIs); and provide selected clinical consultations. 

Collaborations were also established with other clinical specialists (e.g., neurologists, allergists, 

geneticists, metabolic / mitochondrial experts).

CISA activities related to HPV4 include clinical consultation on rare, serious adverse events 

following HPV4 vaccination. For this review, CISA specifically reviewed transverse myelitis 

(TM) cases, which was conducted by Johns Hopkins, with licensure through August 2008; and 

Guillain Barré Syndrome (GBS) cases, which was conducted by Boston Medical Center, with 

licensure through August 2008. In terms of methods, cases were identified through a review of

the VAERS database for reports of TM and GBS for reports received between 6-01-06 and

8-31-08. Medical records were obtained for cases reviewed by CISA investigators and clinical 

expert neurologists. The proposed Brighton case definition was used for confirmation of GBS 

cases [http://www.brightoncollaboration.org/internet/en/ index/definition_guidelines.html], in 

which Level 1 represents the highest level of certainty. The theoretical window of biological 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

52

plausibility for immune-mediated neurologic events is 4 to 42 days following vaccination, which 

was established from the Swine Flu epidemic with GBS (1976-1977). TM is a rare neurological 

disorder caused by inflammation across both sides of one or more adjacent levels, or segments, 

of the spinal cord that can cause axonal demyelination. From 1964 to 2008, there have been 75 

cases reported in the literature following vaccinations (temporal association only), primarily 

following influenza vaccination and hepatitis B vaccination. Conservative estimates of TM 

incidence per year vary from 1 to 5 per million population [Jeffery et.al., Arch Neurol, 1993]. 

The peak ages for a TM diagnosis appear to be between 10 to 19 years and after 40 years of 

age [Berman, Neurology, 1981]. About 1400 new cases of TM are diagnosed each year. There 

are two age ranges, however, that are most common for the disorder to show up: 10-19 years 

old (the recommended age for HPV vaccinations) and 30-39 years old. In younger patients, TM 

may be a first indication of multiple sclerosis. In older adults, it may be a result of a spinal cord 

stroke. Causes include multiple sclerosis, infections, autoimmune or post-infectious 

inflammation, vasculitis, and certain drugs.

Clinical review was conducted of 13 TM cases reported to VAERS after HPV4 immunization, 10 

of which were US cases. Of those, 3 were multiple sclerosis, 2 cases had insufficient

information for evaluations, and 8 cases were TM (7 of these being US cases). Of these 8 

cases, 4 were at the cervical level of involvement and 4 were thoracic. As expected due to 

HPV4 vaccination, these were in females 11 to 26 years of age. They only involved HPV4 

vaccine. A review for confounding conditions revealed 2 cases with a preceding viral illness and 

1 case with a history of allergies and family history of autoimmune diseases. Of the 8 cases, 2 

followed 1 dose and 6 followed 2 doses. With respect to the timeframe from vaccination to 

onset of symptoms, there was a wide range of times following immunization with no temporal 

clustering. There were only 2 cases within the theoretical window of biologic plausibility, one 

from the US and one from Australia. These two cases also had a preceding viral illness. 

GBS is an immune-mediated acute demyelinating polyneuropathy affecting the peripheral 

nervous system. The estimated annual incidence rate of GBS is 1 case per 100,000 population. 

To date, with rare exceptions, most associations between vaccines and GBS have been based 

only upon temporal associations with limited epidemiologic evidence. Evidence for a causal 

association with immunization is strongest for the Swine Influenza Vaccine administered in 

1976-1977. Studies of subsequent influenza vaccines have found small or no increased risk of 

GBS [Institute of Medicine. Influenza Vaccines and Neurological Complications, 2004]. Older 

formulations of rabies vaccine cultured in mammalian brain tissues also carried an increased 

risk of GBS, but newer formulations, derived from chick embryo cells, do not appear to be 

associated with GBS at a greater than expected rate. 

Clinical review of GBS included 52 cases reported to VAERS after HPV4 immunization, which 

were all from the US. Of those, 11 cases did not meet the Brighton case definition, while 13 

were Brighton-confirmed cases (Brighton level 1 (n=5), Brighton level 2 (n=6), atypical GBS

(n=1), and Miller Fisher (n=1). In 1 case reported in VAERS, the symptoms preceded the 

vaccination, 15 cases are pending evaluation, and 12 cases had insufficient information for 

classification. In the medical record review of the 13 GBS cases after HPV4 vaccination, 6 

received HPV4 vaccine only, 6 received HPV4 vaccine + Menactra® (MCV4), and 1 received 

HPV4 + other vaccines. In terms of demographic characteristics, 12 cases were in females 

13-20 years of age and 1 case was in a 56 year old homosexual male. Of the 12 cases, 9 

received 1 dose, 3 received 2 doses, no one received 3 doses, and 1 received an unknown 

number of doses. With respect to the temporal spread, a clustering of 9 cases is observed 

within the window of biological plausibility (e.g., 6 to 13 days); however, this still only represents 

a temporal, not a causal, association with vaccination.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

53

In summary, the limitations of these studies included the usual limitations of VAERS data; the 

analysis is based on medical record review only and the available records may be incomplete; 

and there are no denominator data for doses given, so post-immunization rates of TM or GBS

cannot be calculated. There were 2 cases (1 US) of TM with the window of biological 

plausibility after HPV4 within 4 to 42 days, both of whom received HPV4 vaccination alone. 

There were 9 cases of confirmed GBS within 4 to 42 days after HPV4, 4 of whom also received 

MCV4. The reports show a temporal association only. The evidence is insufficient to support a 

causal relationship. Most of the reports of GBS submitted to VAERS are not confirmed. Only 

about 50% of the cases had adequate medical records to review and met case definition 

criteria. CDC and FDA continue to carefully analyze all reports of GBS and TM submitted to 

VAERS.

On-going CISA studies pertaining to TM, which are being conducted at the Hopkins site as they 

have a referral clinic for TM that receives referrals from across the US, include:

 Comparison of Idiopathic Acute Transverse Myelitis (IATM) With and Without Receipt of 

a Vaccine [Presented at the 24th International Conference for Pharmacoepidemiology 

and Therapeutic Risk Management, 2008]. This was a study of 268 enrolled cases, a 

large number considering the rarity of the disease, comparing those who receive vaccine 

and those who do not receive vaccine. No difference was found. Approximately 10% of 

those cases had received a vaccine within one month proceeding IATM. 

 Risk Factors for Acute Transverse Myelitis: A Self-Controlled Case Series Approach. 

Subjects are currently being enrolled in this protocol.

On-going CISA studies pertaining to GBS, primarily headed by the Boston site, include:

 Post-MCV4 GBS Case Series, which is in the process of being written up.

 Genetics of GBS: Investigation of Vaccine-Associated and Non-Vaccine-Associated 

GBS, for which subjects are being recruited currently.

 Does Re-Vaccination of Patients with a History of GBS Result in a Relapse?

Vaccine Safety Update: VSD Rapid Cycle Analysis Summary

Julianne Gee, MPH, Epidemiologist

Immunization Safety Office

Centers for Disease Control and Prevention

Ms. Julianne Gee presented the work the Vaccine Safety Datalink Project (VSD) has been

engaged in pertaining to the monitoring the safety of the quadrivalent human papillomavirus 

vaccine. The VSD is a collaboration between CDC and 8 managed care organizations (e.g., 

Group Health Cooperative, Northwest Kaiser Permanente, Northern California Kaiser 

Permanente, Southern California Kaiser Permanente, Kaiser Permanente Colorado, 

HealthPartners, Marshfield Clinic, Harvard Pilgrim). Using automated data sources that already 

exist as part of the participating health plans infrastructure, the VSD collects medical and 

vaccination data on more than 8.8 million members annually (3%). The VSD was established in 

1990 to improve the evaluation of vaccine safety through the use of active surveillance and 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

54

epidemiological studies; address the limitations of VAERS; and respond to needs identified by 

two IOM reports. VSD also tests hypotheses suggested by VAERS reports and pre-licensure 

trials.

The VSD has developed a monitoring system for newly licensed vaccines known as the Rapid 

Cycle Analysis (RCA). RCA is an alternative to traditional post-licensure vaccine safety study 

methods, which can often take years to complete. RCA tests specific hypotheses with welldefined outcomes with short defined risk windows. Outcomes of interest are initially based on 

findings from pre-licensure trials and the literature. Later during the course of monitoring, 

outcomes of concern are added to on-going RCA studies that have been identified through

VAERS. Each week, the number of events in vaccinated persons is evaluated and compared to 

the number of expected events based on a comparison group, which is either a historical or 

concurrent comparison group. Using sequential analyses methods, RCA adjusts statistically for 

multiple looks. RCA is a signal detection method for pre-specified events. If a signal is 

detected, VSD/RCA investigators take steps to investigate the signal appropriately.

The objective of the VSD HPV RCA study is to identify potential associations between the 

quadrivalent HPV vaccine and a pre-specified list of adverse outcomes in females ages 9-26 

years. Data are collected from 7 participating sites in which the HPV4 vaccine is monitored in 

two age groups (e.g., youth and adults). The analysis began on August 20th, 2006, because 

that was when at least 50 doses of vaccines were administered in CDC’s VSD population. For 

the purposes of this presentation, Ms. Gee presented results up to July 20, 2008, which take 

into account lags in the automated administrative data and allows the data to stabilize. The 

investigators for this RCA plan to conduct analyses for this vaccine until 350,000 doses are 

reached in the 9-17 year old age group and 150,000 doses are reached in the 18-26 year old

age group. 

The outcomes being monitored include: Guillain Barré Syndrome (GBS), seizures, syncope, 

appendicitis, stroke, venous thromoembolism (VTE) , anaphylaxis, and other allergic reactions 

(a category that was created to monitor other reactions related to hypersensitivity not 

considered anaphylaxis, which includes codes such as urticaria). The exposure windows, 

medical setting, and first occurrence of the outcome in a defined time period are monitored for 

each of these outcomes. Case definitions were created in such a way that would allow 

identification of new onset adverse events.

Adverse events are monitored among the exposed cohort, which are females 9-26 years of age 

receiving quadrivalent HPV vaccine, either alone or with another vaccine. There are two 

comparison groups for the selected outcomes, for which different statistical methods are used. 

The comparison groups are based on the rarity of the outcome. For the more rare outcomes 

like GBS, appendicitis, stroke, and VTE, the investigators use a historical comparison group), 

which allows them to calculate background rates from primarily historic VSD data or other data 

sources such as the Health Care and Utilization Project (HCUP). For concurrent control groups, 

females in the same age range are compared who have either a preventive care visit or a 

vaccination visit during the same time period as the exposed group. For this study, there is no 

formal comparison being performed for anaphylaxis. The reason for this is because the primary 

ICD-9 code for anaphylaxis is non-specific and generates a lot of false positives. Instead, each 

anaphylaxis case identified in the automated data is validated through chart abstraction to 

calculate the incidence rate of anaphylaxis following HPV4. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

55

The Poisson Maximum Sequential Probability Ratio Test (Poisson MaxSPRT) analysis method 

is used for the more rare adverse events in which the observed number of events are compared 

to an expected number from a background rate using historical data. Using this type of 

sequential analysis an association, or signal, is detected if the log likelihood ratio (LLR) exceeds 

the established critical value [Kulldorff M, et al. A Maximized Sequential Probability Ratio Test 

for Drug and Vaccine Safety Surveillance. Submitted for Publication]. With the Flexible Exact 

Sequential Analysis method, a weekly threshold p-value is established to account for the 

continuous monitoring. Each week, the observed number of events are compared to an 

expected number from either a concurrent preventative visit group or a concurrent vaccination 

group in which the investigators match by variables of interest such as age, site, and or date of 

vaccination. The p-value is generated for that week’s test. If that p-value is less than the 

threshold, an association or signal is detected.

The total number of doses that have been administered to females in this study population 

through July 20, 2008 is over 377,000 and total utilization by dose is as follows: 50.4% have 

received dose 1; 31.5% have received dose 1 and 2; and 18.1% have received the full series of 

the vaccine. Among adults, preliminary results show that no signal has been generated for 

GBS, appendicitis, stroke, or VTE. Ms. Gee reiterated that a signal is generated using a 

Poisson MaxSPRT analyses when the LLR exceeds the established critical value for the 

outcome. For these results, Ms. Gee highlighted that the observed number of stroke events

(n=3) exceeded the expected (n=1.58) and there is an elevated RR (1.91). However, since the 

LLR does not exceed the critical value, at this time the data do not show a statistically significant 

association between quadrivalent HPV vaccine and stroke. For the more common outcomes 

among adults, where investigators are using a concurrent comparison group, no signal has

been generated. As a reminder, a signal is generated using the Flexible Sequential Analysis 

method when the binomial test p-value is less than the established threshold p-value.

With respect to the preliminary results for the concurrent comparison in adults, the exposed 

cases are those adverse events that occur within the exposure group, who are females 

receiving quadrivalent HPV vaccine. The unexposed cases are those adverse events that occur 

in a concurrent comparison group. There are two kinds of comparison groups: preventative 

care visit or a vaccination visit. To illustrate the technique used, Ms. Gee reviewed what the 

investigators did for syncope. The 129 syncopal events that occurred among those adult 

females who received 117,974 doses of HPV vaccine were compared to the 57 syncopal events 

that occurred in the 34,917 vaccination comparison visits to calculate the relative risk. Because 

the sequential method was being employed, the test statistic they needed to look at was the 

binomial test p-value and to compare it to the threshold p-value to determine whether the 

binomial was less than the threshold.

Among youth using a historical comparison, no signal has been generated. There is a slightly 

elevated relative risk for VTE (1.96); however, no signal has been generated since the LRR has 

not exceeded the critical value. The investigators for this study, however, are monitoring VTE 

very closely in this analysis and is chart reviewing all VTE cases identified in automated data, 

regardless of whether a signal is generated. They are currently in the process of reviewing 

medical charts of both exposed and unexposed cases, and are collecting additional information 

such as hormonal therapy and other risk factors through these chart reviews. Among the youth, 

using concurrent comparison groups, no signals were observed for seizure, syncope, or other 

allergic reactions. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Using syncope as an example, the investigators are reviewing 452 syncopal events following 

the 259,986 HPV vaccines that have been administered among girls 9-17 years of age and 120 

syncopal events that occurred after 106,252 vaccination visits in which the female received TD, 

Tdap, Menactra®, and or varicella vaccine in order to calculate the relative risk. Due to the 

sequential monitoring that occurs on a weekly basis, the test statistic the investigators needed

to look at in this example was the binomial test p-value (0.56), which was not less than the 

threshold (0.04). Therefore, no signal was generated.

With the attention quadrivalent HPV vaccine has received regarding syncope, CDC wanted to 

show some additional analyses that were conducted. Through logistic regression analysis, the 

investigators compared syncope rates following HPV vaccine with concurrent vaccination rates 

and found no excess risk among the youth or adult groups. They also combined the two age 

groups and again found a null result, with no excess risk. They also conducted additional 

analyses looking at rate of post-vaccination syncope following Td, Tdap, Menactra®, and 

varicella. With respect to the secular trend for post-vaccination syncope from 1996 to June 29,

2008, the rates for post-vaccination syncope are increasing over time.

As noted earlier, given that the primary ICD-9 code for anaphylaxis generates a lot of false 

positives, CDC validated each anaphylaxis case identified in the automated data through chart 

abstraction. Through the automated data, 8 anaphylaxis events were identified among the 

youth in the exposed group and 9 events among those in the comparison group. In the adult 

group, 7 events were identified among those who received vaccine and 2 who did not. Through 

chart reviews of each of these potential cases, none of the codes were true anaphylaxis cases

and none of these cases was vaccine-related. The majority of these cases were miscoded 

diagnoses with a history of allergy or epi pen refills. The rate of anaphylaxis following HPV for 

this study is 0 cases per million doses with a 95% CI of 0-9.76, and what investigators observe 

is within the expected rate of 1.5 cases of anaphylaxis following vaccination per million doses.

While the results of this presentation were only up to July 20, 2008, CDC wanted to let everyone 

know that continued monitoring has been on-going. Since July 20th, CDC has identified one 

adult GBS case in the automated data. The chart review on that case found that this is not a 

confirmed case following quadrivalent HPV vaccine. Therefore, based on a probability of 

observing 0 cases per 420,000 doses that have been administered, the investigators are unable 

to rule out a relative risk of less than 5.

In conclusion, CDC has found that with over 375,000 doses administered, the VSD HPV RCA 

did not find a statistically significant risk for any of the pre-specified adverse events following 

vaccination in either the 9-17 year old age group or the 18-26 year age group. Neither was any

major increase found in the rate of anaphylaxis following HPV4 as compared to previous 

studies. CDC plans to continue monitoring outcomes until the upper limits are reached or until 

the dose limit specified in this design of this study is reached. Even after the formal rapid cycle 

is completed, CDC plans to continue monitoring the more rare adverse events such as GBS, 

VTE, and stroke.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

57

Vaccine Safety Update: Summary of Findings 

for HPV Post-Licensure Safety Monitoring

John K. Iskander, MD, MPH

Acting Director

Immunization Safety Office (ISO)

Office of the Chief Science Officer (OCSO)

Dr. Iskander indicated that this represented the fourth summary of post-marketing safety data 

presented to the ACIP since June 2006 for HPV. This presentation summarized the experience 

of 20 million doses under passive surveillance and > 375,000 doses under active surveillance. 

Reporting to VAERS has been robust since licensure. It is expected that elevated reporting is 

due to publicity and general increase in adverse event reporting (94% of reports non-serious; 

most commonly reported events consistent with pre-licensure trial data). Analysis of more than 

10,000 VAERS reports shows that the vast majority of reported events are classified as nonserious. The most commonly reported events reflect expected local and systemic adverse 

events, many of which were observed in clinical trials. Preliminary data from the VSD rapid 

cycle study do not show associations with any of the eight specific outcomes under study for 

either adolescents or adults. For GBS and anaphylaxis, which are rare clinical events, these 

findings are subject to power limitations. The VSD findings show no overall increase in risk for 

syncope following HPV vaccine relative to other adolescent vaccines. The VSD findings are in 

agreement with published VAERS data indicating increasing post-vaccination syncope among 

adolescents. 

As background, CDC provided the ACIP members with published Australian case series of 

demyelinating diseases and anaphylaxis following HPV vaccine, along with accompanying 

articles intended to provide context. Available data from VAERS, CISA, and VSD do not 

support elevated risks of these conditions. Surveillance for these and other conditions of 

interest is on-going. 

Discussion

Dr. Morse noted that there has been extensive media coverage surrounding some of the more 

severe reported adverse events; however, the information presented alleviated some of the 

concerns that have been raised in those reports. He stressed that this information could be 

more useful if these data were presented in a more press-friendly version. CDC has been 

working on some talking points to better inform the public, and he wondered what the status of 

these were.

Dr. Iskander responded that this issue was brought to the CDC’s attention by ACIP leadership a 

few months ago. CDC was very much in agreement that different types of communications 

materials are needed. At this time, CDC has posted plain language talking points posted at 

CDC.gov/vaccine safety under “featured items.” He welcomed feedback on those materials.

With respect to the VTE cases discussed by Dr. Calugar, Dr. Temte inquired as to whether 

there was an assessment of potential underlying thrombosis.

Dr. Calugar replied that they did not. They reviewed the primary reports and any additional 

follow-up reports, labs, or anything else received. There was nothing related to genetic 

predisposition.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

58

Dr. Slade indicated that in one of the pathology reports, the pathologist did look for genetic 

defects in the case and did not find any. VSD will be looking in their review of the VTE cases as 

well.

Dr. Meissner requested clarification regarding whether there were any reports of anaphylaxis to 

VAERS.

Dr. Calugar responded that there were reports of anaphylaxis to VAERS, but these were not 

presented with respect of time. In 2007 and 2008, there were 26 reports to VAERS. Of those, 

there were 8 serious reports. The numbers match with the numbers presented in Dr. Neal 

Halsey’s publication.

In terms of the small number of patients who had TM, Dr. Meissner inquired as to whether any 

serologic samples were done to look for herpes virus, for example.

Dr. Slade responded that in a couple of cases, the investigators examined some antibody levels 

and they were not found. The two cases that were in the window did have a preceding viral 

illness.

With respect to individuals with GBS who then were re-vaccinated as discussed by Dr. Slade, 

Dr. Katz (IDSA) requested additional information. He also noted that this was remarkable 

information presented from VAERS, VSD, CISA, et cetera that had been needed for so long to 

refute, counter, and be able to engage in discussions pertaining to the misinformation that 

circulates in the media, on the Internet, et cetera. 

Dr. Slade responded that CDC is examining cases using the VSD in which people have a 

history of GBS and then happen to have been vaccinated to determine what happened to them.

Dr. Marcy asked Dr. Dana how long Merck & Company planned to follow the children for 

congenital anomalies, and whether these were only congenital anomalies discovered at birth. 

Dr. Dana replied that they do not exactly follow, but they do attempt to acquire follow-up 

information for as long as two years. They are unable to obtain two years worth of information 

on very many of the cases, but it is their goal to do so for two years.

Dr. Offit noted that, as was stated, there have been reports on CNN and CBS Evening News 

citing sources like Judicial Watch that the HPV vaccine is unsafe for some of the reasons that 

were just shown to suggest that it is not unsafe. While he appreciated Dr. Iskander’s comments 

about having talking points that are plain speaking as being of value, some parents and doctors 

are still concerned about this vaccine. Therefore, perhaps a more aggressive approach is 

necessary to get the ACIP’s voice out to the same types of sources in order to counter 

misinformation. 

Dr. Iskander responded that while he appreciated Drs. Katz and Offit for their comments, 

pointing out that the credit for the data presented belonged to the subject matter experts who 

presented the reviews, the clinical and research networks that support them, and staffers and 

collaborators in the Immunization Safety Office at CDC. He extended his gratitude to all of them 

as well. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

59

Vaccine Safety Update: Vaccine Pregnancy Registry

Adrian Dana, MD

Clinical Risk Management and Safety Surveillance

Merck & Company

Dr. Dana reported on the Pregnancy Registry for GARDASIL® with respect to a description of 

the registry, the methods, and data from the first two years after licensure. The second annual 

report covered the period from June 1, 2006 through May 31, 2008.

 

GARDASIL® is not recommended for use during pregnancy. However, inadvertent exposures 

may occur. The Pregnancy Registry for GARDASIL® is one part of a multi-faceted plan to 

monitor the safety in pregnancy. The Pregnancy Registry for GARDASIL® is operated by 

Merck & Company. The data source is the spontaneous, voluntary reports of pregnancy 

exposures reported to Merck. The registry includes reports from health care practitioners and 

vaccinees. The goals of the registry are to acquire information on pregnancy exposures and 

outcomes; help identify safety signals; and provide information to patients, providers, and

regulators. All reports of exposure to vaccine during pregnancy are monitored closely. 

Enrollment criteria for the formal registry are that the reports must originate in the US, Canada, 

or France; unique patient identifiers are needed in order to identify the patients; the health care 

provider must be identified; and the exposure must be within one month prior to the onset of the

last menstrual period or anytime during pregnancy. Currently, there are 10 cases from Canada 

and 1 case from France. Therefore, the data Dr. Dana presented were basically US data.

With respect to methods, prospective reports are those received before the outcome of the 

pregnancy is known. It is enrolled prospective reports with estimated dates of delivery falling 

within the report period that comprise the primary cohort for rate calculations. Retrospective 

reports, those received after the outcome is known, are also reported. These include initial 

reports after fetal testing reveals an abnormality. Retrospective reports have bias toward 

abnormal outcomes. The primary outcomes of interest include pregnancy outcomes (e.g., 

elective abortions, spontaneous abortions prior to week 20, fetal deaths ≥ week 20, and live 

births); and infant outcomes (e.g., congenital anomalies). Birth defects are categorized 

according to the CDC Metropolitan Atlanta Congenital Defects Program (MACDP). Birth defect 

frequencies are calculated on prospective reports using MACDP methodology, including the 

number affected (live born, fetal deaths, terminations ≥20 weeks) per 100 live born infants. All 

pregnancy reports are monitored as they are received. Appropriate experts are consulted as 

needed, and an independent consultant teratologist reviews the annual report.

Regarding the results, there were 863 enrolled reports with estimated dates of delivery within 

the report period. Of those, 76 were retrospective. The primary cohort is made up of the 787 

prospective reports. There is 1 woman who had a twin pregnancy who has two outcomes 

accounted for. One was a fetal death and one was a live birth. She is the one person who had 

double counting for outcomes. In terms of the report disposition for the 787 in the primary 

cohort is that 18% were lost to follow-up, 17% are pending, and 66% (n=517) have outcomes 

available. Ages (n=730) range from 12 to 38 years with a mean of 20 years and a breakdown 

as follows: 12-15 years (n=77); 16-26 years (n=615); and >26 years (n=38). As expected, the 

vast majority (~92%) of exposures were early in the pregnancy prior to the end of the first

trimester.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

60

There were 26 elective abortions, one of which was associated with anencephaly and 

hypoplastic heart. Of the 34 spontaneous abortions, there was one triplet pregnancy. No 

anomalies were reported among the cases of spontaneous abortion. The age range was 16 to 

37 years with the following breakdown: 16-18 years (n=13), 19-26 years (n=18), >26 years

(n=3). There were 7 fetal deaths among the prospective reports, several of which had other 

contributing factors (e.g., cord accident). There were 454 newborns, of whom 439 were normal 

infants (97%). 14 infants had congenital anomalies, four of which were minor (e.g., labial 

agglutinations, mild metatarsus adductus, mild hydrocele, brown nevus). There was 1 early 

neonatal death at 30 weeks gestation and a birth weight of 700g. Exposure was 12 days 

following the last menstrual period. While no anomalies were noted, the mother had 

antiphospholipid syndrome, which is homozygous for MTHFR mutation and may have 

contributed to the adverse outcome. There were 10 infants with major birth defects in the 

prospective reports including gastroschisis (flu symptoms, dTP, sertraline); hypospadias

(foreskin only; mother on omeprazole); Trisomy 21 ASD, PDA (PDA closed spontaneously); 

schizencephaly and polymicrogyria (diagnosed at 2 months of age; seizures); and pulmonic

stenosis (heart murmur noted at birth). These birth defects were of varying causes and varying 

critical gestational age and some were associated with family history of that anomaly.

In summary of the prospective reports, the rate of spontaneous abortions was 6.9 per 100 

outcomes (95% CI 4.8, 9.6). The reported rate among clinically recognized pregnancies is 

~15% [Scott, 1999]. The rate of fetal deaths in the registry is 1.5 per 100 live births + fetal 

deaths (95% CI 0.60, 3.09). The reported rate is 0.62 to 1 per 100 [Fox, 1997; MMWR, 2007]. 

The overall rate of major congenital anomalies is 2.2 per 100 live born infants (95%CI 1.05, 

4.05). The reported rate is 2.67 per 100 live born infants [Correa, 2007].

There were 76 retrospective reports, including 6 infants with major congenital anomalies (e.g., 

anencephaly (elective abortion); renal anomaly unspecified (MVA, PPROM, fetal death at 26

weeks); unilateral talipes (hormonal contraceptives); schizencephaly (no prenatal care;

delivered at 30 weeks; neonatal death at 8 days); cleft palate (little information); and renal 

agenesis (fetal death at 21 weeks). Two non-registry reports included congenital anomalies: 

Trisomy 18 (no prenatal care; delivered at 36 weeks); and gastroschisis (fetal death at 20 

weeks).

In conclusion, data from the Pregnancy Registry for GARDASIL® are reassuring with respect to 

safety after pregnancy exposures. Rates of spontaneous abortion, fetal deaths, and overall 

congenital anomalies compare favorably to published background rates. Rates of congenital 

anomalies appear to be consistent with background rates. The reported anomalies do not 

appear to show a pattern in that they are varied in type, etiology, and critical gestational age. 

The number of reports with known outcomes remains limited and conclusions are not definitive. 

It is especially difficult to interpret the significance of rare congenital anomalies. Merck will 

continue to monitor the safety of GARDASIL®, including reports of exposure during pregnancy.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

61

Adult Immunization Work Group Overview

Paul Cieslak, MD

ACIP Work Group Chair

Dr. Cieslak clarified that the Adult Immunization Work Group is not charged with making 

substantive changes in any recommendations, but rather is responsible for putting them into a 

format that is useful to internists and family practitioners. The Adult Immunization Working 

Group’s recent activities have included holding monthly teleconference calls to deliberate the 

revisions to the adult immunization schedule; convening focus groups pertaining to the 

usefulness of the adult schedule; and engaging in separate teleconferences with the General 

Recommendations Work Group with respect to the adult section of that document.

To assess the adult immunization schedule, with some CDC funding, investigators at the 

University of Michigan (e.g., Matthew Davis, Dianne Singer, and Sarah Clark) were 

commissioned to convene some focus groups to evaluate health-care providers’ application of 

the 2007-2008 adult immunization schedule, and identify opportunities for improvement of the 

schedule. With respect to their methods, focus groups were conducted in 8 community-based, 

private practices (e.g., family medicine and internal medicine) in 6 metropolitan areas from 

January through April 2008. The 88 respondents consisted of the following: physicians (34%), 

nurse practitioners (4%), physician assistants (1%), nurses (24%), and medical assistants 

(37%). Dr. Cieslak pointed out that the respondents were made up of a convenience sample, 

which he acknowledged to be nothing like a representative sample. 

The major findings were that 22% of the responders almost always ask about immunization 

status, while 47% occasionally or never ask; 45% are very comfortable using adult immunization 

schedule, while 17% have never seen the schedule; and approximately a third correctly 

identified recommended vaccines in three clinical vignettes. The participant were also asked for

suggestions for changes, for which they recommended improved formatting to reduce 

confusion; clarification or expansion of the content, especially for new vaccines; development of 

other versions (e.g., on-line point-and-click ability; on-line decision tool); and for the 2009 

schedule, a legend for blank cells, and to make the age groups more distinct and clarify and 

simplify the Td / Tdap graphic presentation. 

Future activities of the Adult Immunization Work Group are to publish the recommended adult 

immunization schedule in January 2009; complete the revision of Health Care Personnel 

Recommendations, with Healthcare Infection Control Practices Advisory Committee (HICPAC); 

and incorporate the adult immunization recommendations (1991) into the next general 

recommendations. 

2009 Adult Immunization Schedule
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Proposed Changes to the Adult Immunization Schedule 

Dr. Gina Mootrey

CDC / CCID / NCIRD / ISD

Dr. Mootrey reviewed the specific changes to the 2009 Adult Immunization Schedule (Figure 1). 

In addition to increasing the number of age groups (e.g., now 5 groups), some vaccination 

schedule text was removed from the vaccine bars, although that information remains in the 

footnotes. The appearance was changed for Td and Tdap by deleting the hatched yellow bar, 

based upon having received a number of comments that this was very confusing, and additional 

text was added to explain when Td or Tdap was indicated:

Another proposed change is the reordering of the vaccines to make it clearer, particularly in 

relation to contraindications in the Medical and Other Indications Table. In addition in this table 

(Figure 2), the column heading for immunocompromising conditions was revised by deleting the 

words “medication” and “radiation” as it was believed that these were not needed and that 

simpler would be better. Also, the vaccination schedule text was removed from the vaccine 

bars, although the schedule information remains in the footnotes, and the same legend box was 

added for blank spaces in schedule. The hatched yellow bar was deleted for Tdap and text was 

added to explain when Td or Tdap is indicated, along with text to clarify that only Td is indicated 

during pregnancy:
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

63

General footnote enhancements were made as well. To the extent possible, symbols have 

been replaced with text (e.g., <12 months is now “less than 12 months”). 

The HPV Footnote #2 has been revised to mention that vaccine can be given to females as 

young as 9 years of age, “HPV vaccination is recommended for females 11 through 26 years 

(and as young as 9 years) who have not completed the vaccine series.” Human Papillomavirus 

(HPV) Footnote #2 also has been revised to mention that health-care personnel are not at 

increased risk due to occupational exposure, “Health-care personnel are not at increased risk 

due to occupation exposure, and should be vaccinated consistent with age-based 

recommendations.”

Varicella Footnote #3 has been revised to clarify when one or two doses are indicated, “All 

adults without evidence of immunity to varicella should receive 2 doses of single-antigen 

varicella vaccine if not previously vaccinated or the second dose if they have received only one 

dose unless they have a medical contraindication. Adults who previously received only 1 dose 

of varicella vaccine should receive a second dose.” Varicella Footnote #3 also has been 

revised to add verification of herpes zoster by a health-care provider as a requirement for 

evidence of immunity, “Evidence of immunity to varicella in adults includes any of the following: 

4) history of herpes zoster based on health-care provider diagnosis or verification of herpes 

zoster by a health-care provider.”

Measles, Mumps, Rubella Footnote #5 has been revised to clarify the mumps second dose 

recommendation, “A second dose of MMR is recommended for adults who 1) live in a 

community experiencing a mumps outbreak and are in an affected age group.”

Influenza Footnote #6 has been revised to: Clarify occupational indications to include all healthcare personnel and add caregivers, “All health-care personnel, including those employed by 

long-term-care and assisted-living facilities, and caregivers of children less than 5 years old.”
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

64

PPV Footnote # 7 has been revised to include asthma as a chronic lung disease indication, 

“Medical indications: Chronic lung disease (including asthma);” Dr. Mootrey pointed out that this 

revision was made prior to the conversation that occurred earlier in the morning during the 

pneumococcal vaccine presentation and discussions. Based on those discussions, she will be 

including the recommendations that were made regarding cigarette smoking and the language 

pertaining to the American Indian and Alaska Native populations in the schedule.

Hepatitis A Footnote #9 has been revised to include additional information for the 4-dose 

combined hepatitis A and hepatitis B vaccine, “If the combined hepatitis A and hepatitis B 

vaccine (Twinrix®) is used, administer 3 doses at 0,1, and 6 months; alternatively, a 4-dose 

schedule, administered on days 0,7, and 21 to 30 followed by a booster dose at month 12 may 

be used.” Hepatitis B Footnote #10 has been revised to include additional information for the 4-

dose combined hepatitis A and hepatitis B vaccine, “If the combined hepatitis A and hepatitis B 

vaccine (Twinrix®) is used, administer 3 doses at 0,1, and 6 months; alternatively, a 4-dose 

schedule, administered on days 0,7, and 21 to 30 followed by a booster dose at month 12 may 

be used.” Hepatitis B Footnote #10 has been revised to clarify the schedule information for 

special formulation indications, “For adult patients receiving hemodialysis or with other 

immunocompromising conditions, 1 dose of 40 μg/mL (Recombivax HB®) administered on a 3-

dose schedule or 2 doses of 20 μg/mL (Engerix-B®) administered simultaneously on a 4-dose 

schedule at 0,1,2 and 6 months.”

Meningococcal Disease Footnote # 11 has been revised to clarify that revaccination might be 

indicated after 5 years, “Revaccination after 5 years might be indicated for adults previously 

vaccinated with MPSV who remain at increased risk for infection (e.g., persons residing in areas 

in which disease is epidemic).”

While Dr. Mootrey requested that comments not deal with wordsmithing during this meeting, she 

did invite suggestions throughout the following week pertaining to any changes to the schedule 

or the footnotes.

Discussion

Dr. Baker inquired as to whether there were data to support the revised meningococcal

footnote.

Dr. Mootrey responded that this revision was made to keep it simple, and was done with the 

concurrence of the meningococcal disease group.

Dr. Baker noted that the Red Book would have to be changed.

With respect to the pregnancy indication for Td and Tdap, Dr. Middleman (SAM) pointed out that 

stating “Td only” seemed to imply a contraindication for Tdap; whereas, Tdap is permissible in 

terms of provider decision making. Therefore, she suggested that the word “only” not be 

included.

Dr. Grogg (AOA) noted that in certain circumstances, such as when there is pertussis in a 

community, a pregnant woman would be vaccinated. 

Dr. Baker commented that the pregnancy recommendations published in 2008 specifically begin 

with the sentence, “Pregnancy is not a contraindication to Tdap.” That is as permissive as it 

gets. Basically, the cocoon is recommended, which is post-partum immunization with Tdap of 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

65

the mother, all of the family contacts, and caregivers of the infant. Therefore, if Td is given 

during pregnancy, that is a contraindication to administer Tdap because it has occurred a few 

weeks before doing cocoon. With that in mind, she completely agreed that Tdap in pregnancy 

is more practical than cocoon, but they need to be consistent with the ACIP recommendations 

until which time as they are changed.

Dr. Turner (ACHA) inquired as to whether the meningococcal footnote pertained to 

revaccination with polysaccharide or vaccination with conjugate after 5 years. Given that 

polysaccharide is really no longer available, this would not be revaccination for polysaccharide. 

It would be a first time vaccine with conjugate for someone who had received polysaccharide in 

the past and is still living or working in an endemic area. 

Dr. Baker indicated that polysaccharide is currently recommended for revaccination. There is 

no revaccination recommendation for MCV4.

Dr. Turner (ACHA) responded that it was not clear from the footnote that this pertained to MPSV 

not MCV4.

Dr. Fryhofer (ACP) reported that during the next weekend, the Board of Regents of the 

American College of Physicians planned to meet with the hope of endorsing the guidelines the 

ACIP votes on underway. The plan was to have that done by the following Monday. In addition, 

she noted that the Council of Subspecialties Societies, which works with the ACP, has signed 

on to a joint statement regarding vaccination by physicians. There has been a major push 

regarding the medical home and the importance of vaccination, but they realized that many 

patients with chronic medical problems may choose their sub-specialist as their primary care 

home, so the sense of the joint statement is that primary care and sub-specialists should be 

involved. In her role as a member of the AMA Council on Science and Public Health, she 

pointed out that Dr. Tan developed some wonderful cards that complement the adult 

immunization recommendations beautifully. 

Dr. Temte pointed out that the only vaccine not included on Figure 2 was the hemophilus 

influenza B, although on the back it states that “it might be indicated.” Therefore, he wondered 

if there should be a bar to indicate HIV and asplenia in order to be more direct. 

Dr. Mootrey replied that she would take this recommendation back to the work group. They 

have discussed this a number of times, and are willing to engage in the discussion pertaining to 

this issue again.

With respect to the draft of the 2009 Figure 1, Dr. Judson thought “then boost with Td every 10 

years” should be continuous for as long as one lives. There is a break and then it is again 

stated “Td booster every 10 years.”

Dr. Mootrey responded that this was to distinguish that, for those less than 65 years of age, they 

would be substituting one dose of the Td with Tdap. Otherwise, it would be every 10 years. 

Dr. Judson indicated that he would further discuss this with Dr. Mootrey offline.

Dr. Middleman requested further clarification with respect to the meningococcal footnote. For 

example, if someone had meningococcal vaccine with polysaccharide and it had been five years 

but they were still at risk, she wondered if the conjugate would be recommended.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

66

Amanda Cohn (CDC) responded that the recommendation is for person who were previously 

vaccinated with polysaccharide to be vaccinated 5 years later with conjugate vaccine. Adding 

MCV4 may help to clarify that recommendation. At this point, there is no revaccination 

recommendation for persons who were previously vaccinated with conjugate vaccine. 

Dr. Turner (ACHA) indicated that he had read the entire footnote, in which case this statement 

made sense, “Meningococcal conjugate vaccine is preferred for adults with any of the preceding 

indications who are 55 years or younger. Although meningococcal polysaccharide vaccine is an 

acceptable alternative, revaccination after 5 years might be indicated.” That statement, 

following the phrase that polysaccharide is an alterative, appeared to be appropriated. 

Therefore, the segment of the footnote shown should be acceptable.

Motion: 2009 Adult Immunization Schedule

Dr. Temte made a motion to approve the suggested revisions to the 2009 Adult Immunization 

Schedule. Dr. Beck seconded the motion. The motion carried with 15 affirmative votes, 0

abstentions, and 0 negative votes.

Dr. Baker indicated that she was standing in for Dr. Schaffner (NFID), who was unable to attend 

this meeting, to report on his behalf for the NFID’s adult immunization initiative titled, “Saving 

Lives: Integrating Vaccines for Adults into Routine Care” know as a “Call to Action.” This report 

was made available on the information table during this ACIP meeting. This Call to Action 

draws attention to the need to improve adult vaccination rates and addresses some of the 

challenging barriers that must be overcome to boost adult vaccination rates. Underutilization of 

vaccines in adults leads to unnecessary sickness and even death. About 95% or 50,000 or 

more Americans who die every year from vaccine-preventable diseases are adults. Millions 

more are hospitalized, miss work, and cannot fulfill daily obligations. Unfortunately, awareness 

and knowledge of vaccines is low among adults. In a recent NFID consumer survey, 40% of 

adults said that they do not need vaccines since they got vaccines when they were children. 

About a third are not concerned about catching vaccine-preventable diseases or spreading 

them to others. This lack of awareness and knowledge leads to lack of concern, and certainly 

contributes to low vaccination rates. This leads to morbidity and mortality for individuals and is 

a financial burden to our society. For example, the moderately severe seasonal outbreak of 

influenza costs more than $10 billion, tens of thousands of deaths, and hundreds of thousands 

of hospitalizations. About 1 in 3 Americans will get shingles during their lifetime. There are 

many opportunities for adults to be protected through vaccination. The Call to Action makes a 

special mention of vaccination of pregnant women who present a special window of opportunity 

to protect an adult and her newborn simultaneous, or 2-for-1 protection. The Call to Action does 

not present a quick fix, but draws attention to the need for long-term commitment to on-going 

education awareness campaigns aimed at increasing vaccination rates in adults. The goals and 

the messages in this Call to Action are supported by CDC, AARP, ACOG, ACP, AMA, Asian 

and Pacific Islander American Health Forum, IDSA, NFID, and SAM. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

67

Harmonized Schedule Work Group Overview

H. Cody Meissner, MD

ACIP Work Group Chair

Dr. Meissner pointed out that the Harmonized Schedule Work Group included members of the 

ACIP and CDC, as well as representation from AAP, AAFP, Association of Immunization 

Managers (AIM), Society of Adolescent Medicine (SAM), and the Immunization Action Coalition 

(IAC). 

The objective of this work group was to accurately and succinctly present the existing ACIP 

recommendations in the 2009 childhood and adolescent schedules. The schedules were to 

make no new immunization policy, although there was some clarification of existing statements, 

such as adding the minimum interval between dose 1 and dose 3 for the HPV vaccine, which 

was not included in the original HPV ACIP statement. The version of the schedule being 

presented to the ACIP for approval was developed using an iterative process. Input was first 

obtained from schedule work group members during monthly conference calls. ACIP 

recommendations published since January 2008 for rotavirus and influenza were also added at 

this stage. The work group’s revised document was then circulated among CDC subject matter 

experts (SMEs). Comments provided by CDC SMEs were discussed during a monthly work 

group call. A document that consolidated both work group and CDC SME revisions was 

submitted for internal CDC clearance in September 2008. 

The basic layout of the schedule is unchanged from the 2008 version, with three schedules: 0-6 

years, 7-18 years, and a catch-up schedule divide into two sections (e.g., 4 months through 6 

years and 7 years through 18 years). In the past, the version of the schedules published in the 

MMWR differed slightly from the version approved by the ACIP and the version posted on the 

CDC website. This was due to minor changes by the editors of the MMWR. For the 2009 

version, edits have been incorporated into the early drafts of the schedule to minimize changes 

by the MMWR editors. The en dashes (e.g., (hyphens used to indicate a range of numbers)

have been removed, given that interpretation was not always consistent. Some interpret the en 

dash as meaning “to” and others interpret it as meaning “through.” The en dashes were 

replaced with words (e.g., “to” or “through”) to reduce misinterpretation. In addition, symbols for 

“greater than” (>) and “less than” (<) were replaced with words because clinicians occasionally

misinterpret the meaning of the symbols.

Specific Changes Proposed for the 2009 Schedules

Dr. William Atkinson

(CDC / CCID / NCIRD / ISD)

Dr. Atkinson reiterated that the basic principle for this work was not to make new 

recommendations, but instead was to synchronize the schedule represent existing 

recommendations as succinctly and accurately as possible and to make clarifications as 

necessary. He reported that for rotavirus vaccine 0 through 6 and catch-up schedules, the 

footnotes were rewritten to reflect new interval and age recommendations approved by ACIP in 

2009 Immunization Schedule for Children 0-18 Years of Age
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

68

June 2008, which were posted on the ACIP website in July 2008. The following illustration 

reflects deletions as strikeouts and additions in red:

In the table itself, RV at 6 months of age has been italicized with a footnote indicating that a 

dose at 6 months is not necessary.

