DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION

Advisory Committee on 

Immunization Practices (ACIP)

Summary Report

June 23-24, 2010 

Atlanta, Georgia 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Table of Contents Page 

Agenda 4-5 

Acronyms 6-8 

Welcome and Introductions 9-14 

Evidence-Based Recommendations Work Group 

Introduction: ACIP Implementation of an Explicit Evidence-Based Recommendations Format

 Professional Organization Perspectives on Development and Endorsement of Recommendations 

 GRADE (Grading of Recommendations, Assessment, Development, and Evaluation)

 WHO’s Strategic Advisory Group of Experts (SAGE): Approach to Evidence-Based Framework Based on GRADE 

14-45 

Meningococcal Vaccine 

Introduction

 Guillain-Barre Syndrome (GBS) After Receipt of Menactra

 Update on Monitoring of GBS after Receipt of Meningococcal Conjugate Vaccines 

Meningococcal Conjugate Vaccines and BGS 

 Update on Meningococcal Vaccination Programs 

46-73 

Human Papillomavirus (HPV) Vaccines 

HPV Vaccine Update 

73-75 

Hepatitis Vaccines

 Update on Hepatitis Vaccines Work Group

 Trends in Acute Hepatitis B Virus (HBV) Disease 

Hepatitis B Risk Among Persons With and Without Diabetes Mellitus

 Hepatitis B Vaccine Safety and Seroprotection Rates Among Persons with Diabetes Mellitus

 Preview of Proposed Recommendations; Request for Additional Information 

75-100 

Pertussis Vaccines

 Update on Pertussis Vaccines Work Group Activities 

 Update on the Pertussis Vaccine Program 

100-109 

13-Valent Pneumococcal Conjugate Vaccine (PCV13)

 PCV13 VFC Correction 110 

Vaccine Supply 111 

Public Comments Day 1 112 

Wednesday, June 23 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Thursday, June 24 

Agency Updates

 CDC 

 Center for Medicare and Medicaid Services (CMS) 

 Food and Drug Administration (FDA)

 Department of Defense (DoD) 

 Department of Veteran’s Affairs (DVA)

 Heath Resources and Services Administration (HRSA)

 Indian Health Services (I HS)

 National Vaccine Advisory Committee (NVAC)

 National Vaccine Program Office (NVPO) 

112-115 

Influenza Vaccines

 Introduction 

 Influenza Season Update and Summary

 Influenza Vaccine Effectiveness 

 Influenza Vaccine Work Group Update: Seasonal Doses for Children <9 Receiving No Prior 2009 H1N1 Monovalent 

 2009 Pandemic H1N1 Monovalent Vaccine Safety Studies 

116-148 

Respiratory Syncytial Virus (RSV) Immunoprophylaxis

 Introduction

 Epidemiology of RSV Infections 

 History of RSV Immunoprophylaxis 

Summary 

149-157 

Healthcare Reform 

Implications for National Immunization Policy and Practice 

158-164 

Rotavirus Vaccines

 Update on Porcine Cirocovirus in Rotavirus Vaccines 

164-177 

Public Comment Day 2 177-180 

Certification 181 

Participant Roster 182-188 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

MEETING OF THE ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES (ACIP) 

Centers for Disease Control and Prevention

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

June 23-24, 2010 

AGENDA ITEM PURPOSE PRESIDER/PRESENTER(s) 

Wednesday, June 23, 2010 

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

Dr. Larry Pickering 

 (Executive Secretary, ACIP; CDC) 

8:30 Evidence Based Recommendations 

 Introduction: ACIP implementation of an explicit Information Dr. Jonathan Temte 

evidence-based recommendation format (ACIP, WG Chair) 

 Professional organization perspectives on & AAFP: Dr. Doug Campos-Outcalt 

development and endorsement of recommendations AAP: Dr. Joseph Bocchini 

Discussion ACP: Dr. Gregory Poland 

 GRADE (Grading of Recommendations, Assessment, Dr. Holger Schünemann

 Development and Evaluation) Information (McMaster University, Canada) 

 WHO’s Strategic Advisory Group of Experts (SAGE): & Dr. Arthur Reingold (UC Berkeley 

approach to evidence-based recommendations Discussion SPH, SAGE Member) 

 Pilot of explicit evidence-based framework based on Dr. Faruque Ahmed (CDC/NCIRD) 

GRADE 

10 :45 Break 

11:15 Meningococcal Vaccine 

 Introduction Information Dr. Cody Meissner (ACIP, WG Chair) 

 Guillain-Barré Syndrome (GBS) after receipt of 

Menactra & Dr. Priscilla Velentgas (Harvard Pilgrim) 

 Update on monitoring of GBS after receipt of

 meningococcal conjugate vaccines 

 Meningococcal conjugate vaccines and GBS 

Discussion 

Vote 

Mr. Eric Weintraub (CDC/NCEZID) 

Dr. Amanda Cohn (CDC/NCIRD) 

 Update on meningococcal vaccination program Dr. Amanda Cohn (CDC/NCIRD) 

12:30 Lunch 

1:30 Human Papillomavirus (HPV) Vaccines 

 HPV vaccine update Information Dr. Lauri Markowitz 

& (CDC/NCHHSTP) 

Discussion 

1:45 Hepatitis Vaccines 

 Update on Hepatitis Vaccines Work Group Information Dr. Mark Sawyer (ACIP, WG Chair) 

 Trends in acute hepatitis B virus (HBV) disease Dr. Ruth Jiles (CDC/NCHHSTP) 

 Hepatitis B risk among persons with and without & Dr. Dale Hu (CDC/NCHHSTP) 

diabetes mellitus 

 Hepatitis B vaccine safety and seroprotection rates Discussion Dr. Philip Spradling (CDC/NCHHSTP) 

among persons with diabetes mellitus 

 Preview of proposed recommendations; request for Dr. Trudy Murphy (CDC/NCHHSTP) 

additional information 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

3:30 Break 

3:45 Pertussis Vaccines 

 Update on Pertussis Vaccines Work Group activities 

 Update on the Pertussis Vaccine Program 

4:30 13-Valent Pneumococcal Conjugate Vaccine (PCV13) 

 PCV13 VFC correction 

4:45 Vaccine Supply 

 Update on vaccine supply 

5:00 Public Comment 

5:15 Adjourn 

Thursday, June 24, 2010 

8:00 Agency Updates (CDC, CMS, DOD, DVA, FDA, HRSA, IHS, 

NIH, NVAC, NVPO) 

8:15 Influenza Vaccines 

 Introduction

 Influenza season update and summary 

 Influenza vaccine effectiveness 

 Influenza Vaccine Work Group update 

 Vote on number of doses of seasonal vaccine 

required for children age <9 years who received 

no prior 2009 H1N1 monovalent vaccine 

 VFC vote 

 2009 pandemic H1N1 monovalent vaccine safety 

studies 

10:45 Break 

11:00 Respiratory Syncytial Virus (RSV) Immunoprophylaxis 

 Introduction 

 Epidemiology of RSV infections 

 History of RSV immunoprophylaxis 

 Summary 

12:15 Lunch 

1:15 Health Care Reform and its Implications for National 

Immunization Policy and Practice 

1:45 Rotavirus Vaccines 

 Update on porcine circovirus in rotavirus vaccines 

3:15 Public Comment 

Information

& 

Discussion

VFC vote

Information

Discussion

Information

Information

& 

Discussion

Information

Discussion

Vote

VFC Vote

Information

& 

Discussion

Information

Information

& 

Discussion

Information

Information

Discussion

Dr. Mark Sawyer (ACIP, WG Chair)

Dr. Jennifer Liang (CDC/NCIRD) 

Dr. Lance Rodewald (CDC/ NCIRD)

Dr. Lance Rodewald (CDC/ NCIRD)

ACIP Ex Officio Members

Dr. Kathy Neuzil (ACIP, WG Chair)

Dr. Tony Fiore (CDC/NCIRD) 

Dr. David Shay (CDC/NCIRD) 

Dr. Anthony Fiore (CDC/NCIRD) 

Dr. Lance Rodewald (CDC/NCIRD) 

Dr. Frank DeStefano (ISO/NCEZID) 

Dr. Tracy Lieu (Harvard Pilgrim) 

Dr. Hector Izurieta (CBER/FDA) 

Dr. Lance Chilton (ACIP, WG Chair)

Dr. Gayle Fischer Langley 

(CDC/NCIRD) 

Dr. Cody Meissner (ACIP Member) 

Dr. Lance Chilton (ACIP, WG Chair) 

Attorney Sara Rosenbaum 

(ACIP Member) 

Dr. Umesh Parashar (CDC/NCIRD) 

Dr. Margaret Cortese (CDC/NCIRD) 

Dr. Wellington Sun (FDA) 

Dr. Len Friedland (GSK) 

Ms. Kim Dezura (Merck)

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

3:30 Adjourn 

Acronyms 

AAFP American Academy of Family Physicians 

AAP American Academy of Pediatrics 

ABCs Active Bacterial Core surveillance system 

ACHA American College Health Association 

ACP American College of Physicians 

ACIP Advisory Committee on Immunization Practices 

AGREE Appraisal of Guidelines Research and Evaluation 

AIAB Adult Immunization Advisory Board of ACP 

AEs Adverse Events 

AHIP America’s Health Insurance Plans 

AHRQ Agency for Healthcare Research and Quality 

AMA American Medical Association 

ANA American Nurses Association 

AOA American Osteopathic Association 

ARRA American Recovery and Reinvestment Act 

ASTHO Association of State and Territorial Health Officials 

BLA Biologics License Application 

BRFSS Behavioral Risk Factor Surveillance System 

CBER Center for Biologics Evaluation and Research 

CDC Centers for Disease Control and Prevention 

CEAS Clinical Efficacy Assessment Subcommittee of ACP 

CER Comparative Effectiveness Research 

CIDP chronic inflammatory demyelinating polyneuropathy 

CLL childhood lymphoblastic leukemia 

CMS Centers for Medicare and Medicaid Services 

COGS Conference on Guideline Standardization 

COI Conflict of Interest 

COID Committee on Infectious Diseases of AAP 

COPD Chronic Obstructive Pulmonary Disease 

CSAPH Council on Science and Public Health of AMA 

CSTE Council of State and Territorial Epidemiologists 

CVD Cardiovascular Disease 

DHQP Division of Healthcare Quality Promotion 

DoD Department of Defense 

DSMB Data Safety Monitoring Board 

DVA Department of Veterans Affairs 

DVH Division of Viral Hepatitis (of NCIRD) 

EBV Epstein-Barr Virus 

EBRWG Evidence Based Recommendations Work Group’s 

EIP Emerging Infections Program 

EMR Electronic Medical Records 

FDA Food and Drug Administration 

GAVI Global Alliance for Vaccines and Immunisation 

GBS Guillain Barré Syndrome 

GMCs Geometric Mean Concentrations 

GMTs Geometric Mean Titers 

GRADE Grades of Recommendation Assessment, Development and Evaluation 

GSK GlaxoSmithKline 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

HGT Horizontal gene transfer 

HICPAC Healthcare Infection Control Practices Advisory Committee 

HepA Hepatitis A 

HepB Hepatitis B 

HHS Department of Health and Human Services 

Hib Haemophilus influenzae B 

HPV Human Papillomavirus 

HRSA Health Resources and Services Administration 

HTA health technology assessments 

ICD-9 International Classification of Diseases, Ninth Revision 

ID Influenza Division (of NCIRD) 

IgG Immunoglobulin G 

IgM Immunoglobulin M 

IHS Indian Health Services 

ILI Influenza-Like Illness 

ILINet Influenza-Like Illness Surveillance Network 

IPV Inactivated Poliovirus-Containing Vaccine 

ISO Immunization Safety Office 

IU International Units 

JAMA Journal of the American Medical Association 

maxSPRT Maximized Sequential Probability Ratio Testing 

MenACYWCRM Meningococcal Conjugate Vaccine 

MCOs Managed Care Organizations 

MCV4 Quadrivalent Meningococcal Conjugate Vaccine 

MMR Measles, Mumps, Rubella 

MMWR Morbidity and Mortality Weekly Report 

MOE maintenance of effort 

MSM Men Who Have Sex With Men 

NACI National Advisory Committee on Immunization 

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

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

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

NHANES National Health and Nutrition Examination Survey 

NICU Neonatal Intensive Care Unit 

NIS National Immunization Survey 

NNDSS National Notifiable Diseases Surveillance System 

NNHS National Nursing Home Survey 

NREVSS National Respiratory and Enteric Virus Surveillance System 

NVAC National Vaccine Advisory Committee 

NVP National Vaccine Plan 

NVPO National Vaccine Program Office 

NVSN National Vaccine Surveillance Network 

PAHO Pan American Health Organization 

PCR Polymerase Chain Reaction 

PEP Post-Exposure Prophylaxis 

QALY Quality-Adjusted Life Year 

RCA Rapid Cycle Analysis 

RCT Randomized Controlled Trial 

RoB Risk of Bias 

RSV Respiratory Syncytial Virus Immunoprophylaxis 

RTIMS Real Time Immunization Monitoring System 

SAEs Serious Adverse Events 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

SAHM Society for Adolescent Health and Medicine 

SAM Society for Adolescent Health and Medicine 

SBA Serum Bactericidal Antibody 

sBLA Supplemental Biologics License Application 

SCOQIM Steering Committee on Quality Improvement and Management 

SES Socioeconomic Status 

SHEA Society for Healthcare Epidemiology of America 

STD Sexually Transmitted Disease 

Tdap Tetanus and Reduced Diphtheria Toxoids 

UK United Kingdom 

US United States 

USPSTF United States Preventive Services Task Force 

VA Veterans Administration 

VAERS Vaccine Adverse Event Reporting System 

VFC Vaccines for Children 

VIS Vaccine Information Sheet 

VRBPAC Vaccines and Related Biological Products Advisory Committee 

VSD Vaccine Safety Datalink 

VSRAWG Vaccine Safety Risk Assessment Working Group 

VTrckS Vaccine Tracking System 

WG Work Group 

WHO World Health Organization 

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Discussion

Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

June 23, 2010 

Welcome and Introductions 

Dr. Carol Baker 

Chair, ACIP 

Dr. Larry Pickering 

Executive Secretary, ACIP / CDC 

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

Pickering who delivered the administrative announcements. 