For influenza vaccine, in all schedules the tables and footnotes now include annual vaccination 

of children aged 6 months through 18 years; recommendation for vaccination of close contacts 

of children aged 0 through 4 years and of children aged 5 through 18 years with underlying 

medical conditions; and clarification of 2 versus 1 dose, given that this was a source of 

confusion. The following illustration reflects deletions with strikeouts and additions in red:

In the 2008 0 through 6 year influenza table, the yellow highlight contained a small segment of 

purple on the far right because last year the recommendation was through 59 months. Now the 

entire bar is shaded yellow, indicating recommended vaccine for all children through that age. 

In the 7 through 18 influenza table, last year the influenza bar followed the pneumococcal bar 

and was purple. Given that influenza is now a recommendation for all children through 18, the 

bar is now entirely yellow and it has been moved up so that that vaccines recommended for 

routine use are clustered at the top of the schedule.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

69

For varicella vaccine, in all schedules the footnotes were rewritten to more clearly state the 

minimum interval between doses for children aged 12 months through 12 years and persons 

aged 13 years and older. The following illustrations reflect deletions with strikeouts and 

additions in red: 

0 through 6 year schedule:

7-18 year and catch-up schedules

For hepatitis A footnotes, in all schedules the footnote was expanded at the request of 

colleagues in the Division of Viral Hepatitis (DVH) to indicate that specific groups 24 months and 

older that should be vaccinated. The following illustration reflects deletions with strikeouts and 

additions in red for all schedules: 

For Tdap for the 7 through 18 year old schedule, a footnote was added to better define the 

interval between Td and Tdap, which reads, “A 5-year interval from the last Td dose is 

encouraged when Tdap is used as a booster dose; however, a shorter interval may be used if 

pertussis immunity is needed.”

In the meningococcal vaccine footnote for 0-6 year and 7-18 year schedules, the statement 

pertaining to MPSV as acceptable alternative was deleted and the “terminal” modifier was 

retained for complement deficiency indication. There was significant discussion with respect to 

the use of the word “terminal.” There were those in the work group who believed that the word 

“terminal” pertained to medical indications having to do with meningococcal vaccine. A point 

was made that it is “complement component deficiency” not “terminal complement component 

deficiency.” Dr. Atkinson took this issue to the SMEs, and there was agreement initially that 

“terminal” probably was not necessary. There was additional discussion after this document 

was submitted, following which it was believed by people who are influential that in fact this is a 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

70

change in policy that should be vetted through the Meningococcal Work Group before 

embarking upon this important change in policy. Therefore, this issue will be further deliberated 

by the Meningococcal Work Group with respect to the 2010 schedule. In the interim, “terminal” 

will be left in as a modifier of “complement component deficiency.” 

The pneumococcal polysaccharide (PPSV) footnote for the 7 through 18 year old schedule was 

expanded to include cochlear implant and to clarify revaccination. Similar changes were made 

to the footnote in the catch-up schedule. The 7 through 18 year old schedule footnote reads, 

“Administer to children with certain underlying medical conditions (see MMWR 1997;46 [No. 

RR-8]), including a cochlear implant. A single revaccination should be administered to children 

with functional or anatomic asplenia or other immunocompromising condition after 5 years.” It 

was pointed out to Dr. Atkinson that this is probably not the best reference to use, so they will 

likely reference the 2000 pneumococcal polysaccharide statement rather than the 1997 

statement. The point was to be more specific about which children should be vaccinated in 

these age groups. 

A footnote was added to the Haemophilus influenzae type B catch-up schedule regarding

administration of Hib vaccine to persons older than 5 years of age. The footnote is a slight 

modification of the Hib footnote in the adult immunization schedule. This represents a fairly 

major addition to the schedule, which has been overlooked for many years. Therefore, a 

statement has now been added for use of Hib vaccine in older individuals (e.g., older than 59 

months) in order to make it consistent with the wording in the adult schedule. The footnote 

reads as follows:

4. Haemophilus influenzae type b conjugate vaccine (Hib). 

• Hib vaccine is not generally recommended for persons aged 5 years or older. 

No efficacy data are available on which to base a recommendation 

concerning use of Hib vaccine for older children and adults with the chronic 

conditions associated with an increased risk for Hib disease. However, 

studies suggest good immunogenicity in persons who have sickle cell 

disease, leukemia, or HIV infection or who have had a splenectomy; 

administering one dose of Hib vaccine to these persons is not 

contraindicated.

• If the first 2 doses were PRP-OMP (PedvaxHIB® or Comvax®), and 

administered at age 11 months or younger, the third (and final) dose should 

be administered at age 12 through 15 months and at least 8 weeks after the 

second dose.

• If the first dose was administered at age 7 through 11 months, administer 2 

doses separated by 4 weeks and a final dose at age 12 through 15 months.

For the human papillomavirus vaccine catch-up schedule, minimum intervals were removed 

from the table and the footnote wording was modified to emphasize that routine dosing intervals 

should be used. Minimum intervals are indicated in the footnote. The Harmonization Schedule 

Work Group worked closely with the HPV Work Group to develop a single footnote that would 

most accurately reflect the ACIP’s opinion about the use of HPV vaccine, particularly with 

respect to a catch-up schedule setting. The HPV table (Table 1) basically included the minimal 

intervals. Last year the minimal intervals between doses of HPV vaccine were included, but it 

was observed that people were using the minimum intervals for routine vaccination, which 

caused a great deal of concern. Therefore, it was the opinion of both the Harmonized Schedule 

Work Group and the HPV Work Group that they must try to actively discourage the use of 

minimum intervals to vaccinate a woman for HPV vaccine. Hence, the minimum intervals were 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

71

replaced in the table with a statement that says, “routine dosing intervals are recommended.” 

The footnote was revised to reads as follows:

11. Human papillomavirus vaccine (HPV). 

• Administer the series to females at age 13 through 18 years if not previously 

vaccinated.

• Use recommended routine dosing intervals for series catch-up (i.e., the 

second and third doses should be administered at 2 and 6 months after the 

first dose).

• An accelerated schedule is not recommended. However, the minimum 

interval between first and second doses is 4 weeks. The minimum interval 

between the second and third doses is 12 weeks, and the third dose must be 

given at least 24 weeks after the first dose. If the third dose has been 

delayed, administer it as soon as possible [which is the sole policy issue that 

is not otherwise represented in an ACIP statement].

Discussion

Dr. Judson thought it seemed contradictory with HPV to say that the third dose must be given at 

least 24 weeks after the first dose, but that if it is not, the third dose should be administered as 

soon as possible. He expressed concern that saying must implied that it would not work. In 

fact, there are no good data to suggest that there is not a much longer interval that will probably 

result in the same immunogenicity. 

Dr. Atkinson responded that they wanted to include a caveat for cases in which there was a 

lapse in intervals of more than 12 weeks. He thought the issue the group was trying to address 

was that the minimum interval needs to be at least 24 weeks between the first and last dose as 

opposed to a longer interval, which was not the issue the work group had. This was primarily to 

address people squeezing the doses into 16 weeks, which is what the group was actively 

attempting to discourage.

Dr. Judson clarified that the problem he had was that there are no data to address minimum or 

maximum spacing intervals with the precision that is implied by using the word “must.”

Dr. Atkinson replied that he thought the argument was that this was essentially the way that the 

trial was done. The bulk of the data that exist on the HPV schedule, and the one that was used 

in the clinical trials that was a 6-month schedule, mimicked this recommendation with at least 4 

weeks between the first two doses and the third dose given about 6 months after the second. 

Therefore, the recommendation is attempting to approximate the schedule for which there is the 

most robust data. He indicated that the recommendation could be toned down if preferable to 

state “should,” but the HPV experts felt strongly about the recommendation as written.

Dr. Judson maintained that he would opt not to state anything stronger than “should.”

Dr. Chilton indicated that the question he most commonly asked pertained to when 1 dose 

versus 2 doses of influenza vaccine should be given. The suggested footnote goes a long way 

toward improving that; however, if a patient received 1 influenza vaccine in 2005 and sought 

influenza vaccine for 2008, the statement indicates that this patient would need only one 

influenza vaccine. His understanding was that this patient would need at least 2 previous 

influenza vaccines in order to qualify for only 1 in 2008. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

72

Dr. Atkinson replied that Dr. Chilton’s thoughts on this were similar to a lot of other people’s, 

including himself. The intent of the influenza group was that the only situation in which a child 

would receive 2 doses would be if this was their first year or if, in the immediately previous year, 

they received 1 of 2 doses, in which case they would be eligible for 2 doses in the 

chronologically next year. If a child skips a year in between, it would default back to 1 dose. 

The work group believed that the suggested wording represented the spirit of how this should 

be. 

Dr. Baker wondered upon what data this statement was based.

Dr. Atkinson replied that, while he did not know to what degree the recommendation was 

actually supported by data, it was based on the statement that was made by the Red Book

Committee two years ago, which ACIP followed. As best the work group understood it, the 

statement is based on the intent of the Red Book Committee to only indicate two doses in those 

very limited situations, and the intent for the ACIP not to go beyond that which was 

recommended by the Red Book. While they recognize that it is not very biologically plausible 

that a child will suddenly not need to be boosted, this was the best they could do based on 

trying to harmonize the recommendation with those of the AAP. 

Dr. Tony Fiore indicated that this was largely based on a study by Allison in the Journal of 

Pediatrics in 2006, which specifically examined that one situation described. The intent of the 

AAP as best they understood it was to not go beyond what the data in that paper showed. In 

February 2007, the discrepancy between the ACIP’s recommendations and the AAP’s 

recommendations was rectified to restore harmony. 

Dr. Kimberlin (AAP / COID) noted that the deliberations accurately reflected what COID was 

comfortable with in terms of the Red Book recommendations.

Dr. Neuzil indicated that when they had this extensive discussion, the major concern was that 

the primary message would be lost, which is that children need 2 doses their first time. In the 

current recommendation, it still seemed to be lost. For example, all other children age 6 months 

through 18 should receive 1 dose. She could not think of any situation in which a 6 month old 

would only receive 1 dose. Therefore, she believed they needed to continue to work on the 

wording. With a 6-month old, it is impossible that they would have received 1 dose or 2 doses 

the year before.

With respect to the HPV catch-up schedule table, it was not clear to Dr. Sawyer why HPV was 

being singled out to say that routine dosing intervals are recommended. That is generally true 

for all of the vaccines, and this is meant to be an accelerated schedule. With that in mind, he 

requested clarification concerning the difference for HPV compared with other vaccines.

Dr. Atkinson replied that, in the opinion of the HPV Work Group, accelerated schedules should 

not be used. The HPV Work Group does not believe that the available data support an 

accelerated schedule for HPV, which is the message the recommendation was attempting to 

convey.

Dr. Sawyer said that because he suspected that there were limited data to support an 

accelerated schedule for the rest of the vaccinations, he wanted to go on record as objecting to 

pulling HPV out as a separate, unique vaccine in this situation. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

73

Dr. Schuchat clarified that HPV may actually be a unique vaccine. With accelerated schedules 

and catch-up, there is typically a concern about a period of risk for the child who is behind. For 

HPV, the concern is about protection for decades. Essentially everyone up to age 26 who is 

over 12 years of age is in the catch-up mode. The notion is not to get them vaccinated as 

quickly as possible, but is rather to get them protected. Currently, there are data for only a 

certain number of years of follow-up with a particular schedule. There are on-going studies of 

alternate schedules, so eventually it will be understood whether this can be done faster. 

However, there is not the same urgent period of risk. 

Dr. Sawyer suggested that hepatitis B might also be in the same category in a catch-up 

schedule.

Dr. Atkinson noted that there are better data and 25 years of experience with respect to an 

accelerated schedule for hepatitis B.

Dr. Temte wondered whether the work group was working with the electronic medical record 

(EMR) and registry programmers to attain high enough precision to inform practitioners through 

some better intelligence.

Given that this group is also responsible for general recommendations and the overall table that 

contains all of the ages and minimums, Dr. Atkinson responded that they do interact extensively 

with programmers, registry algorithm creators, et cetera. They have not worked as much with 

the EMR representatives, although they have answered endless questions pertaining to 

intervals. The group has worked as best they could to integrate all of the intervals and ages 

from Table 1 in the General Recommendations into the registries so they would accurately 

represent what is included in the tables. 

Dr. Sawyer noted that the varicella recommendation includes a double minimum interval by 

stating, “For children aged 12 months through 6 years the minimum interval between two doses 

is 3 months. However, if the second dose was administered at least 28 days after the first dose, 

it can be accepted as valid” and therefore does not need to be repeated. That creates a 

problem for the IIS community. Certainly, they can choose one or the other of those two 

programs, but if different systems choose different ones there can be a problem. The CDC 

software, Comprehensive Clinic Assessment Software Application (CoCASA), does not always 

choose the true minimum interval as opposed to the language. The other example of this is the 

interval between DTP3 and DTP4. Therefore, he encouraged the elimination of these 

somewhat double minimum intervals. 

Dr. Atkinson replied that the work group discussed the varicella interval at great length. This 

recommendation represented the best they could, and has been extensively vetted. He agreed 

that it created essentially two minimum intervals. Programmers are typically encouraged to use 

one for evaluation purposes; that is, looking at a record of someone who has already been 

vaccinated as opposed to a forecasting algorithm, and to try to use the proper minimum interval 

for a forecasting algorithm as opposed to an evaluation algorithm. He agreed that CoCASA 

sometimes did not concur with this and they are aware of some other similar situations. 

With regard to the HPV interval, Dr. Cieslak indicated that situations have occurred in which 

people have been vaccinated more than 3 but less than 6 months following the first dose. The 

question arises with respect to whether they need to be revaccinated. His understanding is that 

CDC and ACIP are not recommending that such individuals be revaccinated. For that reason, 

he agreed with Dr. Sawyer that “must” should be changed to “should.”
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

74

Dr. Atkinson replied that the work group decided that the data were not sufficiently negative for 

such a situation that they would force those individuals to be revaccinated, particularly given 

that those were the published minimum intervals in the first place. The group decided that if a 

woman received vaccine based upon existing minimum intervals, it would not be recommended 

that she be revaccinated. However, if the interval violates the previous recommended minimum 

interval (e.g., less than 12 weeks), it would be recommended that the dose be repeated. 

With respect to dosing interval of HPV and HBV, Dr. Judson noted that what people really want 

to know is whether an alternate schedule, when it is not specifically recommended, is likely to 

provide inferior coverage. All other information really is not very helpful. He realized they could 

not answer the question definitively, but in the same sense they should not be recommending 

rigid criteria for dosing intervals that cannot be supported by the data. By saying 

“recommended dosing intervals” they were saying “recommended dosing intervals are 

recommended,” so he did not believe this was necessary to add. Regarding the influenza 

acronym conventions, when it is said that the inactivated is trivalent, this implies that the live is 

not trivalent or may not be trivalent. He thought the acronym should adhere to what is actually 

in the vaccine. One is trivalent, inactivated influenza vaccine. The other is trivalent, live 

attenuated influenza vaccine. At some point, the conventions should be rationalized. 

Dr. Atkinson replied that the work group grappled with this a few years ago when they first 

began. He agreed that it is not exactly logical, but the group believed this was the best 

alternative at the time. They certainly could revisit the issue if appropriate.

With respect to the statement, “A 5-year interval from the last Td dose is encouraged. When 

Tdap is used as a booster, a shorter interval may be used,” Dr. Marcy thought Dr. Halpern’s 

data went down to 2 months with a bell-shaped curve going down to 18 months. The N was 

very small, but he did not believe they could just say “a shorter interval” and that they should be 

more specific than that. 

Dr. Atkinson responded that the work group’s standard position has been that there really is no 

absolute minimum interval. Some people wanted to add 2 years, while others argued that there 

are situations where the benefit of giving the vaccine at less than 2 years outweighs the risk of a 

local reaction. Yet people were anxious about saying there is no absolute minimum because 

that is setting policy that does not exist in the current ACIP statement. This was somewhat of a 

negotiated intermediate to find a way to satisfy everyone.

Dr. Marcy stressed that the only data are those generated by Dr. Halpern.

Dr. Baker added that the MMWR published statements say 2 years. While she completely 

agreed personally, she thought they had to be consistent with what is published until there are 

data to say otherwise.

Dr. Atkinson reported that there is wording in the existing Tdap schedule that says the data 

support giving it at as little as “2 years; shorter intervals may be used.” That wording is specific 

in the statement. The work group interpreted that as meaning that 2 years was not an absolute 

minimum; if necessary it could go less than that even though there were no data. This is why 

they have continued to use this wording, and how they have also argued that there is no 

absolute minimum based on the 6- or 7-word phrase that exists in the adult Tdap statement 

currently. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

75

Dr. Baker replied that she did not know whether there were data to support changing the current 

wording. 

Dr. Atkinson stressed that they have not changed the wording. That wording exists. It says 

“shorter intervals may be used,” which is what the recommended wording for the footnote. 

Dr. Baker pointed that it was not what the existing footnote stated. 

Under the 0 to 6 years meningococcal vaccine footnote, Dr. Whitley-Williams (NMA) wondered 

whether they meant to say “Persons who received MPSV 3 or more years previously” or if that 

was changed to “5 or more years.” In the 7 to 18 year footnote, 3 is crossed out and 5 is added. 

Dr. Atkinson responded that the Meningococcal Work Group indicated that, in fact, for children 

less than 10, the interval is 3 or more years and for people 10 or older, it is 5 or more years.

Dr. Cohn (CDC / NCIRD / DBD) added that they made this decision because they were asked to 

not continually have the 3 to 5 years in these footnotes. They do believe, based on the data 

from polysaccharide vaccine, that younger children actually should be vaccinated after 3 years, 

but that it is acceptable to wait 5 years for a person over 10 years old.

Dr. Whitley-Williams (NMA) said that she does receive many questions about 11- to 12-year 

olds who have been vaccinated with the meningococcal conjugate vaccine and whether they 

should be revaccinated 3 to 5 years later. This is not specifically addressed and she thought it 

would be helpful because many pediatricians do look at this schedule and then review the 

footnote. When they do not find the answer, NMA receives calls. She thought it would be 

helpful to specifically state that “for those previously vaccinated with conjugate vaccine, there 

are no data to support revaccination at this time.” 

Dr. Cohn (CDC / NCIRD / DBD) noted that CDC is in the process of revising the vaccine 

recommendation, which should be published in 2009. There will be more data to discuss 

whether children need revaccination before college if they were vaccinated at 11 or 12 years 

old.

Dr. Whitley-Williams (NMA) stressed the importance of including something about this in the 

footnote, given that this is a common question. She thought the fact that it is specifically not 

addressed was causing some of the confusion.

Dr. Atkinson replied that this would not be difficult to include. Perhaps another footnote could 

be included to state, “Revaccination after receipt of MCV is not indicated.” 

Dr. Whitley-Williams (NMA) thought that Dr. Atkinson’s suggestion would solve the problem.

With regard to the hepatitis A footnote for 7- to 18-year olds, Dr. Middleman (SAM) noted that 

the MMWR pertaining to hepatitis A states that, “In areas without existing hepatitis A vaccination 

programs, catch-up vaccination of unvaccinated children aged 2 to 18 years can be 

considered.” There is nothing in the footnote that makes clear that it is acceptable to catch-up 

an adolescent with hepatitis A vaccine. To benefit adolescents, she thought it would be helpful 

to add this to the footnote. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

76

Dr. Atkinson replied that at Dr. Middleman’s suggestion, he approached the Division of Viral 

Hepatitis (DVH) more than once on this issue and originally had included a bullet in the 

suggested footnote that basically stated that older children who wish to be immune may receive 

the vaccine. He also pointed out that the wording is included in the current, existing statement. 

DVH was very specific about their opinion that this exceeded the spirit of the current 

recommendations and they insisted that he remove it and that it be referred to Dr. Sawyer’s new 

Hepatitis A Work Group for consideration. Otherwise, they would not agree to sign off on the 

document. In DVH’s opinion, this is a policy change that was never intended. 

Cindy Weinbaum (DVH) responded that they do plan to raise this issue with the Hepatitis Work 

Group because the initial intent of others who are unvaccinated and wish to be vaccinated was 

specifically included in the context of adult immunization for high risk adults. It was not included 

with the thought of catch-up vaccination for children. Therefore, it would be a departure from 

the initial intent and should be addressed separately. 

Dr. Middleman stressed that this is a point that is not clear to those treating adolescents. It 

appears that many adolescents are requesting the vaccine and are being caught up, and it does 

seem to be permitted in accordance with the MMWR recommendations. It is somewhat 

confusing because the specific recommendation addresses programs, although it is physicians 

reading this and it clearly states “catch-up vaccination of unvaccinated children aged 2 to 18 

years can be considered.” With that in mind, she thought it was important to clarify this either in 

the MMWR or in the schedule because physicians want to immunize and protect their 

adolescents. As an adolescent medicine provider, she wants to catch them up with hepatitis A 

vaccine because she thinks it is in their best interest. 

Cindy Weinbaum (DVH) replied that they hope to address this issue.

Regarding the second dose of MMR and varicella, Dr. Lewis (AHIP) pointed out that essentially 

the practitioners in her area were trying to protect children at an earlier time than waiting until 

kindergarten on the 4 to 6 years. Although there is a permissive recommendation in the 

footnotes and always has been (e.g., essentially the 28 days for MMR and 3 months for 

varicella), and there is a hepatitis A vaccine visit between the 18 months to 2 years, their public 

health department is reticent to help them encourage their physicians to start at 18 months with 

the second dose MMR and varicella because they do not have a permissive statement like there 

is with Dtap that states “See footnote 3” in that space. AHIP suggested the addition of a 

statement that reads, “See footnote 7” and “See footnote 8” in the blank space where everyone 

perceives that MMR and varicella should not be given, so that they will be referred to a footnote 

indicating that they can give it. She did not think that the existing footnote accomplished this 

because it is not included on the chart like it is in the Dtap footnote referral in the blank space. 

The blank space before the 4-year old period does not tell practitioners that they can do 

something within that period. 

Dr. Morse thought the suggestions were wonderful and would likely make this a much better 

document; however, he reminded everyone that these are continuous quality improvements and 

that there would be other opportunities to make suggestions and changes.

With regard to the new pneumococcal statement to be written, Dr. Marcy appealed to Dr. Cohn 

for the term “dormitory” to be clearly defined. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

77

Dr. Atkinson stressed that in order to have this published simultaneously in the MMWR, 

Pediatrics, and American Family Physicians, it must be submitted to AAP by November 14, 

2008 in basically its final form. He requested that those who felt strongly about the suggestions 

they made during this discussion period let him know immediately so he could take them back 

to the work group.

Motion: 2009 Immunization Schedule for Children 0-18 Years of Age

Dr. Meissner made a motion to approve the suggested revisions to the 2009 Immunization 

Schedule for Children 0-18 Years of Age, with the improvements suggested during the 

discussion period. Ms. Ehresmann seconded the motion. The motion carried with 15 

affirmative votes, 0 abstentions, and 0 negative votes. 

[Note: Due to time constraints, this session was moved to the second day of the meeting; however, it appears in this document in 

the order in which it appeared on the agenda for ease of locating it] 

Revised Recommendations for the Use of JE Vaccines for US Travelers

Marc Fischer, MD, MPH

Arboviral Diseases Branch

DVBID, NCZVED, CDC

Dr. Fischer explained that Japanese encephalitis (JE) is a mosquito-borne flavivirus related to 

West Nile virus and St. Louis encephalitis virus. It is the leading cause of encephalitis in Asia, 

occurring throughout most of Asia and areas of the Western Pacific. Other than sporadic travelassociated cases, it does not occur outside of those areas. There are an estimated 35,000 to 

50,000 encephalitis cases due to JE annually. Due to limited surveillance and poor diagnostics, 

this may be an underestimate of the total burden. There is no antiviral therapy to treat this

disease. Supportive care is the only type of treatment. JE is a fairly severe disease, with a 

case fatality report of 20-30% historically. Of the survivors, 30-50% can have significant 

neurologic sequelae.

Japanese encephalitis virus (JEV) is transmitted in an enzootic cycle between Culex

mosquitoes and vertebrate animals. The mosquito becomes infected after biting a viremic 

animal. The infected mosquito then transmits the virus to another animal where the virus can 

amplify further. Although many animals can become infected with JEV, pigs and wading birds 

are the most important reservoirs. If an infected mosquito bites a human, the person may 

become infected. However, JEV-infected humans are a dead end host in the JEV transmission 

cycle because they develop only brief and low levels of viremia. Unlike dengue virus, humans 

do not amplify JEV, and JEV is not transmitted from person-to-mosquito. Other than 

theoretically through blood transfusion, organ transplantation, or mother-to-fetus, JEV is not 

transmitted directly from person-to-person. Therefore, even in endemic areas where human 

cases do not occur due to high vaccine coverage or natural immunity, JEV may still circulate in 

an enzootic cycle, and non-immune visitors to that area may be at risk for disease. Culex

mosquitoes are the principal vectors for both zoonotic and human transmission of JEV 

throughout Asia. In areas of Japan and Korea, for example, there are less than 10 human 

Japanese Encephalitis Vaccine
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

78

cases per year, but there are still areas with enzootic activity and non-immune visitors to that 

area may be at risk for disease. 

JE is primarily a rural disease associated with flood irrigation and rice production. The 

mosquitoes that transmit this feed mostly outdoors at dusk and at night. In endemic areas, it is 

primarily a disease of children, given that adults typically have protective immunity with 

exposure and asymptomatic infection. Susceptible or non-immune adults who come into 

endemic areas with enzootic transmission are at risk for disease. There are some data to 

suggest that, as with West Nile virus, if they are infected, older adults are possibly at higher risk 

for neuroinvasive disease.

There are two general seasonal patterns of JE in Asia: 1) Seasonal epidemics, and 2) Endemic 

or sporadic disease. In temperate areas of Asia (e.g., China, Japan, Korea, Nepal, and 

Northern parts of Vietnam, Thailand, and India) seasonal transmission occurs with summer 

epidemics that usually peak between June and August. In tropical areas of Southeast Asia and

Southern India, seasonal transmission varies with local patterns in bird migration, monsoon 

rains, and irrigation practices, and disease may be transmitted year round without clear 

evidence of a summer peak. These seasonal epidemics can be very explosive. Most recently 

in the summer of 2005 in Uttar Pradesh, India there were thousands of cases over a matter of

several months. 

Estimating the risk of JE disease in travelers is difficult. There are travelers who may spend a 

long time in rural areas where JE virus is being transmitted. Those travelers are probably at 

similar risk to the susceptible, endemic population. Therefore, rates can be extrapolated from 

the resident children who are not immune. Rates may also be extrapolated from nonimmunized US military personnel in endemic areas, who seem to be at similar risk for disease. 

These rates vary greatly depending on whether there is endemic or epidemic transmission, 

ranging from 10 to 200 cases per 1 million persons per week. The 200 cases per million would 

be at peaks of epidemic explosive transmission. With regard to minimum estimates based on 

published cases from 1973-2008, 43 JE cases were identified among travelers world wide. Of 

those, 15 were US travel-related cases, including 6 military cases and 9 civilians or military 

dependents. Estimating the denominator of travelers is also difficult. At the beginning of this 

time period, in the 1970s to 1980s, the estimate was about 2 million travelers per year from the 

US to Asia. More recently, in 2004, the numbers are estimated to be closer to 5 million entries 

of US residents into Asian countries; this does not account for travelers who make multiple trips 

to Asia. Thus, the range is between 2 to 5 and five million travelers. Obviously, the numerators 

are not great. There are probably more cases than the 43 that have been diagnosed and 

reported in the literature, and the full denominators are unknown. Nevertheless, the risk to 

travelers is probably overall less than 1 case per 1 million trips to Asia. Dr. Fischer noted that 

1973 was chosen because prior to that time, there were several hundred cases that were 

described in soldiers in the Vietnam War and Korean conflict. 

The 43 cases reported in literature were further examined to better understand who they are. 

For 36 of them, CDC had some information on demographics. For the others, they had no 

information other than they had been reported as a case of JE. The median age among the 36 

cases was 31 years, but the age range was 1 year of age to 81 years of age. About half were 

male and half were female. None were reported to have received the JE vaccine. With regard 

to outcomes, 5 of the patients died (16%). The last death was in 1995 and was the only known 

JE travel-related death since 1985. For some reason, there seem to be fewer deaths in the last 

decade or two. Of the survivors, about a third reported some sort of disability following the 

infection. Even less data are available with regard to risk factors. In 24 cases (56%), CDC has
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

79

some information about the type of travel and the itinerary. Most striking is that the majority of 

the cases (~70%) were in Asia either as expatriates, on military deployments, or on long-term 

travel (e.g., a period of a month or longer). The other seven patients (~30%) were there for 

shorter time periods, with 2 of them being there for less than 2 weeks. Based on their 

itineraries, all 7 of the shorter-term travelers were in rural or agricultural areas at some point 

during their trips. Also of interest for the 24 cases for whom CDC has travel itinerary 

information, approximately 50% were there during the peak epidemic period for those areas that 

have the seasonal summer transmission. Another 50% were there during other times of the 

year, and were primarily patients who traveled to Indonesia, Southern Vietnam, and Southern 

Thailand where there is sporadic transmission.

CDC’s conclusions from the limited data they have is that overall, the risk of JE for travelers is 

very low, but varies considerably based on the season, destination, duration, and activities 

undertaken while traveling. Prolonged travel in rural areas with active JEV transmission are

likely to be of similar risk as for the susceptible resident population. Shorter-term travelers may 

still be at risk if their itinerary includes outdoor or nighttime exposure in rural areas. Short-term 

travel restricted to major urban areas confers very minimal risk for JE. There have not been 

reported cases in the literature, although there are anecdotal and other reports of a few cases in

patients who were in these areas for shorter periods of time and reportedly did not travel outside 

of urban or suburban areas.

The currently licensed JE vaccine in the US is an inactivated mouse brain-derived vaccine. It 

was originally developed in the 1940s and was used during World War II. The current 

formulation was developed in Japan in the 1960s and was licensed there in 1968. It has been 

used to effectively control JE disease in several Asian countries, particularly Japan, Korea, 

Taiwan, and Thailand. JE-VAX®, the trade name for the licensed vaccine in the US, was 

licensed in the US in 1992. It was manufactured by Biken in Osaka, Japan, and distributed in 

the US by sanofi pasteur.

There were two controlled efficacy trials of the vaccine. The first was with an earlier formulation 

in Taiwan, and a subsequent study was conducted in the mid-1980s that is the basis for the 

licensure of the vaccine [Hoke. N Engl J Med 1988]. This was a randomized controlled efficacy 

trial of inactivated mouse brain-derived JE vaccine from 1984-1985 of more than 65,000 

children 1 to 14 years of age in Thailand. The children were randomized into three groups to 

receive two doses of either JE vaccine (N=43,708) or tetanus toxoid (n=21,516). The two 

groups that received different formulations of the JE vaccine (monovalent and bivalent) were 

combined, given that they had the same findings. Efficacy was evaluated at 2 years. In the JE 

vaccine group there were 2 cases of confirmed JE among the study vaccine and 11 cases 

among the tetanus toxoid, for an overall efficacy of 91%. Given in a 2-dose regimen, which is 

how it is used primarily in Asia among children, this vaccine seems to have very good 

immunogenicity and efficacy, probably due somewhat to preexisting immunity and a natural 

boosting that occurs through mosquito infection. 

However, when immunogenicity studies were conducted among non-immune persons or adults 

from non-endemic countries, the immunogenicity was not as good with 2 doses. These studies 

were conducted primarily in the US Military and one in the British Military (Henderson, 1984) 

deployed to Nepal. Following a 2-dose regimen, immunogenicity was 40% to 80%. When a 3-

dose regimen was administered, the immunogenicity was more comparable to the 2-dose 

regimen among children in Asia and was approximately 90% to 100%. In addition, the 

DeFraites study (1999) administered the vaccine in two different regimens at 0 / 7 / 14 days and 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

80

at 0 / 7 / 30 days. The 0 / 7 / 30 days had significantly higher GMT results and is the basis for 

the currently-licensed 3-dose regimen administered at 0 / 7 / 30 days.

Incidence of hypersensitivity reactions following inactivated mouse brain-derived JE vaccine are 

as follows [Plesner 2003; Takahashi 2000; Berg 1997; CDC 1993]:

Country Cases Denominator Incidence 

per 100,000

Japan (NARRS) 71 9,400,000 doses 1

U.S. (VAERS) 51 813,822 doses 6

Sweden 1 15,000 vaccinees 10

U.K. 1 1,950 vaccinees 50

Denmark 21 41,500 vaccinees 50

Australia 7 4,000 vaccinees 200

U.S. 38 14,249 vaccinees 266

This vaccine has gotten more attention due to adverse events rather than its immunogenicity or 

efficacy. One of the adverse events that received considerable attention is hypersensitivity or

allergic reaction following the vaccine. There is a wide range of estimated incidence of

hypersensitivity depending upon the study, the study methods, whether there were active or 

passive case finding, and the types of case definitions. Findings range between 1 per 100,000 

per dose to 260 cases of hypersensitivity per 100,000 vaccinees. In a study conducted among 

14,000 US Marines being deployed to Okinawa [Berg. Clin Infect Dis 1997] subjects received

the currently licensed JE-VAX® mouse brain-derived vaccine. Among these 14,000 Marines, 

38 experienced hypersensitivity or allergic reactions. Of those experiencing hypersensitivity, 27 

(71%) had urticaria, angioedema, or wheezing; and 11 (29%) had pruritus only, although it 

appeared that this was generalized pruritus and significant enough that the investigators

considered these to be cases of hypersensitivity. Most of the cases were fairly mild and many 

did not present to medical care and were only picked up as part of the active case finding for the 

study itself. Of those experiencing hypersensitivity, 3 had some wheezing or airway issues, 1

had tightening of the throat, and 2 were hospitalized. This is fairly typical of all of the 

surveillance studies that were conducted. 

Another important feature observed in this study was the delayed nature of the hypersensitivity, 

especially in second or third doses. While following the first dose the median time for this type 

of reaction was only a day (with some occurring within hours), for the second and third doses, 

the time was spread out such that the median time for the reaction was four days. One case 

occurred at 14 days. This is the basis for the current recommendation to wait at least 10 days 

following the final dose prior to traveling in order to ensure that there is access to medical care 

in the event of a delayed hypersensitivity reaction. It appears that hypersensitivity reactions are 

more likely to occur in persons with a history of anaphylaxis, urticaria, or allergies. [Berg 1997; 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

81

Plesner 2000] IgE antibodies against the gelatin stabilizer may be responsible for some of 

these allergic reactions [Sakaguchi 2001].

The use of mouse brains as the substrate for virus growth has always raised concerns about the 

possibility of neurologic side effects associated with the JE vaccine. Neurologic events reported 

following inactivated mouse brain-derived JE vaccine include paresthesias, seizures,

encephalopathy, gait disturbance, GBS, and acute disseminated encephalomyelitis (ADEM)

[Matsukura 1980; Ohtaki 1992; Ohtaki 1995; Sohn 2000; Takahashi 2000; Matsui 2002; 

Ferguson 2007; Plesner 2000; Plesner 2003]. Between 1965 and 1973, neurologic 

complications (e.g., encephalitis, seizures, and peripheral neuropathy) were identified at a rate 

of 0.1 to 0.2 cases per 100,000 vaccinees in Japan. Between 1983 and 1996, 10 reports of 

moderate to severe neurologic symptoms (e.g., encephalitis, seizures, gait disturbances, and 

Parkinsonism) followed 384,000 doses of inactivated JE vaccine administered to Danish 

travelers (2.6 per 100,000). No prospective studies have been conducted to determine the 

actual incidence rates or to further evaluate the potential causal effect between JE vaccine and 

these neurologic events have been performed. In Japan, 17 neurologic disorders were reported 

following vaccination from 1996 to 1998 for a rate of 0.2 events per 100,000 doses. In the US, 

two serious neurologic adverse events were reported between 1993 and 1998. Taken together, 

these data further support the conservative recommendations limiting the use of the vaccine to 

travelers at high risk of infection with JE [Takahashi 2000; Plesner 1998]. 

Decisions regarding the use of JE vaccine for travelers must balance the low risk of disease and 

the low probability of serious adverse events following immunization with the high case-fatality 

and substantial sequelae of JE virus and the fact that there is no specific treatment. There will 

soon be two effective vaccines available.

In 1993, shortly after the vaccine was licensed in the US, the ACIP published the following 

recommendations:

“JE vaccine is NOT recommended for all travelers to Asia.”

“JE vaccine should be offered to persons spending ≥1 month in endemic areas during 

the transmission season, especially if travel will include rural areas.”

“Under specific circumstances, vaccine should be considered for persons spending <30 

days in endemic areas, e.g., travelers to areas experiencing epidemic transmission and 

persons whose activities, such as extensive outdoor activities in rural areas, place them 

at high risk for exposure.”

Biken discontinued production of JE-VAX® in the US in 2005. In 2007, sanofi pasteur estimated 

that remaining supplies for civilian travelers would be exhausted by mid-2008. In June 2008, 

sanofi pasteur obtained 25,000 additional doses from the DoD stockpile for use in civilian 

travelers through some remarkable cooperation between the DoD, sanofi pasteur, and HHS. It 

is estimated that there is enough supply to last through the first quarter of 2009. To prolong 

availability, sanofi pasteur continues to restrict purchase to current customers and limit orders to 

9 doses per month. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

82

The current inventory of JE vaccine for civilian travelers will only last for another few months or 

a year at the most. Therefore, consideration must be given to the longer-term picture. In terms 

of licensing a new JE vaccine in the US, availability of several effective JE vaccines in Asia 

makes a controlled efficacy trial unethical and impractical. Plaque reduction neutralization test 

(PRNT) titer of ≥1:10 is accepted as an immunologic correlate of protection for JE. New JE 

vaccines for the US will be licensed based on comparative PRNT immunogenicity study 

showing “non-inferiority” of new vaccine to licensed vaccine, and safety evaluations of the new 

vaccine in ~5,000 subjects [Hombach. Vaccine 2005; Markoff. Vaccine 2000].

A new vaccine known as Ixiaro®, which is an inactivated Vero cell-derived JE vaccine (IC51), is 

manufactured by Intercell in Vienna, Austria. A Biologic License Application (BLA) was filed 

with the FDA in December 2007. The initial indication will be for use in adults ≥18 years. 

Novartis will distribute this vaccine for US civilians. A comparison of the components, dosing, 

and administration of the two inactivated JE vaccines follows:

JE-VAX IC51

Substrate Mouse brains Vero cells

JEV strain Nakayama-NIH SA 14-14-2

Adjuvant None Aluminum hydroxide

Stabilizer Gelatin None

Preservative Thimerosal None

Preparation Lyophilized Liquid

Route Subcutaneous Intramuscular

Primary series 3 doses (0, 7, 30 

days)

2 doses (0, 28 days)

Age group ≥1 yr ≥18 yrs

The pivotal clinical trials for IC51 examined non-inferiority of 2 doses of IC51 (n=361) versus 3 

doses of JE-VAX (n=364); safety and tolerability of IC51 (n=1,993) versus placebo (n=657), 

persistence of neutralizing antibodies at 6 and 12 months, kinetics of neutralizing antibodies, coadministration of IC51 and hepatitis A vaccine, and pooled safety at 6 months after receiving 

IC51 (n=3,558). In the comparative immunogenicity trial of 2 doses of IC51 to 3 doses of JEVAX, PRNT50 ≥1:10 (SA 14-14-2 was used as the target JEV strain for PRNT assay) was 98% 

in IC51 and 95% in JE-VAX, while the GMT was 245 and 102 in IC51 and JE-VAX respectively 

[Tauber. Lancet 2007].
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

83

In the pivotal safety trial for 2 doses of IC51 in 1,993 subjects and placebo in 657 subjects, the 

following adverse events were observed: 

Adverse events IC51

(N=1,993)

Placebo*

(n=657)

Any 1,173 (59%) 372 (57%)

Medically attended 254 (13%) 80 (12%)

Serious 10 (0.5%) 6 (0.9%)

Terminated study 12 (0.6%) 5 (0.8%)

*Aluminum hydroxide adjuvant

Tauber. J Infect Dis 2008

The Japanese Encephalitis Work Group concludes at this point that IC51 is a promising vaccine 

for travelers using a 2-dose schedule (0 and 28 days). In addition, the IC51vaccine has a good 

immunogenicity and reactogenicity profile. No gelatin or murine protein is include, which is 

likely to result in fewer adverse events. However, IC51 has been studied in <5,000 recipients 

and the possibility of rare adverse events cannot be excluded. Post-licensure studies and 

surveillance data will be important to further evaluate safety in a larger population. 

Regarding JE vaccine for children, IC51 will initially be licensed for adults but is being evaluated 

in children. A small immunogenicity study has been completed in India, and other studies are 

planned. There is a pediatric development plan for the vaccine to be licensed in the US, but 

that is probably two to three years away. At least for those two to three years, JE-VAX® will 

remain the only vaccine approved for use in children. In order for that to bridge to the gap until 

IC51 is licensed in children, sanofi pasteur plans to maintain a stockpile of JE-VAX® for use in 

children until 2010.

Current Japanese Encephalitis Work Group activities are to monitor the availability of JE 

vaccine for US travelers; work with HHS, DoD, and sanofi pasteur to mitigate possible supply 

issues; present revised recommendations at the February 2009 ACIP meeting; and address 

future availability of JE vaccine for US children.

Discussion

Dr. Judson said that one thing that struck him in the existing recommendation was that it states 

that the vaccine is not recommended for all travelers, which sounded like an overstatement. 

The reverse of that would be that it is not recommended for most travelers, which is how he has 

counseled people throughout the years. 

Katrin Dubischar-Kastner (Intercell) indicated that Intercell has committed to the FDA to perform 

post-practice safety surveillance in 20,000 subjects, so they will be in a position to have a 

greater safety database relatively quickly after licensure.

Dr. Plotkin (sanofi pasteur) said that having been in Asia recently, he understands that the 

definition of “rural area” may be difficult, given that there are cases occurring in suburban areas 

of major cities. While it was not clear how “rural” could be better defined, it may be useful to 

point out that suburban areas are also possible risk areas as cities expand. Though not certain 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

84

whether it was an urban legend, he requested that the work group comment on possible 

protection against West Nile from the JE vaccine. He was not aware of cross-neutralization 

studies, although they must have been conducted.

Dr. Fischer responded that the work group has deliberated the issue of the definition of “rural.” 

Clearly, there are locations in Asia where rice paddy irrigation comes right to the edges of the 

city, so there could be cases in areas that are just on the periphery of a city. While the vast 

majority of cases occur in true rural and agricultural areas, the work group is aware of the need 

to address this issue. They have discussed whether to define “non-urban” versus “urban” areas

rather than simply using the term “rural.” There have also been cases in resort areas located in 

jungles or rural areas. However, because individuals were in resorts, they did not consider 

themselves to be engaged in rural travel. The group has discussed ways of trying to make this 

clearer. With respect to whether there is cross-protection between JE and West Nile viruses, 

there is one study in China that examined neutralizing between JE and West Nile viruses

specifically. It did not show any cross-protection in people who either had natural JE or had 

received a live attenuated vaccine. There were a number of problems with this study in the 

patients had fairly low neutralizing titers against JE. It is possible that one needs an extensive 

amount of antibody, or to have had multiple infections or exposures for there to be crossprotection. 

Phil Hosbach (sanofi pasteur) clarified that Biken stopped manufacturing products for the US in 

2003, which is when sanofi pasteur engaged in discussions with the military and CDC. The 

stockpile for the pediatric group will expire in 2010, given that it has an expiration date of seven 

years.

Dr. Marcy inquired as to how the stockpile for children would be regulated at the provider level.

Dr. Fischer responded that the plan was to ensure that as the new vaccine becomes available 

for adults, some vaccines will be available for people who want to order it for children. He did 

not believe there would be any need to regulate it, given that an estimate has been made of 

how many doses they will sell to pediatric providers. It is difficult to estimate, but the estimate is 

approximately 3000 to 3500 doses per year, so sanofi pasteur is simply making sure that it has 

enough stockpile.

Phil Hosbach (sanofi pasteur) indicated that the numbers were based on a very rough estimate 

of how many children annually would receive vaccines. They have stockpiled probably more 

than would be needed through 2010. The real limiter is the expiry of the vaccine itself.

Ted Tsai (Novartis) added that they have become aware of additional cases in European 

travelers who have had atypical itineraries (e.g., a short-term exposure or very minimal or 

insignificant exposure to rural areas). Novartis will provide details of those cases to the working 

group so they can take those into consideration as recommendations are finalized. 

Interestingly, one of these cases was in a Russian traveler to Japan, which is not usually 

thought of as a risk area. However, the area continues to have enzootic transmission. He also 

noted that JE and other travel vaccines are not publicly funded nor are they reimbursed for by 

medical insurance. They are out-of-pocket expenditure for travelers and as such, the decision 

to take the vaccine or not should be a matter of individual choice, particularly in view of the fact 

that individuals differ in their perspective of bearing risk for unpredictable events that may have 

dreadful consequences. While ACIP recommendations can set the standard of care, a highly 

restrictive recommendation could have the unintended consequence of inhibiting discussions 

around a vaccination option, which is the opportunity for a traveler to exercise that choice. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

85

Novartis would, therefore, urge the work group to take into consideration the distinction between 

public health-driven recommendations versus providing patient advice in what is, in essence, a 

discretionary purchase. 