Dr. Pickering welcomed everyone to the June 2010 Advisory Committee on Immunization 

Practices (ACIP) meeting. As with the last three ACIP meetings, he indicated that the 

proceedings of this meeting would be accessible to people not in attendance via the World Wide 

Web. He also welcomed those who could not attend the meeting in person. He then 

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

ACIP meeting to assist with various meeting functions: Antonette Hill, Committee Management 

Specialist for ACIP, who was moving to another position within the agency following this 

meeting; Natalie Greene; Leola Mitchell; Tamara Miller, who was moving to North Carolina 

following this meeting; Tanya Lennon; and Suzette Law. He also recognized that the hard work 

of these individuals very much contributes to the success of each meeting, and stressed that 

Miss Hill and Miss Miller would be greatly missed as part of that team. Those with any 

questions were instructed to see him, any of these individuals, or Dr. Baker. He indicated that 

boxed lunches would be provided for a charge during the two days of the meeting in the hallway 

outside of the auditorium, and that coffee and tea would be available in the hallway for the 

duration of the meeting. 

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

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

posted on the ACIP website, generally within one to two weeks after the meeting concludes, 

while meeting minutes will be available on the website within 90 days of the termination of the 

meeting. Members of the press interested in conducting interviews with various ACIP members 

were instructed to contact Tom Skinner for assistance in arranging the interviews. 

Ms. Alba Maria Ropero, Regional Advisor in the Comprehensive Family Immunization Project of 

the Pan American Health Organization (PAHO) office of the World Health Organization (WHO) 

in Washington, DC was in attendance as a guest observer of the ACIP meeting. Dr. Pickering 

indicated that Ms. Ropero is the focal point for influenza, yellow fever, and vaccination week in 

the Americas. He also welcomed to ACIP a new liaison organization, the American Nurses 

Association (ANA). Ms. Katie Brewer has been selected to represent ANA as its liaison 

representative to ACIP. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

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

Liaison Representatives 

 Dr. Greg Poland from the American College of Physicians (ACP) was present during the first 

day of the meeting; Dr. Sandra Fryhofer attended on his behalf on the second day 

 Dr. Mark Netoskie from the America's Health Insurance Plans (AHIP); Dr. Richard Doskey 

attended on his behalf 

 Dr. Jeffrey Duchin from the National Association of County and City Health Officials 

(NACCHO); Dr. Paul Etkind attended on his behalf 

 Dr. Joanne Langley from the Canadian National Advisory Committee on Immunization 

(NACI) 

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

 Dr. Norman Baylor from the Food and Drug Administration (FDA); Dr. Wellington Sun 

attended the second day of the meeting on his behalf 

To avoid disruptions during the meeting, those present were instructed to turn off all cell phones 

or place them in the vibrate mode. Given that the meeting could not begin unless a quorum of 

members was present, all appointed members were asked to return from breaks and lunch in a 

timely manner to participate in the meeting. 

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

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

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

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

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

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

Antonette Hill record their name and provide information on the process. Those who registered 

to make public comments prior to the meeting were instructed to see Ms. Hill to verify that their 

names were listed and to receive any additional information. 

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

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

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

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

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

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

limited conflict of interest (COI) waivers. Members who conduct vaccine clinical trials or who 

serve on data safety monitoring boards (DSMBs) may serve as consultants to present to the 

committee on matters related to those specific vaccines; however, they are prohibited from 

participating in deliberations or committee votes on issues related to those specific vaccines. 

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

with a proviso that he or she abstains on all votes related to that vaccine company. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

The following information was shared pertaining to ACIP: 

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

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

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

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

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

cycle of applications for ACIP membership are due no later than November 15, 2010 for the 

term beginning July 2011. Interested parties were encouraged to complete an application and 

submit it by the deadline. 

Next ACIP Meeting: October 27-28, 2010 

Registration Deadlines: Non-U.S. Citizens 10/8/2010 – U.S. Citizens 10/15/2010 

Vaccine Safety: http://www.cdc.gov/vaccinesafety/ 

Vaccine Abbreviations: 

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

Vaccine Schedules: 

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

Adult Vaccine Scheduler: 

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

This scheduler was developed by National Center for Immunization and Respiratory Diseases 

(NCIRD) of CDC and Georgia Tech. This is very similar to the Pediatric Scheduler, which has 

been published for a couple of years. The Adult Vaccine Scheduler is an interactive, web-based 

scheduler that can be downloaded to people’s computers so that adults can keep track of the 

vaccines they have received and prognosticate what vaccines they need in the future. 

Vaccine Toolkit: 

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

The Vaccine Toolkit was also developed by NCIRD / CDC in conjunction with the American 

Academy of Family Physicians (AAFP) and the American Academy of Pediatrics (AAP). This is 

a providers’ resource for vaccine conversations with parents. 

Dr. Pickering indicated that Dr. Baker had requested an update on the status of ACIP 

provisional recommendations with regard to publications. There has been some delay in ACIP 

making recommendations and final acceptance by CDC of those recommendations (e.g., when 

Dr. Frieden accepts the recommendations and they are published in the MMWR). This is 

currently done in two ways. The first is via policy notes for which provisional recommendations 

are not generally posted, given that these are typically published within 1 to 2 months of the 

ACIP vote. The second is through recommendations and reports, which are longer documents 

for which provisional recommendations are posted as publication time for these documents 

ranges from 6 to 12 months. Work is being done to decrease this publication time. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Recommendations published since the last meeting as either policy notes or recommendations 

and reports (indicated by the RR under the MMWR reference) include the following:

 Publication MWWR 

Topic Date Reference 

JE Encephalitis 3/12/2010 Vol 59(RR01): 1-27 

MCV4 (Menveo) 3/12/2010 Vol 59(09): 273 

PCV13 3/12/2010 Vol 59(09): 253-257 

Rabies 3/19/2010 Vol 59(RR02): 1-9 

Measles, Mumps, Rubella & 

Varicella 5/7/2010 Vol 59(RR03): 1-12 

HPV

 HPV4 in males 5/28/2010 Vol 59(20): 630-632 

HPV2 in females 5/28/2010 Vol 59(20): 626-629 

Rotavirus (SCID) 6/11/2010 Vol 59(22): 687-688 

Anthrax Vaccine Adsorbed 6/25/2010 

Status of publication of ACIP recommendations: 

MMWR Weekly Recommendations and 

Vaccine (Policy Notes) Reports 

2010 Influenza Vaccines N/A Summer 2010 

Yellow Fever Vaccine N/A July 16, 2010 

General Recommendations 

(Combination Vaccines) N/A Summer / Fall 2010 

Measles-Mumps-Rubella 

(HCP) N/A HCP document 

Pneumococcal Vaccine 

(adults) Pending Pending 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Dr. Baker noted that this was a bittersweet time, given that three ACIP members would be 

retiring. Each member was presented with a token of ACIP’s appreciation. She first recognized 

Dr. Susan Lett, Medical Director in the Division of Immunization of the Massachusetts 

Department of Public Health in Jamaica Plain. Dr. Lett has more than two decades of policy 

and program planning experience that has aided ACIP’s deliberations regarding number of 

issues. She has served on a number of national immunization advisory boards, and ACIP has 

been fortunate that she has been able to assist the committee with policy during her past four 

years on the committee. She has made numerous contributions to various ACIP work groups 

(e.g., Combination Vaccines, Influenza Vaccines, General Recommendations, Harmonized 

Schedules, Polio, Rabies, and Rotavirus). Her extensive public health and research and policy 

experience and skills have been a great asset to ACIP, and Dr. Baker stressed that she 

personally had sought Dr. Lett’s guidance regarding potential barriers for what may have 

seemed to be easy implementation issues. Dr. Lett responded that this was a really sad time 

for her to leave ACIP, which had been the greatest honor of her professional career. She 

expressed her gratitude for having had the opportunity to serve on the committee, indicating that 

she looked forward to perhaps continuing to be involved in ACIP work groups. 

Also retiring from ACIP was Dr. Kathy Neuzil, Senior Clinical Adviser for PATH in Seattle 

Washington. Dr. Neuzil is an adult infectious disease physician, who has extensive experience 

in epidemiologic studies and clinical trials. Having served previously as the Liaison 

Representative for the ACP, Dr. Neuzil came well-prepared in 2006 to join the ACIP. She 

chaired the Vaccines and Pregnancy Work Group during her first year, moving later to chair the 

Influenza Work Group. Dr. Baker stressed that Dr. Neuzil had done a marvelous job during the 

past three years, demonstrating tireless devotion, contagious enthusiasm, and uncommon 

wisdom as an ACIP leader. ACIP is grateful to Dr. Neuzil for her service, and as one who 

considers her a friend, Dr. Baker will greatly miss her. Dr. Neuzil replied that it had been a 

privilege and great joy to have been a part of ACIP, and to have worked with such competent 

and dedicated people, including fellow ACIP members, liaison representatives, and the CDC 

staff who support ACIP in so many ways. She thanked them all very sincerely for teaching her 

so much about vaccines, public health, and community service. 

In addition, Dr. Cyro Sumaya, Founding Dean of the School of Rural Public Health and holder 

John and Maureen Cox Endowed Chair in Medicine at Texas A & M Health Science Center in 

College Station, was retiring from ACIP. Dr. Sumaya is a pediatric infectious disease physician 

with special expertise in Epstein-Barr virus (EBV) infections. His outstanding leadership skills, 

extensive experience in public health, and devotion to resolving ethnic disparities have been 

excellent resources to ACIP. Also, his warm manner and great smile have been encouraging to 

Dr. Baker and other committee members. During his 4-year term on ACIP, he has served as 

chair of the General Recommendations Work Group and been a member of the Meningococcal 

Work Group. It was Dr. Sumaya who made the historic motion to recommend universal 

administration of influenza vaccine annually during the February 2010 ACIP meeting. Dr. Baker 

said that she thought she was one of the more lucky members of ACIP because she and Dr. 

Sumaya would both be in Texas, so she hoped that perhaps their paths would cross again 

soon. Dr. Sumaya responded that it had been a distinct privilege to be part of ACIP and to work 

with distinguished colleagues, particularly given what ACIP stands for and the impact that it has 

for the American public and the global community. Immunizations can also affect many people, 

and is one of the primary cornerstones of public health principles and values for preventing 

disease and promoting health. He thanked everyone for what seemed like a quick four years, 

and wished them the best. 

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Discussion

Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

The following conflicts of interest were declared:

 Dr. Janet Englund: Research support to her university from MedImmune, sanofi pasteur, 

Novartis, and Adamas, Inc. 

 Dr. Wendy Keitel: Clinical trial support from Novartis 

 Dr. Cody Meissner: Payments made to Tufts Medical Center by MedImmune and Pfizer for 

participation in clinical trials 

 The remainder of the ACIP members declared no conflicts 

Evidence Based Recommendations Work Group 

Introduction 

Jonathon Temte, MD, PhD, Chair 

Evidence Based Recommendations Work Group 

Dr. Temte thanked the many and varied participants in the Evidence-Based Recommendations 

Work Group (EBRWG) for their thoughtful comments and participation in the telephone 

conferences convened, which allowed them to progress fairly rapidly. He reminded everyone 

that the EBRWG’s charge is to develop a uniform approach to making explicit the evidence 

base for ACIP recommendations, and that this work group was reactivated in November 2007. 

The work group has convened monthly conference calls since January 2008, and has been 

working on guiding principles and reviewing several evidence-based systems for developing 

guidelines that are used by other organizations. 

The work group’s guiding principles are to focus on transparency; use evidence of varying 

strengths; consider individual and community health; adopt / adapt an existing system rather 

than re-creating something that may already exist; continually strive to improve the process; and 

first apply the proposed process to new vaccines and new indications or restrictions of existing 

vaccines. The components of evidence-based vaccine recommendations include key elements 

for consideration (e.g., safety, efficacy, and burden of illness); an assessment method for 

existing evidence; standardized format for recommendations; and a means for reporting of 

elements and evidence in a clear and transparent manner. 

The work group has decided to adopt the Grades of Recommendation Assessment, 

Development and Evaluation (GRADE) framework for rating quality of evidence, and to adapt 

the GRADE system for moving from evidence to recommendations. Within this standardized 

system, the proposed evidence grades include A, B, C, and D, which basically reflect the level 

of confidence in an estimate of effect (e.g., causal relation) from a body of evidence. The 

proposed recommendation categories include: 1) Recommendation For and Recommendation 

Against, and 2) Optional Use. They wanted to move away from the terminology “permissive 

use,” which is the reason for the “optional use” category. He then reviewed the agenda for this 

session, pointing out that the EBRWG discovered that the World Health Organization’s Strategic 

Advisory Group of Experts is on a parallel path to the ACIP EBRWG in terms of applying 

GRADE for vaccine recommendations. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Professional Organization Perspectives: AAFP 

Doug Campos-Outcalt, MD, MPA 

American Academy of Family Physicians (AAFP)

Dr. Campos-Outcalt briefly described the American Academy of Family Physicians (AAFP) and 

its guideline development and endorsement process. AAFP has a total membership of 94,700 

of whom 62,600 are active. The remainder is comprised of resident student and physicians in 

some level of retirement. Of the members, 20% have practices in rural areas. 

Being a generalist physician organization, with most members involved in primary care, AAFP 

receives many requests to review, comment on, and endorse guidelines developed by external 

organizations. The following sample reflects the variety of groups who make such requests of 

AAFP: 

 Government Agencies 

Æ USPSTF (clinical prevention) 

Æ CDC (public health, vaccines, prevention) 

Æ CPSTF (community services) 

Æ EGAPP (genomics) 

 Specialty Societies 

Æ AAFP, ACP, AAP, ACOG, et cetera 

 Specialty Interest Groups 

Æ ACS, AHA, ATS, ALA, ADA, et cetera 

 Agency for Healthcare Research and Quality (AHRQ) 

Æ Does not develop guidelines, but does catalogue them 

The AAFP’s Commission on the Health of the Public and Science selects topics that are 

important to its members. AAFP will petition AHRQ evidence reports, for which there is a 

process. This is often done in collaboration with other specialty groups. AAFP attempts to work 

with inter specialty panels when possible, and uses the GRADE system when developing its 

own guidelines. The staff in the Scientific Activities Division of AAFP staffs the guideline panels. 

The Commission on the Health of the Public and Science is also the responsible group when 

AAFP receives requests from outside organizations to consider, comment upon, and potential 

endorse their guidelines. The Commission on the Health of the Public and Science makes 

recommendations to AAFP’s Board of Directors, which is ultimately responsible for approval. 