Given that sanofi pasteur’s vaccine for children is going to expire in 2010, Dr. Morse requested 

that Dr. Tsai comment on the time table for clinical trials for its vaccine in children and whether a 

gap was anticipated.

Dr. Tsai deferred to Katrin Dubischar-Kastner who responded that Intercell is planning to go into 

pediatric trials in mid-2009. They assume that a US licensure could be obtained within the 

timeframe of the next two to three years. There might be a small gap, but Intercell is committed 

to making the vaccine available to the pediatric population in the shortest possible timeframe. 

With respect to the ages of 1 to 81 with a mean of 31 years, Dr. Morse inquired as to how many 

of those cases were children. 

Dr. Fischer responded that of the travel-associated cases, there were at least two or three. He 

indicated that he would find the exact number and report back to the group.

Convening of the Hepatitis Vaccine Workgroup

Mark H. Sawyer, MD

ACIP Workgroup Chair

Dr. Sawyer reported on the new Hepatitis Vaccine Work Group, which had recently convened its 

first meeting. The terms of reference for this group 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, what dosage and 

schedule; review hepatitis A vaccine long-term immunity to see if updating recommendations is 

warranted; and re-evaluate the catch-up immunization schedule for adolescents based on the 

earlier discussion pertaining to immunization schedules for children.

With regard to hepatitis A among contacts of international adoptees, there have been 27 

hepatitis A cases associated with international adoptions in 21 months. Most travelers followed 

current ACIP guidelines for hepatitis A pre-exposure prophylaxis, but most non-traveling 

contacts have not. As a result, most cases occurred in non-traveling contacts of adoptees and 

their contacts. The work group expects to present on this topic to ACIP in February 2009. 

Pertaining to hepatitis B among diabetics in institutional care, long-term care facilities have 

diverse structures and lack central authority. Of their residents, 15-25% are diabetic. Infection 

control recommendations were first made in 1990 and were updated in 2005. Since 1999, 15 

outbreaks have been investigated that were thought to be likely related to sharing of blood 

glucose testing equipment. As a result, the work group is going to review whether this is a new 

risk group for which immunization should be recommended.

Hepatitis Vaccines
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

86

Regarding vaccine-induced long-term immunity for hepatitis B, in the US, routine hepatitis B 

vaccination starting at birth was recommended in 1991 and has been widely implemented in the 

last 10-15 years. Recent studies suggested that immunity afforded from recombinant vaccine 

may wane substantially after 15 years [Samandari T et al., Pediatrics, 2007; Hammitt LL et 

al.Vaccine, 2007; Bialek SR et al., PIDJ, 2008]. The incidence of acute hepatitis B has 

decreased by 80% in the US since 1991. It is not known whether individuals vaccinated starting 

at birth will need a booster dose of hepatitis B vaccine to maintain immunity through adulthood 

when there is risk of infection based upon lifestyle or professional exposure. The work group 

will evaluate all available data to determine whether it is appropriate to recommend a booster 

dose of hepatitis B vaccine to maintain immunity. 

Concerning vaccine-induced long-term immunity for hepatitis A, in the US, inactivated hepatitis 

A vaccine was incorporated into the nationwide childhood immunization schedule in 2006. The 

vaccine has been available since 1995-1996 and was initially recommended for people at high 

risk of infection. Persons vaccinated as children may become susceptible to infection later in 

life if protection from hepatitis A vaccine does not persist through adulthood. Adults may 

experience more severe disease. Data from a cohort of individuals vaccinated early in 

childhood 10-15 years ago will be reviewed by the work group.

Introduction

Dale Morse, MD, MS

ACIP Work Group Chair

The vaccine discussed by the work group during this ACIP meeting was Anthrax Vaccine 

Adsorbed (AVA), the only FDA approved product to prevent anthrax pre-exposure. The vaccine 

is made from a sterile, cell-free filtrate of avirulent, non-encapsulated B. anthracis

[http://www.emergentbiosolutions.com/pdf/emergent_biothrax_us.pdf], is precipitated by 

aluminum hydroxide, and is manufactured by Emergent BioSolutions. AVA primes the immune 

system to recognize and block protective antigen (PA), which is common to all anthrax strains. 

Vaccine efficacy against numerous anthrax strains has been demonstrated in many animal 

studies.

The anthrax vaccine workgroup was formed during the fall of 2007. They presented material to 

the committee during this meeting as part of their work toward combining the 2000 anthrax 

statement and 2002 supplement into one document. The terms of reference for this work group 

include: 1) review of the existing 2000 statement and 2002 supplement; 2) review of new data 

on AVA including: a) safety and immunogenicity data from an interim analysis of CDC’s dose 

reduction and route change study in anticipation of the FDA evaluation of Emergent 

Biosolutions’ BLA; b) recently published safety studies; c) publications detailing the 2001 

anthrax attacks; d) post exposure prophylaxis with vaccine and antibiotics; and e) pre-exposure 

vaccination; and 3) revision of the existing statement and supplement into a single document. 

2000 ACIP recommendations are as follows [CDC. Use of Anthrax Vaccine in the United 

States: Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb 

Mortal Wkly Rep. 2000 Dec 15;49(RR15):1-20]:

Anthrax Vaccine
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

87

 Pre-exposure vaccination:

 Routine vaccination indicated for groups at high risk of exposure to B. anthracis

 6 doses administered subcutaneously, annual boosters

 Post-exposure prophylaxis:

 Recommended following aerosol exposure to B. anthracis spores

 If available, 3 doses of vaccine (0, 2, 4 weeks)

 Antimicrobial therapy up to 60 days

Following 9/11, the 2002 supplement included recommendations on using anthrax vaccine in 

response to terrorism. The supplement recommended that groups at repeated risk for exposure 

(e.g., LRN personnel in certain situations, remediation workers) be given priority for preexposure vaccination; and endorsed the use of a 3-dose vaccine regimen plus antimicrobials 

under an IND for post-exposure use in civilians [CDC. Use of Anthrax Vaccine in Response to 

Terrorism: Supplemental Recommendations of the Advisory Committee on Immunization 

Practices. MMWR Morb Mortal Wkly Rep. 2002 Nov 15;51(45):1024-6]. 

Since its formation in October 2007, the Anthrax Work Group’s activities have included review 

of: clinical trial data evaluating AVA safety and immunogenicity; review of recent publications of 

the DoD safety experience, to include on-going Vaccine Healthcare Center (VHC) research; the 

DoD programmatic experience; concerns surrounding vaccine safety and efficacy; 2000 / 2002

recommendations regarding first responders; data on birth outcomes for women inadvertently 

vaccinated during pregnancy; and the post-exposure prophylaxis regimen.

Given that the Anthrax Work Group anticipates presenting the new statement to ACIP in June 

2009 and it has been several years since anthrax was presented to the ACIP, during this 

session the committee was presented with background information pertaining to AVA, the only 

licensed vaccine available in the US for pre-exposure use and manufactured by Emergent 

Biosolutions. An overview was provided of several recent publications focusing on safety data, 

in addition to available data from an on-going clinical trial evaluating a change in schedule and 

route of administration. The clinical trial data were presenting during this meeting, given that the 

FDA is considering these data and is scheduled to rule on a BLA by March 5, 2009. 

Anthrax Vaccine Dose Reduction & Route Change Study 

Stacey W. Martin, MSc

Centers for Disease Control and Prevention

Anthrax Vaccine Research Program

Ms. Martin and Dr. Quinn presented results from an on-going clinical trial assessing how to 

optimize the use of AVA, assessing an alternate route of administration, evaluating surrogate 

markers of protection, and evaluating immunologic memory. This is a randomized, double blind, 

placebo controlled Phase IV clinical trial with a Data Safety and Monitoring Board which met at 

least quarterly during the active phase of the study and is chaired by Dr. Stanley Plotkin. The 

study enrolled 1564 healthy, civilian adults who were aged 18-61 years at time of enrollment. 

Exclusionary criteria included specific allergies, immunosuppression, and pregnancy. 

Participant obligation consisted of 25 office visits over 43 months, with 8 injections, 17 blood 

draws, 22 in-clinic exams, and 8 patient diaries. The results summarized during this ACIP 

meeting are presented in greater detail in a recently published JAMA article, a reprint of which 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

88

was included in the committee’s materials [Marano N, Plikaytis BD, Martin SW, et al. Effects of 

a reduced dose schedule and intramuscular administration of anthrax vaccine adsorbed on 

immunogenicity and safety at 7 months. JAMA. 2008;300(13):1532-1543]. This study has a 

complex schedule with 6 treatment groups:

Schedule of Injections 

SQ Placebo CNT S S S S S S S S

IM Placebo CNT S S S S S S S S

4IM AVA S AVA AVA S S S AVA

5IM AVA S AVA AVA S AVA S AVA

AVA S AVA AVA AVA AVA AVA AVA

COM

7IM 

8IM 4IM AVA AVA AVA AVA AVA AVA AVA AVA

8SQ 4SQ AVA AVA AVA AVA AVA AVA AVA AVA

Month 

42

Month 

30

Month 

18

Month 

12

Month 

6

Week 

4

Week 

2

Week

0 Label StudyGroup

Interim Analysis

The top line shows the group receiving the licensed regimen; that is, 6 subcutaneous vaccine 

injections administered at 0, 2 and 4 weeks, 6, 12 and 18 months, followed by 2 annual 

boosters. For route change the direct comparison group is the next group (8IM), those receiving 

vaccine intramuscularly at the same points in time. The next 3 groups (7IM, 5IM and 4IM) are 

allowing the investigators to assess reduced dose regimens. For these participants, some of 

their AVA doses are replaced by Saline doses, which are noted in this table with an “s”. Lastly, 

there is a saline placebo group, with half receiving their injections IM and half SQ. The area in 

grey shows the period of the interim analysis. The column entitled “label” are the labels applied 

to the results presented during this meeting. For the interim analysis, 7IM, 5IM, and 4IM groups

had identical schedules and were combined for the statistical analyses. This is noted in pink. 

Solicited AEs fell into two categories: injection site AEs and Systemic AEs. Injection site AEs 

are those typically reported following immunization and include warmth, tenderness, itching, 

general injection site pain, arm motion limitation (AML), erythema, induration, nodule, and 

bruise. In addition to these, pain was assessed immediately following injection using a visual 

analog scale from 0 to 10. Systemic AEs included fatigue, muscle ache, headache, fever, and 

tender or painful axillary adenopathy. AEs were assessed during clinic exams and were selfreported using AE diaries and telephone follow-up. Timing of exams included pre-vaccination, 

15 to 60 minutes, and 1 to 3 days post vaccination. For doses 3 and 4, there was an additional 

exam roughly 28 days after vaccination.

With respect to the safety interim analysis, for warmth there was a statistically significant 

decrease in the proportion of participants reporting warmth upon changing from SQ to IM 

administration: TRT-4IM (0.0068) versus TRT-4SQ (p=<.0001). It is also important to note that 

the absolute gender difference is also significantly decreased with IM administration. However, 

there remains a statistical difference with respect to reporting of the AE between women and 

men with IM administration: TRT-4SQ 49.1% females and 15.5% males; TRT-4IM 9.8% 

females and 3.6% males; TRT-COM 7.4% females and 3.5% males; CNT-4IM 1.2% females 

and 0.6% males; and CNT-4SQ 0% females and 0% males. The results for most of the other 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

89

injection site adverse events were very similar, except for general injection site pain, arm motion 

limitation, and bruising. No significant difference was found between SQ and IM administration 

for arm motion limitation: TRT-4SQ 13.6% females and 6.1% males; TRT-4IM 12.6% females 

and 7% males; TRT-COM 12.9% females and 10.6% males; CNT-4IM 0.6% females and 1.2% 

males; and CNT-4SQ 0% females and 0.6% males. This is very similar to what was found for 

the AE general injection site pain that was assessed during the scheduled exams and reported 

in the diaries, and gender difference was also detected for pain. Participants in the 

subcutaneous administration group reported significantly more pain upon injection. This 

endpoint is assessed immediately after injection and is different than the general injection site 

pain mentioned earlier:

Pain 

Scale 

Score

TRT4SQTRT4IM

0 3.9 10.32

1 17.2 21.24

2 17.6 22.15

3 20.28 18.51

4 16.4 11.68

5 8.51 7.43

6 5.88 4.24

7 5.263 2.276

8 3.56 1.517

9 0.92 0.1517

10 0.464 0.455

With respect to fatigue, as with all systemic AEs, there was no difference between SQ and IM 

administration with reporting of the AE. However, it is important to note that once again there 

was a significant difference between genders, which held true even amongst the control groups. 

The fact that there were no interactions present in the model indicates that the gender 

difference was somewhat consistent across the treatment groups: TRT-4SQ 10.1% females 

and 6% males; TRT-4IM 11.5% females and 6.2% males; TRT-COM 8.8% females and 7.3% 

males; CNT-4IM 5.4% females and 4.7% males; and CNT-4SQ 7.3% females and 2.4% males. 

For the systemic endpoint headache there were similar findings. There is a gender difference 

across all groups including the controls groups: TRT-4SQ 10.2% females and 4.2% males; 

TRT-4IM 8.3% females and 3.7% males; TRT-COM 6.5% females and 3.8% males; CNT-4IM 

5.4% females and 1.3% males; and CNT-4SQ 3.7% females and 2.7% males.

Serious adverse events are reported to the FDA for all clinical trials and blinded assessments 

are made by an independent medical monitor. Although not standard practice for clinical trials, 

CDC submitted all AEs meeting the minimum definition of an SAE to the FDA. At the time of the 

interim analysis, there were 51 SAEs occurring among 47 participants and none were assessed 

as causally related to the study agent. At the time of this ACIP meeting, there were 231 reports 

of SAEs in 187 persons, with 9 of those events in 7 persons assessed as “possibly” related to 

the investigational agent. This following is a list of those SAEs that have been determined to be 

“possibly” related to the study agent:

 Tear of shoulder supraspinatus tendon

 Generalized reaction night of 6th vaccine 

 Bilateral pseudo tumor cerebri with bilateral disc edema

 New onset of generalized seizures, hydrocephalus consistent with aqueductal stenosis

 New onset bilateral arthralgia

 2 events of invasive breast cancer**

 November 2006 secondary review of VAERs and DoD data found no obvious trend for 

AVRP “possibly” related SAEs among persons receiving AVA
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

90

“Possibly” is defined as a clinical event with a reasonable time relationship to vaccine 

administration, but which could also be explained by concurrent disease or other drugs or 

chemicals. It is important to note that this was is a blinded assessment and the true study group 

of these participants will not be known until early 2009, at which time an unblinded analysis will 

be performed. In November 2006, CDC conducted an extensive review of VAERs and DoD 

data and found no obvious trend for AVRP “possibly” related SAEs among persons receiving 

AVA.

In summary of the reactogenicity data presented, the TRT-4IM group experienced local AEs at 

lower frequencies and while the data were not reviewed during this meeting, also lower severity 

and for shorter durations than did the 4SQ group. Route of administration did not significantly 

influence the occurrence or duration of systemic AEs. Women reported significantly more AEs 

than men for both local and systemic adverse events. However, with respect to systemic AEs 

these differences were statistically similar across treatment groups, even among the control 

groups. To date, there have been 9 SAEs assessed as “possibly” related to the investigational 

agent. In conclusion, IM administration is associated with significantly fewer and less severe 

injection site AEs, and no serious AEs reported during the first 7 months were assessed as 

causally related to AVA.

Immunogenicity Analyses

Conrad P. Quinn, Ph.D.

Chief, Microbial Pathogenesis and 

Immune Response Laboratory

Dr. Quinn reported on the highlights of the immunogenicity serology testing for the interim 

analysis of the CDC anthrax vaccine research program, which were also recently published in 

JAMA. This is a non-inferiority study. Serological data are based on non-inferiority of the antiprotective antigen IgG (anti-PA) antibody responses at week 8 and month 7 in the schedule. 

Month 7 is the critical evaluation point because this represents the completion of the study 

priming series in the context of this study. The primary endpoints for serology include the antiPA IgG geometric mean concentration (GMC), the geometric mean titer (GMT) of those 

responses, and the proportion of participants who achieved a 4-fold rise in titer. The noninferiority criteria from a statistical perspective are that the upper bound of the 95% confidence 

intervals for the ratio of the 4-SQ group to the test groups’ GMC and GMT were <1.5; and that 

the analogous upper bound for the differences in proportions of 4-fold responders was <0.10.

The geometric means were used for a variety of reasons. These are a measure of central 

tendency of the responders, and it is a widely used statistical analysis tool. It has particular 

application in immunology where there may be positively skewed distributions and long “tails” of 

larger values in the data sets, and it is the only applicable tool for log-normally distributed 

dilutional titers. It also provides unbiased estimates of the groups’ central response. Protective 

antigen has been used as a serological analysis tool in anthrax since the term was coined in 

1945. Protective antigen is now known to be a central toxin component which is pivotal to the 

infection process by Bacillus anthracis, the causative agent. Protective antigen is, therefore, 

central to the disease anthrax. It is known from extensive literature from this and the last 

Century that vaccines that protect against anthrax contain all or part of the protective antigen 

protein component. For the purposes of this presentation, although the investigators have 

measured both GMT and geometric mean concentrations, Dr. Quinn focused on concentrations 

because these two metrics are so highly correlated that they offer the same message. They 

have a correlation coefficient of 0.991 and p-value of <0.0001.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

91

Focusing on the high points of the serological data, Dr. Quinn reported that at month 7, the end 

of the priming series, all groups were non-inferior to the licensed regimen for all endpoints. 

Earlier in the schedule at week 8, where the potential to drop the dose at week 2 was evaluated, 

the 4-IM group was non-inferior to the 4-SQ regimen for all three primary endpoints and the 3-

IM group was non-inferior for proportion of participants with 4-fold rise in titer. Also learned from 

the data was that lethal toxin (LTx) neutralization efficacy of the IgG response, the measure of 

the median IgG and ED50 of the neutralization, are highly positively correlated.

With regard to anti-PA IgG GMC, which is non-inferior at month 7, from week 0 there is low to 

no level of response. At week 4, the onset of the immune response is observed. In the 4-SQ 

licensed regimen group and the 4-IM group there are high levels of antibody responses. In the 

3-IM group who did not receive an injection at week 2, there are statistically significantly lower 

levels of response. By week 8, all three groups are responding with high levels of antibody. 

The 3-IM are reaching levels in excess of 50 μg/ml, 52 μg/ml in the GMCs, and the comparison 

of route change from SQ to IM are achieving levels in the 100 μg/ml range. At week 26, 

between vaccinations, a receding of the antibody level is observed. At week 30, in response to 

the 6-month vaccination, there is non-inferiority in three groups (4-SQ, 4-IM, and 3-IM) with very 

high levels of antibody responses. Week 30 is the critical time point as it represents the 

completion of the priming series. At this time point, non-inferiority has been achieved, signifying 

that the preceding events in the immunological profile, the priming of the immune system, are 

equivalent across the three study groups. This is emphasized by the proportions of 4-fold

responders at week 8 and week 30 (month 7) at which times there is non-inferiority for the 

particular endpoints in all three study groups.

The LTx neutralization data were not available for the interim analysis. This part of the study 

remains blinded; therefore, Dr. Quinn was unable to give group assignments. However, he 

stressed that what is very clear from these data is that the correlation between the magnitude of 

anti-PA IgG response and its ability to neutralize anthrax lethal toxin in vitro are very highly 

positively correlated. 

In summary of the AVRP month 7 GMC analyses, the primary decision point for this study, there 

are high levels anti-PA IgG in all groups. There are <0.5% non-responders; GMCs reach >200

μg/ml anti-PA IgG; >98% 4-fold responders; and ≥95% of all responders were at least ≥50 μg/ml 

anti-PA IgG. At this time point in the study, non-inferiority was achieved for all primary 

endpoints. The investigators concluded that the 4-SQ, 4-IM, and 3-IM regimens provide 

equivalent immunological priming. At the week 8 GMC, there were high levels anti-PA IgG in all 

groups: <0.5% non-responders; GMC >50-100 μg/ml anti-PA IgG; ≥95% 4-fold responders; and 

>60-82% of the responders had ≥50 μg/ml anti-PA IgG. Non-inferiority was achieved only for 

the proportion of 4-fold responders. Significantly higher levels of antibody responses were 

observed in females in the 4-IM and 3-IM groups, but not in the 4-SQ group (p=0.12). Also 

observed is that there is a general decrease in antibody response with increase in age, although 

these differences not evident at month 7.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

92

Discussion

Dr. Meissner inquired as to whether it is possible to engineer Bacillus anthracis so that the PA 

gene is antigenically changed such that the antibodies from this vaccine would not protect 

against disease. 

Dr. Quinn responded that it is feasible to genetically engineer protective antigen. Protective 

antigen is very clonal. All of the strains that are sequenced at this point are sequenced to 

protective antigen gene at an extremely high level of identity, indicating that this protein has a 

very specific function and that if it is manipulated too much, it will no longer function. It can be 

manipulated, although there are no specific data to address whether it can be manipulated to a 

point that the vaccine would become ineffective. However, the indications are that manipulating 

this protein too much may make it ineffective as a toxin.

Recommendations of Anthrax Vaccine Work Group

Jennifer Gordon Wright, DVM, MPH

On behalf of the ACIP Anthrax Vaccine Work Group

Dr. Wright outlined the draft Anthrax Statement, presented some background material on AVA, 

and reviewed the work group deliberations and the draft pre-event recommendations. In 

addition, she discussed the issue of delayed doses, as well as post-exposure prophylaxis use of 

the vaccine. She indicated that ACIP members received in their binders a copy of the draft 

statement. In response to feedback regarding the 2000 / 2002 documents, the work group

made a concerted effort to concisely word the recommendations, placing the data and rationale 

in support of the recommendations into other sections of the document. There are 12 sections 

in the new statement. Dr. Wright noted that the sections of most importance to the discussions 

during this meeting of the ACIP were sections 6, Persons at Risk, and Section 9, 

Recommended Uses of AVA.

This vaccine is quite old, with a long history. The vaccine in use in the 1950s and studied 

extensively by Dr. Brachman was the Ft. Detrick formulation, often mistakenly referred to as the 

“Merck” formulation. In the 1960s, the manufacturing process was improved, resulting in 

increased purity and potency. This new formulation was referred to as the “Lansing” 

formulation. In the 1970s it was this “Lansing” formulation which was licensed using data from 

the Brachman studies. The vaccine currently in use is Anthrax Vaccine Adsorbed (AVA), which 

is the same formulation as the one licensed in the 1970s. 

AVA is used in two ways. One is to prevent disease prior to a potential bioterrorism event, or 

pre-event use. AVA is perhaps most commonly used to provide protection from potential 

occupational exposure, such as to prevent disease among laboratorians who routinely work with 

the organism. AVA is also utilized following a bioterrorism event for persons exposed to B 

anthracis spores who are at risk for inhalation anthrax development. The current pre-event 

schedule follows the approved FDA licensed regimen of 6 priming doses administered 

subcutaneously over 18 months, plus annual boosters. A BLA supplement to allow for a change 

in the route of administration and the removal of the 2-week dose is under consideration with 

the FDA and a decision is expected by mid-December.

With respect to the pre-event recommendations, Dr. Wright began with a review of ACIP’s 

recommendations from 2000 and 2002. In 2000, ACIP stated that “routine pre-event 

vaccination with AVA was indicated for persons engaged in work or activities involving 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

93

production quantities or aerosol concentrations of B. anthracis with a high potential for 

aerosolization.” Further, AVA may be indicated for persons in otherwise low risk occupations. 

For example, persons who encounter imported animal products when workplace standards /

restrictions are insufficient to prevent exposure and groups for whom a calculable risk can be 

quantified. AVA was not recommended for first responders, federal responders, medical 

practitioners, and private citizens. Post-exposure prophylaxis was recommended for personnel 

working in areas of a known release. In late 2001, ACIP revisited the pre-event 

recommendations amid concerns of a limited supply of vaccine. ACIP recommended that 

groups at risk for repeated exposure be given priority for pre-event vaccine. Persons not at risk 

for repeated exposures were not recommended to receive pre-exposure or pre-event 

vaccination. The framework for the work group’s considerations of the question, “For whom 

should ACIP recommend routine pre-event vaccination?” included aspects related to burden of 

disease, risk, vaccine safety, vaccine efficacy, vaccine supply, and programmatic implications.

The work group first considered the burden of disease. Currently, there is virtually no naturally 

occurring human disease in the US. There have been two known bioterrorism related events. 

In general, the majority of the work group felt that the current burden of disease is low and does 

not favor recommending pre-event vaccination. However, another anthrax bioterrorism event 

would change the burden of disease. Thus, the work group gave burden of disease a -/+. The 

work group reviewed on-going risk assessment activities and concluded that the risk of an 

individual acquiring anthrax through a bioterrorism event remains indefinable. It varies by 

location, is always evolving, and is time-dependent. The risk varies even based on an 

individual’s occupational roles and duties within that occupation. The draft ACIP 

recommendations Dr. Wright presented during this meeting varied by occupation. The work 

group concluded that for some occupations, such as certain laboratorians, the risk of exposure 

is high and should be a factor in decision making to recommend vaccine. For other occupations 

the risk is unknown and should not be a factor in recommending pre-event use of the vaccine. 

Thus, the work group gave “risk of exposure” a +/-. 

As was presented to the ACIP in February 2008 and again in June 2008, multiple independent 

reviews have been conducted on this vaccine since 1985, in addition to at least 35 publications. 

There is also the military experience with greater than 7 million doses administered to nearly 2 

million persons, as well as the safety data from 1564 participants in the on-going AVRP clinical 

trial, which demonstrated that rates of injection site reactions are similar to other vaccines, and 

are further diminished with IM administration. Although multiple studies have demonstrated the 

vaccine to be acceptably safe, as with most vaccines there is always the potential for a rare 

adverse event to occur. For comparison purposes, the following table demonstrates data 

reported in the 2002 IOM report and compares the percent of persons experiencing AE’s with 

AVA administration to other common vaccines. Reports for subcutaneously administered AVA 

were consistent with the other vaccines:
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

94

AVA Safety Comparisons*

Pain, Any(%) Erythema or 

Swelling(%) Fever(%) Systemic(%)

1 - 9 17 - 26 22 – 35 43 - 85 Tetanus - diphtheria 

(Td)

Anthrax (SQ) 1 - 8 1 - 36 3 - 42 67 - 83

Rabies 2 - 18 3 1 – 18 4 – 52

Influenza 1 - 13 11 - 34 11 – 21 24 – 86

Hepatitis B 0 - 4 10 1 – 99 11 - 43

Hepatitis A 0 - 3 4 - 22 4 – 40 40 – 52

Acellular pertussis 0 - 7 17 – 29 12 – 15 51 – 77

*IOM report, 2002

Slide courtesy of Col Cieslak 

The work group felt that the available data suggest that the risk of serious adverse events is low 

and injection site adverse events will be diminished if the IM indication is approved. Thus, the 

work group felt the safety profile favors pre-event vaccination.

Data on human efficacy is imperfect. However, the best evidence for efficacy of AVA comes 

from the “Brachman Study,” which was conducted in 4 wool mills during the 1950s when 

anthrax infection was common among “wool sorters.” During the study period, there were no 

cases of inhalation anthrax among vaccinees, but five cases of inhalation anthrax occurred 

among unvaccinated persons. This study demonstrated a combined efficacy against cutaneous 

and inhalation anthrax of 92.5% and has been affirmed as the best evidence for efficacy of the 

vaccine by at least two independent advisory panels. Twelve years of data collected by CDC 

from nearly 7000 persons, not including those in the Brachman Study, were reviewed in 1985. 

The panel reviewing these data concluded that “no cases occurred in fully vaccinated subjects 

while the risk of infection continued” and that “these observations lend further support to the 

effectiveness of the product.” In addition, the panel believed that “there was sufficient evidence 

to conclude the vaccine is effective.” In 2002, the Institute of Medicine reviewed the safety and 

efficacy of AVA and determined AVA to be an effective vaccine to protect against anthrax, 

including inhalation anthrax, and that it would be effective against all known strains, as well as 

bioengineered strains. The AVA clinical trial has provided compelling immunogenicity data 

demonstrating a robust immune response. The work group felt that data suggest that the 

vaccine is effective and provides protection against anthrax.

The 2002 statement mentions the “limited” supply of AVA. During 2002, there were 

approximately 2 million doses of AVA manufactured and the DoD utilized the majority of those 

doses. During 2007, there were 9 million doses manufactured. There is a single manufacturer 

for AVA, Emergent BioSolutions, and the vaccine is currently manufactured in one plant, 

although a new facility is currently undergoing qualification and validation. The current 

manufacturing facility has been renovated, with an improved production process and quality 

systems resulting from the renovations. Current annual production capacity is 8-9 million doses, 

with future capacity possible of reaching 30-35 million doses once the new facility is online. The 

vaccine is commercially available for purchase. The work group felt that at the current time, 

vaccine supply was sufficient to favor pre-event vaccination.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

95

With respect to the work group’s draft recommendations for the pre-exposure / pre-event use of 

AVA, Dr. Wright reported that the work group made a conscious effort to breakdown the 

persons for whom pre-event vaccine would or would not be recommended into recognizable 

categories. Each group is clearly defined on pages 12-16 in the draft statement and includes 

the following:

 General Public

 General Public/Medical Personnel

 Pregnant/Breastfeeding Women

 Pediatric Populations

 Occupational Exposures

 Persons Handling Animals/Animal Products

 Laboratorians

 Postal Processing Facilities

 Military Personnel

 Response Efforts

 Environmental Investigators/Remediation Workers

 Emergency and Other Responders

The General Public includes medical personnel, pregnant / breastfeeding women, and pediatric 

populations. The work group decided to keep medical personnel in the General Public category 

because inhalation anthrax is not transmissible from person-to-person, and post-exposure 

prophylaxis would be sufficient for medical personnel involved in the treatment of exposed and 

potentially ill persons. The General Public section also includes pregnant and breastfeeding 

women, as well as pediatric populations. The following table reflects the work group 

recommendation in tabular form, with the 2000 recommendations in the middle column for 

comparison:

Pre-Event Vaccination 

General Public

Pregnant Women Not well addressed Discussed later

Breastfeeding Not well addressed Discussed later

Women

Not 

Recommended

Pediatric Not addressed

Populations

(pg 36)

Not 

Recommended

General Not Recommended

Population

(pg 36)

Population 2000 2008, Draft

 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

96

The category for Occupational Exposures includes persons who handle animals and animal 

products, laboratorians, persons working in postal processing facilities, and military personnel. 

The recommendation for animal and animal product handlers is the same as in 2000. Only 

persons for whom industry standards are not sufficient (or veterinarians working in areas of high 

incidence are recommended for pre-exposure vaccination. The recommendation for 

laboratorians was re-written to make it clear and concise. Only laboratorians who routinely work 

with B anthracis spores and are therefore at risk of repeated exposure are recommended to 

receive pre-exposure vaccination:

Pre-Exposure Vaccination Occupational Exposures

Only for persons 

at risk for 

repeated 

exposure to B. 

anthracis spores

Working with 

cultures; activities 

with potential for 

aerosol 

production

Laboratorians

(pg 37)

Only for persons 

for whom industry 

standards are 

insufficient; in 

areas of high 

incidence

Only for persons 

for whom industry 

standards are 

insufficient; in 

areas of high 

incidence

Animals/Animal 

Product Handlers

(pg 37)

Population 2000 2008 Draft

Persons in postal processing facilities were not addressed in the 2000 / 2002 documents. Due 

to the presence of biodetection systems designed to rapidly identify the presence of B anthracis 

in these facilities, these persons are not recommended to receive pre-event vaccination. The 

recommendation for military personnel has not changed, but was re-written for clarity:

Pre-Event Vaccination 

Occupational Exposures

Recommended if 

Dept of Defense 

determines 

calculable risk of 

exposure to 

aerosolized B. 

anthracis spores

If calculable risk 

assessed, may be 

indicated

Military

(pg 37)

Not recommended 

due to presence of 

biodetection

systems

Postal Processing Not addressed

Facilities

(pg 37)

Population 2000 2008 Draft

 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

97

“Persons engaged in response efforts” includes environmental investigators / remediation 

workers as well as emergency plus other responders. Environmental investigators and 

remediation workers are persons with a known risk of repeated exposure to aerosolized B 

anthracis spores due to their occupation. Because these groups have a known risk repeated 

exposures to aerosolized B anthracis spores based on their occupation, they remain 

recommended for vaccination, as in 2000.

The draft statement defines emergency and other responders as “including, but not limited to, 

police departments, fire departments, hazardous material units, government responders, and 

the National Guard...” These groups were not recommended for pre-event vaccination in 2000. 

In 2002, these groups were again not recommended, in part due to vaccine supply issues. Draft 

language was presented to ACIP in June 2008 and the work group took the discussions from 

that meeting into consideration when revising the language.

The work group initially agreed on the following language, which was included in the draft 

statement received with the background materials in this meeting’s binders, “Occupational 

groups <as defined on page 15> who may be engaged in response activities in areas with of B. 

anthracis spore contamination (e.g., site investigation, building evacuation, maintenance of 

critical infrastructure, suspicious substance/“white powder” incidents) and therefore may be 

exposed to aerosolized B. anthracis spores, but for whom a calculated risk assessment does 

not exist, may consider pre-event vaccination on a voluntary basis and under the direction of a 

comprehensive occupational health and safety program.” However, over the past few weeks in 

preparation for this meeting, the work group reviewed the language and the majority of the 

members felt the intent was not sufficiently clear. Therefore, the work group drafted what Dr. 

Wright referred to as Option 2.

The majority of the work group prefers Option 2. Option 2 states, “Occupational groups 

engaged in response activities <as defined on page 15> are not routinely recommended to 

receive anthrax vaccine due to lack of a calculable risk assessment. However, selected groups 

with potential engagement in response activities that may lead to exposure to aerosolized B. 

anthracis spores may choose to offer their workers pre-event vaccination on a voluntary basis 

and under the direction of a comprehensive occupational health and safety program.”

Discussion

Speaking as a member of the committee rather than the Chair, Dr. Morse commented on 

emergency and other responders, given the extensive struggle with the proper manner in which 

to word the recommendation. He stressed that his comments were his personal opinions 

versus those of the work group. With respect to how he reached the decision upon what he 

would recommend, it is known that the burden of disease is extremely low in the US. Very few 

groups engage in work activities involving potential anthrax exposure. This is limited to 

production workers handling imported hides with inadequate, below industry standards and a 

limited number of lab workers. It is a potential BT agent. The US experienced an anthrax BT 

event in 2001 in which media and legislative leaders were targets. Most victims were postal 

workers. First responders were not affected. First responders are not at risk of inhalation 

exposure when transporting patients with inhalation anthrax as it is not transmitted person-toperson. There have been no confirmed anthrax events or exposures since 2001, but there were 

many white powder incidents in which testing was done to rule out anthrax. First responders 

generally use personal protective equipment (PPE) when assessing credible threats and white 

powder incidents. Even if they did not, specimens are tested for anthrax and if positive, 

preventive treatment could be provided. There are currently no scientific data documenting that 
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first responders have an exposure and there is a lack of calculable risk assessment data to 

indicate that first responders are at greater risk than any number of occupational groups, 

including media, legislative, and postal workers. It is not ACIP’s charge nor do they have 

security access to data to conduct risk assessments for potential BT events. The evidence that 

has been provided in the past has not always been accurate. ACIP’s charge is to make 

recommendations based on criteria which include burden of disease, safety, immunogenicity, 

efficacy, feasibility, and cost-benefits using scientific or evidence-based data. To change that 

premise and make recommendations on hypothetical, political, or future potential theoretical 

considerations in the absence of scientific evidence would undercut the credibility of ACIP’s 

recommendations. As New York State’s former Commissioner (1979-1991), Dr. David Axelrod 

said, "We must remain devoted to the canons of science that are so much a part of the practice 

of medicine and the practice of the allied arts. To do otherwise would be to build public policy 

on quicksand." On this basis, Dr. Morse said he would not recommend routine or universal

anthrax immunization for first responders. However, the practice of medicine is an art as well as 

a science. ACIP members are often asked to make recommendations where the science is 

incomplete, inconclusive, or even contradictory and for which they have had to rely on sciencebased expert judgment and consensus. This and the last meeting’s ACIP decisions on 

pneumococcal vaccine are prime examples of this. In the case of anthrax, the science suggests 

that the risk of exposure for first responders is minimal and that the risk can be further reduced 

by proper use of PPE. From Dr. Morse’s perspective, the risk is likely to be extremely low, but it 

is not zero as they have seen. White powder can contain anthrax, risk assessments may not 

always be accurate, PPE may not be used or may fail, and post-exposure prophylaxis while 

effective is not always competed as demonstrated by the 2001 anthrax attack where only 44% 

of persons initiating antimicrobial prophylaxis reported taking it for the recommended 60 days. 

Finally, public health practitioners emphasize prevention. While he was a Cub Scout, Dr. Morse 

said he was never a Boy Scout but had always admired their creed to be prepared. The first 

responders who protect and put their lives on the line for Americans follow the same creed and 

are trained to use safety precautions to minimize risk. Thus, if responder groups choose to use 

an FDA licensed anthrax vaccine because they either are privy to confidential classified or 

military information on risk not available to ACIP, or wish to have the higher level of protection 

the vaccine provides, they should be able to make their own informed decisions on vaccination 

in consultation with their occupational health and safety programs. Of note, since the vaccine is 

licensed, they are able to do this regardless of ACIP’s recommendation. The work group’s 

permissive language proposed for ACIP endorsement allows the vaccine to be used under 

those circumstances and is something that Dr. Morse said he could support. In his view, the 

language used in the second option was clearer and is also similar to language that was 

approved earlier in the day for PPV23 in Alaska Natives and Native Americans specifically not 

routinely recommending, but allowing for use under special circumstances. 

It was not clear to Ms. Ehresmann why the permissive language about vaccination for first 

responders stated, “under the direction of a comprehensive occupational health and safety 

program.” She wondered if the intent was that if a fire station, city, or some broader group did 

not make this recommendation, it would not be suggested for responders to go to their 

individual providers. 

Dr. Wright responded that this meant the occupational health and safety program for a first 

responder group would be the one to mount any sort of vaccination campaign and follow-up 

rather than it being the state, local, or county public health department. It would not preclude an 

individual from acquiring the vaccine from his or her private practitioner.
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Dr. Cieslak pointed out that an incident related to anthrax, because there is an incubation 

period, is unlike many other things for which first responders are called upon. He wondered 

what selected groups ACIP had in mind when they mentioned “selected groups with potential 

engagement and response activities that may lead to exposure.” 

Dr. Wright replied that this is defined in the statement as “including, but not limited to, police 

departments, fire departments, hazardous material units, government responders, and the 

National Guard.” They recognized that they may not have captured everyone so they used the 

phrase “included, but not limited to” so that other groups could be added.

Dr. Judson expressed his support for Option 2.

Dr. Neuzil noted that she had some concerns in June 2008 stressing the voluntary nature of this 

recommendation. However, she felt that those concerns were addressed based upon this 

presentation and expressed her support for Option 2.

Dr. Sumaya said he was leaning toward Option 2, but with respect to the discussion on serious 

AEs, he requested clarity regarding whether there had been sufficient mining of all of the data 

available and all sources such as the military in particular, to feel very comfortable in saying that 

the serious AEs are minimal to nearly none. 

Dr. Morse responded that the review of safety data had been extensive and thorough since the 

previous statements, including the review of over 35 published studies.

Col. Cieslak reminded everyone that the safety data, including the 35 published studies, were 

presented during the February 2008 ACIP meeting. As he stated then, many of the 35 

published studies were quite small. Many of them examined very specific endpoints, for 

example, one studied only optic neuritis. Taken individually, each of those studies certainly had 

faults and flaws. However, taken collectively, he thought they presented an overwhelming 

picture of a relatively safe vaccine. While he did not pretend that everything was known about 

this vaccine and that there could be adverse events that occur at incredibly low frequencies, the 

cumulative weight of all of the evidence points to a very safe vaccine, with experience with well 

over 7 million doses. Thus, he thought the data were as good as it was going to be currently. 

Dr. Mike McNeil, NCIRD pointed out that an adjunct CDC collaborative anthrax vaccine safety 

activity is the Vaccine Analytic Unit (VAU). The VAU is a unique research infrastructure and 

partnership between the CDC, the Department of Defense (DoD) and the FDA for studying 

potential longer-term or rare and unusual vaccine adverse events. The VAU uses the DoD’s 

Defense Medical Surveillance System (DMSS) database to conduct epidemiological studies on 

the longer term safety of anthrax and other biodefense vaccines. The DMSS database was 

recommended as the best source for studying rare anthrax vaccine adverse events by the IOM 

when it met in 2002 to advise CDC on conducting both the clinical trial and on examining longerterm safety of the vaccine. This is a unique collaborative effort that permits CDC to have ongoing access to the DoD’s DMSS database. To date, a number of hypothesis testing studies 

have been conducted by the VAU. The optic neuritis study has been published. In addition, 

hospitalizations following receipt of multiple near concurrent vaccines including the anthrax 

vaccine have also been examined. There are approximately five other VAU anthrax vaccine 

safety studies that are ongoing and there are others planned. The VAU has also conducted 

ongoing reviews of the VAERS data and a summary of anthrax vaccine data in VAERS is 

included in the document provided to the committee. Through the VAU and in collaboration with 

the military, a pilot study is also being conducted with some data mining software similar to that 
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used by VAERS and the FDA with its Adverse Event Reporting System (AERS) database to 

determine whether there are some adverse event associations that may not yet have been 

detected in either VAERS or identified from the published anthrax vaccine safety literature. 

Regarding the phrase “selected groups may choose to offer their workers” Dr. Marcy pointed out 

that some groups “may choose not to offer their workers.” This will cause the group and 

individuals to be in conflict with one another. For example, a fire department may not want to 

give its fireman the vaccine, but the firemen may want the vaccine. This seemed to be setting 

up conflict as opposed to the individual choosing to accept vaccination. He could envision that 

some groups may not wish to pay for this and would expect workers to obtain it at their own 

expense. 

Dr. Messonnier responded that there had been a lot of activity over this wording throughout the 

previous week. The work group could commit to further wordsmithing of the statement. The 

intent was that individual providers do not have a lot of experience with this vaccine and 

generally do not stock it. Therefore, if first responders present at their physicians’ offices 

requesting anthrax vaccine, while there is nothing to stop a provider from obtaining it, most 

providers would likely not feel comfortable addressing the risks / benefits of this vaccine 

compared to a more generally available vaccine. Given that this is an occupational exposure, 

the intent was to task organizational groups with taking responsibility for their workers by 

offering the vaccine to them. This includes not only administering the vaccine, but also 

everything involved in mounting a vaccination educational campaign so that workers can make 

voluntary decisions, as well as addressing adverse follow-up. The concern was that this should 

be part of a comprehensive occupational health and safety program just like making certain that 

PPE fits. 

Dr. Marcy replied that the phrase should then read “should choose to offer their worker” rather 

than “may choose,” because otherwise they would not be taking responsibility. He did not like 

“should consider.”

Dr. Messonnier said that “should choose” reverted back to “recommended for,” to which the 

work group did not agree.

Dr. Judson suggested that perhaps they were simply viewing this from different angles. 

Employers always have the responsibility to decide what benefits they will and will not offer their 

employees based on a number of priorities and resource limitations. This is not something 

ACIP can drive through a national recommendation.

Dr. Temte inquired as to the cost of a full immunization program for an individual, and whether 

there would be any statutory requirement to report individuals to anyone.

Ms. Ehresmann offered what she thought was an interpretation about what was being said 

about the occupational health component. Perhaps it was that if an organization chose to offer 

this to their employees, they should be the ones to offer the programs as the employers. 

Dr. Marcy responded that while he understood that, it left the conundrum of the individual who 

wanted it versus the group who says they do not choose to offer it. With respect to the 

argument that it is not readily available, neither is Yellow Fever vaccination, but individuals can 

order it. There is no rush in getting pre-exposure.
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Dr. Messonnier clarified that she was not saying that an individual could not acquire it from his 

or her own provider. She thought the work group was simply concerned that this would not be a 

very efficient way to do this. As Ms. Ehresmann noted, the work group did not envision an 

occupational group contacting the health department. Instead, they anticipated that a particular 

occupational group would mount their own campaign and their workers could be educated about 

and decide whether to volunteer to take the vaccine. The intent of the language about an 

occupational health program was to shift responsibility if an organization chose to mount a 

campaign to the organization that is engaged in other occupational health activities. 