This process has evolved over time, and now includes a tool with specific procedures. The 

following example illustrates the tool that AAFP uses: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Typically, three to four members review a guideline and evaluate several of its aspects, 

including the scope and purpose, stakeholder involvement, rigor of development, clarity and 

presentation, applicability to family physicians, and editorial independence. For the rigor or 

development, consideration is given to whether a systematic search was conducted, whether 

the selection criteria clearly described, whether the quality of the included studies is assessed, 

whether recommendation methods are clearly described, whether benefits / side effects / risks 

are considered, whether the overall strength of evidence assessed, and whether there is an 

explicit link between the evidence and the recommendations. AAFP likes for guidelines to have 

been disseminated for external review and comments, and specifies an updating procedure. 

AAFP basically places guidelines into three categories: Endorsement, Endorsement with 

Reservations, or Not Endorsed. To be endorsed, guidelines should include the following 

characteristics: 

 Specific, clear, and unambiguous recommendations that are applicable to family medicine 

settings 

 Overall quality ranked as good, or ranked as fair (with rationale for endorsement) 

 Based on an evidence report or systematic review conducted with sound methodology 

 Strong, key recommendations are supported by good quality evidence 

 Guideline development process is editorially independent from funding sources 

 Should include a conflict of interest policy that minimizes the effects of potential conflicts on 

the guideline development process 

All of AAFP’s guidelines and endorsements can be found on the AAFP web site: 

http://www.aafp.org/online/en/home/clinical/clinicalrecs.html?navid=clinical+recommendations 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

The AAFP is very supportive of the ACIP adopting a standardized evidence-based process to 

arrive at ACIP recommendations for vaccines. 

Professional Organization Perspectives: AAP 

Joseph A. Bocchini, Jr. MD 

Department of Pediatrics 

Louisiana State University Health Sciences Center – Shreveport 

Chairperson, American Academy of Pediatrics 

Committee on Infectious Diseases 

Dr. Bocchini reported that the American Academy of Pediatrics (AAP) was founded in 1930 and 

currently has approximately 60,000 members worldwide comprised of general pediatricians and 

pediatric medical and surgical subspecialists. AAP’s mission is to attain optimal physical, 

mental, and social health and well-being for all infants, children, adolescents, and young adults. 

Because it recognized the need for a transparent evidence-based approach for its policies and 

endorsement, AAP established a Steering Committee on Quality Improvement and 

Management (SCOQIM) in 2001. This committee was charged with the responsibility for 

oversight of development of clinical practice guidelines within AAP and the AAP endorsement 

process. SCOQIM members include individuals with expertise in practice, technology, and 

evidence-based medicine. Liaisons are included from AHRQ and the National Association for 

Children’s Hospitals and Related Institutions. 

SCOQIM issued their first Policy for Classifying Recommendations for Clinical Practice 

Guidelines in 2004. This Policy established a very clear evidence quality appraisal format with 

assessment of benefit versus harm for recommendations. These guidelines are currently under 

revision [Pediatrics 2004;114:874-877]. AAP is currently considering GRADE or a modification 

of GRADE as one of the options to revise this protocol. AAP currently recommends greater 

transparency and application of evidence grading to all clinical policies [Pediatrics 

2008;121:643-646]. 

In addition to establishment of new rules for evidence review, SCOQIM is also assessing AAP’s 

internal policy categories to determine whether they need modification as well. AAP’s internal 

policy categories include the following: 

 Policy Statement: Statement of advocacy, direction, or a public health position of concern to 

AAP, including recommendations 

 Clinical Report: Offers guidance for the pediatrician in the clinical setting, addressing best 

practices and state of the art medicine without formal recommendations 

 Clinical Practice Guideline: Based on a comprehensive literature review and data analyses 

with formal rules of evidence in support of each recommendation made 

 Technical Report: Based on a literature review and data analyses but does not contain 

recommendations 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

The following illustrates the current AAP grading system for clinical guidelines: 

Grading Recommendation Strength 

Evidence Quality 

Preponderance 

of Benefit or 

Harm 

Balance of 

Benefit and 

Harm 

A. Well designed RCTs or diagnostic studies 

on relevant population Strong 

B. RCTs or diagnostic studies with minor 

limitations;overwhelmingly consistent 

evidence from observational studies 

C. Observational studies (case-control and 

cohort design) Rec 

Option 

D. Expert opinion, case reports, reasoning 

from first principles Option No Rec 

X. Exceptional situations where validating 

studies cannot be performed and there is a 

clear preponderance of benefit or harm 

Strong 

Rec 

The Committee on Infectious Diseases (COID) felt that there were some components of the 

current AAP grading system that are not applicable to vaccine-related statements; therefore, 

AAP has chosen not to use this grading system. The COID differs somewhat from other 

organizations in that AAP develops its own policies for vaccine recommendations, and COID is 

responsible for development of vaccine policy. The COID consists of 12 members along with 

liaisons from CDC, CPS, FDA, NIAID, NICHD, NVPO, and PIDS. The COID has established a 

strong relationship with ACIP. Members serve as liaisons on relevant ACIP working groups. 

Through liaisons, the COID provides input into work group deliberations. The committee 

conducts independent reviews of data, with a goal to reach harmonized recommendations. 

COID develops vaccine-related policy statements for AAP Members, and has used IDSA / 

USPHS guidelines for evidence rating. Statements become AAP Policy following approval by 

the AAP Board of Directors and publication in Pediatrics. 

Because AAP agreed that greater transparency and a guide for examining evidence were 

needed, COID has used the current US Public Health Services Grading System for Ranking 

Recommendations and Clinical Guidelines for vaccine recommendations, shown in the following 

illustration: 

[From: Prevention of Rotavirus Disease: Updated Guidelines for Use of Rotavirus Vaccine. Committee on Infectious Diseases. Pediatrics 

2009;123:1412-20] 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

With regard to AAP endorsement of externally developed clinical guidelines, SCOQIM uses the 

Conference on Guideline Standardization (COGS) checklist to assess quality [held in New 

Haven, Connecticut on April 26, 2002: http://gem.med.yale.edu/cogs/]. This statement was 

developed to be used prospectively as guidelines were developed; however, SCOQIM also 

uses them to evaluate any guideline sent to AAP for its approval. COGS statements include 18 

items critical for understanding a guideline, similar to those used by AAFP. This includes an 

evaluation of the systematic evidence review and evidence grading, including the criteria used 

to rate quality of evidence, how evidence was used to create recommendations, and the system 

describing strength of recommendations. COGS statements are submitted to Board and 

Executive Committee of AAP for approval. AAP can choose to endorse, not endorse, or affirm. 

If data are thought to be beneficial to pediatricians, but are not of the quality that would permit 

endorsement, a statement can be affirmed to make practitioners aware of the data. 

In conclusion, AAP would support a transparent, evidence-based process to arrive at ACIP 

recommendations for vaccines. 

Professional Organization Perspectives: ACP 

Gregory A. Poland, MD, MACP 

American College of Physicians 

Dr. Poland first announced that in July 2010 a new international learned society for 

vaccinologists would be officially launched called the Edward Jenner Society, about which 

further information may be obtained at http://www.edwardjennersociety.org 

He then explained that the American College of Physicians (ACP) is the United States (US) 

largest medical specialty organization. ACP has 129,000 members representing internists, subspecialists in internal medicine, residents and fellows in training, and medical students. The 

ACP headquarters is in Philadelphia and there is an office in Washington, D.C. 