Dr. Salmon (NVPO) reported that Option 2 created a lot of email traffic at a very high level of 

HHS over the previous few days. He thought that the general concern pertained to the wording 

that it is not routinely recommended, which may discourage individuals who may feel that their 

best option would be using whatever risk assessment is available to obtain the vaccine. There 

was a memo in September 2008 from Secretary Chertoff to Secretary Leavitt in 2008 in which 

he discussed the very real possibility of anthrax as a biological threat. The larger point was that 

if people were leaning toward Option 2, before such a vote, it may be worthwhile to bring in 

others within HHS and other departments, such as the Department of Homeland Security, to 

weigh in on this issue. He thought people were comfortable with Option 1, but if the consensus 

was leaning toward Option 2, perhaps other representatives should participate in the work group 

discussions. 

Dr. Besser (COTPER) acknowledged Dr. Morse’s comments earlier about the role of the ACIP, 

which is clearly to weigh the available science to make recommendations. He thought the work 

group had framed two permissive options that would allow the first responder community, based 

on an assessment of risk, to make a decision for their own organizations. While Options 1 and 

2 had different slants, that was his read of both. His understanding of Option 2 was that if the 

New York City Police Department decided that based on the risk in that city it was important for 

their workers to have this vaccine, it would be consistent with the ACIP recommendations. That 

may allow them to use Homeland Security dollars to provide that as an added protection to their 

workers. This was not true with the previous recommendations. He stressed that it was 

critically important for the ACIP to focus upon the science and stop there. If the science is not 

available, the ACIP should not be expected to go beyond that.

Dr. Cieslak noted that the science is limited in terms of risk. He said he frankly did not see the 

value of a permissive recommendation, given that people did not need ACIP’s permission to 

administer the vaccine. Given those facts, he would prefer a statement that simply said, “We do 

not have enough information about risk to make a recommendation. It appears that the vaccine 

is safe and is probably effective, but in the absence of data, we can make no recommendation 

about which groups may benefit” and leave it at that. Then the first responders groups would 

still have the option of weighing the risks as they understood them with whatever tools they 

have in their areas. 

Dr. Schuchat reminded everyone that the first sentence in both options addresses the lack of a 

calculable risk assessment, that there may be a risk assessment, but people may not have 

access to it. Certainly, ACIP does not have access to the risk assessment for thousands of 

communities in real time. Therefore, she thought that ACIP was being asked to examine what 

had been learned since 2001 / 2002 about the vaccine, safety, immunogenicity, dose, et cetera 

in order to update the understanding of the performance of the vaccine. She thought the work 

group was trying to frame the concept that they really did not know the risk to the police 

department in New York City, for example, but someone might. The previous recommendations 

suggested that even if someone did know the risk, they were not supposed to use the vaccine.
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Dr. Zink (St. Louis University) said that as a health care provider, he thought the 

recommendation was too weak for most to feel comfortable that they have a safe harbor to 

actively purchase, inventory, and prescribe this vaccine. He expressed concern that an issue 

not fully grasped by the group was that the ACIP’s recommendations are very important, if 

stated properly, in the event that emergency responders seek grant funding from various 

sources to obtain the vaccine to move forward with a worker comprehensive occupational health 

safety program of vaccination. The Department of Homeland Security’s Chief Medical Officer, 

Dr. Jeffery Runge, really wanted to hear something much more clear than Option 2. He 

believed that Option 1 would be much easier in policy discussions to place this vaccine into the 

authorized equipment list so that those who require support from the federal government can 

submit a grant. Currently, they cannot submit a grant because it would not be supported. There 

is much more to this in terms of safe harbors for prescribing physician and the ability to garner 

grant funding for emergency responders. He thought that Option 2 would be so diluted that it 

would not meet either of those tests. 

Dr. Brandis (Retired Fire Chief of St. Louis County, Missouri) concurred with Dr. Zink and said 

that he generally preferred Option 1 as well. For Option 1, he suggested changing the 

statement “for whom a calculated risk assessment does not exist” to “for whom a calculated risk 

assessment may exist” because some people may have knowledge of risk. If that was not 

satisfactory, he suggested in Option 2 on the third line changing “due to lack of a calculated risk 

assessment” to “due to our lack of a calculated risk assessment.” He also suggested in the 

fourth line changing “may choose to offer their workers” to “may offer their workers.” He felt 

very strongly that occupational physicians needed to be involved because as HAZMAT techs 

they must have physicals annually or every two years based on the doctors’ wishes and desires. 

That includes post-exposure to various chemicals, chest X-rays, blood work, pulmonary function 

tests, fit to duty to wear PPE, et cetera. 

Dr. Judson stressed that the ACIP recommendations did not prevent anyone from buying or 

using a licensed vaccine and distributing it through an individual licensed to administer 

vaccines. The decision should be local and it should be paid for locally.

Dr. Beck noted that as with so many situations facing the ACIP, it is not a simple approach. 

There were a couple of issues conflicting him as he tried to consider this. First, he thought they 

all had a sympathy for trying to protect first responders if, in fact, they are in harm’s way. He did 

not see that as a conflict. He also did not see an issue in terms of the evidence. The ACIP has 

taken an action on something when the evidence was not the best they would have liked. As 

long as they assess and use the best available evidence to make decisions and clearly disclose 

that from a transparency point of view, then they have met their responsibility in reaching a 

conclusion. It appeared to him they had done that. He was not persuaded by the idea that 

somebody else may know something that they do not. The ACIP cannot make an assessment 

on something they do not know. The ACIP made an assessment based upon what they do 

know and made a conclusion in accordance with that. To do otherwise would undermine their 

credibility. If the ACIP transcends their area of responsibility (e.g., ensuring that responders can 

get funding), they are stepping outside of their appropriate jurisdiction. It is not ACIP’s role to 

provide a way for people to get funding, even if it is justifiable. If something needs to be 

changed in the Homeland Security Funding, it should be handled through Homeland Security, 

not ACIP. 
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Monique Mansoura (HHS), a member of the work group, said she thought it was important to 

bring into this conversation that those in government who are responsible for conducting risk 

assessments with regard to threats had recently made some very significant statements. Most 

significant was Secretary Chertoff’s memo to Secretary Leavitt stating specifically that the 

determination had been that a significant potential for a domestic emergency involving anthrax 

exists. This statement built upon previous statements and assessments that the Department of 

Homeland Security has made that both anthrax and multi-drug resistant anthrax present threats 

to national security. In the context of the ACIP’s deliberations, and fully appreciating the 

importance of limiting this discussion to the science base, she thought it was important to 

acknowledge that those who have responsibility to make risk assessments have made very 

significant statements in recent months. 

Dr. Morse responded that the work group did take this into consideration, which is why they 

allowed for this to be taken into consideration by people who have that information beyond the 

ACIP’s purview. 

Motion: Option 1 Pre-Event Vaccination Recommendation

Ms. Ehresmann made a motion to approve Option 1 Pre-Event Vaccine Recommendation as 

written. Dr. Judson seconded the motion. No vote was taken on the motion at this time, given 

that further discussion ensued.

Dr. Cieslak said that Drs. Salmon’s and Mansoura’s comments led him increasingly to the 

conclusion that use of the vaccine should not be made on the strength of an ACIP 

recommendation, but instead should be made upon the strength of Secretary Chertoff’s 

recommendation. The ACIP has only certain information and does not have the intelligence 

information to which Secretary Chertoff is privy. To Dr. Cieslak this was why a recommendation 

for use of the vaccine in first responders should originate from someplace other than ACIP.. 

It seemed to Dr. Chilton that it was within the purview of the ACIP to state explicitly that its 

evaluation of the data indicates that the vaccine is safe and effective—period. Others will have 

to decide the other half of the equation, which is the benefit that might accrue to those who are 

at risk that the ACIP cannot assess. 

Dr. Sawyer said he arrived at the meeting prepared to vote on the very restrictive 

recommendation up to including not recommending it at all without any caveats. With regard to 

the motion on the floor, he reiterated others’ opinions that this does need to be processed 

through some sort of occupational health program in order to ensure that the proper education 

occurs before individuals make a decision about receiving this vaccine. 

Trying to place this in perspective, Dr. Judson pointed out that the ACIP and any occupational 

health person would have only one piece of substantive risk data—it is a numerator of one. In 

the history of the world and the history of the United States, there has been only one 

documented anthrax bioterrorism event. It caused 22 cases and 5 deaths, which could be 

handled on one floor of one medium-sized hospital in the country. As far as is known, it was 

perpetrated by a government employee working in a government laboratory. It took the FDA 

millions of dollars and five years to assess this. Therefore, with respect to risk, Homeland 

Security and the federal government should be asked to exercise greater security over their own 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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laboratories and personnel who are working with the agent, and for the FDA to move faster with 

proof, molecular biology, and genetic typing equipment. It should not have taken five years. 

As a point of order, Dr. Pickering reminded those presented that ACIP is an advisory committee 

that offers its advice to Dr. Gerberding and on to HHS. Therefore, if there are data in HHS that 

override recommendations from ACIP, changes can be made and people can be immunized as 

believed appropriate. 

Dr. Salmon (NVPO) thought it was fair to say that the ACIP could not consider information that 

had not been shared with them, and memos between secretaries is probably not helpful. His 

office would be happy to facilitate having someone from Homeland Security work with the work 

group to provide additional information that would help to make a more informed decision in this 

matter. It was his understanding that ACIP already had a recommendation against vaccination 

of first responders; thus, the ACIP does have a history of making a recommendation on this 

issue. 

Dr. Schuchat pointed out that the circumstances under which this work group was reconstituted 

and charged was to review what has occurred since the last time the ACIP made 

recommendations on anthrax vaccine. Given that there was new knowledge, new data, new 

publications, and new information on anthrax vaccine, they recognized that it was time to update 

them. There was discussion of classified information, access, and what kind of scope the ACIP 

work group would have. The idea was that the work group would focus on the science and the 

knowledge about the vaccine’s performance, dose, route, and safety, and would not delve into 

matters that are handled in other places. There is an outdated ACIP statement, and this 

session offered the opportunity to assess whether to move forward with a vote and the 

remainder of the presentations. 

With regard to the September 23, 2008 memo from Secretary Chertoff, Dr. Morse noted that the 

beginning of the memo reads, “There is not currently a domestic emergency involving anthrax. 

Additionally there is not currently heightened risk of an anthrax attack. We have no credible 

information indicating an imminent threat of anthrax involving bacillus anthracis.”

Dr. Meissner thought what Dr. Schuchat said made a great deal of sense, given that the 

potential threat of an act of bioterrorism with anthrax is a constantly moving target that, even if 

information was shared with the ACIP at this time, it would be only one snapshot. He did not 

believe it was the function of this committee to remain appraised of the risk of such an act of 

bioterrorism. It made more sense to address the science related to the vaccine rather than the 

risk of an attack. 

Dr. Dixie Snider (CDC) said that as Executive Secretary of the ACIP when the anthrax 

statement was first published, he wanted to let people know that the chair at that time was 

briefed by the National Security Council regarding the threat at that time. The views about 

threat do change over time, and it is difficult to build a recommendation based upon what is in a 

memo currently or even in the head of Secretary Chertoff.

At this point, Dr. Morse reminded everyone that there was a motion and second on the floor for 

Option, and that the work group had expressed a preference for Option 2 because of how this 

would be interpreted in terms of routine recommendations. This was implied in Option 1, but 

people had clearly picked up on the potential that voting on Option 1 would imply that the ACIP 

was recommending that vaccination be considered for all 3 million first responders. 
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Motion Withdrawal: Option 1 Pre-Event Vaccination Recommendation

Ms. Ehresmann withdrew the motion to approve Option 1 Pre-Event Vaccine Recommendation 

as written. Dr. Judson withdrew his second to the motion. Dr. Morse confirmed that the motion 

and second for Option 1 were removed. 

Motion: Option 2 Pre-Event Vaccination Recommendation

Dr. Beck made a motion to approve Option 2 Pre-Event Vaccine Recommendation as written. 

Dr. Temte seconded the motion. The motion carried with 13 affirmative votes, 0 abstentions, 

and 2 negative votes.

Dr. Wright then shifted the focus of the discussion to delayed doses of pre-exposure 

vaccination, indicating that there is one published study specifically addressing relatively long 

gaps between vaccinations [Pittman, et al. Antibody response to a delayed booster dose of 

anthrax vaccine and botulinum toxoid. Vaccine 20 (2002) 2107-2115]. This study measured 

anti-PA IgG response in 279 DoD personnel who had served in either Operation Desert Storm 

or Desert Shield. These persons had received either 1, 2, or 3 doses of AVA 18-24 months 

prior to the initiation of the study. Study recruits had sera drawn to assess initial titers, were 

provided the next dose of vaccine, and had anti-PA IgG measured one month later. Of those, 

99.3% of persons had a measurable anti-PA IgG in the 1-month follow-up sera. Overall, the 

GMT increased 139-fold. The group who had only received 1 dose of AVA 18-24 months prior 

had the lowest GMT increase, but even their response was 78-fold. In addition, there were no 

negative safety findings related to the delay in dose receipt. The work group felt that in light of 

the only available evidence it was prudent to make a recommendation similar to that of other 

vaccines. That is, “Available AVA specific data suggests that increasing the interval between 

doses does not adversely affect the ultimate serologic response achieved, nor post-vaccination 

safety. Therefore, as with other vaccines, interruption of the vaccination schedule does not 

require restarting the entire series or the addition of extra doses.”

Discussion

No discussion was offered.

Motion: Delayed Dosing

Dr. Chilton made a motion to approve the Delayed Dosing Vaccine Recommendation as written. 

Dr. Neuzil seconded the motion. The motion carried with 15 affirmative votes, 0 abstentions, 

and 0 negative votes.

Regarding post-exposure prophylaxis (PEP), Dr. Wright indicated that PEP is utilized to prevent 

inhalation anthrax among persons with a high likelihood of exposure to aerosolized B. anthracis

spores. The current accepted regimen is 3 doses of AVA administered at 0, 2, 4 weeks plus 

antimicrobials. AVA is not licensed for use in this manner and is administered under either an 

IND or an Emergency Use Authorization (EUA). In 2000, ACIP recommended that antimicrobial 

therapy should be continued for at least 30 days and possibly longer. If available, vaccine 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

106

should be provided and antimicrobials discontinued following the 3rd dose of vaccine. In 2002, 

ACIP endorsed the use of 3 doses of vaccine in combination with antimicrobials, along with 

language regarding the use of antimicrobials. The work group felt that the 2000 and 2002 

statements provided confusing and unclear language as to the recommendations for the use of 

PEP and that concise recommendations were needed to address the target groups to receive 

PEP, as well as the duration of antimicrobial use. 

Prior to making recommendations for the use of PEP, the work group considered the safety and 

effectiveness of the vaccine, as well as the safety and effectiveness of antimicrobials. Because 

AVA and antimicrobials are so intertwined in a post-exposure setting, the work group

considered data on both as part of the process. With respect to data to support post-exposure 

use of anthrax vaccine, the work group reviewed data from non-human primates suggesting that 

inhaled B. anthracis spores may persist up to 100 days. The work group also heard from 

anthrax immunologists that antibody titers peak 10-14 days following the 3rd dose of vaccine, so 

that vaccine provides benefits following discontinuation of antimicrobial agents. Pertaining to 

data to support 60 days post-exposure use of antimicrobials, the work group reviewed data 

regarding incubation periods for inhalation anthrax have been suggested to be as long as 43 

days and as short as 1 day [Brachman 1980; Meselson M, 1994]. Given that antibody titers will 

not peak until 10-14 days following the 3rd dose of vaccine, exposed persons will require 

protection before the immune system begins to respond to the vaccine. Regarding antimicrobial 

agents utilized post-exposure, the approved antimicrobials for use post-exposure use include: 

Ciprofloxacin, Doxycycline, and Levofloxacin. Amoxicillin (if MIC < 0.125 mcg/mL) may only be 

only used under IND / EUA. Following the 2001 BT event, thousands of people were offered 

post-exposure antimicrobial therapy. Similar AEs were reported after 30 days for Ciprofloxacin 

and Doxycycline and most AEs were mild. Because exposed persons were taking 

antimicrobials as long as 100 days following these events, adherence was studied and 

demonstrated to range from 21% to 64% of persons adhering to their prescribed dose and 

amount of time. Perception of risk was a stronger predictor of adherence than the occurrence of 

AEs. 

In terms of efficacy, there are no clinical trials of AVA and antimicrobials in humans, and most of 

the current knowledge comes from limited non-human primate studies. The work group

reviewed one small study of non-human primates exposed to aerosolized B. anthracis spores

[Friedlander AM, et al. J Infect Dis 1993; 167:1239-43]. The study authors concluded that 

survival following discontinuation of antimicrobials was improved when AVA was combined with 

antimicrobials.

The work group concluded that vaccination maximizes protection, especially with imperfect 

adherence to antimicrobials and with the potential for long-term spore germination and growth. 

Antimicrobials can provide early protection and will provide protection for the duration of their 

use. The work group therefore concluded that unvaccinated persons need both AVA and 

antimicrobials to provide protection following exposure to aerosolized B. anthracis spores.

Dr. Wright then presented the work group’s draft recommendations for the post-exposure

prophylaxis use of the vaccine, which was divided into four categories: 

 Previously unvaccinated persons following any inhalation exposure

 Pediatric populations

 Previously vaccinated persons with repeated occupational exposures (Remediation 

Workers / Environmental Investigators)

 Pregnant / Breastfeeding women
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Focusing first upon previously unvaccinated persons and pediatric populations, Dr. Wright 

indicated that the wording for previously vaccinated persons recommendation is as follows [full 

wording is in the draft document, page 38]:

60 days of appropriate antimicrobial prophylaxis combined with 3 doses of AVA is the best 

available protection against inhalation anthrax.

Vaccine should be offered within 10 days of the exposure.

Peak serologic response occurs within 10-14 days following the 3rd dose of anthrax 

vaccine. To prevent a lapse in protection, persons for whom vaccination was delayed

should extend antimicrobial use to 10-14 days after the 3rd dose, even though this practice 

may extend antimicrobial use past 60 days.

Based on the best available evidence, the work group felt that 60 days of appropriate 

antimicrobial prophylaxis combined with 3 doses of AVA provides the best available protection 

against inhalation anthrax. Further, vaccination should be offered within 10 days of the 

exposure. Because peak serologic response occurs within 10-14 days following the 3rd dose of 

anthrax vaccine, persons for whom vaccination was delayed should extend antimicrobial use to 

10-14 days after the 3rd dose. 

In coordination with AAP, the work group developed the following recommendation for the postexposure use of AVA in pediatric populations [draft document, page 39]:

Anthrax vaccine is not licensed for use in pediatric populations and has not been studied 

in children. The use of AVA in pediatric populations in a post-event setting with a high 

risk of exposure to aerosolized B anthracis spores is not contraindicated; however, its 

use is considered a precaution. The risks and benefits of using post-exposure 

vaccination in children will be considered based on the specific circumstances of an 

event and exposure prior to making a recommendation on use of AVA in children. 

Antimicrobial agents should be employed, as described above in Antimicrobial 

Considerations for Pediatric Use.

 

Discussion 

Dr. Cieslak expressed concern about “10-14 days” for the previously unvaccinated persons 

recommendation, inquiring as to whether 14 days were needed or if 10 would be sufficient.

Dr. Judson said it was not clear what to do with this information

Dr. Quinn clarified that on average the response requires 14 days to reach peak, so in order to 

have a specific time point that encompasses the maximum level of safety, he would suggest 14 

days.

Dr. Temte requested clarification regarding whether the full 60 days should be recommended for 

the antimicrobial regardless of when the vaccination series was started, understanding that the 

antimicrobials could extend past 60 days depending upon when vaccination was begun. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

108

Dr. Messonnier responded that the full 60 days should be recommended, pointing out that the 

work group tried to be very concise with this recommendation. It is licensed for 60 days and the 

recommendation is meant to be at least 60 days. The full explanation is that if someone begins 

late, they should go at least past the end of the third dose.

Dr. Meissner inquired as to why the statement was being made about the combination of 

vaccine and antibiotic being preferential to antibiotic alone. 

Dr. Judson responded that the idea was double coverage.

Dr. Wright replied that this pertained to the finding of the potential for inhaled spores persisting 

up to 100 days. If antibiotics are terminated at 60 days, but spores germinate and begin to grow 

at day 70, there would be no protection at that point. 

Dr. Morse added that only 44% took antibiotics for 60 days following the 2001 anthrax attacks, 

so the combination would afford additional protection.

Dr. Judson thought that rather than peak antibody response, they needed to know under what 

dosing circumstances antibody levels would fall below a protective level and, therefore, would 

make antibiotic coverage crucial. He did not believe they should simply throw out the arbitrary 

numbers of 10-14 days, given that there was nothing to indicate that antibody levels never just 

“fall off a cliff.” The half-life is 28 days or so. It was not clear to him what the sample sizes were 

at the intervals shown in Dr. Conrad’s data.

Dr. Messonnier responded that the correlate of protection is unknown, given that there are no 

data. Perhaps when the anthrax vaccine clinical trial and all of its components, including the 

animals studies are completed and analyzed, there will be more data. The 10-14 days is a 

vestige of what most say it takes after general antibacterial vaccines to attain protection. Dr. 

Quinn likes 14 days because it is the only data available, which is for the peak antibody 

responses. There are no data to indicate whether it could be 10 instead. 

Dr. Plotkin (sanofi pasteur) reported that the last case in the Sverdlovsk exposure was 43 days 

after the release, so there is evidence for a germination of spores rather late. He disagreed 

about the correlates, stressing that he thought they were very clear. In rabbits and monkeys, it 

has been established that a certain titer of anti-PA antibody is uniformly protective. Therefore, 

he thought they were dealing with a lot of factual materials. He thought the 3-dose regimen to 

be clearly effective in raising PA antibodies to what is apparently a correlate of protection. 

Therefore, he did not believe there was difficulty in making the proposed recommendation. With 

respect to pediatric use, it is true that it has never been used in children. Dr. Plotkin said he 

was party to a consultation with a group from NIH about the pediatric use of this vaccine in 

which it was acknowledged that there are no data. There was a suggestion of perhaps 

acquiring data in children who are exposed to anthrax in the Indian subcontinent, for example, 

but those data are not yet available. Nevertheless, he thought that the data for safety and 

efficacy of this vaccine were such that making the recommendation not to use it until the ACIP 

had a meeting and recommended it after an exposure was much too conservative. He thought 

it should be said, in effect, that there are no data, the vaccine is believed to be safe and 

effective based on data in adults, and in the event of an exposure that involves children, it 

should be used. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

109

With respect to the pediatric recommendation, Dr. Chilton expressed concern with the 

statement, “its use is considered a precaution,” given that this did not entirely make sense. 

Therefore, he preferred that this statement be changed regardless of what they decided the use 

should be in children. He thought that something to the effect of Dr. Plotkin’s suggestion would 

be more appropriate (e.g., there are no data, the vaccine is believed to be safe and effective 

based on data in adults, and in the event of an exposure that involves children, it should be 

used). 

Dr. Kimberlin (AAP / COID) indicated that the intent was to clearly state that pediatric use is not 

a contraindication, and also to imply that since it has not been studied, it should not be used 

liberally either. This is where the phrase “its use is considered a precaution” came from. As 

long as the intent was clear and the wording suggested that it is not to be used on an active 

basis without the additional input of the agencies that would be making determinations of what 

the risk really were, it would be satisfactory to the AAP. 

Dr. Messonnier indicated that the wording is consistent with the language in the pregnancy 

recommendation as well. “Precaution” and “contraindication” are defined earlier in the 

document where more context is provided around these and do represent standard terminology.

Dr. Sumaya said he would view the word “precaution” not in a sense that it should not or could 

not be given, but that it may be given following a very deliberate assessment of the risks and 

benefits.

Dr. Sawyer agreed that the word “precaution” is standard among the lexicon of immunizations. 

Most people who deal with vaccine recommendations understand what that means. However, 

the problem for him pertained to the word “will” in the phrase “use of post-exposure vaccination 

in children will be considered,” which implies that some body is going to do that. Dr. Plotkin 

interpreted that as ACIP. Therefore, he suggested changing “will” to “should” be considered by 

whoever is available to consider it. This would make Dr. Sawyer comfortable that people would 

not be prevented from giving this to children if they believed it to be appropriate. 

Dr. Cieslak agreed with Dr. Sawyer, indicating that he did not care for the language and thought 

the plain sense of what they wanted to recommend was something like, “There are no data 

attesting to the efficacy in children; however, given the extraordinary morbidity associated with 

anthrax in the setting of a known exposure, it is likely to be more helpful than harmful.” 

Motion: PEP in Previously Unvaccinated Persons and Pediatric Populations

Dr. Sawyer made a motion to approve the Post-Exposure Prophylaxis and Antimicrobials

recommendation and Pediatric PEP recommendations as stated, with the two changes 

discussed: 1) Eliminate “10 to 14 days” in the PEP recommendation and replace it with “14 

days” and 2) In the pediatric recommendation, change the word “will” to “should” and include 

language to the effect that “There are no data attesting to the efficacy in children; however, 

given the extraordinary morbidity associated with anthrax in the setting of a known exposure, it 

is likely to be more helpful than harmful.” Dr. Baker seconded the motion. The motion carried 

with 15 affirmative votes, 0 abstentions, and 0 negative votes.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

110

Dr. Wright next discussed the work group deliberations pertaining to post-exposure prophylaxis

in previously vaccinated persons with repeated occupational exposures. Persons with repeated 

occupational exposures for this discussion included remediation workers and environmental 

investigators, persons who are recommended for pre-event vaccine. The 2000 

recommendations did not address PEP for partially / fully vaccinated persons. In 2002, ACIP 

recommended that partially or fully vaccinated persons exposed to aerosolized B. anthracis

spores receive at least a 30-day course of antimicrobial PEP. Antimicrobial PEP was not 

needed for fully vaccinated persons working in biosafety level 3 conditions, or fully vaccinated 

persons wearing appropriate personal protective equipment (PPE) unless the PPE was 

disrupted. Following the 2001 BT events, the previous ACIP guidance was often interpreted as 

“following last exposure.” With a low threshold for PPE disruption, some workers were on 

antimicrobials for greater than 12 months.

Given that the work group previously discussed the safety / effectiveness of the vaccine and 

antimicrobials, both pre- and post-exposure, Dr. Wright opted not to discuss them again during 

this session. The work group considered long-term safety and effectiveness of antimicrobials, 

as well as effectiveness of PPE. Civilian adherence data from 2001 suggested that adherence 

to antimicrobial regimens ranged from 21-64%. There are no adherence data among 

remediation workers who had longer duration of antimicrobial use. There are limited safety data 

on the long-term use of levofloxacin and the FDA has recently warned of the risk of tendonitis /

tendon tears with quinolone use [http://www.fda.gov/cder/drug/InfoSheets/HCP/

FluoroquinolonesHCP.htm]. Due to the lack of adherence data among remediation workers, as 

well as the lack of safety data for antimicrobials, the work group felt the long term safety and 

effectiveness of antimicrobials was unknown.

Personal protective equipment, as defined by NIOSH in the draft statement is a “powered airpurifying respirator with full-facepiece and high-efficiency particulate air (HEPA) filters, 

disposable protective clothing with integral hood and booties, and disposable gloves.” PPE is 

protective if properly selected, assembled and fitted, but is considered the last line of defense in 

the hierarchy of controls. The work group concluded that if properly selected, assembled, and 

fitted, PPE was effective. 

The work group concluded that fully vaccinated persons wearing PPE do not need 

antimicrobials, but may seek additional protection through their occupational health services if 

desired. Partially vaccinated person and fully vaccinated persons wearing no PPE should be 

provided 30 days antimicrobial PEP and continue with their vaccine. Fully vaccinated persons 

with breached PPE should also receive 30 days antimicrobials and continue vaccine; whereas,

workers with no previous vaccine should receive 60 days antimicrobial PEP and begin 

vaccination. The full wording of the recommendation is as follows [draft document, page 38]:

ACIP believes that the combination of vaccine and appropriate PPE provides effective 

protection for fully vaccinated persons working in occupations with repeated exposure to 

potentially aerosolized B. anthracis spores. Antimicrobial PEP is therefore not needed 

for fully vaccinated workers wearing appropriate PPE while working in environments 

contaminated with B. anthracis spores unless their PPE is disrupted. 

A 30 day course of antimicrobial PEP is recommended for partially vaccinated workers, 

fully vaccinated workers wearing no PPE, and fully vaccinated workers for whom PPE is 

disrupted; these workers should also continue with their licensed vaccination regimen. A 

60 day course of antimicrobial PEP, along with starting the licensed regimen, is 

recommended for previously unvaccinated workers. Fully vaccinated workers who desire 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

111

additional protection may consider antimicrobial PEP under the direction of their 

occupational health program.

Discussion 

 

It was not clear to Ms. Ehresmann why, if someone was fully vaccinated, the recommendation 

read “continue vaccine.”

Dr. Wright responded that this pertained to annual boosters.

Dr. Neuzil inquired as to whether the recommendation would be the same as the previous 

recommendation upon which they just voted if an individual was exposed who had no previous 

vaccine.

Dr. Wright responded that essentially it would be the same, except the occupationally exposed 

individuals would continue beyond the three doses of AVA with the fully licensed regimen. If 

these are remediation workers who were not previously vaccinated, they probably should have 

been or perhaps have not started their series yet. Therefore, they should continue with the full 

six doses. In the immediate period, they would be treated the same as the PEP regimen, which 

is the first three doses of vaccine.

Dr. Sawyer requested background and clarification regarding the asterisk in the table shown for 

2008 for fully vaccinated individuals with PPE + PPE for whom no antibiotic is recommended, 

which states that individuals “may seek additional protection through occupational health 

services.”

Dr. Wright responded that this pertained to the last statement in the second paragraph of the 

2008 recommendation found on page 38 of the draft document, “Fully vaccinated workers who 

desire additional protection may consider antimicrobial PEP under the direction of their 

occupational health program.” 

Referring to the part of the statement reading “30 day course; continue vaccine,“ Dr. Marcy 

requested clarification regarding whether that meant that if someone was exposed after 4 weeks 

when they had their third dose, they should have their next dose at 6 months.

Dr. Wright replied that this was correct—the individual would simply continue on with his or her 

schedule. They would not be given an immediate boost.

 

Motion: PEP in Previously Vaccinated Persons with Repeated Occupational Exposures

Dr. Sawyer made a motion to approve the Post-Exposure Prophylaxis in Previously Vaccinated 

Persons with Repeated Occupational Exposures recommendation as stated. Dr. Chilton 

seconded the motion. The motion carried with 15 affirmative votes, 0 abstentions, and 0

negative votes.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

112

Birth Defects among Infants Born to Women 

Who Received Anthrax Vaccine in Pregnancy

CAPT Margaret Ryan

Naval Health Research Center 

CAPT Ryan indicated that concerns have been raised about the use of anthrax vaccine in US 

military professionals, and that civilians share these concerns. Concerns have included 

reproductive health issues, even though there may be little biologic plausibility for inactivated 

vaccines causing reproductive harm. Anthrax vaccine was originally considered by FDA as 

Pregnancy Category C. The US military has vaccinated over 1 million healthy young adults 

since 1998, and observational data are available on their reproductive health experiences.

The objective of the Naval Health Research Center study was to evaluate infants born to military 

women who were inadvertently vaccinated against anthrax in early pregnancy, and compare the 

prevalence of major birth defects with that of infants born to military women who were 

vaccinated against anthrax, but not in early pregnancy. The comparison group was selected 

particularly because they were comparable in terms of their deployability, their health status, 

and because they were in the group of people who should be getting vaccines but were not 

vaccinated in early pregnancy. 

The general methodology was to link data from the central DoD vaccine database to data from 

the DoD Birth and Infant Health Registry. These are electronic data on healthcare outcomes 

among infants that are compiled in the DoD Center for Deployment Health Research in their 

particular project titled the DoD Birth and Infant Health Registry. Those data were used to

perform multivariable logistic regression modeling, which were adjusted for confounding by 

other variables, including: maternal age, race / ethnicity, marital status, service branch, military 

pay grade, infant plurality, infant gender, and gestational age. The DoD Birth and Infant Health 

Registry evaluates data on all live births and healthcare encounters in the first year of life 

among all infants born to DoD beneficiaries. This system includes all recorded inpatient and 

outpatient care from civilian and military facilities. ICD-9-CM codes are leveraged for 

diagnoses.

This study was actually conceived in 1998 when the original mandate for anthrax vaccination 

came to the DoD. With regard to the preliminary results (2001-2002), the original regression 

model using only 1998-1999 data revealed a small, marginally significant association between 

anthrax vaccination in the first trimester of pregnancy and birth defects in those infants. 

Preliminary results were shared with DoD and civilian policymakers in 2001-2002 era, at the 

point of peak interest in the issue. The outcome of that was that an anthrax vaccine consent 

form, given to civilians in December 2001, included information about birth defect concerns. 

The MMWR published a “Notice to Readers: Status of US Department of Defense Preliminary 

Evaluation of the Association of Anthrax Vaccination and Congenital Anomalies” in February

2002 [51(06);127]. The manufacturer’s product insert included reference to findings. The FDA 

reclassified anthrax vaccine as Pregnancy Category D.

Limitations and concerns of the study are that vaccination status and dates are based on 

military vaccine databases. The first trimester exposure window is based on ICD-9-CM coding 

related to gestational age. Birth defects diagnoses are based on ICD-9-CM coding. With 

respect to addressing the limitations and concerns (2002-2007) there was a validation effort of a 

large sample of vaccine records against archived paper records in the VA Records 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

113

Management Center in St Louis (n = ~12,000). Obstetric records were reviewed for cases in 

which gestational age could affect exposure classification (n = ~5500). Pediatric birth and 

healthcare records were reviewed by professionals who were blinded to exposure status in 

order to validate ICD-9-CM coded birth defects (n = ~ 200). The results of the updated 

analyses were that among 115,169 infants born to military women (1998-2004) 37,140 infants 

were born to women ever vaccinated against anthrax (the primary focus of concern for the 

comparison group) and 3,465 infants were born to women vaccinated in the first trimester. All of 

that exposure would be inadvertent, given that the DoD policy would be to defer vaccine in 

pregnancy, so those pregnancies were not recognized at the time of vaccination. Birth defects 

were slightly more common in infants born to women vaccinated in the first trimester of 

pregnancy (OR=1.18, 95% CI=0.997-1.41). The odds ratio could not be closer to marginal 

significance. In fact, this was drawn out to three decimal points to show that the lower limits of 

the confidence bound are below 1.0. This association was only statistically significant when 

alternative referent groups were used. Only the vaccinated post-pregnancy referent group 

might reflect that pre-pregnancy, pre-conception may be a risk in and of itself. Only in 

comparing to the 18,000 infants born to women vaccinated post-pregnancy in that referent 

group did the investigators find that the statistical significance is just barely significant, again 

drawing it out to three decimal points. In comparing to the infants born to never vaccinated 

women (n = 78,000) there is statistical significance with about the same order of magnitude of 

the odds ratio. The primary analysis did not include never vaccinated women on purpose 

because they are considered to be less comparable to the exposed group (e.g., women who 

were eligible to receive vaccine) because they are in a deployable status. The never vaccinated 

women demographically different. They tend to be older, officers, and less likely to deploy. 

Among individual birth defects that might be driving the association where the increased 

prevalence is observed, only atrial septal defect (ASD) was significantly associated with first 

trimester anthrax vaccination (OR=1.38, 95% CI=1.04-1.82). However, this finding was not 

statistically significant if cases of isolated ASD in preterm infants were excluded, as may be 

clinically appropriate. In most birth defects surveillance systems, ASD in premature infants is 

considered a normal variant and is generally excluded as a defect. Not that preterm babies 

cannot have ASDs, but most of the ASDs coded in premature infants resolve and are not 

considered classic defects. Also, this finding was not statistically significant if adjustment for 

multiple comparisons was applied. A separate point is that maternal vaccination pre-pregnancy 

or in late-pregnancy was not associated with an increased risk of birth defects. Alternative 

explanations exist for finding a small association between any exposure that is also associated 

with late-recognition of pregnancy and adverse outcomes.

The tiny elevated prevalence without statistical significance in the primary model is a difficult 

finding to deal with. There are potentially alternative explanations for finding such a small 

association. One point argued in the discussion points of the publication was that the difference 

between women vaccinated during pregnancy and all of the women who were vaccinated, but 

not during pregnancy, in some sense might be summed up that they simply did not recognize 

their pregnancies. Late recognition of pregnancy itself has been associated in other studies 

with small, marginally significant adverse outcomes, including birth defects. It is a confounding 

issue of late recognition pregnancy potentially associated with other exposures that might not be 

experienced by the women if the pregnancy was recognized. The co-authors of the study 

concluded that, “Although the small observed association may be unlikely to represent a causal 

relation between vaccination in early pregnancy and birth defects, this information should be 

considered when making decisions about administering anthrax vaccine to pregnant women.”
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

114

Discussion

Dr. Meissner requested clarification regarding when the women in the control group were being 

vaccinated against anthrax. 

CAPT Ryan replied that the women were vaccinated sometime during the observation period of 

1998-2004, but not during pregnancy.

Dr. Marcy pointed out that “may be unlikely” was a double hedge. “Unlikely” is a hedge and 

“may be” is a hedge. He suggested removing “may be” and stating “is unlikely.”

CAPT Ryan said she could comment only that they struggled mightily with the language. 

With respect to the multivariable model, Dr. Cieslak noted late recognition of pregnancy was 

reported as a possible confounder, but it was also said that gestational age was included in the 

model. In the non-vaccinated members of the cohort of pregnant women, Dr. Cieslak wondered 

what was used for gestational age and whether the investigators controlled for time of 

recognition of pregnancy.

CAPT Ryan responded that the gestational age of what week of pregnancy was exposed was 

known. The unvaccinated women were not vaccinated during pregnancy. The time of 

recognition of pregnancy is not a variable in the model that can be defined, so it remains as a 

confounder. 

Dr. Neuzil suggested that the investigators should still have been able to get an idea with more 

precision than first trimester. For example, most pregnancies are unrecognized for the first 

three or four weeks. With that in mind, she wondered if this could be examined in a more 

precise manner than just first trimester. 

CAPT Ryan responded that they did do so. Some parsing was done of the exposure windows 

because rules were made and estimated gestational age at vaccination was defined. Sensitivity 

analyses were conducted, moving the exposure window from very small to large. There was 

really no substantial change from about a 1.1 to 1.2 odds ratio. The investigators did not find a 

particular window of exposure that was driving the findings. 

Dr. Zink inquired as to whether any primary verification was done of the CPT codes or if it was a 

complete CPT code based retroactive review.

CAPT Ryan replied that it was ICD-9 codes and that they validated the birth defects among the 

sample charts they could obtain on the actual birth defect cases. However, it is not complete. 

Dr. Zink asked in how many cases for which the charts were reviewed for primary verification 

mistakes were found.

CAPT Ryan responded that there were approximately 200 specific cases with that degree of 

validation. The investigators did find mistakes, the actual percentages for which could be found 

in the paper. They primarily found birth defects not coded that should have been as opposed to 

non-birth defects coded as birth defects. Because PDA, for example, is such a difficult 

diagnosis, it was excluded from the analyses. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

115

Recommendations for Anthrax Vaccination 

of Pregnant and Breastfeeding Women

Jennifer Gordon Wright, DVM, MPH

On behalf of the ACIP Anthrax Vaccine Work Group

Dr. Wright next presented the Anthrax Work group’s deliberations and draft recommendations 

for the use of AVA in pregnant or breastfeeding women. AVA is not a live vaccine and there is 

no biologically plausible mechanism for a reproductive effect [Wiesen A and Littell C, JAMA 

2002]. The FDA re-categorized AVA as a “Pregnancy Category D” agent based on preliminary 

analysis of the data just presented. A category D agent is one in which FDA feels there is 

positive evidence of human fetal risk based on data from experience or human studies. 

However, the potential benefits may warrant use of the drug despite the potential risks.

In 2000, ACIP stated that no studies had been published and pregnant women should be 

vaccinated against anthrax only if the potential benefits of vaccination outweighed potential risks 

to the fetus. The 2000 document did not distinguish between pre-event and post-exposure use, 

but the DoD currently exempts pregnant women from pre-event vaccination if the pregnancy is 

reported. In 2000, ACIP stated that no data suggested an increased risk for side effects or 

temporally associated adverse events associated with vaccination of breastfeeding women and 

that administration of non-live vaccines during breastfeeding was not medically contraindicated

[CDC. Use of Anthrax Vaccine in the United States: Recommendations of the Advisory 

Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2000 Dec 

15;49(RR15):1-20]. 

ACIP has developed new pregnancy guidelines to ensure that recommendations on vaccination 

of Pregnant and Breastfeeding Women (BFW) are developed using a consistent, rigorous 

process and presented with clarity and uniformity. The Pregnancy Principles Document states 

how and where within the statement pregnancy and breastfeeding should be addressed and 

provides 7 core topics for work group’s to review. As far as is known, the Anthrax Work Group

is the first work group to fully utilize this process in the development of recommendations

[http://www.cdc.gov/vaccines/recs/acip/ downloads/preg-principles05-01-08.pdf]. 

The Anthrax Work Group followed the recommendations set forth by the ACIP Pregnancy 

Principles document and reviewed 4 of the 7 recommended “core topics.” The work group

reviewed available data regarding disease burden, vaccination during pregnancy /

breastfeeding, and alternatives to vaccination. The work group did not specifically review cost 

effectiveness as there are no issues unique to pregnancy to require this analysis, nor did the 

work group review logistics in the context of this discussion because the use of AVA in a postexposure manner would be coordinated by public health authorities. In the draft statement the 

work group states that additional research is needed, but did not recommend specific studies. 

The ACIP Pregnancy Principles document requests that work groups specifically state whether 

pregnancy / breastfeeding is a precaution or a contraindication to vaccination. When a 

condition is a precaution, vaccination may be indicated if benefits outweigh the risks. When 

contraindicated, vaccine will not be administered. 

The work group considered the following issues during the discussion of AVA administration 

during pregnancy or breastfeeding: burden of disease specific to this population; 

immunogenicity / efficacy of the vaccine in the population; safety of the vaccine, to include 

trimester specific issues; and alternatives to vaccination in a post-exposure situation. Similar to 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

116

the previous discussion on pre-event vaccination, the majority of the work group felt the current 

burden of disease is low and does not favor recommending pre-event vaccination. However,

another anthrax bioterrorism event would change the burden of disease. Thus, the work group

gave burden of disease a -/+. 

As previously discussed, AVA produces a robust immune response in non-pregnant adults. 

However, there are no AVA data specific to immune response among pregnant or breastfeeding 

women. The work group reviewed studies of two other vaccines conducted on pregnant women 

and noted that pregnancy did not appear to decrease efficacy of the reviewed vaccines [Baker, 

et al. Immunization of pregnant women with group B streptococcal type III capsular 

polysaccharide-tetanus toxoid conjugate vaccine. Vaccine. 2003 Jul 28;21(24):3468-72; 

Quiambaio, et al. Immunogenicity and reactogenicity of 23-valent pneumococcal polysaccharide 

vaccine among pregnant Filipino women and placental transfer of antibodies. Vaccine. 2007 

May 30;25 (22): 4470-7]. The work group felt that the available data on immunogenicity of AVA 

was favorable in making a recommendation for vaccination when indicated. 

The work group reviewed two studies regarding the impact of AVA on pregnancy. The first

study reviewed followed 385 women vaccinated for anthrax prior to becoming pregnant

[Relationship between Prepregnancy Anthrax Vaccination and Pregnancy and Birth Outcomes 

Among US Army Women.” JAMA. 2002.287:12(1556-1560). The study did not support the 

hypothesis that AVA administration resulted in decreased pregnancy rates or adverse fetal 

outcomes among those vaccinated pre-pregnancy. There was also no evidence of miscarriage, 

infertility, or other reproductive problems, although the study was not powered to detect low birth 

incidence adverse outcomes. The second study reviewed by the work group was the study just 

presented by CAPT Ryan, which evaluated 37,140 infants born to vaccinated women [Ryan, 

MAK, et al. Birth Defects among Infants Born to Women Who Received Anthrax Vaccine in 

Pregnancy. Amer J Epi; July 2008]. The study utilized ICD-9 codes for birth defect diagnoses. 

Alternative referent groups were utilized to compare vaccinated groups to each other and to 

never vaccinated women. As reported, birth defects were slightly more common in infants born 

to women vaccinated in the first trimester of pregnancy only when compared with women 

vaccinated post-pregnancy and never vaccinated women. The authors further explored 10 

specific birth defects with 5 or more cases per exposed or referent group. Of the 10 defects, 

only atrial septal defect represented a statistically significant increase from the referent group. 

This association was not significantly significant when isolated ASD cases in preterm infants 

were removed from analysis, nor when adjustment for multiple comparisons was made. 

The work group believes that any birth defect is concerning and should be prevented. 

Population-based surveillance systems in the US suggest that 3-4% of all children have a birth 

defect. The work group felt that this study found neither strong nor consistent associations 

between AVA and birth defects. The association for birth defects in general was seen when 

comparing exposed infants to those born to never-vaccinated women, as well as those 

vaccinated post-pregnancy. Never vaccinated women differed from vaccinated women in 

several demographic characteristics. 

The ICD-9 code for atrial septal defect includes patent foramen ovale, which is commonly found 

in pre-term infants. The work group concluded the more appropriate analysis was the one in 

which pre-term infants were excluded. This analysis found no association between vaccination 

and the birth defect. The number of women vaccinated during the first trimester may be 

indicative of late maternal recognition of pregnancy, which may be a marker for other risk 

factors and has been associated with a small increased risk for a number of birth defects. In 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

117

fact, the work group felt this study provided additional confidence in the safety of AVA use 

during pregnancy. 

Maternal vaccination has not been established to cause birth defects and other inactivated 

vaccines are recommended for use in at-risk women during pregnancy. Because there are no 

additional studies of AVA use during pregnancy, the work group reviewed two additional vaccine 

studies which evaluated safety during pregnancy [Baker, et al.. Vaccine. 2003 Jul 

28;21(24):3468-72; Quiambaio, et al. Vaccine. 2007 May 30;25(22):4470-7]. There is also 

animal evidence that stimulation of the maternal immune system may be associated with a 

decreased risk of birth defects [Holladay, et al. Teratology. 2000;62:413–19; Yitzhakie, et al. J 

Repro Immunology. 1999;45:49–66].

There are also no data regarding the safety of AVA in breastfeeding women, but there is no 

biologic plausibility to suggest increased risk for adverse events. ACIP previously recognized 

that administration of other inactivated vaccines during breastfeeding is not medically 

contraindicated [Centers for Disease Control and Prevention. General recommendations on 

immunization recommendations of the Advisory Committee on Immunization Practices

(ACIP). MMWR. 2006; Vol. 55 (No. RR-15)]. 

The work group felt that the available evidence signifies that AVA does not indicate an 

increased risk to pregnant women, their unborn babies, or to breastfeeding women and their 

infants. In addition, the work group felt the Ryan paper provided reassurance that the vaccine 

does not cause devastating birth defects when inadvertently administered to pregnant women. 

Thus, the safety evidence was felt to be in favorable in making a recommendation for 

vaccination when indicated.

The work group also reviewed alternatives to vaccination. In a pre-event setting where the risk 

is low, the alternative is to defer vaccination. In a post-event setting, ACIP has recommended 

the optimal regimen for persons exposed to inhalation anthrax to be 3 doses of vaccine plus at

least 60 days of antimicrobials. The alternative to this regimen would be antimicrobials alone. 

As previously discussed, vaccination as a component of PEP maximizes protection with spore 

germination and late outgrowth and when there is imperfect adherence to antimicrobials.

Antimicrobial agents provide protection for the duration of their utilization. Unvaccinated 

persons need both in combination to provide protection following exposure to aerosolized B 

anthracis spores. The work group felt that relying on 60 days of antimicrobials alone for 

pregnant or breastfeeding women exposed to aerosolized B anthracis spores was not an 

acceptable alternative to AVA plus antimicrobials. Thus, the available post-exposure alternative 

to vaccination was not favorable. The work group concluded that the burden and severity of 

disease in the event of exposure may be high. There is no biologic plausibility for decreased 

immunogenicity of the vaccine during pregnancy or increased risk of birth defects. In fact, the 

available safety data were reassuring to the work group that AVA used during pregnancy is 

safe. In addition, the post-exposure alternatives to vaccination are not acceptable for women 

exposed to aerosolized B. anthracis spores.

Dr. Wright then presented the work group recommendations for the use of AVA in pregnant and 

breastfeeding women, starting with pre-event use in pregnant women.

The work group felt that while the vaccinating during pregnancy is acceptably safe, it makes 

sense to be cautious, as with other vaccines , and to defer vaccination if there is no immediate 

risk of exposure. The work group’s recommendation for the pre-event use of vaccine is, “In a 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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pre-event setting, where the risk of exposure to aerosolized B. anthracis spores is presumably 

low, vaccination should be deferred until after pregnancy.”

The work group felt that “Breast feeding is neither a precaution nor a contraindication to 

vaccination. In a pre-event setting vaccination does need not be deferred if the mother’s 

occupation puts her at risk for encountering B. anthracis.”

The work group felt that “In a post-event setting with a high risk of exposure to aerosolized B. 

anthracis spores, pregnancy is neither a precaution nor a contraindication. Pregnant women at 

risk for inhalation anthrax should receive AVA and 60 days antimicrobials as described in 

Antimicrobial Considerations for Pregnant or Breastfeeding Women.” An additional sentence 

was included here stating that, “Pregnant and lactating women exposed to B. anthracis should 

be counseled as to the risk- benefit profile of post-exposure prophylaxis use of the vaccine as 

well as the recommended antimicrobial therapy” follows the pregnancy and breastfeeding 

recommendations, given that there may be some side effects associated with the antimicrobials 

as well.

Discussion

Dr. Baker commended the use of the guiding principles, pointing out that the language of the 

recommendations was very clear and reasonable. With respect to the sentence “Pregnant and 

lactating women exposed to B. anthracis should be counseled as to the risk-benefit profile of 

post-exposure prophylaxis use of the vaccine as well as the recommended antimicrobial 

therapy,” Dr. Baker said she was convinced that anyone who is exposed to anthrax needs 

medical counseling. Therefore, she wondered why pregnant women were being made to feel 

that they were at extra risk for a vaccine or antimicrobial situation with this sentence.

Dr. Wright replied that the sentence could be moved to the beginning of all of the 

recommendations.

Dr. Judson agreed that this could be simplified, given the evidence presented. Any pregnant or 

lactating woman exposed to anthrax or in a high-risk pre-exposure setting should receive 

vaccine and antibiotics—period.

Dr. Duchin (NACCHO) said he could envision a number of scenarios in which there could be a 

potential anthrax attack during which it would not be that easy to determine the population at 

risk. Potentially many people would present, some of whom may live 1500 miles from where 

the event occurred asking for vaccine as was observed with the anthrax letters. Thus, the issue 

of counseling is not a trivial one. Health care providers will have to discern who truly is at risk 

and there may not be a great deal of information to help them do so. 

Dr. Judson replied that the committee could only go so far.

Dr. Baker pointed out that the ACIP is supposed to be a science- and data-based advisory 

committee and largely it is, except for pregnant women. She wondered when vaccines in 

pregnant women would be studied.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Motion: AVA Use In Pregnant / Breastfeeding Women 

Ms. Ehresmann made a motion to approve the four proposed statements collectively for AVA 

use in Pregnant / Breastfeeding Women as stated. Dr. Baker seconded the motion, with the 

eradication of statement, “Pregnant and lactating women exposed to B. anthracis should be 

counseled as to the risk-benefit profile of post-exposure prophylaxis use of the vaccine as well 

as the recommended antimicrobial therapy.” The motion carried with 14 affirmative votes, 1 

abstention, and 0 negative votes. 

 

Dr. Thomas Zink

Emergency Room Physician

Occupational Medicine

Dr. Zink indicated that he was representing the Institute for Biosecurity at St. Louis University, 

as well as the Emergency Responder Teams who are working diligently to acquire the same 

kind of protection that the National Guard Weapons of Mass Destruction Civilian Support Teams 

have. Dr. Zink stressed that he is a proponent of the notion of civilian-driven bio-defense 

wherein civilians take part in their own future with respect to preparedness and community 

resilience. By that he meant to say that they would like to assess their own threats and choose 

their own FDA-approved countermeasures, with the help of health care professionals. He said 

he observed the struggles of the ACIP in 2000-2001 and beyond in wrestling with making 

recommendations for bioterrorism preparedness, especially with respect to smallpox and 

anthrax, and was very sympathetic regarding the difficulty of this task. That said, anthrax is not 

an everyday epidemiological issue. This is a matter that must be contemplated within the 

context of the war the terrorists have brought to the US’s front door. This does not lend itself to 

the usual tools of epidemiology. This is war. This is also about security risks. It is not about the 

risk that someone might lose investments in the stock market. It cannot be calculated based on 

charts, so advice is sought from the security risk professionals, which St. Louis University has 

done. The security risk professionals state that in order to understand security risks, one must 

determine whether there is a threat, vulnerability, and an impact should something go wrong. 

Dr. Zink drew the group’s attention to a document that was distributed to the committee earlier 

in the day that was developed by St. Louis University, which addresses why there is a threat. 

Declassified information has confirmed that known enemies of the US, including Al-Quada, have 

anthrax weaponization expertise. There is a probability of vulnerability. The US has already 

suffered a covert attack that was multi-wave, multi-site, and lethal. These issues are covered in 

the document. With respect to the potential impact, the World Health Organization (WHO) and 

many others have attempted to model what it would mean if the US was attacked with anthrax, 

and they have concluded that anthrax is just as destructive when it is weaponized as a nuclear 

bomb. There exists threat, vulnerability, and impact. Dr. Zink requested that the ACIP 

members review and critique the document. The threat is real and is continuing. The US is 

vulnerable and the risk-to-benefit ratio is not known. The numerator may be of an uncertain 

value, but it is certainly not zero. Therefore, he beseeched the ACIP not to dismiss this issue 

simply because a number could not be put to the risk. The last thing that should be done in this 

war on terrorism is to identify those who are vulnerable. By using language to recommend who 

Public Comments Day 1
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120

should and should not be vaccinated, ACIP will be putting a target on the back of those who 

they do not think should routinely be vaccinated. Instead, he implored ACIP members as much 

as he admired them, to develop a very simple statement that basically reads, “Voluntary 

vaccination against anthrax is an appropriate consideration for any civilian who assesses, with 

the advice of their health care professional, a personal high risk of exposure to anthrax due to 

their occupation, place of business, method of commute, location of domicile, or choice of 

recreation.” The key points were that it is voluntary, it is a consideration, it is not a mandate to 

vaccinate, it is based on the advice of personal health care professionals, it is in the confines of 

a patient-physician relationship, it is high risk, and it addresses personal choices and the 

repercussions of those. 

Bill Brandis 

Retired Fire Chief of St. Louis County, Missouri

Bill Brandis asked the ACIP in June 2008 to consider allowing first responders who are 

responding to white powder calls to have the vaccine available on a voluntary basis if they so 

desire to make use of it. At the time of this October 2008 ACIP meeting, over 30 cities in 9 

states and DC have been in touch with the St. Louis and Kansas City Federal Bureau of 

Investigation (FBI) offices to report white powder incidents. He appreciated the time that ACIP 

had taken to listening to responders. He had the pleasure of leading the men and women into 

these calls, and was happy to say that he brought them all home safely. He still feels they need 

to be protected by giving them a voluntary option to be vaccinated.

Dr. Tom Waytes

Vice President of Medical Affairs

Emergent BioSolutions 

Dr. Waytes thanked Dr. Wright and her work group for the incredible amount of work they put 

into this effort over the past year. In reviewing the draft recommendations, he tried to put 

himself in the place of someone who might believe that because of their occupation they might 

be at increased risk of exposure to anthrax spores released in a bioterrorism event. If that were 

the case, he would like to know that ACIP considered at least two key issues before making a 

decision regarding whether one should have access to the vaccine pre-exposure. One of the 

issues pertains to the fact that this is not a natural disease. The intentional release of anthrax is 

a totally unpredictable human event. Trying to assess a risk for a particular group can be very 

difficult. Even if a risk is assessed, it could change rapidly. For example, someone working at a 

postal sorting machine in Detroit may suddenly learn that anthrax-laden letters were released in 

Cleveland or Chicago and that person’s perception of risk would change very quickly. 

Therefore, he expressed hope that there would be a provision in the recommendation for local 

risk assessment. In addition, a person at occupational risk may not feel comfortable that postexposure prophylaxis would give them all the protection needed. For example, if a strain of 

anthrax was used that was resistant to antibiotics, a post-exposure program may not work at all. 

If a recognition of a release occurred much later than when the release and exposure took 

place, that could render post-exposure prophylaxis less effective. With that in mind, he 

encouraged the ACIP membership to consider including permissive language in their 

recommendation so that persons who, with the concurrence of their occupational health clinics, 

could make the determination that perhaps they may benefit on pre-exposure use of the 

vaccine, and that the language not impede them from doing so.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

121

 

Dr. Stanley Plotkin

sanofi pasteur

Dr. Plotkin noted that the ACIP received an email from Dr. Meryl Nass and that he wanted to 

speak to the accusations in that email, first regarding the fact that the vaccine is different. The 

vaccine is different in two respects. The organism producing the PA is different and the first 

vaccine was alum-precipitate and current vaccine is alum-absorbed. However, the active 

principle remains the protective antigen, so to say that the vaccines are different requires a lot of 

interpretation. Second, it was said in the email that the schedule was not respected. In fact, all 

of the vaccinees received the 0-week, 2-week, 4-week, 6-month, and annual schedule, so the 

schedule was respected. Third, it was said that safety was not reviewed after 48 hours. 

However, the first author of the study, Dr. Brachman, saw the patients at each dose (e.g., 0-

week, 2-week, 4-week, 6-month, and annually) and nurses were in touch with the patients as 

well. No serious complaints were lodged. With regard to efficacy, it has been emphasized that 

the active principle is the protective antigen. The protective antigen has been shown in tests in 

rabbits and monkeys to protect against aerosol disease. Obviously, the only human data are 

from the original study in which two cases of inhalation anthrax were placebo patients, three 

were unvaccinated, and there were no cases in the vaccinated group. The animal data are 

clearly supportive, and a new human study is ethically impossible. Finally, Dr. Plotkin noted that 

it was said that he has a conflict of interest as Chairman of the Data Safety Monitoring Board 

(DSMB), apparently because he knows too much about anthrax. Be that as it may, the 

committee was composed of people other than himself, all of whom reviewed the data. 

Therefore, he did not believe that the results of the DSMB were in any way biased.

Thursday, October 23 

CDC / CCID / NCIRD

Dr. Schuchat reminded everyone that the next national immunization conference would be 

convened in Dallas, Texas from March 30 to April 2, 2009. The abstract deadline for that 

meeting is November 14, 2008. With respect to vaccine acceptance, an update was presented 

during the June 2008 ACIP meeting regarding the measles situation. Subsequent to that 

meeting, CDC published an MMWR in August 2008. Toddler immunization coverage was 

reported in the September 4, 2008 MMWR, which showed sustained high levels of immunization 

in that age group. Less than 1% of children had received no vaccine by the 19- to 35-month 

survey. CDC continues to focus upon promoting vaccine acceptance, with one of the areas of 

effort pertaining to communication and developing better, more flexible, and appropriate 

communication tools. CDC has a communication toolkit mapped out and new materials should 

become available over the next several months. Rather than engaging in a major launch when 

the entire package is ready, the information will be posted on the CDC website as it becomes 

available. The idea is to address parental needs with formats that are more user-friendly and to 

serve those who require various amounts of information.

Agency Updates
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

122

Center for Medicare and Medicaid Services (CMS)

CAPT Linda Murphy reported that as of October 20, 2008, she now has a site on CMS’s 

website. The site has been revised, but is not easy to find. The short way to locate it is to go to 

www.cms.hhs.gov, type VFC into the search box. Or select the link to 

www.cms.hhs.gov/MedicaidSCHIPQualPrac/Downloads/VFC_RMR.pdf - 2008-10-20. This 

document lists regional administrative fees from lowest to highest in terms of the maximums 

they could be and what they currently are to the best of CAPT Murphy’s knowledge. She 

indicated that anyone with questions should feel free to contact her. Dr. Pickering requested 

that CAPT Murphy provide the link to him and he would facilitate its distribution to all the 

members and liaison groups. 

Department of Defense (DoD)

Given that the group had already heard extensively about anthrax and Japanese Encephalitis 

vaccines, two vaccines of particular interest to the military, Col Ted Cieslak said he would not 

belabor them further. The DoD is in the late stages of development of a bivalent adenovirus 

types 4 and 7 vaccine. However, they are re-thinking some issues regarding that vaccine in 

light of the recent outbreaks of adenovirus type 14 disease to determine whether that vaccine 

provides any protection, or whether it needs to be reengineered to include adenovirus 14. Thus, 

the ACIP would be hearing more about that during future meetings. The DoD is also making 

progress on Chikungunya vaccine, which he expected the ACIP to hear about in the mid-term 

future. 

Department of Veterans Affairs (DVA)

Nothing to update.

Food and Drug Administration (FDA) 

Dr. Norman Baylor reported that the FDA convened a Vaccines-Related Biological Products 

Advisory Committee to discuss the use of Madin-Darby canine kidney cells for production of live 

attenuated influenza vaccine, a cell line which is potentially tumorgenic. The focus of the 

meeting was to begin clinical trials with the vaccine made in those cell lines. The FDA is in the 

process of reviewing the outcome of that meeting. The vote was split, with a majority voting to 

proceed with clinical trials. In addition, the FDA recently published a global guidance document 

on global vaccines, which represents the first step in developing recommendations for sponsors 

to guide them in how FDA will license vaccines that are not for diseases endemic in the US. 

The equivalent in Europe is Article 58, which allows the Europeans to evaluate vaccines that are 

not developed for their country. Dr. Baylor also reported that a workshop pertaining to 

adjuvants would be convened December 2-3, 2008 in Bethesda, Maryland. This workshop is 

co-sponsored by CBER / FDA and NIAID / NIH. Its purpose is to: 1) assess the scientific 

knowledge base regarding vaccine adjuvants; 2) identify gaps in knowledge and the ability to 

evaluate vaccine adjuvants and adjuvanted vaccines; and 3) facilitate the implementation of a 

global research agenda to address the identified gaps and improve the safety and efficacy 

assessments of adjuvanted vaccines for the treatment and prevention of infectious disease. 

With respect to the FDA’s consideration of changing or eliminating the pregnancy category, Dr. 

Baylor indicated that they are trying to eliminate the cumbersome categories of C8 P and C and 

D from the regulations, given that the current regulations are very complicated. While this has 

not yet been finalized, it is moving in that direction. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Health Resources and Services Administration (HRSA)

Dr. Geoffrey Evans noted that October 2008 marked the 20th anniversary of HRSA, which 

began in 1988. HRSA anticipates having a press release soon that details some of its important 

milestones, which he plans to distribute to the ACIP members. With regard to the status of the 

autism hearing, HRSA still expects decisions in the theory one hearings, which were held in 

2007. In a status conference a couple of weeks earlier, the court indicated that they would not 

be making a decision any earlier than November 7, 2008. Dr. Evans anticipates that it will 

probably be December or even later. The court is getting close to issuing decisions for general 

causation, as well as the three test cases for the combined theory, which is predominately 

related to the MMR vaccine Only Theory. In May and July 2008, the court heard both general 

causation and test cases for the Thimerosal-Only Theory. Dr. Evans said that he conservatively 

expected that the results of this would not be out until late 2009 or 2010. There was going to be 

a third theory, both general causation and test cases, scheduled in September 2008. However, 

this was cancelled by the court after the petitioners indicated that they did not intend to provide 

any new evidence and would rely solely on the evidence from the theory one hearings. There 

does not now appear to be a theory three; however, the court noted in its website posting dated

September 29, 2008, that if in the future the petitioners were to approach the court with a third 

theory that is significantly different from the first two theories, the court will consider best way to 

evaluate such a theory. Some are speculating that mitochondrial disorders might be the third 

theory. Whether the court will agree to an omnibus hearing format or will simply conduct 

individual hearings and cases is unknown.

On October 9, 2008 the Department published an Interim Final Rule which removed the 

category of vaccines containing live or rhesus-based rotavirus vaccine, with the associated 

injury of intussusception. This change is actually technical in nature. Dr. Evans reminded 

everyone that the Vaccine Injury Table includes a list of injuries and conditions, and prescribed 

time frames, that allow a legal presumption of vaccine causation. The Secretary has the 

authority to modify the Table, but does so after a Notice of Proposed Rule Making, a six-month 

public comment period, including a public hearing, and publication of the Final Rule detailing the 

changes. When a new vaccine or new injury is added, there are eight years of retroactive 

coverage and two years in which to file claims that date back that far. Rotavirus was licensed in 

1998 and the excise tax was imposed in July 1999. Also in 1999, the ACIP withdrew the 

rotavirus vaccine recommendation. Based on the evidence leading to that decision, in 2002 the 

Secretary added a second category box to the Table. The original category in July 1999 was 

the general category of rotavirus vaccines. A more specific, oral rhesus-based vaccine category 

was added in 2002, with the associated injury, intussusception. That provided petitioners the 

legal presumption for those cases. The program received about three dozen RotaShield® 

claims, the last of which was filed in 2004. Given that the vaccine is no longer being 

administered and the statute of limitations of three years for an injury has expired, the Secretary 

believes no more claims can be pursued. Due to the potential for confusion, the secondary 

category has now been removed. This is published as an Interim Final Rule, the comments for 

which must be submitted by November 10, 2008. The general category of rotavirus remains 

with no medical condition or injury specified. Anyone filing a claim for an injury thought to be 

rotavirus vaccine-related, would need to prove causation. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Dr. Evans also announced that in September 2008, HRSA awarded a contract to the Institute of 

Medicine (IOM) to study adverse events associated with certain childhood vaccines. Part of the 

legislation that created the program mandated IOM studies, which were published in 1991 and 

1994, which were the basis for Table modifications by the Secretary in 1995 and 1997. This 

$1.7 million contract calls for the IOM to conduct a similar evaluation, for which HRSA expects 

the IOM to issue a consensus report in approximately two years. The vaccines under study 

include varicella, both influenza vaccines, hepatitis B, and HPV. The decisions regarding which 

vaccines to study were based primarily upon programmatic needs, but other factors were 

considered as well (e.g., the number of vaccines distributed, public and media interest in 

vaccine safety, et cetera). The IOM plans to convene public meetings with invited speakers, 

with opportunities for the public to provide input. Once the report is published, the Department 

will consider findings in consultation with the Advisory Commission on Childhood Vaccines 

(ACCV), and may choose to develop proposals to modify the Table once again. 

Indian Health Services (IHS) 

Ms. Amy Groom reported that the HHS has launched an initiative to promote influenza 

vaccination among healthcare personnel. As part of that initiative, IHS has launched their own 

plan and will be promoting the vaccination of IHS healthcare personnel as well as tracking and 

reporting that for all of its sites. In addition, she thanked the ACIP for the revisions to the 

pneumococcal polysaccharide vaccine language. IHS is very pleased with that and appreciates 

the ACIP’s support of that issue.

National Institutes of Health (NIH)

Ms. Carolyn Deal called the group’s attention to an NIH funding opportunity announcement 

(FOA) posted on August 28, 2008, the title of which is “Research to Advance Vaccine Safety.” 

The two funding mechanisms for this FOA are PA 08-256 (RO1) and PA 08-257 (R21). The 

purpose of this FOA is to encourage Research Project Grant (R01) applications from 

institutions / organizations that propose to support research that will contribute to the overall 

understanding of vaccine safety. This R01 research opportunity invites studies that address 

scientific areas potentially relevant to vaccine safety such as: 1) physiological and 

immunological responses to vaccines and vaccine components; 2) how genetic variations 

affect immune / physiological responses that may impact vaccine safety; 3) identification of 

risk factors and biological markers that may be used to assess whether there is a relationship 

between certain diseases or disorders and licensed vaccines; or 4) the application of 

genomic / molecular technologies to improve knowledge of vaccine safety. Further 

information may be located at: http://grants.nih.gov/grants/guide/pa-files/PA-08-256.html.

National Vaccine Program Office (NVPO)

Dr. Dan Salmon provided a general update on the status of the national vaccine plan, reporting 

that the HHS plans to submit a draft Strategic National Vaccine Plan to the IOM in midNovember 2008. The IOM has scheduled four stakeholder meetings, the first of which is 

December 1, 2008 in Irvine, California. This stakeholder meeting will focus on vaccine research 

and development. Subsequent meetings will be convened on February 2, April 14, and June 4, 

2009. The IOM will develop a final report of its recommendations around the end of 2009. The 

NVPO and other HHS agencies, departments, and the NVAC will define a process to obtain 

additional input from expert stakeholders, including ACIP members, on the draft plan. Input will 

also be solicited regarding how to develop measurable milestones. This process will occur in 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

125

2009. Four public engagement meetings will be convened pertaining to the draft plan between 

January and March 2009, with the final plan anticipated to be complete in early 2010.

HHS is engaged in efforts to improve vaccination rates among health care providers, with the 

goal of reaching the Healthy People 2010 objectives of 60% vaccination coverage. In 2007, the 

vaccination rate of healthcare providers was less than 50%. The intent is to achieve the Healthy 

People 2010 objective by partnering with other organizations to promote influenza vaccination. 

HHS has designed a toolkit to provide resources for healthcare organizations, healthcare 

professional schools, professional health associations, and healthcare provider leaders to gain 

information about influenza and to share it with their colleagues and employees. The toolkit is 

comprised of links to several websites and a presentation, journal article, fact sheets, posters to 

be used for promotion and education, and materials regarding influenza vaccination. The 

internet links were all chosen for their proven success in prevention and education about 

influenza vaccination. HHS has other activities developed with respect to the goal of improving 

immunization rates among healthcare providers, which includes development of an article 

highlighting the problem for professional organization newsletters and / or journals. An initiative

was announced by Dr. Wright, the Principal Deputy Assistant Secretary for Health, at his 

keynote address at the 2008 National Influenza Vaccine Summit meeting. With CDC, there has 

been documentation of low vaccination rates among long-term care staff and unknown rates 

among healthcare students, with a focus on groups for 2008’s initiative. A teleconference was 

held with Dr. Wright and healthcare professional unions, long-term care associations, and 

healthcare professional schools and students. Of the 80 groups invited, 28 attended. NVPO, 

with CDC, will conduct a survey in October 2008 of medical, osteopathic, and nursing colleges 

pertaining to immunization policies. There has been a first-time effort with NIH clinical centers 

and the Indian Health Service to measure and report influenza and immunization rates for their 

healthcare personnel using electronic records.

National Vaccine Advisory Committee (NVAC)

Dr. Gus Birkhead briefly summarized what occurred during the September 2008 NVAC meeting 

with respect to three working group reports. He first noted that NVAC is moving toward not only 

issuing reports, but also tracking implementation of them. The Adolescent Working Group 

completed its work and presented its final report. NVAC hopes to keep the Adolescent Working 

Group functional, at least in terms of helping to track the implementation. The Immunization 

Information System Working Group also submitted its final report, which NVAC will be tracking 

in terms of implementation. The Adult Working Group reviewed HHS adult immunizations 

programs (e.g., CDC, Indian Health Service, HRSA, Medicaid) to identify potential issues to 

explore, and will expand to more broadly consider adult immunization issues. 

The Vaccine Finance Work Group is an effort at NVAC to reach consensus among a variety of 

medical, insurer, employer, and consumer groups. This group voted on final recommendations 

to the Assistant Secretary during its September 2008 meeting. The goal was to ensure 

universal access to all vaccines recommended by the ACIP for children and adolescents without 

financial barriers. The recommendations reflect some of the compromises necessary when 

working on a consensus basis with these types of policy recommendations. The Vaccine 

Finance Work Group developed recommendations in the following areas:

1. Use VFC vaccine for underinsured children and adolescents in public health clinics

2. Cover vaccine administration in VFC for all eligible children and adolescents, not only 

Medicaid children who are VFC-eligible, but also the other categories of other VFCeligible children for whom there is currently no vaccine administration fee available
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

126

3. Improve Medicaid reimbursement for vaccine administration

4. Improve business practices in private provider offices 

5. Reduce financial barriers to vaccinate the privately insured

6. Activities of federal agencies

7. Activities of state agencies

8. Vaccination in complementary venues, particularly in schools, ensuring that there is 

adequate funding through 317 and other mechanisms to cover the cost of school-based, 

mandated vaccines, and through promotion of shared public and private approaches to 

help fund such efforts 

With regard to the insurance arena, the Vaccine Finance Work Group considered barriers to 

vaccination among privately insured children. One recommendation pertaining to this issue was 

that public and private health insurance plans should voluntarily provide first-dollar coverage; 

that is, there should be no deductibles and co-pays for any ACIP recommended vaccines. 

Other recommendations pertaining to this issue involve educating insurers and employers about 

the value of immunization and the need for first-dollar coverage. In the past, there have been 

recommendations for mandating insurance coverage. Due to the consensus nature of the 

working group, that recommendation was not re-endorsed by NVAC. The plan is to work with 

the industry in a voluntary manner to attempt to improve coverage under private insurance 

plans, including those ERISA-exempt plans that are not regulated by states. In terms of 

recommendations for federal agencies, one of the conclusions was that delays in official 

publication of ACIP statements are one of the causes of delayed coverage by insurance, so 

there was a recommendation that CDC should substantially decrease the time to official 

publication of ACIP recommendations to expedite coverage decisions.

In conclusion, Dr. Birkhead noted that the full set of NVAC recommendations was in the process 

of being submitted to the Assistant Secretary of Health and will be posted on the NVAC website 

when that process is complete. 

Discussion

Dr. Pickering acknowledged that there is a delay in time from approval by ACIP and the 

publication of MMWR recommendations. However, there is an extensive clearance process

through which all recommendations must proceed. There is an effort underway to shorten the 

process as much as possible. For example, provisional recommendations go through clearance 

and are published on the ACIP website within two weeks of the ACIP meeting. While they will 

continue to try to shorten the timeframe, there are some obstacles that ACIP simply cannot 

reduce any further.

Dr. Temte indicated that, as soon as recommendations are posted on the ACIP website, the 

American Academy of Family Physicians (AAFP) begins using them to generate policy for the 

AAFP in an effort to move recommendations forward more rapidly. 

An inquiry was posed regarding whether there was any special funding to accompany the NIH 

“Research to Advance Vaccine Safety” FOA. Ms. Deal responded that this FOA was intended 

to encourage research in a particular area that would fall in normal RO1 and R21 funding 

opportunities. At this time, there are no special funds to accompany these announcements.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

127

Delayed and Diminished Rotavirus Activity after the 

Introduction of Rotavirus Vaccine in the United States

Umesh D. Parashar, MD, MBBS

Division of Viral Diseases

National Center for Immunization and Respiratory Diseases

Dr. Parashar reported on behalf of Dr. Jacqueline Tate (CDC / CCID / NCIRD) who was unable 

to attend this ACIP meeting, given that she was deployed on an epidemic investigation.

Dr. Parashar reminded everyone that the ACIP had recommended two vaccines for rotavirus 

over the past two years. In February 2006, the first vaccine, RotaTeq®, was licensed. That 

same month, the committee recommended routine use in US infants. In April 2008, Rotarix®, 

the second vaccine, was licensed. During the June 2008 ACIP meeting, Rotarix® was also 

recommended for routine use in US infants. The use of Rotarix® is just beginning nationally, so 

much of the data presented during the October 2008 ACIP meeting related to the impact of 

RotaTeq® vaccination, which is the more mature program.

Limited data were shown on vaccine uptake and coverage. Dr. Parashar explained that timely 

data are not yet available from the National Immunization Survey on Rotavirus Vaccine 

Coverage, but there are data available from a sentinel registry platform that CDC operates, 

which includes data from six sites for the period of the third quarter of 2006 through the fourth 

quarter of 2007. For those sites, Dr. Parashar showed quarterly levels of vaccine coverage, 

with the first dose of RotaTeq® vaccine in infants who were three months old in these registries 

at that time. While the trend is relatively consistent across the six sites, there are some 

variations. By the end of 2007, 50% to 60% of infants who were three months old in these 

sentinel sites received the first dose. Thus, vaccination uptake is increasing. The date from the 

first and second quarter of 2008 suggest that uptake has increased further to approximately 

70% to 80%. Therefore, uptake is maturing and appears to be reaching the levels of uptake 

observed for other vaccines such as pneumococcal and varicella.

Dr. Parashar described data from a national laboratory surveillance program that CDC operates, 

the National Respiratory and Enteric Virus Surveillance System (NREVSS). NREVSS is a 

passive, voluntary laboratory reporting system. Approximately 60 laboratories located 

throughout the US have participated in this program over the past eight years: 

Rotavirus Vaccines
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

128

These laboratories report aggregate data to CDC on a weekly basis regarding the number of 

specimens tested for rotavirus and the number that are positive. This is a very simple 

surveillance system that is not arduous for the laboratories, which send CDC a simple form that 

basically states, “This week we ran X tests for rotavirus and X were positive.” This has been a 

very useful system for many reasons, including documentation of the unique spatial-temporal 

pattern of rotavirus activity in the US. Looking at the following map, a very consistent pattern of 

disease activity is observed each year: 

Rotavirus Seasonality

Nov Dec Jan Feb Mar Apr May

Disease activity first begins in the southwest in November and December, and has shifted more 

recently to January and February. However, it takes a two- to three-month period before activity 

begins to occur and peak in the northeast. Although there are some hypotheses, the reason for 

this phenomenon remains unknown. 

With regard to the methods for this presentation, data were compared for 2007-2008 season 

with 2000-2006 seasons. Timing of the season was taken into consideration for defining the 

start of season. Investigators used the first of two consecutive weeks when the proportion of 

positive tests in the system was more than 10% through all of the laboratories. The peak of the 

season was defined as the week with the highest proportion of tests that were positive. The end 

of the season was defined as the last of two consecutive weeks when the median proportion fell 

below 10% positivity. Absolute trends in rotavirus testing and detection were also examined; 

that is, the number of tests conducted and the number of tests that were positive. To avoid any 

biases from reporting, this analysis was restricted to a subset of laboratories (e.g., 

approximately 33 that reported data consistently). The number of rotavirus tests and the 

number of positive tests in the current season were compared with the pre-vaccine seasons 

from 2000 to 2006. Both the median and minimum were compared.

When the proportion of rotavirus positive tests from 2000-2006 were compared to those during 

2007-2008 by week of year, around December or January the proportion rises above the 10% 

cutoff for the start of the season. Observed in the pre-vaccine era was that the season started 

in approximately December or January and peaked some time in mid-March. During the peak 

of the season, approximately 40% of tests were reported as positive. The season typically 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

129

ended by the end of June to early July. The season onset was delayed for the current season 

that recently ended. Therefore, the 10% threshold was not reached until almost March, which 

was a delay of 12 to 15 weeks from the typical timeline. At the peak, which was also delayed 

compared to the pre-vaccine peak, the overall percent positive only reached 16% to 17%. The 

season ended at a fairly typical time consistent with the pre-vaccine era. With delayed onset, 

there was a lower magnitude of activity, and because the season ended at the same time as 

previously, the last season turned out to be shorter.

With respect to the absolute trends based on the number of tests done and the number positive 

from the subset of consistent labs from each year from 2000 to 2008, there were pre-vaccine 

winter peaks. In the current season, the pattern of testing was somewhat broadened, so there 

was a much longer period over which the tests were performed. The total number of tests for 

rotavirus was higher, and even though the peak appeared to be lower, it was a broader peak. 

That is, the number of tests increased 11%, but the number of tests that were rotavirus-positive 

in these laboratories declined by 67% compared with the median during the pre-vaccine era:

There was a consistent pattern of reduction observed in the examination of data from all 

laboratories individually. Thus, this was not driven by one or two large laboratories that 

experienced a reduction. For each laboratory, the following graphic represents the reduction in 

percent positivity. If a laboratory had a reduction from 50% positive in the pre-vaccine era to 

25% currently, that represents a reduction of 50%. The reductions are tremendous, with almost 

16 of the 33 laboratories experiencing a reduction of more than 75% compared to the prevaccine era in the proportion of tests that were positive. Only one laboratory experienced an 

increased proportion of positivity and one had a smaller reduction, but most of the reductions 

were consistent and large in magnitude in proportion of tests positive.

With respect to the limitations of these data, reporting to NREVSS is voluntary and rotavirus 

testing is not part of standard clinical practice, so it is not clear who gets tested and who does 

not. Patient-level information is not available, so there is a potential for double-counting patients. 

With respect to aggregate data, there is no information on the age of patients.

In conclusion, Dr. Parashar summarized that compared to the 2000-2006 seasons, the 2007-

2008 season was delayed by a median of 15 weeks, was diminished in magnitude with peak 

proportion positive 57% lower, and was shorter by a median of 12 weeks. Overall, there was an 

11% increase in the total number of tests performed, but a 67% decrease in the number of 

positive specimens detected.

Effectiveness of Pentavalent Rotavirus 

Vaccine in United States Clinical Practice

Julie A. Boom, MD, Director

Infant and Childhood Immunization

Center for Vaccine Awareness & Research

Texas Children’s Hospital

Dr. Boom presented on research that resulted from a grant from CDC that was awarded to the 

City of Houston and subsequently to the Texas Children’s Hospital (TCH). She expressed 

gratitude for the opportunity to work with CDC colleagues Drs. Jacqueline Tate, Manish Patel, 

and Umesh Parashar who made this project possible. She also indicated that this group had no 

disclosures to report. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

130

TCH’s project had three primary objectives, which were to: 1) determine rotavirus prevalence in 

children 15 days through 23 months of age with acute gastroenteritis (AGE) who presented to 

Texas Children’s Hospital (TCH) emergency department; 2) assess the pentavalent rotavirus

vaccine effectiveness (VE) in this study population; and 3) evaluate the feasibility of using an 

immunization registry to determine VE. TCH is in a unique position to do this, given that its 

emergency department sees 80,000 and admits over 14,000 patients per year. In addition, the 

hospital has played a key role in the development and implementation of the local immunization 

registry for Houston and Harris County. Currently, approximately 84% of children about four 

months to six years of age have two or more immunizations in that registry, although it is not yet 

one of CDC’s sentinel sites. In addition, faculty (including Drs. Boom, Amy Middleman, Carol 

Baker, and C. Mary Healy) have gathered to form the Center for Vaccine Awareness and 

Research at this hospital. That initiative has made projects like this possible.

From February through June 2008, active rotavirus disease surveillance was conducted among 

emergency room patients and inpatients at TCH. Children were enrolled using convenience 

sampling during busy evening and weekend hours. The emergency room triage log was used 

to identify any child with a chief complaint of vomiting, diarrhea, or fever. These children were 

then approached and assessed for eligibility. Children 15 days through 23 months of age with 

symptoms of diarrhea and / or vomiting were offered participation and consented for enrollment. 

Diarrhea was defined as the occurrence of three or more loose stools in a 24 hour period, while 

vomiting was defined as one or more episodes within a 24 hour period. Patients with symptoms 

for 11 or more days were ineligible for participation. In addition, patients who were 

immunocompromised, who did not reside within the Greater Houston area, or whose parents did 

not speak either English or Spanish were excluded from participation.

Parents were asked questions assessing demographics, symptoms, duration, and severity of 

illness. If the child produced a dirty diaper during their stay in the emergency room, fecal 

specimens were tested using an EIA (Premier Rotaclone®). If the quantity was sufficient, 

remaining fecal specimens were sent to CDC for confirmatory testing and strain typing. For all 

case and control patients, parents were asked for a copy of the child’s immunization records at 

the time of enrollment. Records were also requested for up to three immunization providers. 

The investigators then searched the Houston-Harris County Immunization Registry (HHCIR) for 

any vaccine information for those patients. A second registry query was conducted after study 

conclusion to capture immunization information for children whose records were entered after 

enrollment. Analyses were performed using SAS statistical software version 9.1. For casepatients and rotavirus-negative AGE and ARI controls, a dose of vaccine was counted if it had 

been administered at least 14 days prior to presentation. Patients for whom an immunization 

record could not be obtained were excluded from analysis. Unconditional logistic regression 

controlling was used for the age at presentation and the month and year of birth to calculate an 

adjusted odds ratio of vaccination by dose (versus no vaccination). Analysis using HHCIR as 

the source of control data only assessed the effectiveness of a full series of RV5. For controls 

enrolled from the HHCIR, a dose of vaccine was counted if it had been administered at least 14 

days prior to the date when the control patient was the same age as the matched case-patient. 

Conditional logistic regression was used to calculate the odds ratio of vaccination by dose 

(versus no vaccination). For both analyses, vaccine effectiveness by dose was calculated as (1 

- odds ratio of vaccination) × 100%.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

131

The case population was compared to three control groups. The first group consisted of 

rotavirus negative patients. All children who were identified as part of AGE surveillance and 

enrolled whose fecal specimen tested negative for rotavirus disease served as the first control 

group. As a second control group, children 15 days through 23 months of age with acute 

respiratory infection (ARI) symptoms but who did not meet AGE case inclusion criteria were 

offered participation and consented for enrollment. These patients were selected as they 

represented a ready population of otherwise healthy children who also presented to the TCH 

emergency room. Similarly to case patients, ARI patients who were immunocompromised, did 

not reside within the Greater Houston area, or whose parents did not speak either English or 

Spanish were excluded from participation. Age-matched children selected from HHCIR 

comprised the third control group. HHCIR is a local, comprehensive repository of immunization 

data for children and includes immunizations administered by both pubic and private providers. 

Although HHCIR is not a population-based registry, data for 84% of all children ages 4 months 

to 6 years residing the in Greater Houston area are located in the immunization registry. In 

early 2008, 62% of public and 51% of private providers reported immunizations administered to 

HHCIR.

Regarding the results of the surveillance efforts, 608 children were approached by using the 

emergency room triage log, and 400 (66%) were eligible and enrolled. The most common 

reason for non-enrollment was that the parent declined. Of enrollees, 57% (n=228) were male 

and 69% (n=277) were Hispanic. 205 (51%) had fecal specimens obtained for testing, and 90 

(44%) children with fecal specimens tested positive for rotavirus. Compared to rotavirus 

negative and ARI control patients, rotavirus positive children were older at the time of enrollment 

(median age of 17 months compared to 10 months and 8 months respectively, p<0.001). 

Rotavirus positive patients were more likely to have prior treatment for fever or oral treatment for 

dehydration (all p values <0.05); they were more likely to be described by their parents as 

sleepy and less playful (all p<0.01); and were more likely to have vomiting at presentation 

(p<0.0001). The parents of rotavirus negative patients were more likely to report that their 

children had normal behavior during the illness (p<0.0001). There were no differences between 

the groups with regard to gender, ethnicity, prevalence of diarrhea, or the need for inpatient 

admission. With regard to rotavirus prevalence with age, patients testing positive for rotavirus 

increased with increasing age.

With respect to strain data identified to date, approximately 50% of the group had strains for 

G3P8; 25% for G1P8; 11% had mixed-strain typing (G1,2,3,P[8]: 6%; G1,2P[8]: 2%; G1,3,4P: 

3%), and about 10% were untypable (GUP[8]: 8%; GUP[U]: 2%). 

Vaccine effectiveness was calculated using the formula (1 – odds ratio) x 100%. The ageadjusted vaccine effectiveness for a full three-dose series was 89% using RV negative controls, 

and 85% using ARI controls. Point estimates of vaccine effectiveness were calculated at 65% 

for children who had received one dose of vaccine, and 72-82% for children who had received 

two doses. Using data from the immunization registry, vaccine effectiveness was calculated at 

82% for a full three-dose series.

In conclusion, vaccine effectiveness for a three-dose series (85-89%) was similar to prelicensure estimates (86-96%). The immunization registry data proved to be an acceptable 

alternative for calculating VE. This study had several limitations: 1) the sample size was 

moderate; 2) data were collected from a single center; 3) there was enrollment of a large group 

of Hispanic patients, which could affect generalizability to other studies; and 4) patients were 

enrolled seven days a week, but coverage was not 24 hours a day.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

132

Despite these limitations, through review of hospital laboratory testing data it was confirmed that 

only 12 eligible patients with rotavirus diarrhea treated at the hospital were not enrolled during 

the study. Given that this was the first season to conduct surveillance at this site, investigators 

were unable to compare how the age-specific detection rates and overall number of rotavirus 

and AGE patients in 2008 compared with the epidemiology of disease in the pre-vaccine era. 

Regarding future studies, it is important to continue to monitor vaccine effectiveness because 

there will now be a monovalent and a pentavalent vaccine in use in the community. Individuals 

also may receive a combination of these products. As vaccinated children become older, it will 

become important to monitor the duration of their protection. Also, given the constant evolution 

of rotavirus genotypes, it will be important to monitor protection against various strains and 

changes in strains as a result of vaccine selection pressure.