With regard to background, ACP’s Clinical Efficacy Assessment Subcommittee (CEAS) was 

established in 1981. Members are all internists / subspecialists and methodologists, and are full 

time practitioners. There is stable membership on CEAS, with members serving up to 5 years 

and the chair serving up to 4 years. No external funding is accepted for CEAS; it is funded by 

ACP. There is conflict of Interest vetting of each member. CEAS does not endorse consensus 

statements or other groups’ guidelines. Instead, CEAS delivers two products: 1) Clinical 

Guidelines, which involves a systematic review of available evidence and a guideline statement 

with recommendations; and 2) Clinical Guidance Statements, which involves review of available 

guidelines and summary recommendations. 

Guideline topics are selected based on the prevalence of the disorder or the issue, potential 

impact on mortality and morbidity, effective health care / intervention available, areas of 

uncertainty and evidence that current performance is deficient, cost, likelihood of availability of 

strong evidence, and relevance to internal medicine. Systematic evidence reviews for clinical 

guidelines are ACP sponsored. These used to be done internally, but now usually are done by 

AHRQ. The process of a good systematic review is incredibly intense and generally cost about 

$200,000. ACP nominates topics to the AHRQ’s Evidence-based Practice Centers for 

systematic review and evidence report. ACP collaborates with other societies after extensive 

negotiations regarding what the evidence review would involve and evidence levels. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Medline, NGC (national guidelines clearinghouse) search, and experts in the field are all polled 

for information. The Appraisal of Guidelines Research and Evaluation (AGREE) instrument is 

used to rate guidelines [http://www.agreetrust.org]. ACP also summarizes other guidelines and 

recommendations and offer sometimes offer summary recommendation based on other’s 

guidelines. 

The guideline development process involves formulating questions for the evidence review; a 

systematic evidence review, with a background evidence-review paper and a guideline paper 

that offer the actual recommendations; CEAS meetings and conference calls; CEAS Guideline 

Sub-Panel conference calls; and extensive internal ACP review by approximately 60 people; 

and external review by specialty societies, Annals of Internal Medicine, and others. The 

development process takes approximately 18 to 24 months on average. It is approved by the 

sub-panel, CEAS, the ACP Education Committee, and the Board of Regents. Guideline and 

background papers are then typically submitted to the Annals of Internal Medicine where they 

undergo independent peer-review. The shelf life of ACP guidelines is anticipated to be on 

average about 5 years. The following is an example of the grading system ACP uses: 

ACP Guideline Recommendation 

Grading System 

Strength of Recommendation 

Quality of Evidence Benefits clearly outweigh risks and burden OR 

risks and burden clearly outweigh benefits 

Benefits finely balanced with 

risks and burden 

High Strong Weak 

Moderate Strong Weak 

Low Strong Weak 

Insufficient evidence to 

determine net benefits or 

risks 

I-recommendation 

* Adopted from the classification developed by the Grading of Recommendations, Assessment, Development,and 

Evaluation (GRADE) workgroup. 

For years, the ACIP recommendations were not endorsed by the ACP guidelines committee 

because they were not evidence-based. Instead, they were endorsed by the ACP Adult 

Immunization Advisory Board (AIAB), then by the Education Committee, and then by the Board 

of Regents. The ACP AIAB was able to convince the ACP leadership that it was important to 

sign on to the ACIP schedule even though it did not meet ACP evidence-based criteria. The 

efforts of the ACIP EBRWG have been monumental and were started largely due to input / 

pressure from the ACP and other societies. The ACP appreciates this effort and strongly 

supports a standardized evidence-based approach for developing the ACIP recommendations 

on vaccine policy. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

GRADE 

Holger Schünemann, MD, PhD 

Chair, Department of Clinical Epidemiology & Biostatistics 

Michael Gent Chair in Healthcare Research 

McMaster University, Hamilton, Canada 

Dr. Schünemann explained that the GRADE framework in general is based upon the framework 

for evidence-based healthcare decisions, which results from the integration of clinical state and 

circumstances, population values and preferences, and best research evidence. Expertise is 

required to do this. There is a need to assess whether evidence is actually available. Some 

would propose that there always is evidence and that when there is a question there is 

evidence. The evidence may not be complete and it may only be relevant for certain aspects of 

the question, but typically when there is a question, some form of evidence exists. It also 

means that when there is better research, there will be greater confidence in the evidence and 

the decisions that follow from this evidence. Better research means that there must be some 

form of hierarchy. Shown in the following illustration is a typical hierarchy for evidence that is 

from the Canadian Task Force for Preventive Services from about 30 years ago: 

Hierarchy of evidence

based on quality

STUDY DESIGN

 Randomized Controlled

Trials

 Cohort Studies and Case

Control Studies

 Case Reports and Case

Series, Non‐systematic

observations

 Expert Opinion

BIAS

Typical hierarchies of evidence have expert opinion at the bottom, which does not bode 

particularly well for the experts, and randomized controlled trials (RCTs) at the top. All of this is 

based on the assumption that expert opinion is associated with the greatest bias and RCTs are 

associated with the least amount of bias. Dr. Schünemann proposed that this hierarchy was 

entirely too simplistic, quoting Albert Einstein who said, “Everything should be made as simple 

as possible but not simpler.” He asked the audience whether they would feel comfortable 

explaining the following concepts, which all more or less have to do with whether an estimate of 

effect for a certain population for whom guidelines are likely to be applied is actually correct: 

 Confounding, effect modification, and external validity 

 Concealment of randomization 

 Blinding (who is blinded in a double blinded study?) 

 Intention to treat analysis and its correct application 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

 P-values and confidence intervals 

He posited that few people would feel comfortable with this because special training is required 

to assess evidence. Dr. Schünemann referred to a publication in the British Medical Journal in 

2003 in which investigators made fun of themselves and RCTs titled, “Parachute use to prevent 

death and major trauma related to gravitational challenge: systematic review of randomised 

controlled trials” [Gordon CS smith, Jill P Pell]. Lo and behold, the investigators did not find any 

RCTs. If Dr. Schünemann were to pose the question, “Why do you believe that parachutes 

actually prevent death and injury when jumping from an airplane?” after some deliberation, 

people would say that it is because the effects are so large. It is based on many observations 

that parachutes actually do prevent deaths. RCTs are not needed when effects are very large. 

In fact, the evidence from the US Parachutte Association reported 821 injuries and 18 deaths 

out of 2.2 million jumps in 2007. The risk estimates can be calculated, with the relative risk 

reduction being > 99.9 % (1/100,000). At the same time, if assessing the first parachutes, 

theory alone and gravitational theory would not help to make decisions because the first 

parachutes did not work. 

In health care, there are very few such large effects. Nevertheless, when dealing with large 

effects, RCTs are not needed. However, the evidence hierarchy shown is far too simplistic. Dr. 

Schünemann stressed that expert opinion is not a form of evidence and should not be at the 

bottom of the hierarchy—it actually should be required to evaluate various forms of evidence. 

Clearly, many things can go wrong with RCTs and many things can be good about 

observational studies, such as large effects that increase the confidence that an estimate of 

effect is actually correct. 