Reduction in New York Hospitalizations for Diarrhea and Rotavirus

Dr. Hwa-Gan Chang

New York State Department of Health

Dr. Chang expressed her gratitude for the opportunity to present this study, and acknowledged 

her colleagues from the New York State Department of Health and CDC. She offered special 

thanks CDC for the grant that provided the opportunity to conduct this study.

Rotavirus is estimated to cause approximately 55,000 to 70,000 hospitalizations per year 

among children less than five years of age in the United States. Rotavirus is not reportable in 

most states, and testing for rotavirus infection is not always performed when a child seeks 

medical care for acute gastroenteritis. In New York, all general acute care hospitals are 

required to submit inpatient data to the Statewide Planning and Research Cooperative System 

(SPARCS). This provides the capability to track trends in diarrhea and rotavirus-associated 

hospitalizations. Because not all hospitals routinely test for rotavirus, sentinel hospitals with 

sufficient admissions and testing were selected to monitor trends. 

The study population included children one month to 18 years of age with a focus on children 

under three years of age who were hospitalized with ICD-9-coded diarrhea and rotavirus in their 

primary or secondary discharge diagnoses from 2003 through 2008. Eleven hospitals that had 

averaged greater 50 diarrhea admissions per year, with at least 25% of those admissions with 

rotavirus-coded diagnoses from 2000 through 2004 for children less than five years of age, were 

selected as sentinel hospitals. These data were used to track trends in diarrhea and rotavirusassociated hospitalizations, rotavirus hospitalizations by age group, and costs of hospitalization 

for diarrhea and rotavirus. New York State also maintains an Electronic Clinical Laboratory 

Reporting System (ECLRS) that provides laboratories a mechanism to electronically submit 

laboratory test results to the NYSDOH for all reportable conditions. The eleven sentinel hospital 

laboratories were contacted to request submission of all their positive and negative rotavirus 

test results through ECLRS from January 2008, so rotavirus hospitalization trends can be 

verified.

Diarrhea and rotavirus admissions have had similar trends over time, with peaks during the 

winter months. The numbers of diarrhea and rotavirus-associated hospitalizations were 

substantially lower in 2008. There was a reduction of 56% for the number of diarrheaassociated hospitalizations in 2008 compared with 2003 to 2005, and rotavirus associated 

hospitalizations had an 85% reduction. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

133

With respect to the percent of rotavirus-associated hospitalizations among children one month 

to three years of age from 11 sentinel hospitals for January through June 2005 to 2008, it was 

demonstrated that in 2008, rotavirus activity peaked in April at 27%, compared with 2005 and 

2006 peaks in March at 56%. The number of rotavirus-associated hospitalizations decreased 

84% in 2008 when compared to 2005 to 2007. Regarding the percent of rotavirus-associated 

hospitalizations by age group in 11 sentinel hospitals, the percent reduction was 84% for ages 

12 to 35 months—the age group most likely to be immunized. However, there were also 

reductions in children aged 36 to 59 months (91%) and 60 months to 18 years (80%), 

suggesting possible herd immunity effects. 

In 2008, the total hospital cost for rotavirus at the 11 sentinel hospitals was approximately $1 

million from January through June. This cost was a significant reduction from the same period 

for the previous three years, during which the hospital costs were about $4 million each year. 

Costs for all hospitals demonstrate that diarrhea-associated hospitalization costs were over $68 

million for each year from 2005 to 2007, with a $22 million reduction in 2008. Overall costs for 

rotavirus-coded hospitalizations were reduced from over $15.2 million in 2005 to 2007 to $3.4 

million in 2008.

The investigators also compared trends in the rates of positivity for rotavirus test results 

between 11 sentinel hospitals and their associated labs for 2008 compared to hospital 

discharge data. A total of 555 patients aged < 3 years from 11 sentinel hospital laboratories

were tested for rotavirus between January 1 through July 31, 2008. Of these, 90 (16%) were 

positive for rotavirus. With regard to the percent of rotavirus tests that were positive in 2008, 

there were peaks in April (27%) and May (28%). The percent of diarrhea hospitalizations due 

to rotavirus from 11 sentinel hospitals in 2008 shows a similar pattern as the laboratory reports: 

Trends in percent positive rotavirus hospitalizations and 

lab tests for children <3 yrs for 11 sentinel hospitals and 

associated labs, New York, Jan – July, 2008

0

10

20

30

40

50

60

January February March April May June July

2008ECLRS 2008hospital 2005-07hospital

4% 6%

14%

27% 28%8

18% 12%

2005-2007 Hospital Data

2008 Hospital Data

Percent positive for rotavirus

Laboratories serving four sentinel hospitals provided the investigators with all rotavirus test 

results for 2005 through 2008. Data verify the results from the hospital discharge data that 

rotavirus activity has diminished, and the onset was delayed in 2008 when compared with 

previous years. In conclusion, a review of New York State hospitalization data for trends in 

diarrhea and rotavirus for January though June 2008 compared to the three previous years 

showed an apparent delay in rotavirus onset and peak activity. There was a significant 

reduction in hospitalizations and costs for diarrhea and rotavirus illnesses. Additionally, there 

were significant reductions in rotavirus hospitalizations among non-immunized older age 

groups, suggesting possible herd immunity from the recent introduction of the rotavirus vaccine. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

134

Discussion

Dr. Morse expressed excitement regarding this preliminary information, which is showing similar 

results in different parts of the country and which hopefully will continue. He inquired of Dr. 

Parashar what was occurring in other countries using the vaccine and those not using the 

vaccine.

Dr. Parashar replied that there are a few countries in Europe and Latin America using rotavirus 

vaccines as part of routine immunization. While data similar to that presented are not yet 

available from these countries on vaccine impact, work is being done with countries in Latin 

America to generate similar evidence and examine trends in disease and vaccine effectiveness 

in those settings. There is also interest in studying neighboring countries to the US, such as 

Canada, that are not using the vaccine, to examine trends this season to determine whether 

what is being observed in the US is truly different or just a random natural variation. It is very 

unlikely to be random natural variation, given that there are 15 years of pre-vaccine data that 

have not shown variation anything like this trend. 

Dr. Temte noted that they are observing the same trends in Wisconsin. Intrigued by the 11% 

increase in the samples being submitted, he wondered whether they were seeing an ecological 

replacement of rotavirus with norovirus.

Dr. Parashar cautioned against making too much of that. With NREVSS, upon which that data 

are based, it is unknown how testing patterns might change in laboratories. A few large 

laboratories could skew the data substantially. Probably more reliable are data from New York 

State in which diarrhea hospitalizations for all causes are counted. Those data show a 

reduction overall and not an increase. The investigators will continue to monitor this over time 

to determine whether there is a change in strains of rotavirus that might not be adequately 

protected from vaccination that might emerge, or potentially a replacement from any other 

etiologic agent of diarrhea that might fill the rotavirus niche. He said he would not use the 11% 

increase to imply a replacement, given that there are too many limitations with not knowing the 

testing patterns and reporting biases. The New York State and other data suggest there is an 

overall reduction in diarrhea events of all causes.

Dr. Englund congratulated CDC and the investigators for providing this rapid feedback. She 

thought the data should provide an incentive and reassurance to healthcare providers who, in 

some areas, are reluctant to implement new vaccines. Therefore, it is important to make this 

information public. Pediatricians have some worldwide responsibilities. While in the US 

hospitalizations are being prevented, in other countries mortality is of concern. Hence, these 

data will be of great interest to the entire international community.

Dr. Marcy agreed with respect to developing countries. He inquired as to whether investigators 

were examining two versus three or one versus two doses in South or Central America to 

determine the efficacy against severe, dehydrating diarrhea.

Dr. Parashar responded that they are involved in other similar studies in the US and outside the 

US. The only country currently using RotaTeq® routinely is Nicaragua, which introduced it a 

couple of years ago through a donation program from the manufacturer. The manufacturer is 

involved with partners in the country to determine vaccine effectiveness and impact. It is a very 

similar design, so there soon will be data regarding one- and two-dose effectiveness. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

135

With regard to the New York Studies, Dr. Judson asked whether the investigators were able to 

estimate whether rotavirus vaccine is cost-saving rather than just cost-effective.

Dr. Morse responded that a longer review would be required to determine the cost of vaccine as 

well as savings. Obviously, there is a tremendous amount of savings in hospitalization costs, 

but also important to examine are outpatient reductions, emergency room visits, et cetera. 

Dr. Neuzil responded to some of the comments about international studies, largely based on Dr. 

Parashar’s work. The WHO estimates there are more than half a million deaths per year from 

rotavirus, predominately in Africa and Asia. Through GAVI Funding, the Rotavirus Vaccine 

Program (a collaboration between the WHO, the USCDC, and PATH) is working with Merck and 

GSK to test these vaccines in impoverished populations in Asia and Africa. Dr. Neuzil said she 

was very happy to report that an interim analysis of the GSK vaccine in South Africa has shown 

83% efficacy against severe disease, comparable to what is observed in Latin America. This 

could translate to tremendous public health impact. She indicated that data from Malawi would 

be available the next week, while the data on the Merck vaccine would be available in 2009. 

There are very exciting results in the developing world.

Dr. Langley (Canadian National Advisory Committee on Immunization) indicated that Canada’s 

regulatory approvals for RotaTeq® and Rotarix® are later than in the US, so their statements 

are published later. Currently, their statement only encourages providers to offer the vaccine. 

There is no recommendation for a universal program because Canada’s illness data showed 

considerably less impact than in the US at the time they were making that decision. However, 

there is a system in place that goes back two to three years to study certain hospitals’ 

emergency room visits and hospitalizations. It is a point prevalence survey conducted during 

the winter months once the rotavirus season starts. These data should be available in 2008, at 

which time Dr. Langley offered to provide the information to ACIP.

Dr. Pickering noted that in Dr. Boom’s and others’ data, it was shown that vomiting without 

diarrhea can be a manifestation of rotavirus and that was one of the enrollment criteria. He 

inquired as to how many children Dr. Boom had with only vomiting, and from how many of those 

rotavirus was recovered. He also noted that in Dr. Parashar’s Texas Children’s data, 45% of 

the strain was G3. He wondered if that had been observed for the rest of the country, and if so, 

where it was encouraging, given that most of the strains in the vaccine studies were G1. 

Dr. Parashar responded that G3 accounts for about half of the strains in the Texas study. There 

will be more data, given that the strains from this season are still being characterized. One 

additional piece of data that this study will provide is effectiveness of the vaccine specifically 

against G3 strains. There were cases in the large trial of G3, but even in the one season of this 

one study, there were more cases in the whole of clinical trials, so this will provide additional 

evidence. Dr. Parashar requested that the representative who was present from their laboratory 

comment on their national strain surveillance system Dr Gentsch, head of the rotavirus 

laboratory at CDC, commented that although firm data were not yet available, G3 strains 

certainly appear to be more prevalent in the US this year than in the past few years. 

Dr. Boom replied that she would have to get back to Dr. Pickering on the exact number of 

children who had vomiting only. Interestingly during the emergency room stay, if children had 

vomiting only, during those few hours it was rare for the study team to be able to obtain stools 

from them for testing.

 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

136

Dr. John Iskander

Associate Director for Science

Immunization Safety Office

Dr. Iskander reported that Dr. Melinda Wharton assumed duties as Acting Director of the 

Immunization Safety Office effective October 14, 2008. Dr. Wharton brings extensive subject 

matter, programmatic, and leadership experience in the immunization arena and in vaccine 

safety specifically. She will lead the ISO transition to from CDC’s Office of the Director to the 

Division of Healthcare Quality Promotion (DHQP), National Center for Preparedness, Detection, 

and Control of Infectious Diseases (NCPDCID). This effort began on October 1, 2008. 

In addition, Dr. Iskander pointed out that there were several recent vaccine safety articles of 

cross-cutting interest. Two of these publications were included in the background materials 

provided to the committee:

 Chang S, Pool V, O'Connell K, et al. Preventable Mix-ups of Tuberculin and Vaccines: 

Reports to the US Vaccine and Drug Safety Reporting Systems. Drug Saf. 

2008;31(11):1027-33.

 Kohl KS, Magnus M, Ball R, et al. Applicability, reliability, sensitivity, and specificity of six 

Brighton Collaboration standardized case definitions for adverse events following 

immunization. Vaccine. 2008 Sep 19.

 Wood RA, Berger M, Dreskin SC, et al. An algorithm for treatment of patients with 

hypersensitivity reactions after vaccines. Pediatrics. 2008 Sep;122(3):e771-7.

Of special interest to CDC’s clinical partners and vaccine providers is the vaccine 

hypersensitivity management algorithm, developed by the Clinical Immunization Safety 

Assessment Network, or CISA. We look forward to its use and evaluation in practice settings:

Copyright ©2008 American Academy of Pediatrics

Wood, R. A. et al. Pediatrics 2008;122:e771-e777

FIGURE 1 An algorithm for the management of suspected allergic reactions to vaccines

 

Immunization Safety Office Update
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

137

Measles, Mumps, Rubella and Varicella 

(MMRV) Vaccine Safety Working Group Update

Jonathan Temte, MD, PhD, University of Wisconsin

Chair, MMRV ACIP Vaccine Safety Working Group 

Dr. Temte reported that the MMRV Vaccine Safety Working Group was formed following a 

discussion at the February 2008 ACIP meeting, during which preliminary data from the Vaccine 

Safety Datalink (VSD) Project and Merck-sponsored post-licensure studies were presented. The 

findings suggested an increased risk for febrile seizures during the first to second week 

following first-dose measles, mumps, rubella, and varicella (MMRV: ProQuad®) vaccine among 

children aged 12–23 months. During the February meeting, ACIP recommended removing the 

preference for MMRV vaccine over separate administration of MMR and varicella vaccines. The 

following recommendation was published in the MMWR in March 2008 [1CDC. Update: 

Recommendations from the Advisory Committee on Immunization Practices (ACIP) Regarding 

Administration of Combination MMRV Vaccine. MMWR. 57(10);258-260]:

"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)." 

With regard to the terms of reference for the working group, the CDC Immunization Safety 

Office (ISO) serves as the lead on a risk assessment that is in progress. The goal of the risk 

assessment is to evaluate the post-licensure safety data on the risk of febrile seizures after 

MMRV vaccine as compared to MMR plus Varicella vaccines, identify data gaps, and propose 

additional analyses or studies. The working group is also charged with reviewing encephalitis 

cases after the MMRV vaccine, and communicating vaccine safety findings related to MMRV 

vaccine with ACIP and the public in a clear and transparent manner. During this session, the 

focus was primarily on the first term of reference. 

The second term of reference is that of risk management, which will be under the lead of the 

CDC Division of Viral Diseases. The purpose of the risk management effort is to formulate 

policy options for use of the MMRV vaccine for ACIP, considering benefit of vaccination and

potential risks of vaccine adverse effects. An additional goal is to identify and reconcile 

potential inconsistencies in existing ACIP statements related to measles, mumps, rubella, 

varicella vaccination and febrile seizure prevention. This activity will begin in November 2008. 

Dr. Temte noted that MMRV vaccine is currently not being distributed due to issues unrelated to 

safety or efficacy.

The Working Group has had a time-intensive meeting schedule. Since June 2008, this working 

group has met a total 16 hours by phone or in person. Most time has been spent reviewing and 

interpreting data from the VSD and Merck studies of MMRV vaccine use and febrile seizure risk. 

The group has consulted with numerous experts in areas of epidemiology, virology, 

immunology, and vaccine safety. Through mutual agreement among work group members, 

Merck scientific staff and sponsored researchers have participated in some meetings regarding 

MMRV Vaccine Safety
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

138

discussion of VSD and Merck-sponsored study data interpretations. However, Merck did not 

participate in working group evidence synthesis or in any policy-related discussions.

This working group has also put a lot of effort in to developing an evidence framework to assess 

the risk of febrile seizures after the MMRV vaccine. This is based on the IOM, WHO, and draft 

ACIP Evidence-Based Working Group frameworks. The work group has synthesized the 

evidence for febrile seizure risk after MMRV vaccine, with a focus on dose one. In addition, the 

group has proposed suggestions for further analyses to enhance the strength of evidence 

related to risk for febrile seizures.

In conclusion, Dr. Temte acknowledged the considerable amount of effort the MMRV Vaccine 

Safety Work Group put forth for this discussion. 

Vaccine Safety Datalink Project: 

Review of MMRV and Febrile Seizures Study

Eric Weintraub, MPH

Immunization Safety Office, CDC

Presented on behalf of:

Nicola Klein, MD, PhD

Northern California Kaiser Permanente

for the VSD Investigators and MMRV RCA Team

Mr. Weintraub acknowledged that he was delivering this presentation on behalf of Dr. Nicola 

Klein from Northern California Kaiser Permanente and the Vaccine Safety Datalink (VSD) 

Project investigators and the MMRV Rapid Cycle Analysis Team. He reviewed preliminary 

results from the VSD study evaluating the risk for confirmed febrile seizures in children aged 12

to 23 months following receipt of MMRV dose one. These data were presented by Dr. Klein 

during the February 28, 2008 ACIP meeting. Additionally, he summarized preliminary data on 

the risk for febrile seizures in children aged 4 to 6 years of age at one VSD site. 

These data were derived from the VSD. As noted in an earlier presentation, the VSD is a

collaboration between CDC and 8 managed care organizations (i.e., Group Health Cooperative, 

Northwest Kaiser Permanente, Northern California Kaiser Permanente, Southern California

Kaiser Permanente, Kaiser Permanente Colorado, HealthPartners, Marshfield Clinic, Harvard

Pilgrim). Using automated data sources that already exist as part of the participating health 

plans infrastructure, the VSD collects medical and vaccination data on more than 8.8 million 

members annually (3%). The VSD was established in 1990 to improve the evaluation of 

vaccine safety through the use of active surveillance and epidemiological studies; address the

limitations of VAERS; and respond to needs identified by two IOM reports. VSD also tests 

hypotheses suggested by VAERS reports and pre-licensure trials.

Using the VSD, the investigators for the safety study of the MMRV vaccine conducted near realtime surveillance, also termed a rapid cycle analysis (RCA), for specified outcomes during the 0 

to 42 days following MMRV vaccine in seven VSD sites, excluding Southern California Kaiser 

Permanente (the site where the Merck-sponsored MMRV study was conducted). The VSD 

study population included children aged 12 to 23 months who had received the first dose of 

MMRV. One outcome monitored was seizures, for which the first seizures of any etiology in a 

42-day period were assessed. The following ICD-9 codes from automated data were used to 

identify seizures: 345.* (epilepsy) and 780.3* (convulsions, febrile convulsions, other 

convulsions). These codes were also limited to emergency department visits or hospitalization 
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visits. Other outcomes monitored for RCA included: ataxia, meningitis / encephalitis, 

thrombocytopenia, arthritis, and allergic reactions.

As the RCA moved forward, a signal for seizures was detected in the 0 to 42 day period 

following MMRV, when compared with historical rates in MMR recipients. Temporal scan 

statistics found significant clustering of seizure cases on days 7 to 10 after MMRV vaccination 

and after MMR and varicella vaccination (MMR+V), administered on the same day. These two 

findings prompted an epidemiologic study in VSD to assess the risk for febrile seizures during 

days 7 to 10 after MMRV vaccination.

For the VSD MMRV follow-up epidemiologic study, the population included children aged 12 to 

23 months who received MMRV or MMR+V. The MMRV was a contemporary cohort from 

January 2006 through August 2007. The MMR+V group was a largely historical cohort dating 

back to January 2000 through August 2007. Again, only dose one was examined. Charts were 

reviewed for children with seizures during the 7 to 10 day post-vaccination period. For 

confirmation of febrile seizures, the investigators looked for diagnosis in the chart of a febrile 

seizure associated with an emergency department visit or a hospitalization visit. For the risk for 

confirmed febrile seizure during days 7 to 10 after vaccination of MMRV compared to MMR+V, 

the unadjusted rates of febrile seizures were calculated. The rates were approximately 9 per 

10,000 vaccinations among MMRV recipients, and 4 per 10,000 vaccinations among MMR+V 

recipients. Using logistic regression, adjusted for age and influenza season, the odds ratio 

when comparing MMRV versus MMR+V was 2.3 with a significant p-value and confidence 

intervals from 1.6 to 3.2. In addition, models were run controlling for simultaneous vaccination, 

trends in seizures, VSD sites but none were deemed to be significant confounders.

Another interpretation is to examine the attributable risk for MMRV compared to MMR+V, which 

was approximately 5.2 per 10,000 children or doses. For every 10,000 children who receive 

MMRV instead of a separate MMR+V, there will be approximately 5 additional febrile seizures 7 

to 10 days after vaccination. This can also be thought of as the inverse of the attributable risk 

for MMRV compared to MMR+V in the 7 to 10-day window (number needed to harm) 1,923 

(95% CI 1,235, 4,545 ). In this interpretation, there would be 1 additional febrile seizure 7 to 10 

days post-vaccination for approximately every 2000 children vaccinated with MMRV instead of 

MMR+V.

Regarding rates of post-vaccination unconfirmed seizures among children aged 4 to 6 years, 

within the 7 to 10-day window, rates for febrile seizures are approximately 10 to 15 times lower 

in this age group when compared to the younger children. In comparing MMRV to MMR+V in 

either window, these differences are not statistically different. Also very important is that these 

numbers are very small. There were only 4 cases in the 7 to 10 days following MMRV and 14 

cases for the 0 to 42 days following MMRV, which is very few cases. It is important to 

remember that this represents findings from the largest VSD site and that these are 

unconfirmed, non-chart reviewed seizures [Northern California Kaiser Permanente VSD site 

(1995-2008)].

To summarize, in children 12 to 23 months, RCA surveillance detected a seizure signal 

following MMRV clustering 7 to 10 days after vaccination. The adjusted odds ratio is 2.3 for 

having a confirmed febrile seizure 7 to 10 days post-MMRV compared to MMR+V. The 

increased risk with MMRV cannot be explained by other factors such as simultaneous 

vaccination, temporal trends in seizures, VSD site, age, or influenza season. The attributable 

risk for febrile seizures on days 7 to 10 after MMRV is one per approximately 2000 doses when 

compared to separate MMR+V. Regarding the children aged 4 to 6 years of age, the current 
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VSD analysis conducted at one site using automated data found that seizure events were rare 7 

to10 days after MMRV. The current analysis has limited power to assess the risk of seizures 

after MMRV.

ProQuad® (MMRV) Post-Licensure 

Observational Safety Study Febrile Seizure Results

Patricia Saddier, MD, PhD

Epidemiology Department

Merck Research Laboratories

Dr. Saddier indicated that she is supervising the ProQuad Observational Safety Study that 

Merck is conducting as a regulatory commitment in collaboration with the research team at 

Kaiser Permanente Southern California. The principal investigator of the study is Dr. Steve 

Jacobsen. This presentation focused on the final results of the Febrile Seizure Component of 

the study. 

With regard to background of the study, febrile seizures may occur after febrile illnesses, which 

are very common in young children, and after a vaccine resulting in fever (e.g., MMR, DTaP, 

pneumococcal vaccine). Clinical trials of ProQuad® given as a first dose in the second year of 

life have shown that fever was significantly more frequent after ProQuad® than after MMR+V 

given at the same time, with about half of the fever episodes occurring 5 to 12 days following 

ProQuad®. The FDA asked Merck to assess the rate of febrile seizures following ProQuad® in 

a post-licensure study. The interim results of the analysis in about half of the final sample size 

were presented during the February 2008 ACIP meeting.

The objectives of the Post-Licensure Safety Study were established in collaboration with the 

FDA. The study was designed as a descriptive study with two pre-specified objectives. The 

primary objective pertained to febrile seizure. The incidence of febrile seizure, 5 to 12 days 

after a first dose of ProQuad® given to children 12 to 60 months of age, was the primary 

endpoint of the study. Other time windows were also specified in the protocol, including the 0 to 

30 day window, which was the duration of the follow-up pre-specified for both study objectives. 

The 0- to 4-day window was also pre-specified, with the understanding that febrile seizures 

occurring in this time window are unlikely to be related to MMRV, MMR, or Varicella. It was also 

anticipated that concomitant vaccines known to be associated with febrile seizure in this time 

window may be different between the ProQuad® and the MMR+V groups due to varying 

recommendations and availability over time, which was the case with respect to Prevnar®. The 

second study objective was to assess the general safety of ProQuad® in all children 12 months 

to 12 years of age vaccinated with ProQuad® as a first or second dose, with a follow-up period 

of 30 days. Given that this presentation focused on febrile seizures, Dr. Saddier did not provide 

results from the general safety evaluation, with the exception of specific results for seizure after 

the second dose. 

The 30-day follow-up was pre-specified in the protocol because viral replication may occur 

throughout this time window. Animal studies show viral replication for up to 4 weeks following 

inoculation for VZV vaccine strain and measles Moraten strain [Moffat et al. J Virol (1998) 72, 2: 

965-74; and Valsamakis et al. J Infect Dis (2001) 183: 498-502]. In clinical trials, fever, 

measles-like rash and varicella-like rash have also been reported throughout the entire followup period. Dr. Saddier reviewed the largest MMRV pre-licensure clinical trial conducted in 2000 

and 2001 in which ProQuad® was administered as a first dose in the second year of life and 

compared to measles, mumps, rubella vaccine (MMR) and varicella vaccine (V) administered at 
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the same time. Children were followed for adverse events for 42 days postvaccination. There 

was a peak of fever in the 5 to 12 day period for both vaccines, which was higher for ProQuad®. 

There was also fever reported throughout the remainder of the follow-up period. There was a 

peak of measles-like rash in the 5 to 19 days following vaccination, but still some reports of 

measles-like rash later. There were more reports of varicella-like rash in the 5 to 19 days 

following vaccination, but still reports of varicella-like rash later, especially in the third and fourth 

week following vaccination. Overall, animal and clinical trial data are suggestive of viral 

replication during the first month following vaccination. This is why a 30-day follow-up was prespecified for the post-licensure safety study. 

The post-licensure study was an observational cohort study, with an objective of including at 

least 25,000 children vaccinated with a first dose of ProQuad®. The final study population 

actually includes 69,000 children vaccinated with ProQuad® as a first or second dose, and the 

same number of matched controls vaccinated with MMR+V. The analysis for the febrile seizure 

objective was conducted on approximately 31,000 of these children in each group. All study 

results were reviewed and interpreted by an external, independent study Safety Review 

Committee (SRC). 

To put rates of events observed after ProQuad® into perspective in this descriptive study, 

several comparison groups were used. The primary comparison group was a group of historical 

controls vaccinated with MMR+V given at the same visit, before ProQuad® was available at 

Kaiser Permanente in February 2006. Children in the comparison group were individually 

matched to ProQuad® recipients with respect to age, gender, and calendar date of vaccination. 

Febrile seizure cases were identified following a two-step procedure. First, all potential cases 

were identified from the automated medical record database. All vaccinated children with a 

healthcare contact in the outpatient, emergency department, or hospital setting having any ICD9 diagnosis code for epilepsy or convulsions were identified [ICD-9 diagnosis codes used for 

detection of potential seizures: 345.X (epilepsy); 780.3X (convulsion, febrile convulsion, other 

convulsion); 779.0 (neonatal seizures); 333.2 (myoclonus)]. Their medical records were 

reviewed and abstracted. This information was then reviewed by an adjudication committee 

composed of three Kaiser-Permanente physicians otherwise unrelated to the study. The role of 

the adjudicators was to review the information independently and to determine, using the 

Brighton Collaboration case definition, whether the case was a confirmed febrile seizure.

With respect to the results of the febrile seizure analysis after first dose of ProQuad®, there 

were 31,298 children receiving ProQuad® between February 2006 and June 2007 in this 

analysis. Of these, 99% were in the second year of life when they were vaccinated. The 

historical comparison group had the same number of children (n=31,298) vaccinated with 

MMR+V given at the same time between November 2003 and January 2006. These children 

were individually matched to ProQuad® recipients on age, gender, and date of vaccination 

(month and day) in an attempt to control for potential seasonality effects and other variables. 

Although no formal comparison was pre-specified for febrile seizure in the study protocol, the 

relative risk and risk difference were presented to facilitate the understanding of the results and 

to help compare them to the VSD study. Results on the main time windows of interest are 

summarized as follows: In the 0- to 4-day time window, there were 9 cases of febrile convulsion 

in the ProQuad® group and 7 in the MMR+V group. Almost all of these cases also received 

DTaP or Prevnar® at the same time. In the 5- to 12-day window, the primary period of interest, 

there were more febrile seizures in the ProQuad® group than in the MMR+V group. The 

relative risk was 2.2, significantly increased, and the risk difference, also called attributable risk, 

was 0.4 per thousand vaccinees. In the 13- to 30-day window, not a pre-specified window of 
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interest, the rate of febrile seizure after ProQuad® was actually lower than after MMR+V, with a 

relative risk of 0.6. Overall, in the 0- to 30-day or in the 5- to 30-day, which may be the more 

relevant theoretical window of biological plausibility, the incidence of febrile seizure was the 

same in the two groups, and there were virtually no additional febrile seizures following 

ProQuad® compared to MMR+V. On a graph providing more details on when the febrile 

seizures occurred during the 30-day window, focusing on the 5- to 30-day window, in the 5- to 

12-day window there were more febrile seizures in the ProQuad® group; however, beyond day 

12 there were more febrile seizures in the MMR+V group. The febrile seizures were not 

necessarily due to vaccines and could be related to intercurrent febrile illnesses.

Regarding the importance of the adjudication procedure, there were coding practice changes at 

KPSC during the study period. These resulted in a documented increase in code use in 

general, primarily in the emergency department and outpatient settings. As a result, more 

seizure codes were used during the ProQuad® than during the MMR+V comparison period. 

However, when examining the medical records for many of these cases, there were no new 

seizure events that day. The codes actually corresponded to follow-up visits for prior seizure or 

a history of seizure, not new seizure events. With regard to febrile seizure codes in all children 

under 12 years of age at KPSC, not just the children in the study, a slight increase was 

observed from 2004-2007 in the proportion of hospitalizations having a seizure code. However, 

there was a nearly three-fold increase in seizure code use from 2004-2007 in the emergency 

room setting.

There are limited data on the rate of seizures among recipients of the second dose of 

ProQuad®. None of these seizures were adjudicated. The data are from the General Safety 

analysis of the post-licensure safety study that was conducted among one to 12-year-olds. Of 

the children receiving the second dose, 95% were 4 to 6 years of age. The analysis, based on 

the emergency room and hospital setting, showed in the 5- to 12-day period that there was 1 

case with a seizure code in each group. In the 0- to 30-day period, there were 5 cases in each 

group with a seizure code. The cases involved children with a code for epilepsy, febrile 

seizures, or other seizure disorders and they were not reviewed or adjudicated.

The study’s strengths are: 1) The MMR+V controls were closely matched to the ProQuad®

recipients in an attempt to control for seasonality effect and other factors; 2) The cases were 

adjudicated by a committee using medically accepted febrile seizure criteria. The procedure 

showed that many seizure codes in outpatient and emergency room settings did not meet the 

case definition. These codes corresponded to previous seizures, but not to new seizure events; 

3) Study data were reviewed by an independent Safety Review Committee.

There were several limitations to the study, including 1) the absence of adjustment for year-toyear variation in febrile infectious diseases. The role of concomitant vaccines was assessed by 

a stratified analysis separately for DTaP and pneumococcal conjugate vaccine. This analysis 

did not suggest that the vaccine could influence the results beyond day four. 2) Additionally, 

medical records were unavailable for 10% of cases.

In conclusion, based on animal and clinical trial data, viral replication may occur during the first

month after vaccination. Confirmed febrile seizures after the first dose of ProQuad® given in 

the second year of life are rare. The incidence after ProQuad® was 1.4/1000 and 1.3/1000 in 

the MMR+V group. The adjudication procedure was important to improve the validity of results. 

Comparison of adjudicated febrile seizure data for ProQuad® to MMR+V shows an 

approximately two-fold increase in febrile seizures in the 5- to 12-day period, with an attributable 

risk of 0.4/1000 [95%CI: 0.0, 0.7]. However, there was no increased risk of febrile seizure in the 
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30 day period. The attributable risk was 0.1/1000 with virtually no additional febrile seizure over 

30 days in children vaccinated with ProQuad®, compared to children vaccinated with MMR+V.

Regarding febrile seizures after the second dose, clinical trial data show a lower rate of fever 

after a second dose of ProQuad® administered three months after the first dose in the second 

year of life. The fever rates were 9% after the second dose versus 24% after the first dose in 

the same children. Limited data from the post-licensure study suggest no increase in seizures

following MMRV versus MMR+/-V. The incidence of seizure code was the same in each group, 

and was extremely low. 

In terms of next steps, the final study report, including general safety results, will be sent to 

CBER by year’s end. Early results, including the final febrile seizure report, were sent to CBER 

in August 2008. The ProQuad® label was updated in February 2008 to include the interim

study results for the 5- to 12-day and the 0- to 30-day periods. The label update with the final 

study results was submitted to CBER last month. As a reminder, ProQuad® is not currently 

being distributed in the US due to manufacturing issues unrelated to vaccine safety or efficacy. 

MMRV Vaccine Safety Working Group: Interim 

Synthesis of Evidence for Febrile Seizure Risk after 

MMRV Vaccination and Considerations for Future Activities

Karen Broder, MD

Immunization Safety Office, CDC

Dr. Broder expressed her appreciation for the opportunity to present the interim synthesis of the 

evidence for febrile seizure risk after MMRV vaccination, and to discuss some considerations for 

future activities. She indicated that she was presenting on behalf of the MMRV Vaccine Safety 

Work Group, whom she thanked for their tremendous contributions. In this presentation, Dr. 

Broder offered background information on febrile seizures; presented an evidence framework 

for risk assessment; discussed the interim evidence synthesis for dose one MMRV vaccine; and 

offered some considerations for future activities. 

Febrile seizures are seizures that occur in febrile children who do not have an intracranial 

infection, metabolic disturbance, or a history of afebrile seizures. They usually occur between 

the ages of 6 to 60 months, and the peak age is 14 to18 months, which coincides and overlaps 

with the age at which the first dose of MMRV is recommended. Febrile seizures affect 2% to 

5% of young children in the US. Generally, they have an excellent prognosis. Children with 

simple febrile seizures are not at greater risk for epilepsy than the general pediatric population. 

Febrile seizures are thought to be caused by an age-related increased susceptibility to seizures 

induced by fever. The peak temperature is a major determining risk factor. Certain infections, 

particularly roseola, have a higher likelihood of febrile seizure than other infections. With 

respect to vaccination, DTP and MMR vaccines are transiently associated with increased risk 

for febrile seizures.

To rapidly assess the evidence for febrile seizure risk, the work group developed an evidence 

framework, incorporating criteria used primarily in three other frameworks from the Institute of 

Medicine (IOM), World Health Organization (WHO), and draft guidance from the ACIP 

Evidence-Based Recommendations Working Group (EB WG). The framework considered 

three separate lines of vaccine safety evidence. Consideration was first given to the clinical 

importance of the adverse events (AEFI) (febrile seizures); however, the work group has

deferred these discussions and they will be assessed after the October ACIP meeting. The 
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work group focused on the other two lines: population-based risk and biological plausibility. For 

the population-based risk, the epidemiologic evidence regarding a possible causal relationship 

between the vaccine exposure and the AEFI was assessed. For the biological plausibility, the 

biological plausibility of the association between the immunization and the AEFI was assessed. 

It is important to note for this assessment, the association should be explicable biologically 

according to known facts in the natural history and biology of the disease, antigen, and / or host 

response.

To synthesize the vaccine safety evidence, the work group examined the methods and results 

of two unpublished, post-licensure studies of dose one MMRV (ProQuad®) vaccine and risk for 

febrile seizures [VSD study Principal Investigator (PI): Dr. Klein; and Merck-sponsored study PI: 

Dr. Jacobsen]. The group then reviewed the pre-licensure data for MMRV, MMR, and varicella 

vaccines and other relevant medical literature to assess the biologic plausibility of an increased 

risk for febrile seizure. Consultations were held with numerous experts to assess biological

plausibility, including many people in the room. Dr. Broder particularly acknowledged Dr. Judy 

Beeler from the FDA, who serves on the working group and who contributed a great deal to this 

assessment. Finally, a work group member survey was conducted to obtain input from 

members to rate the quality of the evidence. The draft guidance from the Evidence-Based 

Working Group was used to rate the quality of evidence for the risk. Dr. Broder acknowledged

Dr. Ahmed for sharing this guidance and consulting with this work group, recognizing that the 

group had to move their risk assessment forward before the guidance was completed.

There were four levels for the grade of evidence: high, moderate, low, and very low. For the 

moderate and low categories, the changes in research might change the confidence in the 

estimate or change the estimate itself. With this evidence framework in mind, Dr. Broder 

discussed the interim evidence synthesis for febrile seizure risk after dose one MMRV vaccine. 

Dr. Broder summarized the main findings of the VSD and Merck-sponsored studies of MMRV 

and febrile seizures (presented earlier in the meeting). Both studies compared rates of 

confirmed febrile seizures after dose one MMRV vaccine, with rates after separate injections of 

dose one MMR and varicella vaccines administered at the same visits. Compared with the 

group that received the MMR and varicella vaccines at the same visit,(the MMR+V group), the 

VSD study found a statistically significant increased risk for febrile seizures during the 7 to 10 

days after MMRV vaccine. The odds ratio was 2.3 and the attributable risk was 5.2 per 10,000. 

The VSD did not assess risk for confirmed febrile seizures in other time periods. As a reminder, 

the VSD examined febrile seizures that were associated with an emergency department or a 

hospital visit. As Dr. Saddier described, the Merck-sponsored study found a statistically 

significant increased risk of febrile seizures during the 5 to 12 days after MMRV vaccination, 

compared with MMR+V. The relative risk was 2.2 and the attributable risk was 3.8 per 10,000. 

Although it was not a primary window of interest, the Merck-sponsored study did observe a nonsignificant decreased risk during the 13 to 30 days after vaccination (relative risk 0.6) compared 

with the MMR+V group, and they found no statistically significant difference in the risk in the 0 to 

30 days after vaccination between the two groups. As a reminder, febrile seizures in the Merck 

study included those that were associated with outpatient visit as well as ER and hospital visits. 

Pertaining to the work group’s interim assessment of the quality of evidence for the two different

risk patterns in the early and late periods during the month after the MMRV vaccination, the 

evidence grades were determined based on a survey using a numerical scoring system. They 

were pleased to have 25 of the 26 members of the working group making this assessment, and 

feel this truly reflects the consensus of the working group. The work group rated the quality of 

evidence during the first two weeks after vaccination to support an increased risk for febrile 
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seizures in the MMRV versus MMR+V groups as high, both for the population-based risk data 

and for the biological plausibility line of evidence. It was the work group’s opinion that the 

quality of evidence was less strong for the observed decreased risk in the MMRV group relative 

to the MMR+V group during the third and fourth weeks post-vaccination. The work group rated 

the population-based risk data as low-moderate and the biological plausibility line of evidence

as low. 

For the population-based risk assessment, the work group used domains that were drawn from 

some of the sources described earlier that were used to develop the evidence framework. The 

work group considered the VSD and Merck-sponsored studies separately. With respect to 

study design, both studies were observational, historical cohort studies with a comparison 

group. As a reminder, the MMRV was licensed in 2005, and the historical group comprised 

subjects in years before the vaccine was licensed. Both studies looked at a contemporary 

cohort of approximately 30,000 to 40,000 MMRV recipients. It is worth nothing that the 

comparison group for the MMR+V group recipients was about 10 times larger in the VSD study. 

The strength of association between the risk for febrile seizure after MMRV vaccine as 

described earlier, was about two-fold, and the confidence intervals around the point estimate for 

risk in the VSD study were very tight, with a confidence interval range of 1.6 to 3.2, and the 

odds ratio was 2.3. The work group’s assessment was that the VSD and Merck-sponsored 

studies demonstrated remarkable consistency. Dr. Broder particularly acknowledged the 

contributions of Dr. Elizabeth Andrews, the pharmacoepidemiologist on the Working Group who 

had no involvement in either study and who contributed to this assessment.. The rest of the 

working group contributed as well.

With respect to consistency, the point estimates for the studies were very similar. A two-fold 

increase in febrile seizure risk was observed. Additionally, findings were statistically significant. 

It is important to note that the studies used independent study populations, so there was no 

overlap in study subjects. Moreover, the studies arrived at a similar time window of risk through 

completely different methods. With regard to the specificity of the adverse event, febrile 

seizures are non-specific events that can occur from many etiologies. However, it is important 

to remember that febrile seizures only occur in persons with fever. The febrile seizures clearly 

occurred after vaccination, so there was a clear temporal relation to the vaccine.

Regarding the studies’ strengths as assessed by the working group, the VSD study’s strengths 

were its access to a very large and geographically diverse population and availability of more 

than 99% of charts available for review to confirm the diagnosis. The strengths of the Mercksponsored study included a rigorous record review using the Brighton Collaboration case 

definition for febrile seizures, and use of an independent Adjudication Committee to confirm the 

diagnosis.

In terms of the limitations of each study, both studies suffered as the comparison groups were 

either largely historical or completely historical. Additionally, neither study examined year-toyear variation in febrile infections as part of their models. The confirmation of febrile seizures 

was done differently. It was viewed that a potential limitation in the VSD study was that there 

was no external adjudication process. A potential limitation in the Merck-sponsored study was 

that the adjudicators were not blinded to the year of vaccination, and the year of licensure for 

ProQuad® was known. The missing records were not considered a limitation for the VSD study, 

but as noted, 9% of the Merck-sponsored fever cases did not have charts available to confirm 

the diagnosis.
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With regard to post-licensure experience with febrile seizures after MMR or varicella

vaccination, with MMR, Barlow and Davis studied about 137,000 children aged less than 7 

years vaccinated with MMR in the VSD [Barlow, Davis, et al; NEJM 2001]. This study identified 

an increased risk for febrile seizure during the 8 to 14 days after vaccination. Compared with 

unvaccinated children, the relative risk was 2.83 and they observed approximately 1 additional 

febrile seizure per 3,000 to 4,000 children vaccinated. Therefore, it is known that MMR is a risk 

factor for febrile seizures in this transient window. Regarding the varicella vaccine, the best 

post-licensure study was conducted by Black and colleagues of approximately 35,000 children 

aged 12 to 23 months vaccinated with varicella vaccine. This study identified no increased risk 

for febrile seizure during the zero to 30 days after vaccination, when controlled for coadministration of the MMR vaccine [Black S et al. NEJM, Pediatric Infectious Diseases Journal, 

1999].

Regarding the biological plausibility assessment for increased risk for febrile seizures in children 

receiving MMRV vs. MMR+V, the workgroup assessed that there is strong biological plausibility 

for increased febrile seizure risk after MMRV compared with MMR+V during days 5 to 12 after 

vaccination. They considered vaccine properties, immunogenicity, host response and clinical 

context in coming to this assessment. Because of its critical importance to the evidence 

synthesis, Dr. Broder reviewed the logic for the biological plausibility assessment. With respect 

to vaccine properties, the MMRV used in the US (Proquad®) has about seven times more 

varicella antigen content than the varicella-only vaccine (Varivax®). MMRV has the same 

measles antigen content as MMR vaccine on the market in the US. However, with 

immunogenicity, MMRV induces similar antibody titers to varicella as MMR+V vaccines. MMRV 

induces higher antibody titers to measles than the MMR+V vaccines, suggesting higher levels of 

measles vaccine virus replication following MMRV vaccine compared with separate 

administration of MMR+V; however, as far as is known, virology studies have not been 

conducted to assess this hypothesis. In natural measles infection, active viral replication 

throughout the body occurs 7 to 14 days after exposure [Sources: ProQuad® package insert, 2-

2008; Long. Principles and Practices of Pediatric Infectious Diseases, Third Edition. 2008]. 

Looking at the host febrile responses, significantly higher rates of fever and measles-like rash 

were reported in clinical trials after MMRV compared with MMR+V [ProQuad® Package insert, 

2-2008]. Fever and measles-like rash usually occurs during 5 to 12 days after vaccination. 

Additionally, the probability of reported fever increased with increasing measles antibody 

response [Kuter B. et al. Human Vaccines. 2006] in the MMRV and MMR+V groups. In terms of 

the clinical context, febrile seizures occur in the setting of fever.

The pre-licensure trial data for vaccine-related fever and systemic rash during days 0 to 42 with 

MMRV or MMR+V shows that in this time period, 21.5% of MMRV recipients had a fever of 

102°F or higher compared with 14.9% of the MMR+V recipients. There were higher rates of 

measles-like rash and no statistical difference in the rates of varicella-like rash [Source: 

Package insert 2-2008 and unpublished data from Merck on 10-20-08]. 

With respect to the evidence synthesis for a decreased risk for febrile seizures 3 to 4 weeks 

after MMRV vaccine compared with separate injections of MMR+V, the work group used the 

same domains previously used to make the assessment. Data were only available from the 

Merck-sponsored study; VSD did not assess risk in this window for confirmed febrile seizures. 

The observed decreased risk in strength of association was not statistically significant in the 

Merck-sponsored study. The point estimate was 0.6 and the 95% confidence intervals were 0.3 

to 1.1. The assessment for the specificity of adverse event and temporal relation are the same. 

The study’s strengths are the same as described earlier. The work group thought the limitations 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

147

were the same with respect to the Merck-sponsored study findings in the 1 to 2 week postvaccination window described above.

The work group considered that there were two reasons unrelated to vaccine that might account 

for the observed decreased risk in the MMRV group relative to the MMR+V group in the 13 to 

30 days after vaccination. First, they must acknowledge that it could be a chance finding rather 

than a true decrease. Second, it is possible that a historical cohort bias effect could lead to this 

observation. For example, there are different patterns of co-infection that may have been 

present across years, particularly for severe influenza. If there were higher febrile infection 

rates in the historical cohort, that effect could lead to increased rates of febrile seizures postvaccination in MMR+V recipients. This would affect estimates for all time windows.

With respect to what is known from the post licensure experience in the 13 to 30 days postvaccination with MMR or varicella vaccine, in the Barlow and Davis study, which looked at the 

137,000 children vaccinated with MMR, in the 15 to 30 day window, a similar risk for febrile 

seizures was observed compared with compared with unvaccinated children. The relative risk 

was 0 .97. The risk for the 8 to14 day window was closer to 3. In the varicella vaccine 

literature, the Black study identified no increased risk throughout the 0 to 30 days once one 

controlled for co-administration of MMR vaccine. It did not specifically break it down into 

intervals. 

The work group spent a good deal of effort considering the biological plausibility for the 

observed decreased risk for febrile seizures in the MMRV versus MMR+V recipients during the 

13 to 30 days after vaccination. They consulted with many experts within and outside the 

working group, reviewed the literature, and despite a thorough attempt, found no compelling 

biological reason to explain the decreased risk during the 30 days after vaccination. The work 

group does put forward two theoretical reasons that arose in discussions, which they do not 

think were likely. One possibility is that because it is known that there are different host 

response patterns immunologically to MMRV and MMR+V, it is theoretically possible that 

MMRV may induce more robust or earlier immune earlier response and could offer short-term 

secondary protection from infectious illnesses and febrile seizure in the days to weeks that 

follow. A social effect is also possible. It is known that children who receive MMRV are more 

likely to have fevers during the 5 to 12 days following vaccine than those who receive MMR+V

and if this leads to changes in their daycare or play group attendance and they receive less 

exposure to other infectious diseases, this might offer short-term protection from febrile seizure

a few days to weeks later. In order to explain either of these effects from vaccine virus 

replication, one would need to observe fevers occurring in a different pattern in the later window. 

A peak would need to be observed in fevers in the MMR+V group, or a decrease would need to 

be observed in fevers in the MMRV group. Again, febrile seizures need to occur when fever is 

present.

This issue was evaluated more closely in the VSD by examining outpatient visits for medicallyattended fever by day after vaccine in 7 VSD sites among children aged 12 to 23 months during 

2000 to 2008. The pattern of outpatients fever visits associated with ICD9 code 780.6 was 

plotted for and 4 different patterns of vaccination (MMRV, MMR+V, MMR and varicella). The 

rate per 100,000 doses administered as well as the days since vaccination were shown in a 

graph. Dr. Broder highlighted three findings. First, fevers appear to be clustered around days 5 

to 12 after vaccination in all of the measles vaccine groups (MMRV, MMR+V, and MMR), which 

is what one would expect. Second, the height of the MMRV curve is higher than the MMR+V 

curve. Of interest is that the peak height for the MMRV curve appears to be about two times 

higher than the peak height of the MMR+V curve, which is very consistent with what was 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

148

observed in the febrile seizure data. Third, a close examination of the window further out in the 

13 to 30 days after vaccination reveals that there is no apparent cluster for fever after MMR+V 

vaccine, and there is no apparent dip in the fever curve for MMRV, relative the MMR+V. Taken 

together, the findings presented support the high-grade quality of evidence for biological 

plausibility for the increased risk of febrile seizures observed after MMRV compared with 

MMR+V 5 to 12 days after vaccination, and the low-grade quality evidence for biological 

plausibility for decreased risk for febrile seizures after MMRV compared with MMR+V in the 13 

to 30 days after vaccination. 

After reviewing the evidence, the work group made two interim conclusions regarding risk for 

febrile seizures after dose one MMRV vaccine. First, 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 one MMRV vaccine and increased risk for febrile seizures 

during the 5 to 12 days after vaccination; the magnitude of the risk is about 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. Second, compared with separate dose one

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.

Regarding considerations for future MMRV vaccine activities, the work group plans to complete 

the risk assessment for dose one MMRV and febrile seizure. The work group has proposed an 

epidemiological study in the VSD population to assess confirmed febrile seizure risk after dose 

one MMRV vaccine in periods other than 7 to 10 days, including risk during 0 to 30 days after 

MMRV vaccine. The VSD is conducting additional analyses in the automated seizure data that 

includes about 40,000 more MMRV recipients than the analysis presented to the ACIP in 

February 2008. Following the review of the automated data, a formal epidemiologic study plan 

will be developed by the VSD investigators. The work group will continue to work with the VSD 

to assess new data as it becomes available. Additionally, the work group will consider a need to 

propose additional analyses or studies that may be conducted in various research venues

outside the VSD.

Regarding the assessment for dose 2 MMRV and febrile seizure risk, febrile seizures are less 

common in children aged 4 to 6 years, which is the recommended age for dose 2 of MMR, 

varicella, and MMRV vaccines [Johnston M. Nelson Textbook of Pediatrics. 2007]. The VSD 

and Merck-sponsored febrile seizure studies were conducted for dose 1. . However, in light of 

the dose 1 findings, the work group is reviewing dose 2 safety data from pre-licensure studies 

and post-licensure data on unconfirmed seizures after vaccination. The work group recognizes

that in the pre-licensure data there are lower fever rates in children ages 15–26 months 

receiving dose two MMRV vaccines compared with dose one MMRV in 1035 children 

[ProQuad® Package Insert, February 2008]. Similar fever rates were observed in children aged

4 to 6 years receiving MMRV (N=397) compared with MMR and varicella vaccines separately 

[Reisinger et al. Pediatrics, 2006]. The rate is about 10% for both groups for fever >102o F or 

warm to touch. There were no febrile seizures reported in study subjects receiving dose two

MMRV vaccines in clinical trials [Personal communication with Dr. Kuter, Merck on 10-20-08].
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

149

As a reminder, post-licensure data came from unconfirmed seizures from automated data after 

vaccination, and charts were not reviewed in the VSD or Merck-sponsored studies for the dose 

2 assessment. In the VSD, dose 2 subjects were defined as children aged 4 to 6 years with no 

MMR or varicella vaccine dose in the past 12 months. Because VSD generally has very good 

coverage for childhood vaccines, it is very likely that the vast majority of these children had 

received one dose of MMR vaccine. The work group did not have the specific proportions of 

which were dose 2. In the Merck-sponsored study, dose 2 subjects were defined as children 

aged 1 to 12 years who received MMR and varicella vaccines in the past [Personal 

communication with Dr. Kuter on 10-20-08]. For most children in MMR+V group, it was the 

second dose for the MMR component. More than 95% of these subjects were aged 4 to 6 

years.

The following summary table reflects the results from the VSD and Merck-sponsored studies

about the dose two MMRV versus MMR and varicella vaccines and unconfirmed seizures from 

automated data. There were very few seizures of any etiology in the second dose recipients. 

The rate of seizures in the five to 12 days after vaccination with dose 2 MMRV compared with 

what we saw after dose 1 MMRV was about 10 to 15 times lower in the second dose group:

34

Summary Results from VSD and Merck-sponsored 

Studies Unconfirmed Seizures from Automated Data

Dose 2 MMRV vs. MMR and Varicella Vaccines

Post-vaccination 

Interval 

VSD*

All aged 4–6 years 

Merck** 

1-12 years old 

(>95% aged 4–6 years) 

Weeks 1–2 7–10 days

MMRV: 0.7 per 10,000

(4 per 56,535) 

MMR+V: 0

(0 per 44,836)

5–12 days 

MMRV: 0.4 per 10,000

(1 per 25,212)

MMR+V: 0.4 per 10,000

(1 per 24,788)

Weeks 1–4 0-42 days

MMRV: 2.5 per 10,000

(14 per 56,535) 

MMR+V: 2.0 per 10,000

(9 per 44,836)

0-30 days

MMRV: 2.0 per 10,000

(5 per 25,212)

MMR+V: 2.0 per 10,000

(5 per 24,788)

*Data from Northern California Kaiser Permanente only, 1995-2008

**Includes codes for seizure and epilepsy; Permission from Merck on 

10/17/08

The work group has several other activities under way. They will begin to assess the evidence 

regarding the clinical importance of febrile seizures. This is based on medical data as well as 

perceptions and beliefs. The group is very fortunate that the University of Colorado is 

collaborating with CDC to conduct a providers’ survey about perceptions of febrile seizure 

severity and MMRV use among physicians, which is currently underway. During the February 

2008 ACIP meeting, two encephalitis cases were presented from the VSD study, and the work 

group has arranged for these cases to be reviewed by two neurologists to confirm the 

diagnoses. This information will be present at a later ACIP meeting. In addition, the work group 

will develop policy options for use of MMRV for the ACIP to consider. For this, consideration will 

be given to the risks and benefits of dose 1 and dose 2 as routinely recommended by ACIP.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

150

MMRV Supply 

Dr. Kim Haupt

Merck & Company, Inc.

Dr. Kim Haupt reported that although Merck had hoped to return Proquad® to the market in 

early 2009, they recently communicated to the CDC Stakeholder Group, the MMRV Vaccine 

Safety Working Group, and its customers that this is no longer feasible. Merck will continue to 

prioritize the production of Varivax® and Zostavax®. Although Merck currently has an adequate 

of supply of Varivax® and can fully support the 2-dose recommendation for varicella, there are 

prolonged back orders for Zostavax®. Once the backorders are filled and cleared, and the 

inventory is rebuilt for Zostavax®, Merck will be in a better position for the re-launch of 

Proquad® and is committed to returning Proquad® to the market. Although a firm date could 

not be provided at this time, Dr. Haupt assured participants that as more information became 

available regarding the demand and supply of Zostavax®, Merck would update the CDC 

Stakeholder Group, the MMRV Vaccine Safety Working Group, and its customers. They do 

anticipate that they will have more information regarding the supply of Proquad® in time for the 

February 2009 ACIP meeting.

Discussion

Dr. Neuzil inquired as to when Merck expected the backlog issue with Zostavax® to be 

resolved.

Dr. Haupt responded that this topic would be addressed during the vaccine supply update.

In terms of biological plausibility for what might be seen in the Merck studies as a compensatory 

decrease in febrile seizures, Dr. Judson referred to the statement made during the presentation 

that hypothetically it is possible that a very small minority of children are actually prone to febrile 

seizures and that the MMRV triggers those early. Those individuals who are susceptible are

then taken out of the pool for the remaining 30 days and are not vulnerable to febrile seizure

from other causes. He did not believe that this was true; however, there are other situations in 

which a compensatory decrease can be caused by an early reduction of susceptibles.

Dr. Temte responded that this discussion was thoroughly vetted throughout the committee. The 

work group had a very long list of potential explanations that they evaluated through 

consultation with a number of experts, both in vaccine safety and neurology. Rather than 

including the entire laundry list of potential explanations in the presentation, only the 

explanations that the work group believed were the most plausible were presented.

Regarding the planned provider survey about perceptions of febrile seizure severity, Dr. 

Sumaya suggested that it may be of interest to ensure that the febrile seizure activity is in no 

way more severe or more likely to lead to anything else in these cases.

Dr. Cieslak commented that the graph of Febrile Outpatient Visits by Day Since Vaccination was 

nicely done and was worth a thousand words. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

151

Dr. Temte acknowledged the incredible amount of time put forth by CDC’s lead staff, 

consultants, the Merck-sponsored investigators, the VSD representatives, and all of the 

members of the work group who devoted countless hours of time to compile and assess this 

information. 

Dr. Marcy inquired as to what the work group used as its definition of “febrile seizure.” 

Dr. Broder replied that the work group had not adopted a work group-specific definition for 

“febrile seizure.” Instead, they considered what the studies used. In the VSD, febrile seizure 

was confirmed in the charts. That is, when abstracted there was some notation in the chart 

indicating that the doctor thought that a child had a febrile seizure. No formal case definition 

was applied beyond that by the work group.

An inquiry was posed regarding what proportion of varicella-like rashes was observed in the 5-

to 12-day window.

Dr. Saddier responded that in the clinical trial it was 2.1% in the MMRV group and 2% in the 

MMR+V group, overall.

Dr. Broder added that in the package insert in the 42 days, the varicella-like rash is 2.1% of the 

MMRV group and 2.2% of the MMR+V group. They were not aware of data on the 5 to 12 days.

Dr. Seward indicated that the only randomized placebo-controlled trial conducted with varicella 

vaccine used a similar dose of varicella virus that is used in Proquad®, the rival study. There 

was a difference in rash and the attributable rash from the vaccine was 2% during the study 

period. With regard to the figure in the paper, most of the rash was in the 5- to 15-day time 

period. There was relatively little in the later part, up to 42 days. Varicella has been isolated 

out as far as 41 days post-vaccination. The study quoted was 25 years ago, there was no 

varicella vaccine, and most of the trials were conducted in older children. The range on those 

trials is from 1 to 12 years with a mean age of four. Comparing that to these data for 12 to 23 

months it somewhat different. Unfortunately, the work group really struggled to find data with 

varicella vaccine alone in that age group. The numbers are remarkably small because in 

moving forward with all clinical programs, MMR+V and one injection in each arm was used, so it 

is very difficult to provide information on varicella alone in this particular age group. 

Regarding the definition for “febrile seizure,” Dr. Marcy said this may explain the difference in 

the attributable risk. The Brighton Collaboration definition is very strict. When physicians say it 

is a febrile seizure, they often take the word of the parent. Therefore, small shakes due to chills,

eyes rolling up as part of the Bells Phenomenon of closing the eyes, and other things have been 

described by parents as seizures though they are not. 

Dr. Broder clarified that those types of problems are more likely to occur in the outpatient 

setting. The Merck-sponsored study counted febrile seizures that occurred in an outpatient 

setting. The VSD was restricted to the emergency room and hospital settings, so the child had

to have a physician diagnosis of a febrile seizure associated with an emergency room or 

hospital visit. It is possible with a more rigorous review that would have changed the findings to 

some extent.

Dr. Marcy added that he was the adjudicator and most of the cases in the Merck study were 

emergency visits and other outpatient clinics, so that difference still remains by the strictness of 

the definition.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

152

 

Nidhi Jain, MD, MPH

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Jain reported that the National Immunization Survey: Teen Results, 2007 was published in 

the MMWR October 10, 2008 and is available online. Referring to the 2008 Adolescent Vaccine 

Schedule, she pointed out the first three vaccines were the new vaccines since 2005: Tdap, 

meningococcal vaccine, and HPV4 (for girls), which are recommended for routine administration

to adolescents aged 11 to 12 years. If adolescents have not received those vaccines during the 

recommended visit, they should receive them at the earliest opportunity between 13 and 18 

years. Healthy People 2010 objectives have been established for adolescents 13 to 15 years. 

The coverage goal is 90% for 3+ doses of HepB, 2+ doses of MMR, 1+ dose of a tetanuscontaining vaccine (either Td or Tdap), and 1+ dose of varicella among those without a prior 

history of the disease. 

Regarding methods, the NIS-Teen uses the same sample frame methodology as the infant NIS 

that has been conducted for infants 19 to 35 months since 1994. This is a random digit dialing

(RDD) telephone survey. This survey is added on to the infant NIS in which households are 

also screened for adolescents 13 to17 years old. If one is present in the household, the parent 

is also interviewed about that teen. Consent is obtained to contact the vaccination providers, 

and those providers are mailed an immunization history questionnaire to collect their 

documented vaccination information. Different from the NIS for children, the NIS-Teen in 2007 

was only conducted in the fourth quarter of 2007.

Again, the sample for the NIS-Teen is based on a random digit dialing system. There was an 

initial sample of approximately 400,000 telephone numbers of which 327,000 (82%) were 

determined to be working numbers. Of those, 85,000 (26%) were identified to be actual 

households and the investigators were able to screen 69,000 households (82%). After 

screening, it was determined that 6500 (10%) had an age-eligible teen. From that, 5474 (84%) 

completed the household teen survey. From these teens, 75% (n = 4114) gave consent to 

contact their providers. Of households with completed interviews, 2947 (54%) teens had 

adequate provider records returned to determine vaccination coverage estimates. To conduct 

the analysis, the investigators used SUDAAN software because of the complex weighting of the 

survey data. Point estimates and 95% confidence intervals were determined, and chi square 

and t-tests were used to test differences, with a p-value of less than 0.05.

Regarding demographic characteristics of the NIS-Teen sample, about half were female; 61.7% 

were non-Hispanic White; 14.5% were Non-Hispanic black; 17% were Hispanic; and 6% were 

other racial / ethnic groups. About half of teens live in suburban areas and 16% live in rural 

areas, and most live above poverty. Regarding maternal education, less than half of mothers of 

teens have a high school or less education. About two-thirds of teens have private insurance; 

30% have public insurance; and about 7% have no insurance. With regard to where teens are 

receiving vaccinations, more than half, or 57% of teens had their provider-reported vaccinations 

National Immunization Survey: Teen Results
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

153

returned by private practice clinics; 21% had provider-reported vaccinations returned by public 

clinics or federally qualified health centers; and 12% were vaccinated at a mix of facility types. 

A few went to hospital-based, STD, school or teen clinics.

In terms of overall vaccination coverage among adolescents 13 to 17 years of age for the 

vaccines mentioned, in 2007 coverage for TD or Tdap was 72.3%; Tdap alone was 30.4%; 

MCV4 was 32.4%; and one dose of HPV4 was 25.1% among adolescent females. Regarding 

childhood vaccines, 88.9% received two doses of MMR and 87.6% received three doses of 

HepB. Among those without a history of varicella disease, 75.7% had received one dose of 

VAR; and among those without a history of disease, only 18.8% had received two doses of 

VAR.

Breaking down TD and Tdap coverage by vaccine type and age, overall, there has been an

increase of 12.2 percentage points compared to 2006. Coverage in Tdap alone increased 

approximately 20 percentage points in the past year. More of the younger teens ages 13 to 14 

years have received Tdap, while older teens received TD. This is probably because Tdap was 

not available when the older teens received their booster shots. With regard to coverage of 

meningococcal vaccine (MCV4) , overall coverage has increased about 20 percentage points

between 2006 and 2007. Across the age groups, coverage did not differ significantly.

This meeting represented the first time reporting HPV4 coverage since the vaccine 

recommendations were published in March 2007. The estimated coverage of one or more 

doses of HPV4 vaccine among female adolescents aged 13-17 years was 25.1%. Coverage 

did not differ significantly by age. Among the 25% of females who initiated HPV vaccination, 

23.5% had received all three doses and completed the series. Over time, this is expected to 

increase because there is an interval required for the vaccine. Given that this survey was 

completed in the fourth quarter of 2007, it is likely that some of these girls completed the doses 

after the survey was completed.

In terms of coverage of childhood vaccinations, overall coverage with MMR was high in 2006 

and 2007, with 88.9% of teens having received two or more doses. Coverage with hepatitis B 

vaccine was high, increasing to 87.6% in 2007, which is a six-point increase compared to 2006. 

There is higher coverage among the younger age groups 13 to 14 years old, and they were 

likely vaccinated at birth according to universal recommendations made in 1991. Among the 

older teens about 15% are not vaccinated. 

Regarding varicella disease and vaccination, overall 92% of adolescents are protected from 

varicella either through having had the disease or from receiving at least one dose of the 

vaccine, which represents a small increase from 2006. Having varicella disease has decreased 

from 69.9% to 65.8%. More 13 to 14 year olds have been vaccinated than have had the 

disease. More of the older teens have had the disease rather than being vaccinated. Since 

2006, it is recommended that persons older than 13 years receive two doses of varicella 

vaccine to prevent disease outbreaks and complications. In the survey, among teens who have 

never had varicella before, two-dose coverage was only 18% overall. It is slightly higher among 

the younger groups.

Progress toward achieving HP2010 objectives of 90% coverage among adolescents 13 to 15 

years of age was also assessed. There has been improvement since 2006. Comparing 2006

and 2007, the goals for HepB and MMR have just about been met at close to 90%; however, the 

varicella and tetanus booster are below the goals.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

154

There are limitations to the NIS-Teen. Bias may remain due to survey non-response and the 

missing households without landline phones. This is estimated to be less than 10%. Also, it 

was assumed that coverage among adolescents with adequate provider data is the same as 

coverage among adolescents without adequate provider data, which may either underestimate 

or overestimate the rates. Some vaccinations may have been missed if some of the provider 

records that were assumed to be complete were not. For example, records could be missing 

vaccinations that were given in non-traditional settings like emergency rooms. In addition, there 

were low response rates for overall households and number of adolescents who had returned 

provider data.

In conclusion, there has been an increase in coverage for most of the vaccines. There has 

been good uptake of the new adolescent vaccines, including Tdap, MCV4 and HPV4. Some 13 

to 14 year olds are still receiving TD vaccines and not Tdap, the reason for which needs to be 

determined. Some older teens can now receive Tdap, given that the interval between TD and 

Tdap can be shortened. It is also important to ensure that girls initiating the HPV4 series 

receive all three doses, which will need to be further monitored in the future. Childhood 

vaccination coverage is high; however, 15% of teens are still not protected against hepatitis B 

infection, and there is low coverage among the two-dose varicella vaccination schedule.

Recommendations are to emphasize to parents and providers the pre-teen visit at age 11 to 12 

years for preventive services, including vaccinations. Providers should be encouraged to review 

adolescent immunization records and administer missing vaccinations at all health care visits. 

Simultaneous administration of vaccinations at the same visit should also be encouraged. 

Systems should be implemented to remind providers and parents when vaccines are due for 

adolescents.

Current plans for monitoring adolescent vaccination coverage include the expansion of the NISTeen to a full year. National and state-specific estimates are being collected in order to 

examine vaccination coverage by race, socioeconomic status, and geographic area. These 

data will be available in July 2009. Potential bias is also being evaluated in the NIS-Teen

survey due to the exclusion of cell-phone-only households and non-response. An NHIS 

provider record check will be conducted beginning the fourth quarter of 2008. Different 

sampling strategies will be developed to ensure the representativeness of NIS-Teen, and an 

address-based sample frame and cellular phone sample frame are being considered to ensure 

representative results.

Discussion

Dr. Morse asked whether Dr. Jain and colleagues would follow influenza vaccine in teens in the 

future.

Dr. Jain responded that they would. The sample this year was small and coverage was very 

low, so they did not report that. They hope that next year, after the new recommendations for 

all adolescents, that coverage will be higher.

Dr. Sawyer noted that there has been a lot of attention recently about complementary sites for 

vaccinations, particularly for adolescents based on data that they may not go to their regular 

care provider. He was surprised to see that the coverage rates in this study across the age 

spectrum for the meningococcal vaccine, and to a lesser extent varicella, did not really drop off 

from age 13 to 17. He wondered if that suggested that they actually were getting into care more 

than was thought. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

155

Dr. Jain responded that they do have data about how many visits adolescents made in the past 

year. These data have not been analyzed to date. Improvement in vaccination coverage may

be due to high media attention on adolescent vaccinations. In 2006, there were some 

differences in MCV4 coverage among the age groups, but in 2007 there were none. They are 

trying to collect information about the complementary sites of vaccination.

Regarding the children who are not vaccinated at age 16 to 17 years old, Dr. Marcy pointed out 

that there are requirements for high school entry. He wondered whether the schools were not

following through and whether these children had access. 

Dr. Jain replied that it is possible that some of the individuals in this age group may not be in 

school (e.g., they could be dropouts). For this study, they have not asked questions about 

home schooling. Therefore, it is unknown whether these children are actually in school.

Dr. Judson said that while things may have changed, he did not think every state had a

requirement for two doses of MMR or any other vaccine for entry into high school. He said he 

did know that if it was not carried out in 9th grade in most inner cities, a lot of the key target 

population will be lost due to dropping out of school or changing schools or residence. There 

are a lot of challenges to school-based immunization programs. 

 

Dr. Jain replied that MMR coverage was very high at 89%. 

Dr. Lance Rodewald added that there is potential for a longer time period for the recall, so 

sometimes there is a record problem. These are all provider-verified records, and if the records 

did not travel with their current provider, there is more of a chance that they may be missed as 

well. The school-based coverage measured for MMR vaccination is quite high at an average of 

about 98%.

Influenza Surveillance

Anthony Fiore, MD, MPH

Influenza Division, NCIRD, CDC

Dr. Fiore reported that thus far, there has been very little activity in the current influenza season 

that began a few weeks before this meeting. He explained that influenza surveillance system 

shows that influenza activity often peaks in January and February. Thus far this season, only 

six states have reported sporadic activity, and CDC has received few virus isolates from the 

United States thus far:

Influenza Vaccines
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

156

Antigenic characterization data from May 18, 2008 through September 19, 2008 demonstrates 

the following: Since May 18th, CDC has characterized 108 viruses. Of these, many are from 

the Southern Hemisphere. Amongst the 55 Influenza A(H1N1) viruses characterized, 53 (96%) 

are similar to the strain in the vaccine for this coming season, A/Brisbane/59/2007. Amongst 

the 15 Influenza A(H3N2) viruses characterized, all 15 (100%) were similar to 

A/Brisbane/10/2007 (e.g., selected 2008-09 vaccine strain). Among the 28 Influenza B viruses 

characterized, 23 (82%) were in the B/Yamagata lineage, which is represented in the vaccine by 

the B/Florida/04/2006 (e.g., selected 2008-09 vaccine strain). Of the strains circulating, about 5 

(18%) are in the B/Victoria lineage. Over the past 10 years, there has often been co-circulation 

of the B/Yamagata and B/Victoria lineages. With the limited numbers currently, it appears that 

Yamagata has the early lead among B viruses. However, Dr. Fiore cautioned not to make too 

much of the relatively small number of viruses characterized in terms of what can be predicted 

for the upcoming season. 

With regard to influenza vaccine coverage and effectiveness studies, NIS data from the 2006-

2007 season were published in the MMWR in September 2008. Some coverage data were 

presented during the June 2008 ACIP meeting. In the three years since the vaccination 

recommendation for all 6 to 23 month olds was passed, there have been relatively low 

increases in coverage over that time period. In the 2004-2005 season, 33.4% of children in this 

age group received 1 or more doses and 17.6% were fully vaccinated. In the 2005-2006 

season, 31.9% of children in this age group received 1 or more doses and 20.6% were fully 

vaccinated. In the 2006-2007 season, 31.8% of children in this age group received 1 or more 

doses and 21.3% were fully vaccinated. 

Data from the study by Zaman et al. published in the New England Journal of Medicine, was 

presented to the work group recently by Dr. Mark Steinhoff. This information was of such 

interest to the work group, they believed it should be brought to the attention of the full ACIP. 

This randomized controlled trial was conducted in Bangladesh in 2004 and 2005 amongst 340 

pregnant women who received either influenza vaccine or pneumococcal polysaccharide 

vaccine (control) during their third trimester. These women and their infants were followed-up 

throughout their pregnancies and for the first six months following birth. A number of outcomes

during that timeframe were examined, including febrile respiratory illness among the infants; 

laboratory-confirmed influenza among the infants; and febrile respiratory illness among mothers. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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By the end of the study, the infants in the control group had more cumulative cases of influenza 

as compared to those infants whose mothers had received influenza vaccine in the third 

trimester. Three of the key findings in this study were that clinical effectiveness was 28.9% 

against respiratory illness with fever, and there was 62.8% effective in preventing laboratoryconfirmed influenza among infants born to women who were vaccinated. Clinical effectiveness 

for prevention of respiratory illness with fever was 35.8% among mothers. It is not clear how 

generalizable these results are for the US, and additional studies need to be conducted in order 

to better understand the benefits of influenza vaccination for the infants born to vaccinated 

women. Infants under 6 months of age cannot be immunized, and there is very low coverage 

among pregnant women. These are powerful results and should be of interest to clinicians who 

provide care for pregnant women and young infants who are at high risk of severe influenza. 

With respect to CDC’s plans for monitoring antiviral resistance and vaccine effectiveness, this 

past season the interesting new wrinkle that influenza virus provided was the emergence of 

oseltamivir resistance among influenza A(H1N1) viruses. The season was characterized by a 

predominance of influenza caused by the other two circulating viruses, A(H3N2) and B in most 

US communities. However, by the end of the 2007-2008 season, of the 1026 influenza

A(H1N1) tested for oseltamivir resistance, 11.9% (n=123) were resistant. This compares to the 

previous season when it was only 0.7% (n=4 of 588). This represented a large increase during 

the 2007-2008 season (as of July 15, 2008); however, when adjusted for subtype prevalence, 

an estimated 2.1% of influenza A and B viruses in circulation in the US were resistant to 

oseltamivir. These data were reflected in worldwide data at the end of the 2007-2008 Northern 

Hemisphere season as reported on the WHO website (Reported to WHO as of July 18, 2008). 

Of the 7535 influenza A(H1N1) viruses tested, 1203 (16%) were resistant to oseltamivir, which 

is somewhat higher than that observed in the US.

In terms of the current status of antiviral resistance, testing shows that neuraminidase inhibitor 

resistance is being observed in influenza A(H1N1) viruses only. There is no neuraminidase 

inhibitor resistance among influenza A(H3N2) and influenza B viruses. All of the influenza 

viruses tested remain sensitive to zanamivir, the other neuraminidase inhibitor that is used. 

Oseltamivir-resistant influenza A(H1N1) viruses tested are sensitive to adamantanes 

(rimantadine and amantadine), although approximately 10% of oseltamivir-sensitive influenza 

A(H1N1) viruses were resistant to adamantanes in the US’s last season. Those that are 

resistant to oseltamivir do not seem to be resistant to the adamantanes at this point. However, 

adamantane resistance among other influenza viruses is very common (e.g., over 99% of 

influenza A(H3N2) viruses tested are resistant, and the influenza B viruses are not sensitive to 

adamantanes).

Regarding some key considerations at the onset of the new season with regard to antiviral 

resistance, it seems likely that oseltamivir-resistant influenza A(H1N1) viruses will circulate in 

the US. The overall prevalence of oseltamivir resistance in the US during the 2008-2009 

season is difficult to predict, but will depend on the prevalence of resistance among H1N1 

viruses and the prevalence of H1N1 among circulating influenza viruses. Also of note is that 

CDC has some preliminary data [US: N Dharan et al IDSA 2008; EU: ECDC 2008] indicating 

that the virulence of oseltamivir-resistant H1N1 viruses does not appear to be different from 

those that are sensitive to oseltamivir. That is, persons who are infected with these viruses 

actually found out by accident when tested later. They had the same clinical picture and did not 

have different exposures, nor did their family members.
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Pertaining to antiviral resistance issues at the start of the 2008-2009, vaccination should be 

encouraged and should be effective against the currently circulating Oseltamivir-resistant 

influenza A(H1N1) viruses. The antiviral recommendations have not been changed for 

treatment and chemoprophylaxis, with neuraminidase inhibitors remaining the drugs of choice 

(e.g., Oseltamivir or Zanamivir). Adamantanes are not recommended at this juncture due to the 

high resistance levels in H3N2 and B. CDC has worked to improve the representativeness of 

surveillance for antiviral resistance by collecting viruses from throughout the country in a more 

representative fashion, and will provide that data to the work group and potentially ACIP as 

needed. CDC is also working toward increasing laboratory testing capabilities for antiviral 

resistance. At this point, most laboratories cannot do this, but in the future the hope is this 

technology will be available. Surveillance data will be provided throughout the season and 

discussed in the ACIP Influenza Vaccine Work Group. Additional treatment or 

chemoprophylaxis guidance should be considered if widespread circulation of resistant viruses 

is observed.

With regard to the plans for annual influenza vaccine effectiveness assessments, four US sites 

have been funded for three years to estimate vaccine effectiveness for lab-confirmed medically 

attended outcomes. In the past season, one site was conducting rapid vaccine effectiveness

estimates and provided an in-season vaccine effectiveness estimate. This season, the four US 

sites that are funded for the next three years will be examining vaccine effectiveness in all 

groups recommended for vaccination by ACIP. Depending upon how the season goes, this 

should be powered to permit age-specific vaccine effectiveness estimates for outpatient visits 

for influenza. The plan is to produce one within-season estimate and a final estimate at the end 

of the influenza season. Additionally, two of these sites are funded for a separate project to 

assess humoral and cell-mediated immunologic responses to inactivated vaccine (TIV) in 

persons aged 50+ as part of CDC’s interest in vaccination of the elderly.

Update on Vaccine Effectiveness Studies, Adult 

Vaccination, and Influenza Vaccine Effectiveness in the Elderly

Kathy Neuzil, MD, MPH

Chair, ACIP Influenza Vaccines Work Group

Dr. Neuzil reminded everyone that last year, the work group extended the universal 

recommendation in children through age 18. They were asked to reconsider current vaccination 

recommendations for adults 19-49, which the work group has been discussing. An estimated

50% of adults in this age group already have an indication for annual vaccination. These 

include women who will be pregnant during influenza season and their contacts; persons who 

are contacts of children younger than five years old, adults 50 years of age and older, and / or 

children and adults with chronic medical conditions that confer higher risk of influenza 

complications; and healthcare workers. All adults may receive the vaccine if they wish, given 

that there has always been a permissive recommendation in this age group.

In terms of the critical factors assessed by the work group in consideration of expanding annual 

vaccinations to include all healthy adults, the usual issues reviewed for this type of analysis 

were contemplated (e.g., vaccine supply, vaccine safety, vaccine effectiveness, disease burden, 

cost-effectiveness, feasibility, acceptability, and implementation). Based upon these 

considerations, the work group believed that at this point, further information was needed to 

inform this decision about vaccination recommendations for young adults. Work group 

members were convinced about the burden of illness in this age group and the safety and 

effectiveness of the vaccine. However, in order to determine whether moving from a permissive 
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recommendation to a full recommendation would make any difference in terms of coverage 

rates and acceptability of this vaccine in this age group, there needs to be a clearer 

understanding regarding why coverage rates among currently recommended adult groups 

remain low. The coverage rates for healthcare workers, pregnant women, and contacts of highrisk groups remain well below recommended levels. Therefore, it is not clear whether more 

adults would seek out vaccination if the recommendation was changed from permissive to 

universal. Also unclear is what motivators might increase adult coverage and what the barriers

are to vaccinating in non-medical sites (e.g., workplace, retail settings). The childhood 

recommendation was recently expanded, so the work group believed it would be worthwhile to 

examine the impact of this recommendation before moving forward with any changes in the 

adult recommendation. 

With respect to vaccination recommendations for healthy adults 19-49, the work group 

expressed continued support for routine vaccination of contacts of persons at risk for influenza 

complications, including healthy adult contacts of persons 50 years old or older, persons 

younger than 5 years old, pregnant women, and persons with chronic medical conditions. The 

work group also expressed continued support for the permissive recommendation for adults. 

That is, any healthy adult who wants to be vaccinated should be vaccinated, and an ample 

supply of various vaccine formulations should be widely available (+/- preservative, nasal and 

injected vaccines). They also expressed continued support for innovative efforts to vaccinate 

adults in non-medical settings without a prescription (e.g., clinics in community settings such as 

retail, pharmacies, and workplaces; and public-private partnerships).

The work group also discussed influenza vaccine effectiveness in the elderly. The impetus for 

these deliberations was recent publications with vastly differing estimates of effectiveness for 

influenza vaccination in the elderly. Post-licensure observational studies are very important 

tools for monitoring vaccine effectiveness. Such studies related to influenza vaccine in the 

elderly are particularly challenging to perform and interpret. The work group recognizes that 

there are confounding issues, such as selection biases. The dogma was that inadequate 

adjustment for medical co-morbidities would usually underestimate vaccine effectiveness, but it 

has recently been observed that adjusting for co-morbidities may also overestimate vaccine 

effectiveness depending upon the methodology. It is difficult to adjust for other characteristics 

of vaccinees versus non-vaccinees (e.g., vaccine seeking behavior) in these observational 

studies, which often rely on automated databases. It is also known that all of the recently 

published studies rely on non-specific and limited outcome measures. Influenza causes a range 

of non-specific clinical syndromes, and frequently studies are being reviewed that focus on one 

clinical syndrome. Also known is that these clinical syndromes are non-specific, and that using 

a non-specific clinical outcome attenuates the efficacy of vaccine effectiveness. The 

Bangladesh study described by Dr. Fiore was a perfect example of this, in which estimate for 

vaccine effectiveness in the infants against clinical respiratory illness was approximately 28%, 

but in laboratory-confirmed influenza illness it was 62%. There are no laboratory-confirmed 

outcomes measured in many recently published observational studies of vaccine effectiveness 

in the elderly.

A recent re-analysis of a randomized controlled trial of influenza vaccine in persons 60 years of 

age and older was published as a letter in The Lancet. Not only was this a randomized 

controlled trial, the gold standard for controlling for co-morbidities, it also used a laboratoryconfirmed outcome. Overall, there is a point estimate for vaccine effectiveness of 58%. 

Importantly, this is similar in 60 to 69 year olds (59%) and 70 years old and above (57%), with 

wide confidence intervals because of the numbers in those 60 to 69 years of age and 70 years 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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of age and above. The authors also studied seroprotection rates, which are also similar among 

the age groups studied. The following table illustrates the findings:

 “Mortality benefits of influenza vaccination in elderly people.” 

The Lancet. August 2008, Volume 8, page 460.

In summary, the Influenza Work Group recognizes that influenza causes substantial morbidity 

and mortality in the elderly population; that influenza vaccine is safe and efficacious in the 

elderly population; and reaffirms the recommendation that all persons 65 years of age and over 

should receive influenza vaccine each year. Additionally, contacts of persons 65 years of age 

and over should receive influenza vaccine each year. The work group also supports efforts to 

conduct prospective, population-based studies with laboratory-confirmed endpoints that can 

overcome some of the limitations described to monitor influenza vaccine effectiveness on an 

annual basis. The work group also encourages efforts to increase vaccine immunogenicity in 

the frail elderly population. Future plans are to review studies of new adjuvanted vaccines, 

novel delivery methods, and alternative doses and schedules for this age group.

CDC’s Dr. David Shay shared information with Dr. Neuzil regarding a planned study in the 

Emerging Infections Program surveillance system of vaccine effectiveness in adults 50 and 

over. This will be a case controlled study examining the effectiveness in preventing influenzaconfirmed hospitalizations in areas of 10 states beginning in the 2008-2009 season. Cases will 

be defined as those hospitalized with community-acquired influenza infections as diagnosed by 

clinician-ordered tests. Controls will be those not hospitalized with influenza or respiratory 

infection up to the hospital admission date of the corresponding case. They will be matched by 

a 5-year age band and county of residence. This study will be conducted for three consecutive 

influenza seasons, with a goal to enroll 1200 cases and 1200 controls.

Dr. Neuzil then requested that the manufacturers present make brief statements with respect to 

their plans for alternative vaccines in the elderly.

Ted Tsai of Novartis Vaccines reported that Novartis markets an adjuvanted seasonal vaccine 

for the elderly in Europe called Fluad® that is adjuvanted with an oil and water emulsion called 

MF59. The vaccine has been licensed since 1997 in some European countries, where more 

than 40 million doses have been distributed. Chiron, which was subsequently acquired by 

Novartis, developed this vaccine but never undertook any clinical efficacy or effectiveness 

studies. However, an investigator in Valencia, Spain (Joan Puig-Barberá, PhD, MPH, MD)
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conducted case controlled studies across two influenza seasons. He examined the impact of 

vaccination for hospitalizations among the elderly over 65 years of age for acute pneumonia, 

acute coronary syndrome, and acute cerebrovascular accident. He used many of the same 

adjustments that have been reported in the literature in the administrative database studies, 

including propensity scores for vaccination. Because it was a case-control study, he was able 

to conduct face-to-face interviews with cases and controls, and was able to administer an 

instrument (e.g., the Barthel Index) to measure disability. After all adjustments, he found 

significant reductions for pneumonia, acute coronary syndrome, and acute cerebrovascular 

disease. These results were published in Vaccine. ACIP members were provided a copy of the 

article. Dr. Tsai offered to facilitate a future session on this issue. With respect to superiority,

Dr. Tsai indicated that Novartis is engaged in the second year of a three-year observational 

study in Lombardy, Italy in a database vaccine and medical outcome database link study to 

examine clinical impact. Results for this study will be available in 2010. The placebo-controlled 

study Dr. Neuzil mentioned was conducted with a vaccine FLUVIRIN® that was manufactured 

by one of the companies that Novartis acquired. This formulation of FLUVIRIN® is the 

tetravalent formulation of the trivalent vaccine distributed in the US, and contains two influenza 

B virus strains. In comparing results across different age groups, it is important to bear in mind 

that FLUVIRIN® is a tetravalent vaccine. 

Peggy Reynolds of GlaxoSmithKline reported that approximately 5 years ago, GSK began 

clinical development of an adjuvant TIV vaccine intended for use in the elderly with the hope of 

improving efficacy. This is an oil and water emulsion. Beginning in September 2008,

enrollment into an efficacy trial began. The plan is to enroll 43,000 individuals and the primary 

endpoint will be efficacy against culture-proven influenza, along with other secondary endpoints

(e.g., safety, immunogenicity, multiple disease outcomes).

Marie G. Mazur of CSL Biotherapies reported that CSL Biotherapies has proprietary adjuvant 

called ISCOMATRIX®,which is included in a number of vaccines. ISCOMATRIX® may boost 

the effectiveness of vaccine applications. CSL Biotherapies has recently completed a Phase II 

clinical trial in people over 60 years of age, and are currently analyzing the data. They should 

be ready to comment on the results later in 2008.

Michael Decker of sanofi pasteur indicated that in about 2000 or 2001, sanofi pasteur began 

developing a high-dose influenza vaccine, unadjuvanted, for use in the elderly. Phase I and II 

studies were conducted at Baylor and Rochester in coordination with NIH. A large Phase III trial 

was recently completed, the results of which will be presented in a poster at ACAC / IDSA. That 

study demonstrated statistically significantly superior immunogenicity results by every measure 

for all components of the vaccine, including pre-specified criteria for superiority. sanofi pasteur 

believes that this vaccine has the potential to offer major public health improvement, and is 

currently awaiting CBER’s response to sanofi pasteur’s proposed licensure strategy.

Discussion

Dr. Morse recapitulated that in terms of adult vaccine, the work group appeared to have found

sufficient evidence for the committee to consider universal immunization based on the burden of 

disease, safety, cost-effectiveness, and vaccine supply. The remaining questions pertained to 

feasibility and implementation issues. He inquired as to whether the remaining questions were 

sufficient to delay bringing the issue for a vote before the end of the decade.
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Dr. Neuzil responded that any adult 19 to 49 years of age may receive influenza vaccine. The 

major issue with respect to the vote pertained to whether a universal recommendation would 

increase coverage. The work group believes further information is needed, particularly given 

that influenza vaccine coverage remains low in many groups. Universal vaccination has 

recently been recommended to another large group, and the work group believes that it is 

important to determine whether ACIP’s recommendations are having any impact on increasing 

coverage. Vaccine uptake in the 6 to 23 month-old age group is disappointing, and it appears 

that the age-based recommendation has done little to improve coverage in this group. Perhaps 

more emphasis is needed on studies to better understand how to improve coverage.

Dr. Morse asked whether anyone was studying whether immunizing a parent when they bring 

their child in would help to increase uptake. 

Dr. Neuzil responded that she did not know whether anyone was pursuing the issue of 

pediatricians giving vaccines to adults and / or adults giving vaccines to children.

Dr. Marcy indicated that there is a section on infectious diseases at the academy that 

specifically discussed that at a meeting in Boston a couple of weeks prior to this ACIP meeting. 

While this practice is encouraged, not all pediatricians want to immunize adults. Moreover, 

while adults are quick to volunteer their children for a vaccine, they do not want to do it 

themselves.

Ms. Ehresmann reported that the University of Minnesota is trying to break the Guinness Book 

of World Records for flu shots given in one day, which is currently 3271. The University of 

Minnesota launched a major campaign with a goal of breaking this record. Perhaps this 

competition could be expanded to other schools in order to launch this effort on a broader scale. 

Dr. Campos-Outcalt (AAFP) pointed out that family physicians frequently vaccinate children and 

adults together and that the AAFP’s members are accustomed to doing this.