There is another issue with evidence hierarchies. In what should be a simple recommendation 

for the use of oral anticoagulation in patients with atrial fibrillation and rheumatic mitral valve 

disease, the following table represents the evidence and recommendations of three 

organizations: 

Evidence Recommendation Organization 

B Class I AHA 

A 1 ACCP 

IV C SIGN 

A practitioner looking at this evidence would likely have been very confused, particularly given 

that the three organizations reviewed exactly the same five RCTs. While not concerned about 

the different judgments, Dr. Schünemann was concerned that at the time, there was little 

information regarding why these evidence ratings were categorized as they were. The 

transparency related to making the assessment about the evidence and development of these 

recommendations can be improved. 

This is part of the rationale for forming the GRADE Working Group. The aim of the GRADE 

Working Group is to develop a common, transparent, and sensible system for grading the 

quality of evidence and the strength of recommendations. This is an international group of 

guideline developers, methodologists, and clinicians from throughout the world (>100 

contributors) since 2000. Groups include ACCP, AHRQ, Australian NMRC, BMJ Clinical 

Evidence, CC, CDC, McMaster, NICE, Oxford CEBM, SIGN, UpToDate, USPSTF, and WHO. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

The GRADE systems has experienced wide uptake by the following: 

 World Health Organization 

 Allergic Rhinitis in Asthma Guidelines (ARIA) 

 American Thoracic Society 

 American College of Physicians 

 European Respiratory Society 

 European Society of Thoracic Surgeons 

 British Medical Journal 

 Infectious Disease Society of America 

 American College of Chest Physicians 

 UpToDate® 

 National Institutes of Health and Clinical Excellence (NICE) 

 Scottish Intercollegiate Guideline Network (SIGN) 

 Cochrane Collaboration 

 Infectious Disease Society of America 

 Clinical Evidence 

 Agency for Health Care Research and Quality (AHRQ) 

 Partner of GIN 

 Over 40 major organizations 

Much of this is work has been published in a series of 16 articles that were developed for WHO 

beginning in 2005 for the Advisory Committee for Health Research, which reviewed WHO’s and 

other organizations’ guideline development, and formulating a recommendation for WHO 

regarding how the process could be improved. A very complete process was laid out for 

guideline development that ranged from prioritizing problems and scoping of questions to 

developing recommendations and evaluating the impact of guidelines, as reflected in the 

following illustration: 

Prioritize problems & scoping 

Ø

Establish guideline panel and develop questions, including outcomes 

Ø

Find and critically appraise systematic review(s) and / or 

Prepare protocol(s) for systematic review(s) and 

Prepare systematic review(s) (searches, selection of studies, data collection, and analysis) 

Ø

Prepare an evidence profile 

Ø

Assess the quality of evidence for each outcome 

Ø

Prepare a summary of findings table 

Ø

If developing guidelines: assess the overall quality of evidence and decide on the 

direction (which alternative) and strength of the recommendation 

Ø

Draft guidelines 

Ø

Consult with stakeholders and / or external peer reviewers 

Ø

Disseminate guidelines 

Ø

Update review or guidelines when needed 

Ø

Adapt guidelines, if needed 

Ø

Prioritize guidelines / recommendations for implementation 

Ø

Implement or support implementation of the guidelines 

Ø

Evaluate the impact of the guidelines and implementation strategies 

Ø

Update systematic review / guidelines 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Dr. Schünemann presented a brief case scenario to illustrate how the GRADE system was 

applied at WHO. A 13-year-old girl who lived in rural Indonesia presented with influenza 

symptoms and developed severe respiratory distress over the course of the 2 previous days. 

She required intubation. The history reveals that she shared her living quarters with her parents 

and her three siblings. At night, the family’s chicken stock also shared this room, and several 

chickens had died unexpectedly a few days before the girl fell sick. The way avian influenza is 

approached is by considering the potential interventions (e.g., antivirals, such as neuraminidase 

inhibitors, oseltamivir and zanamivir). They followed a structured approach for developing 

questions. Guidelines should deal with actionable items, and often background questions are 

addressed in guidelines. However, background questions usually do not lead to 

recommendations. They usually include questions such as: What is Avian Influenza? What is 

the mechanism of action of oseltamivir? Foreground questions lead to actionable items and 

recommendations, and usually deal with issues that assess whether benefit outweighs potential 

harm: In patients with avian influenza, does oseltamivir therapy improve survival? 

Framing a foreground question is extremely important for developing clinical practice guidelines, 

and involves specifying the population, intervention, comparison, and outcomes. For example: 

Population: Avian Flu / influenza A (H5N1) patients 

Intervention: Oseltamivir 

Comparison: No pharmacological intervention 

Outcomes: Mortality, hospitalizations, resource use, adverse outcomes, antimicrobial 

resistance 

A framework for developing recommendations and clinical questions should consider all 

important outcomes that are relevant for clinical questions. Frequently, recommendations that 

focus on single and particular outcomes were evaluated in studies rather than beginning with 

the clinical question and then evaluating the evidence. Choosing outcomes mean that there 

must be clarity about the following: 

 Desirable outcomes 

Æ lower mortality 

Æ reduced hospital stay 

Æ reduced duration of disease 

Æ reduced resource expenditure 

 Undesirable outcomes 

Æ adverse reactions 

Æ the development of resistance 

Æ costs of treatment 

 Every decision comes with desirable and undesirable consequences 

Æ Developing recommendations must include a consideration of desirable and 

undesirable outcomes 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

It is also important for decision makers and guideline authors to consider the relative importance 

of outcomes when balancing these outcomes to make a recommendation. One way to do this is 

to decide which outcomes are critical for decision making; which are important, but not critical 

for decision making; and which are of low importance. Moreover, relative importance may vary 

across populations and across patient groups within the same population. Once a guideline 

panel decides that an outcome is critical, the quality of the evidence and effects associated with 

it should then be evaluated in order to make the most informed decisions. 

GRADE separates two issues in terms of the quality of the recommendation: 

1) Two Recommendation Grades: Weak / conditional / optional or strong (for or against an 

intervention) 

Æ Balance of benefits and downsides, values and preferences, resource use and 

quality of evidence influence the strength of a recommendation 

2) 4 Categories of Quality of Evidence: Recognizing that this is a continuum, these categories 

are used to improve communication: ⊕⊕⊕⊕ (High), ⊕⊕⊕{(Moderate), ⊕⊕{{(Low), 

⊕{{{(Very low). These are just labels. The importance is the conceptual underpinnings: 

Æ methodological quality of evidence 

Æ likelihood of bias 

Æ by outcome and across outcomes 

In the context of making recommendations, the quality of evidence reflects the extent of 

confidence that the estimates of an effect are adequate to support a particular decision or 

recommendation. To illustrate, Dr. Schünemann shared a cartoon of two weathermen, one of 

whom says, “I think that there is a 40% chance of showers and, a 10% chance we know what 

we’re talking about.” This expresses the likelihood of and the confidence in an outcome. The 

effect estimate in this illustration is 40% and the confidence that these two meteorologists are 

reporting the truth is 10%. That is due to the fact that they may have used poor models for 

prediction, or the evidence for creating these models may be poor. The same is true in health 

care. There are sometimes confidence intervals that are very narrow, but nevertheless the 

evidence supporting these confidence estimates and the point estimate are very low. 