Dr. Schuchat noted that among the factors the work group considered was acceptability; that is, 

the concept of whether a universal recommendation might be more or less acceptable than the 

permissive one that exists currently. There have been discussions about the value of a public 

engagement exercise regarding the permissive versus universal recommendation—something 

that might help bring some societal values to the deliberations of the ACIP. While one question 

pertains to whether coverage would increase with a universal recommendation, another 

question concerns whether push-back about requirements or recommendations might have 

unintended consequences. While the issue of acceptability is not always considered formally 

when ACIP makes recommendations, for this issue it may be relevant.

Dr. Ken Schmader (AGS) indicated that AGS wanted to go on record to strongly support the 

statements of the Influenza Work Group on influenza vaccine in the elderly as articulated by Dr. 

Neuzil. 

Dr. Judson said that based on his discussions with physicians and his prior experience in public 

health, he believed that a lot of the inability to achieve greater uptake of influenza vaccine was 

due to scientific questions that have not been adequately answered. There are too many 

reports that vary widely in terms of efficacy. A major issue that must be dealt with for any study

to move forward pertains to residual immunity in study subjects either as a result of infection 

with constantly circulating viruses or prior immunizations. Someone who is not immunized this 

year is not completely susceptible. In fact, they probably will be resistant to most viruses they 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

163

encounter if they have been immunized on a regular basis previously and / or have been 

infected. For the elderly, the healthy person bias is an issue. This was probably the answer to 

the astounding finding in which influenza vaccine was reported to reduce mortality by 50% until 

someone pointed out many of the deaths occurred before the influenza season even arrived. 

Many of the people getting the vaccine were actually healthier than those who did not get it. It is 

reported as being anywhere from 40% to 90% effective, which needs to be made more precise. 

Dr. Neuzil acknowledged that influenza is a greater challenge than any other vaccine, given that 

it changes every year and an annual vaccination is needed. There is a body of evidence that 

substantiates that what influences and supports an individual decision more than anything else

is a provider recommendation to obtain an influenza vaccine. Therefore, it is incumbent upon 

providers to recommend influenza vaccine to their patients. 

Charles E. Rupprecht VMD, MS, PhD

Chief, Rabies Program

PRB / DVRD / NCZVED / CCID / CDC

Dr. Rupprecht provided an update on human rabies vaccine supply and reported upon the 

related proposed actions. The last quarter was perhaps the most challenging one in 2008, and 

was a reminder that rabies is the most significant zoonosis that health departments deal with 

routinely. The usage rates of vaccine during the busy summer months sometimes exceeded 

more than 1600 doses per day. The autumnal equinox put things back into balance with the 

advent of cold weather and the reduction of some animal reservoir activities, particularly in the 

North Temperate Zone. 

The vaccine situation has been volatile, with the pendulum swinging back and forth between 

which company had available supplies of vaccine. Until September, only post-exposure 

prophylaxis was being utilized during the waning summer months. Obviously, it was a dilemma 

to have to have password-supplied risk assessments at the local level. Conflicts arose between 

the practice of medicine and the practice of public health. While the sanofi pasteur product will 

remain available only for post-exposure prophylaxis, the Novartis product reentered the market 

in October for post-exposure prophylaxis only without a password requirement. The preexposure vaccine supply was suspended for prioritized first responders throughout most of the 

summer, but has now been resumed with the reentry of Novartis. The largest population base 

that was not receiving supplies during the summer were veterinary schools; however, this 

supply has resumed as well. 

Medical education for the public at large and providers remains a challenge. This is illustrated 

by a recent Epi-Aid request for which two of CDC’s officers deployed to Montana to try to 

mitigate this situation. In this setting, more than 100 families were evaluated for application of 

rabies post-exposure prophylaxis after “contact” with a dead rabid bat that was brought to a 

school for Show-and-Tell. 

To date the ad hoc working group has a multidisciplinary nature, and adds approximately one 

new national work group member each month. Both HHS and non-HHS members continue to 

strive toward improvements in medical education and means of getting proper information to 

risk groups. 

Rabies Vaccine Supply
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From the standpoint of semantics, it is important to recognize that there was no true vaccine 

shortage in 2008, per se, versus often severe limitations (e.g., interruptions in supplies; supplies 

remaining less than ideal).. Clearly, there were times in which the tipping points for use of the 

recommendations were nearly reached However, the tipping points for a shortage were never 

reached by definition, which is, “Based upon a combination of historical animal rabies 

surveillance data, prior mass human rabies exposure situations, and conventional aggregate 

commercial seasonal distributions of product over time, a national shortage in biologicals would 

be forecast when expected PEP needs are projected to out strip estimated rate of use of 

available supplies of human rabies vaccines or immune globulins.” There have been no human 

cases that resulted from the supply interruptions and importantly, no individuals who were truly 

exposed went without reception of prophylaxis. 

A draft of interim recommendations for human rabies prevention in the event of a forecast 

shortage of biologicals used in prophylaxis was previously distributed to ACIP, and favorable 

comments were received. On the basis of those recommendations, not only was a shortage 

averted, but also the draft recommendations are now in their second version that will be utilized 

only if that tipping point were to come into play. 

Significantly, use of alternative schedules, such as the elimination of the fifth (final dose) of 

vaccine in a naïve patient during PEP, was one of the recommendations by the work group. 

Based upon review of the draft document by ACIP members, the suggestion was made to 

evaluate this option for routine PEP use, regardless of a vaccine shortage. Therefore, an ACIP 

work group is being formed with the thesis that there is no substantive reason why the fifth dose 

in post-exposure prophylaxis would be supported significantly because, based on a modern 

understanding of rabies virus pathobiology, there is no recrudescence over time, no absolute 

magical seroprotective titers that once in decline allows rabies virus to re-occur, followed by 

acute disease and death thereafter. To this effect, Dr. Cieslak will chair this group and Dr. Lett 

will serve as another ACIP member. Other national work group members will soon be 

announced. The focus of this work group will be to review evidence for eliminating the last PEP 

dose; develop draft recommendation for an altered schedule; discuss these during the February 

2009 ACIP meeting; and present a statement for consideration of a vote. The source of 

evidence for the ACIP work group will be modern rabies virus pathogenesis concepts, basic 

immunization principles and kinetics, published literature on clinical trials, epidemiological 

surveillance on PEP failures, and consultation with industrial partners.

In summary, supplies of biologicals used in human rabies prophylaxis are expected to remain 

less than ideal over the next year. As in 2008, CDC, FDA, HHS, industry, state health 

departments, and other national stakeholders will continue to work together toward productive 

solutions to mitigate current human rabies vaccine supply issues. Deliberations of an ad hoc 

national rabies working group resulted in the development of draft interim recommendations 

related to contingency actions that would be utilized in the event of any forecast actual 

shortages in the future. Formation of an ACIP work group to consider a reduced vaccine 

schedule for PEP is one outgrowth of this process, regardless of a vaccine shortage.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Discussion

Dr. Christine Hahn, CSTE, indicated that the experience in Idaho was the potential conflict with

the clinical urge to administer vaccine. However, they found that a lot of times diagnostic 

testing was going to be done but the provider either was not aware or was too anxious to wait 

for the test result. Once they were told to hold off because they would be given results in 24 

hours, most were willing to wait once they knew it would be okay to do so. They had a similar 

situation with a dead bat experience in which they were able to save hundreds of potential 

vaccines from being given based upon waiting for testing. This was a good experience because 

she was under the impression that providers were very aware of the 10-day observation window 

for domestic dogs, cats and ferrets, but many were not. 

Dr. Marcy pointed out that articles were published in Vaccine in July and PLoS in April regarding 

intradermal vaccine, and requested that Dr. Rupprecht comment on this.

Dr. Rupprecht replied that the intradermal route for vaccination for pre- or post-exposure is not 

new or novel. It was licensed at one time in the US. From a global sense, it is still the way to 

approach this situation in a cost effective manner, particularly in developing countries. There is 

currently a pending IND to re-examine the utilization of intraderma vaccination during preexposure immunization to provide support during a shortage and to demonstrate significantly 

the immunogenicity and safety in naïve and previously vaccinated individuals, globally and in 

the US. As those data are generated, CDC will update ACIP. 

Dr. Jeanne M. Santoli 

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Dr. Santoli reported on the vaccine supply with respect to Hib vaccines, varicella-containing 

vaccines, and hepatitis A vaccines for which shortages have been experienced during 2008. 

The Hib vaccine shortage began in December 2007 with a voluntary recall of certain lots by 

Merck. CDC’s interim recommendations called for deferral of the booster dose at ages 12-15 

months, except for infants at increased risk for Hib disease. With respect to vaccine availability 

during the shortage to date, Hib vaccines manufactured by sanofi pasteur (ActHIB® and 

Pentacel®) have been used for all children except AI / AN living in AI / AN communities. AI / AN 

children living in AI / AN communities have received Merck’s unrecalled PedvaxHib® from 

CDC’s stockpile. Merck was originally projected to return to the US market during fourth quarter 

of 2008. On October 17, 2008, Merck released a public statement that they will not return to the 

US market until mid-2009. The reason for the delayed return is an additional manufacturing 

process change requiring a regulatory filing with FDA that must be approved prior to return to 

market. No changes have been made in the Hib recommendations at this time. Deferral of the

booster dose will continue for children 12-15 months of age, except for those at increased risk of 

Hib disease. Children at increased risk of Hib disease include those with asplenia, sickle cell, 

leukemia, other malignant neoplasms, and AI / AN children. AI / AN children living in AI / AN 

communities will be provided with PedvaxHib® from CDC’s stockpile. Providers should register 

and track children in whom the booster dose is deferred to facilitate recall. CDC is working 

closely with sanofi pasteur as they review their current Hib vaccine supply and capacity to serve 

Vaccine Supply
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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the US market. At this time, sanofi pasteur is confident that they have sufficient Hib doses 

(ActHIB® and Pentacel®) to cover the 3-dose series through mid-2009. The CDC stockpile 

currently has sufficient PedvaxHib® to provide vaccine for AI / AN children living in AI / AN 

communities for the new expected duration of the Hib shortage.

With respect to varicella-containing vaccines, the current and projected supply of single antigen 

varicella vaccine is sufficient for anticipated demand in 2008 and 2009, including the second 

dose catch-up. Zoster vaccine is being produced, but there are currently distribution delays of 

approximately 8-14 weeks. MMRV vaccine is not currently available. Merck will provide an 

update on return to market once production capacity issues for zoster vaccine are resolved.

Regarding hepatitis A vaccines, Merck is not currently accepting orders for pediatric and adult 

hepatitis A vaccines (Pediatric & Adult VAQTA®). Merck estimates that Pediatric VAQTA® will 

be available in the fourth quarter of 2008 and adult VAQTA® will be available in the first quarter

of 2009. GSK production and supply of their pediatric and adult hepatitis A vaccines (pediatric 

and adult Havrix®) and their adult hepatitis A/hepatitis B combination vaccine (Twinrix®) are 

currently in good supply to meet demand. Although vaccine has not been available from one of 

the manufacturers, no changes have had to be made in the current recommendations.

Discussion

Dr. Morse inquired as to whether burden of disease was being followed during these shortages 

to examine any impacts.

Dr. Schuchat responded that CDC has surveillance for Hib and hepatitis A with state and local 

health departments. However, zoster is not under surveillance. Varicella surveillance is actively 

conducted in some states, but not others. With Hib, the particular issue is to strongly encourage 

providers, laboratories, and state health departments to ensure that cases of hemophilus 

influenza disease result in serotyping being conducted because there are many cases in 

children under five in which isolates are not serotyped, so it is not possible to confirm whether 

the cases are due to B or otherwise. There have been efforts to reach out to states and 

providers, but further efforts would be beneficial.

Dr. Sawyer indicated that in California the monovalent Hib vaccine from sanofi pasteur is 

reaching short supply, but the Pentacel® product is available. In the current financial climate, 

he wondered whether there were any projections regarding whether any state or local 

jurisdictions may experience difficulties in obtaining enough Pentacel® since it is more 

expensive, and whether that would cause jurisdictions to cut back further in Hib use.

Dr. Santoli replied that because this shortage was expected to end by this time, there was not a 

lot of information available about how the purchase of Pentacel® was affecting spending on the 

part of state and local jurisdictions that contribute funds to protect their children. Pentacel® has 

only been available on the CDC contract for grantees since August. CDC has heard concerns 

from universal states that a change in what they had planned for spending due to the hib 

shortage may compromise their abilities to pay for the complement of vaccines. However, this 

has been anecdotal rather than any type of systematic information. 

Dr. Lett indicated that Massachusetts, a universal state, has an advisory committee that decides 

what vaccines are used in the state that is chaired by the Massachusetts Chapter of the AAP 

and has representation from the Family and Physician Chapter, Nurse Practitioners, et cetera. 

This advisory committee approved emergency use of Pentacel® in August. In September, they 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

167

approved expanded use of Pentacel® for the duration of this problem. It has been very slow 

and hard work to convince providers to switch to Pentacel® even in a shortage. Therefore, 

Massachusetts targeted the 100 largest providers because they were afraid they would not be 

able to meet providers’ orders with single antigen Hib vaccine. Slowly, the acceptance of 

Pentacel® has increased to over 50%, and Massachusetts is now in negotiations about its 

Pentacel® allocations. This reflects how successful they have been, although it took three 

months of constant communications, workshops for providers, et cetera. It is very difficult to get 

providers to incorporate new vaccines quickly into their practices. They typically have to make 

changes in their electronic databases and electronic medical records, and like to have time to 

think about changes in practice in combination vaccines. They also had to vote to approve use 

of additional state funds for the premium that Pentacel® is going to cost. This will decrease the 

rapidity with which they can increase uptake of Pentacel®, but thus far it is going well and they 

are having to ask providers not to switch unless the allocation can be increased. They have 

received an increase in the allocation once from CDC. 

Overview

Jennifer L. Liang, DVM, MPVM

Meningitis and Vaccine Preventable Diseases Branch

National Center for Immunization and Respiratory Diseases

Dr. Liang reminded those present of the ACIP recommendations for tetanus toxoid, reduced 

diphtheria toxoid, and acellular pertussis vaccine (e.g., Tdap), which are as follows: 

 Adolescents aged 11 through 18 should receive a single dose of Tdap instead of Td for 

booster immunization against tetanus, diphtheria, and pertussis if they have completed 

the recommended childhood DTP / DTaP vaccination series (2005). 

 Adults aged 19 through 64 years old and have not previously received a dose of Tdap, a 

single dose of Tdap should replace a single dose of Td for booster (2006). 

There are currently two Tdap products available as a single dose booster in the US. The first is 

AdacelTM formulated by sanofi pasteur, which is licensed for both adolescents and adults. The 

second is Boostrix®, formulated by GSK, is currently licensed only for adolescents 10-18 years 

of age. GSK has filed for US approval for use of Boostrix® in adults 19-64 years of age, which 

is currently under review. 

Tdap (Boostrix®) in Adults
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

168

Immunogenicity and Safety of Boostrix® in Adults 19-64 Years of Age

Wayde M. Weston, PhD

GlaxoSmithKline Biologicals

Dr. Westin reported on data that GSK has collected on the immunogenicity and safety of 

Boostrix® in adults 19-64 years of age. Boostrix® is GSK’s tetanus toxoid, reduced diphtheria 

toxoid, and acellular pertussis vaccine. Boostrix® is currently licensed in 63 countries 

worldwide, with over 14.9 million doses distributed globally since its first approval in 1999. In 

2005, Boostrix® was approved in the US for adolescents 10-18 years of age. The file for US 

approval for use in adults 19-64 years of age is currently under review.

The goals of the adult development program are to demonstrate seroprotection against 

diphtheria and tetanus comparable to currently available Tdap vaccine; demonstrate 

immunogenicity of pertussis components and assess with respect to disease protection through 

immunobridging; evaluate immunogenicity when co-administered with influenza vaccine; and 

evaluate reactogenicity and safety relative to currently available Tdap vaccine. To address the 

objectives of the program, GSK conducted two clinical trials: Study 007 and Study 008. Study 

007 is the pivotal safety and immunogenicity study. Study 007 is comprised of 1522 subjects 

who received Boostrix® and 762 subjects who received Tdap comparator (AdacelTM). Study 

008 is a co-administration study with influenza vaccine. This study is comprised of 748 subjects 

who received Boostrix® co-administered with Fluarix® and 702 subjects who received 

Boostrix® one month after Fluarix®. In total, 2972 adults 19-64 were vaccinated with Boostrix®

in clinical trials. Assessments in both studies included antibody levels prior to vaccination and 

one month after vaccination, solicited local and general adverse events, and unsolicited AEs 

and serious adverse events. Subjects in both studies could not have had a Td vaccine within 

the previous five years, nor could they have ever had a Tdap vaccine. In total, there were 2972 

adults 19 through 64 years of age received a Boostrix® vaccination in these clinical trials.

With regard to an increase in seroprotection after vaccination in Study 007, serprotection rates 

for both diphtheria and tetanus, as well as percentages of subjects with 10 times the 

seroprotective level of antibody, approached 100% following vaccination for both diphtheria and 

tetanus for both Boostrix® and AdacelTM. In Study 008, the percentages of subjects with 

antibody values at or above the defined cutoff levels were similar between the co-administered 

vaccines group and the sequential vaccines group for diphtheria and tetanus. Regarding antipertussis antibody levels in Study 007 before and after vaccination with Boostrix® or AdacelTM, 

the investigators examined onIy antibodies to antigens that were shared by the two vaccines 

(e.g., pertussis toxoid, filamentous hemagglutinin, and pertactin). For all three antigens, 

multifold increases in antibody levels were observed following either vaccine at one month 

following vaccination. 

In Study 008, post vaccination antibody levels for pertussis were seen to increase multifold in 

both the subjects receiving both vaccines together and subjects receiving Boostrix® one month 

after Fluarix®. Antibody levels for Boostrix® co-administered with Fluarix® were lower than for 

when Boostrix® was given one month after Fluarix®. Similar results were observed in a study 

of sanofi pasteur’s AdacelTM vaccine co-administered with Fluzone®, so this may represent a 

class effect for co-administration of Tdap and flu vaccines. This effect is not likely to be 

clinically important, given that efficacy in with regard to pertussis protection was not directly 

addressed in either the pivotal study (007) or the influenza vaccine co-administration study 

(008). This question was addressed in this program in the same way that was done for 

Boostrix® in adolescents via immunobriding to efficacy data and antibody data obtained with 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

169

DTaP vaccines. In a study conducted in Germany, GSK’s DTaP vaccine Infanrix® has shown 

efficacy of approximately 89% of protecting children against WHO-defined pertussis. Infanrix®

contains the same pertussis antigens as does Boostrix®, but in greater amounts. Antibody 

levels were compared for pertussis antigens in the Infanrix® efficacy study with those observed 

in the Boostrix® studies. The Boostrix® antibody levels were at least as high as those following 

Infanrix® in the group in which protection was demonstrated. It can be inferred from this 

comparison that Boostrix® should be protective as well. 

Pertaining to change in anti-pertussis antibodies over time, GSK continues to follow these 

subjects to examine antibody persistence to vaccine antigens. Levels of all three antibodies 

remained elevated relative to pre-vaccination values at one year following vaccination, with 

similar results observed for diphtheria and tetanus antibodies one year after vaccination. GSK 

plans to make future assessments and 3, 5, and 10 years post-vaccination.

Regarding Study 008, in terms of increase in seroprotection after vaccination for influenza 

antigens, rates shown by percentages of subjects with antibody titers greater than 1:40 seemed 

to be similar for both the Boostrix® and Fluarix® co-administration group and for Fluarix® given 

alone in the sequential administration group. No differences were observed between the groups 

in post-vaccination flu GMT or in the percentages of subjects with 4-fold or greater rise in 

antibody titer between the co-administration and sequential administration groups.

With respect to the reactogenicity data obtained in the pivotal safety and immunogenicity study, 

overall reporting of solicited local symptoms (e.g., injection pain, redness, or swelling reported 

within 15 days of vaccination) was greater in the Adacel® group than in the Boostrix®. There 

were statistically significant differences in subjects reporting any level of injection site pain at 

61% for Boostrix® and 69% for Adacel®, injection site redness at 21% for Boostrix® and 27% 

for Adacel®, and swelling at 18% for Boostrix® and 26% for Adacel®. A few subjects reported 

symptoms with Grade 3 intensity. Reporting of Grade 3 local events was similar between the 

two treatment groups with the exception of swelling with a diameter of at least 50 mm, which 

was more frequently reported in the Adacel® at about 2.8% of subjects versus 1.4% in the

Boostrix® group. There is a statistically significant difference here, but with the caveat that 

there are very few subjects reporting that intensity of an event.

Solicited general symptoms (e.g., fatigue, fever, GI, headache) within 15 days of vaccination 

was generally similar between the two treatment groups with the exception of subjects reporting 

fatigue of Grade 3 intensity, which was reported more frequently by Boostrix® recipients (2.5%) 

versus Adacel® (1.2%). This represents a statistically significant greater percentage for 

Boostrix®. Solicited general symptoms for subjects reporting any level of fever (e.g., ≥37.5°) 

were similar, which was reported by about 8% of Adacel® recipients and 5.5% of Boostrix®. 

Again, this represents a statistically significant difference between the groups. 

Unsolicited AEs were reported by 17.8% of Boostrix® subjects and 22.2% of Adacel® subjects

in the pivotal safety and immunogenicty study. There were no apparent differences between 

the groups in the nature of the reported AEs or SAEs. SAEs were reported by 21 subjects in 

Boostrix® group (1.4%) and by 13 subjects in the Adacel® group (1.7%). There were 2 

fatalities, one of which was in the Boostrix® group from ovarian cancer, and one of which was in 

the Adacel® group from myocardial infarction.
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

170

Conclusions from this program are that, in adult subjects, Boostrix® provides diphtheria and 

tetanus seroprotection comparable to that provided by the adult-approved US-licensed Tdap 

vaccine. Immune responses to acellular pertussis antigens is consistent with protection against 

disease, when given alone or co-administered with influenza vaccine. Boostrix® caused no 

interference with immune response to co-administered influenza vaccine. The safety and 

reactogenicity profile of Boostrix® is generally similar to that of adult-approved Tdap vaccine, 

with a generally lower incidence of local reactions compared to the US-licensed Tdap vaccine. 

Upon approval, Boostrix® will provide US practitioners with an additional choice for providing 

adults with the recommended Tdap vaccination.

Discussion 

Dr. Morse note that a couple of years previously when recommendations were approved for 

Tdap in adults, the age group >65 years was not included because of the lack of an FDAapproved product. It was his understanding that some clinical trials were underway to examine 

vaccine in that age group, about which he requested further information and a timeframe.

Dr. Weston responded that GSK is planning to conduct such trials, which they expect to begin in 

2009.

Dr. Morse pointed out that there is a potential gap in 7 to 9 year olds that would not be covered. 

He wondered whether any breakthrough disease was being observed in this age group. If so, 

he wondered if there were any clinical trials planned to study expansion of vaccine into this 

group.

Dr. Messonnier replied that in general, pertussis surveillance has some difficulties. It has been 

five years since the first of the series of pertussis statements were written, so CDC is planning 

to review all of the guidance to ensure the impact of the statements over the years. The plan is 

to consolidate the statements. ACIP will hear more about the pertussis surveillance data and 

will be able to engage in discussions about this over the next year or so. 

Dr. Englund requested further information regarding the ages, median ages, and ranges in 

GSK’s adults. She also inquired as to where these studies were conducted. For the 

immunobridging study, she said she personally would have preferred to see results given as a 

GMC with some type of confidence intervals or standards deviations. 

 

Dr. Weston responded that these studies were conducted entirely in the US. The investigators 

stratified for ages in both studies, and had similar distribution amongst the different age strata. 

There was good representation of all of the age ranges across the enrollment spectrum. 

Dr. Judson said it appeared that the antibody responses to the three pertussis antigens were a 

quarter to a third lower in those who received co-administration with Fluvax®. This appeared to 

be more significant than Dr. Westin indicated.

Dr. Weston replied that this was correct. The levels of pertussis antibody observed in the coadministration group were, in fact, lower than what was observed in the sequential 

administration group. Based upon the bridging analysis, this is not likely to be clinically 

significant. 
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

171

Ms. Stinchfield noted that when ACIP approved Tdap, they wrote into the recommendation for 

healthcare workers who had been vaccinated but were exposed to pertussis that they should 

have post-exposure prophylaxis, and there was to be further study of this issue. This is an 

interesting time in hospitals, given that the majority of staff members have received Tdap. They 

do not want to wear masks or take antibiotics. With that in mind, she requested that CDC offer 

an update on the status of the study. 

Dr. Messonnier responded that CDC funded a study to examine this issue. However, the study 

was funded at a time when pertussis incidence was decreasing in the study site at Vanderbilt 

and there were not enough exposures to result in data upon which to base changes in the 

recommendations. This is one of a series of issues which CDC plans to review with the reconvening of the Pertussis Work Group. This will likely be another reconsideration of expert 

opinion as opposed to there being sufficient data upon which to make a decision. 

Kelly Moore, Tennessee, added that while she was not part of the Vanderbilt study she spoke 

with Dr. Edwards recently who indicated that they had recruited about half of the number of 

subjects needed. There has been an increase in pertussis activity in Tennessee in recent 

months, so they are hopeful that better information will be available soon.

Dr. Leonard Friedland (GSK), who works with Dr. Weston, reiterated that the seroprotective 

levels for the influenza antibodies were excellent in all subjects who received Boostrix® either 

with influenza vaccine or without. There was a slightly lower geometric mean antibody 

concentration when the influenza vaccine was given with Boostrix®. This was seen also with 

the currently licensed Tdap vaccine with adults. GSK believes this is a class effect. The actual 

antibody concentration meet the FDA criteria for immunobridging versus the infant data. 

Dr. Cieslak noted that for pertussis, the data shown did not indicate what percentage of subjects 

reached a protective level. He wondered if there was such information for pertussis.

Dr. Weston responded that there really are no defined correlates of protection for pertussis, 

which is why GSK used the immunobridging in the way that they did.

No public comments were offered during the second day of the meeting.

Public Comments Day 2
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

172

With no further business posed, Dr. Morse officially adjourned the meeting.

I hereby certify that to the best of my 

knowledge, the foregoing Minutes of the 

October 22-23, 2008 ACIP Meeting are 

accurate and complete. 

_____________________ 

 Date ________________________________

Dale Morse, M.D., M.S. Chair,

Advisory Committee on 

Immunization Practices (ACIP)

Certification
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

173

Advisory Committee on Immunization Practices (ACIP)

Committee Membership Roster

March 12, 2008

CHAIRMAN

MORSE, Dale L., M.D., M.S.

Assistant Commissioner, Office of Science

New York State Department of Health

1483 Corning Tower, ESP, Room 1420

Albany, New York 12237

TERM: 07/01/05-06/30/09

EXECUTIVE SECRETARY 

PICKERING, Larry K., M.D.

Senior Advisor to the Director

National Center for Immunization & Respiratory Diseases

Centers for Disease Control and Prevention

1600 Clifton Road, NE, Mailstop E-05

Atlanta, Georgia 30333

Members 

BAKER, Carol J., M.D.

Professor of Pediatrics

Molecular Virology and Microbiology

Baylor College of Medicine

One Baylor Plaza, Room 302A, MS BCM320

Houston, Texas 77030

TERM: 07/01/06-06/30/10

BECK, Robert L., J.D.

Consumer Representative 

19 Hardwood Road

Lake Monticello

Palmyra, Virginia 22963

TERM: 07/01/05-06/30/09

CHILTON, Lance, M.D.

General Pediatrics and Adolescent Medicine,

Young Children's Health Center

Professor, Department of Pediatrics

University of New Mexico School of Medicine

306-A San Pablo SE

Albuquerque, New Mexico 87108

TERM: 07/01/07-06/30/11
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

174

CIESLAK, Paul, M.D.

Medical Director, Immunization Program and

Program Manager, Acute & Communicable Disease Prevention

Oregon Public Health Division

800 NE Oregon St., Suite 772

Portland, Oregon 97232

TERM: 07/01/07-06/30/11

ENGLUND, Janet, M.D.

Associate Professor of Pediatrics, University of Washington

Clinical Associate, Fred Hutchinson Cancer Research Center

Division of Inf. Disease, Immunology and Rheumatology

Children’s Hospital and Regional Medical Center

4800 Sand Point Way NE #R5441

Seattle, Washington 98105

TERM: 07/01/07-06/30/11

JUDSON, Franklyn, M.D.

Professor, Departments of Medicine and Preventive Medicine & Biometrics

University of Colorado at Denver and Health Sciences Center

4200 East Ninth Avenue, B119

Denver, Colorado 80262

TERM: 09/19/2007 – 06/30/2011

LETT, Susan, M.D., M.P.H.

Medical Director, Immunization Program

Division of Epidemiology and Immunization

Massachusetts Department of Public Health

305 South Street

Jamaica Plain, Massachusetts 02130

TERM: 07/01/06-06/30/10

LIEU, Tracy, M.D., M.P.H.

Professor and Director

Center for Child Health Care Studies

Department of Ambulatory Care and Prevention

Harvard Pilgrim Health Care and Harvard Medical School

133 Brookline Avenue, Sixth Floor

Boston, Massachusetts 02215

TERM: 07/01/04-06/30/08

MORITA, Julia, M.D.

Medical Director

Immunization Program

Chicago Department of Public Health

2160 West Ogden

Chicago, Illinois 60612

TERM: 07/01/04-06/30/08

NEUZIL, Kathleen, M.D., M.P.H.

Senior Clinical Advisor, PATH

Clinical Associate Professor of Medicine,

University of Washington

PATH - 1455 Northwest Leary Way

Seattle, Washington 98107

TERM: 07/01/06-06/30/10
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

175

 

SUMAYA, Ciro Valent, M.D., M.P.H. & T.M.

Founding Dean

School of Rural Public Health and

Cox Endowed Chair in Medicine

Texas A&M University System Health

Science Center

TAMU 1266

College Station, Texas 77843-1266

TERM: 07/01/06-06/30/10

TEMTE, Jonathan, M.D., Ph.D.

Associate Professor

Department of Family Medicine

University of Wisconsin School of Medicine and Public Health

777 South Mills Street

Madison, Wisconsin 

Term: 04/22/08-06/30/11

Ex Officio Members 

Centers for Medicare and Medicaid Services (CMS)

MURPHY, Linda

CDR, USPHS

Senior Health Insurance Specialist

Centers for Medicare & Medicaid Services

7500 Security Boulevard S2-01-16

Baltimore, Maryland 21244

Department of Defense (DOD) 

HACHEY, Wayne, DO, M.P.H.

LTC, USA, MC

Director, Preventive Medicine & Surveillance

Office of the Assistant Secretary of Defense

Force Health Protection and Readiness

Skyline 4, Suite 403

5113 Leesburg Pike

Falls Church, Virginia 22041-3258

CIESLAK, Theodore (Ted) M.D.

Col, MC

Defense Department Liaison Officer

Centers for Disease Control and Prevention

COTPER, MS D-44

1600 Clifton Road, NE

Atlanta, GA 30333
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

176

Department of Veterans Affairs (DVA) 

NICHOL, Kristin Lee, M.D.

Professor of Medicine

University of Minnesota

Chief of Medicine

VA Medical Center

1 Veteran Drive

Minneapolis, Minnesota 55417

Food and Drug Administration (FDA)

BAYLOR, Norman, Ph.D.

Director

Office of Vaccines Research Review

1401 Rockville Pike

WOC I Room 355N HFM-405

Rockville, Maryland 20852

HOUN, Florence M.D., MPH

Deputy Director

Office of Vaccines Research Review

Center for Biologics Evaluation 

And Research Food and Drug Administration

1401 Rockville Pike

WOC I Room 355N HFM-405

Rockville, Maryland 20852

Health Resources and Services Administration (HRSA)

EVANS, Geoffrey, M.D.

Director

Division of Vaccine Injury Compensation

Healthcare Systems Bureau

Health Resources and Services Administration

5600 Fishers Lane, Room 11C-26

Rockville, Maryland 20857

JOHANN-LIANG, Rosemary, M.D.

Chief Medical Officer

Division of Vaccine Injury Compensation

Healthcare Systems Bureau

Health Resources and Services Administration

5600 Fisher Lane, Room 11C-26

Rockville, Maryland 20857

Indian Health Service (IHS)

CHEEK, James E., M.D., M.P.H.

Director, Division of Epidemiology & Disease

Prevention

Office of Public Health Support

Indian Health Service

5300 Homestead Road, NE

Albuquerque, New Mexico 87110

National Vaccine Program Office (NVPO)

GELLIN, Bruce, M.D., M.P.H.

Director

National Vaccine Program Office, Department of HHS of Public Health & Science

200 Independence Avenue, SW Room 729-H

Washington, D.C. 20201
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

177

National Institutes of Health (NIH)

CURLIN, George T., M.D.

Medical Director

DMID/NIH

6610 Rockledge Drive

Room 6119, MSC 6603

Bethesda, Maryland 20892-6603

Liaison Representatives

American Academy of Family Physicians (AAFP)

CAMPOS-OUTCALT, Doug, M.D., M.P.A.

Associate Head

Department of Family & Community Medicine

University of Arizona College of Medicine, Phoenix

550 E. Van Buren

Phoenix, Arizona 85004

American Academy of Pediatrics (AAP) 

BOCCHINI, Joseph A., Jr., M.D.

LSU Health Sciences Center in Shreveport

Children’s Hospital of LSU

Health Sciences Center in Shreveport

1501 Kings Highway

Shreveport, Louisiana 71130

Red Book Associate Editor

KIMBERLIN, David, M.D., FAAP

Committee on Infectious Diseases

University of Alabama at Birmingham

Division of Pediatric Infectious Diseases

1600 Seventh Avenue South

CHB 303

Birmingham, AL 35233-1711 

American College Health Association (ACHA) 

TURNER, James C., M.D.

Executive Director

Department of Student Health Executive Director

National Social Norms Institute

Professor of Internal Medicine

University of Virginia Elson Student Health Center

400 Brandon Ave.

P.O. Box 800760

Charlottesville, VA 22908-3708 

American College of Obstetricians and Gynecologists (ACOG) 

GALL, Stanley, M.D.

Department of OB/GYN

University of Louisville

School of Medicine

550 South Jackson Street

Louisville, Kentucky 40202 
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178

American College of Physicians (ACP)

POLAND, Gregory A., M.D.

Professor of Medicine, Infectious Diseases

Molecular Pharmacology and Experimental

Therapeutics, and Pediatrics

Mayo Medical School

Mayo Clinic and Foundation

611 C. Guggenheim Building

200 First Street, S.W.

Rochester, Minnesota 55905

American Geriatrics Society (AGS)

SCHMADER, Kenneth, M.D.

Chief, Division of Geriatrics

Duke University Medical Center

Director, GRECC (182)

Durham VA Medical Center

Durham, NC 27705 

America’s Health Insurance Plans (AHIP)

LEWIS, Tamara, M.D., M.P.H.

Medical Director, Community Health and Prevention

Intermountain Healthcare

36 South State Street

21st Floor

Salt Lake City, Utah 84111 

American Medical Association (AMA)

TAN, LITJEN (L.J), MS, Ph.D.

Director, Infectious Diseases, Immunology, &

Molecular Medicine

515 N. State Street

Chicago, Illinois 60610 

American Osteopathic Association (AOA)

GROGG, Stanley, E., D.O.

Professor of Pediatrics

Oklahoma State University - CHS

Medical Director, Osteopathic Medical Educational Consortium of Oklahoma (OMECO)

1111 W. 17th Street, Ste. 250

Tulsa, Oklahoma 74107

American Pharmacists Association (APhA) 

FOSTER, Stephan L., Pharm.D.

Professor and Vice Chair

CAPT (Ret) U.S.P.H.S.

University of Tennessee College of Pharmacy

Department of Clinical Pharmacy

910 Madison, Suite 324

Memphis, Tennessee 38163

Association for Prevention Teaching and Research (APTR) 

McKINNEY, W. Paul, M.D.

Professor & Associate Den

School of Public Health and Information Sciences University of Louisville

555 South Floyd Street

Louisville, KY 40202
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

179

Biotechnology Industry Organization (BIO)

LEWIN, Clement, Ph.D., MBA

Vice President

US Government Affairs & Strategy

38 Sidney Street

Cambridge, Massachusetts 02139

Canadian National Advisory Committee on Immunization (NACI) 

LANGLEY, JOANNE, M.D.

Professor of Pediatrics

IWK Health Center

Infectious Diseases

5850 University Avenue

Halifax, NS B3k 6R8

Department of Health, United Kingdom

SALISBURY, David M., CB FRCP FRCPCH FFPH

Director of Immunization

Department of Health

510 Wellington House

133-155, Waterloo Road

London SE1 8UG, ENGLAND, U.K.

Healthcare Infection Control Practices Advisory Committee (HICPAC) 

GORDON, Steve, M.D.

Cleveland Clinic

Department of Infectious Diseases

MS S-32

9500 Euclid Avenue

Cleveland, Ohio 44195

Infectious Diseases Society of America (IDSA) 

KATZ, Samuel L., M.D.

W C Davison Professor and Chair Emeritus

Infectious Diseases Division, Room T0915

Duke Children’s Health Center

Erwin Road

Durham, North Carolina 27710

National Association of County and City Health Officials (NACCHO)

DUCHIN, Jeffrey S., M.D.

Chief, Communicable Disease Epidemiology & Immunization Section

Public Health – Seattle & King County

Associate Professor in Medicine, Division of Infectious Diseases

University of Washington

401 5th Avenue, Suite #900

Seattle, Washington 98104

National Foundation for Infectious Diseases (NFID) 

SCHAFFNER, William, M.D.

Professor and Chair

Department of Preventive Medicine

Vanderbilt University School of Medicine

Village at Vanderbilt, Suite 2600

1500 21st Avenue South

Nashville, Tennessee 37212 
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180

National Immunization Council and Child Health Program, Mexico (NIACCHO)

RICHARDSON, Vesta, M.D.

General Director

National Center for Health of Infancy and Adolescence

Francisco de P. Miranda #177

Primer piso

Colonia Merced Gomez 01600

MEXICO, D.F., MEXICO 

National Medical Association (NMA) 

WHITLEY-WILLIAMS, Patricia, M.D.

Professor of Pediatrics

Chief, Pediatric Infectious Diseases

UMDNJ-/Robert Wood Johnson Medical School

MEB 322

One RWJ Place

New Brunswick, New Jersey

National Vaccine Advisory Committee (NVAC)

BIRKHEAD, Guthrie S., M.D., M.P.H.

Chair, NVAC

Deputy Commissioner

Office of Public Health

New York State Department of Health

Room 1415 Corning Tower

ESP Albany, NY 12237

Pharmaceutical Research and Manufacturers of America (PhRMA) 

BRAGA, Damian A.

President, Sanofi Pasteur – US Discovery Drive

Swiftwater, Pennsylvania 18370

PARADISO, Peter, Ph.D.

Vice President, New Business/Scientific Affairs

Wyeth Vaccines

500 Arcola Road

E Dock

Collegeville, Pennsylvania 19426

Society for Adolescent Medicine (SAM) 

MIDDLEMAN, Amy B., M.D., M.P.H., M.S.Ed.

Associate Professor of Pediatrics

Baylor College of Medicine

Adolescent Medicine and Sports Medicine Section

6701 Fannin Street, CCC 1710.10

Houston, Texas 77030

Society for Healthcare Epidemiology of America (SHEA)

KEYSERLING, Harry L., M.D.

Professor of Pediatrics, Division of Infectious Diseases, Epidemiology and Immunology

Emory University School of Medicine, Department of Pediatrics

2015 Uppergate Drive, NE

Atlanta, GA 30322
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Participant Roster

Last Name First Name

Abraham Brian

Abramson Jon

Agnew Kevin

ALLAVOINE Thierry

Armoni Judith

Ault Kevin

Bahta Lynn

Baker Carol J.

Banach Stephanie

bandell allyn

Battaglino-Cahill Elizabeth

Baylor Norman

Beck Robert L

Bednarczyk Robert

Beigi Richard

Berg Jeff

Birkhead Guthrie

Blalack Gary

Blazek Nicole

Bowser Andy

Bowser Andrew

Boyle Jeff

Bozof Lynn

Bradley Kimberly M.

Brooks Dennis

Bunge Graciela

Burgess Margaret

Burke Sheila

Campos-Outcalt Doug

Carpentier Sallie

Cary Donna

Chaney Mike

Chang Hwa-Gan

Chilton Lance

Cieslak Paul

Cieslak Ted

Clover Richard

Coelingh Kathleen

Colwell Chris

Cooney Lenore

Cooper Steven

Daley Matthew

Dana Adrian
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Deal Carolyn

Decker Michael

Dewasthaly Shailesh

Diamond Liad

Dinovitz Richard

Dosanjh Jagdeep

Dubin Gary

Dubischar-Kastner Katrin Luise

Duchin Jeffrey

Duggan Goldstein Sarah

Ehresmann Kristen

El-Badry Nina

Ellis Laura

Englund Janet

Ferguson Gerald

Fikry Christopher

Fischer Marc

Forte Serene

Fossas Tracy

Friedland Leoanrd

fryhofer sandra

Gaffoglio Diane

Gall Stanley A

Garman Patrick

Gaskins Diana

Gellin Bruce

Gershman Mark

Goad Jeffery

Gould Philip

Grabenstein John

Grogg Stanley

Gurunathan Sanjay

Hahn Christine

Halsey Neal

Hannan Claire

Haupt Richard

Hecht Herb

Hertel Carla

Humphrey Franklin Donelle

Ismail Shainoor

Jackson Melonie

JAMES PETER

Jelks Deborah

Johann-Liang Rosemary

Johansen-Lundén Kari

Johns Lisa

Johnson David

Johnson Mitch

Jones Eric

Judson Franklyn N
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Karlebach Shara

Katz Samuel

Kelly Kevin

Keyserling Harry

Kimberlin David

Kinsinger Linda

Kitchen Chester

Kruzikas Denise

Kuter Barbara

Laird Susan

Lake Jason

Langley LeBlanc Joanne

Lanman Gregory

LeBlanc Julia

Lee Lucia

Leger Marie-Michele

Leighton Leslie

Lett Susan

Lewin Clement

Lewis Tamara

Lewis Danielle

Lillibridge David

Lovell Ethan

Macartney Kristine

Malhame Melissa

Mallon Dan

Mansoura Monique

Marcy S Michael

Marcy Stephan Michael

Mascarenas Cesar

Mason Dean

Mazur Marie

McCormick Mary Ann

McGowan Diane

Meigs Wendy

Meissner Cody

Middleman Amy

Miller Elaine R.

Milley Frankie

Moore Laura

Moore Kelly

Morse Dale

murphy linda

Murphy Trudy

Museru Oidda

Nass Meryl

Neuzil Kathleen

Nicholas Daena

Nowell Mackenzie

Noyes Kimberly
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Obara Timothy

O''Brien Katherine

Ockers Sandra

Offit Paul

Ogden Tracy

Omer Saad

O''Neill Kevin

O''Neill Brian

Owais Aatekah

Paradiso Peter

Parikh Shefali

Penrod Deborah

Peter Georges

Peterson Diane

Plotkin Stanley

Pugh Pearl

Quinn Conrad

Quinn Jane

Randall Lisa

Ray Jill

rennels margaret

Richards Steve

Ross David J.

Rubin Lorry

Ryan Margaret

Saddier Patricia

Salisbury David

Sammons David

Sawyer Mark

Sayers Cynthia

Schaffner William

Schmader Kenneth

Schupper Ellen

Schwartzberg Gerald

Scott Laura

Seaman Vincent

Searfoorce Amy

Seehafer Darin

Sherner James

SIEVERT ALAN

Skjeveland Eric

Smith Theresa

Smith Parker

Soeters Heidi

Southall Jennifer

Stein Gary

Stinchfield Patricia

Strikas Raymond

Strikas Raymond

Strutton David
Advisory Committee on Immunization Practices (ACIP) Summary Rep October 22-23, 2008

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Stuerke Stacy

Sumaya Ciro

Sun Wellington

Swain Chris

Sylvester Gregg

Talarico John

Tan Litjen (L.J)

Temte Jonathan

Thomas Lonnie

Topping Richard

Tran Trung

Tsai Theodore

Turner James

Tursi James

Vernon Thomas

Vigliarolo Peter

Vittas John

Walker Matthew

Ward Joel

Waytes Tom

Weston Wayde

Wexler Deborah

Whitley-Williams Patricia

Wighton Timothy

Wilson Paul

Worcester Sharon

Wu Carol

Yaksich JoAnna

Yamauchi Terry

York Laura

Yu Patricia

Zimmerman Richard

Zink Thomas