The definition provided for the grades of evidence include: 

 ⊕⊕⊕⊕/A/High: Further research is very unlikely to change confidence in the estimate of 

effect. 



 ⊕⊕⊕{/B/Moderate: Further research is likely to have an important impact on confidence in 

the estimate of effect and may change the estimate. 

 ⊕⊕{{/C/Low: Further research is very likely to have an important impact on confidence in 

the estimate of effect and is likely to change the estimate. 

 ⊕{{{/D/Very low: Any estimate of effect is very uncertain. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

With respect to determinants of quality, randomization results in greater confidence in estimates 

of effect so RCTs are of high quality (⊕⊕⊕⊕), while observational studies are of low quality 

(⊕⊕{{); however, many factors can lead to bias and many things can go wrong in RCTs. 

Factors that can lower confidence in estimates of effects include: 

 Limitations in detailed design and execution (risk of bias criteria)

 Inconsistency (or heterogeneity)

 Indirectness (PICO and applicability)

 Imprecision (number of events and confidence intervals)

 Publication bias 

Factors that can increase confidence in estimates of effects include: 

 Large magnitude of effect 

 All plausible residual confounding may be working to reduce the demonstrated effect or 

increase the effect if no effect was observed 

 Dose-response gradient 

Examples of design and execution / risk of bias include: 

 Inappropriate selection of exposed and unexposed groups, failure to adequately measure / 

control for confounding 

 Selective outcome reporting 

 Failure to blind (e.g., outcome assessors) 

 High loss to follow-up 

 Lack of concealment in RCTs 

 Intention to treat principle violated 

The Risk of Bias (RoB) Table is a tool used by the Cochrane Collaboration. Dr. Schünemann 

shared an example in which the authors examined 30 RCTs that fulfilled their inclusion criteria 

for adverse effects as a result of using formoterol for asthma [From Cates, CDSR 2008]. To 

assess the trials, the investigators used three key methodological criteria: concealment of 

randomization, blinding, and whether there was selective outcome reporting. About half of the 

studies did not report on adverse events, although they had the data. The RoB table is too 

complicated for clinicians who have to deal with more important problems, but this can be 

utilized by adequately trained individuals. It also means that an overall judgment of the 

underlying quality of the evidence is required. In this case, given that about half of the studies 

did not report on adverse events, any estimate of effect in relation to adverse events would 

probably be met by less certainty than if these studies had reported on adverse events. Thus, 

there is a reason to lower the quality of evidence for RCTs. Another example shared by Dr. 

Schünemann pertained to anticoagulation and reduction in mortality in patients with cancer for 

which the trials were of much better quality, with few things done wrong. The guideline panel 

rightly decided not to lower the quality of evidence because the RCTs were done well [Akl E, 

Barba M, Rohilla S, Terrenato I, Sperati F, Schünemann HJ. “Anticoagulation for the long term 

treatment of venous thromboembolism in patients with cancer”. Cochrane Database Syst Rev. 

2008 Apr 16;(2):CD006650]. 

If there is inconsistency of results between RCTs or observational studies, an explanation 

should be sought in terms of whether there are differences in the patients, intervention, 

comparator, and outcomes that explain differences in results between studies. If this remains 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

unexplained, confidence may be lowered in the overall estimate of effect across studies. Dr. 

Schünemann shared an example of a Cochrane review from the immunization literature 

pertaining to how reminders can increase the uptake of immunizations [Jacobson Vann JC, 

Szilagyi P. Patient reminder and recall systems to improve immunization rates. Cochrane 

Database of Systematic Reviews 2005, Issue 3, Art. No.: CD003941. DOI: 101002/14651858. 

CD003941.pub2.] In this example, five studies all showed similar effects and appeared to vary 

due to random influences. The overall estimate of effect was that there is an increase in the 

odds ratio of 1.58 (1.26, 1.99) for an uptake of immunization across these five studies. There is 

not a lot of reason to believe that these five studies measured anything differently. 

An alternative example from the same type of review involves a different intervention of patient 

reminders in a subgroup that dealt with preschool children. The intervention in the two studies 

was highly efficacious; however, the odds ratio differed greatly between them at 6.77 (4.57, 

10.02) and 1.92 (1.51, 2.43), so confidence in the overall estimate of effect would be lowered by 

the inconsistency between the two studies despite the fact that both show efficacy. These are 

important considerations, especially given that sometimes a threshold must be used for when 

an intervention really becomes efficacious. 

Directness of evidence is related to the concept of generalizability, transferability, and 

applicability though it is slightly different in that it goes beyond these concepts. The interest is in 

the differences in populations / patients (e.g., have information on children and are interested in 

making recommendations about neonates; have information on women in general and are 

interested in making recommendations about pregnant women); interventions (e.g., interested in 

making recommendations for a vaccine when information comes from older vaccines); 

comparator appropriateness (e.g., comparator included in the evidence should relate to the 

question of interest); and outcomes (e.g., does seroconversion actually mean cases prevented). 

Another concept pertains to indirect comparisons, particularly in the context of comparative 

effectiveness research. For example, perhaps there is an interest in comparing Vaccine A to 

Vaccine B but the only comparison possible is an indirect comparison between A versus C and 

B versus C or Vaccine A versus a Placebo and Vaccine B versus a Placebo. Relative estimates 

of effect can be calculated, but the certainty would be lower. 

The fourth criterion is publication bias, which should always be suspected with research not 

being published in particular with small “negative” trials, when there are only a few small 

“positive” trials, and when there is a lot of for profit interest. There are various methods to 

evaluate whether there are publication biases, though none of these is perfect. The fifth 

criterion of imprecision pertains to small sample size. When there are a small number of events 

or very small studies, there are usually wide confidence intervals, which results in uncertainty 

about the magnitude of effect. This can be interpreted as the extent to which confidence in 

estimate of effect is adequate to support a decision. 

With regard to what can raise quality, a large magnitude in effect (RRR 50%/RR 2). When there 

is a very large effect, quality may be raised by two levels (RRR 80%/RR 5). The common 

criteria would be that everyone used to do badly before the intervention, but following the 

intervention almost everyone does well (e.g., parachutes to prevent death when jumping from 

airplanes). There are also examples from health care. In an intervention to increase the uptake 

of immunizations in which telephone reminders were used, three observational studies were 

found by the systematic reviewers. There was a large number of participants and the effect 

across these studies comes with a relative risk (RR) >2, which would increase the confidence 

that this particular intervention worked in this context. Dose response relationships can also 

raise confidence. A common example is that the more a patient’s blood is thinned, the higher 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

the risk of bleeding. There is a good example from the observational study literature, not related 

to immunization, on children diagnosed with childhood lymphoblastic leukemia (CLL). 

Physicians frequently use prophylactic CNS radiation to reduce the risk of CLL recurring. 

However, this radiation comes with the risk of secondary CNS malignancies 15 years after 

cranial irradiation. When investigators assessed the evidence related to this, they found that 

children who received no radiation had about a 1% (95% CI 0% to 2.1%) incidence of CNS 

malignancies, a 12 Gy radiation dose led to a 1.6% (95% CI 0% to 3.4%) incidence, and 18 Gy 

to a 3.3% (95% CI 0.9% to 5.6%) incidence. 

The third criterion pertains to whether all plausible confounding may be working to reduce the 

demonstrated effect or increase the effect if no effect was observed. In terms of whether all 

plausible residual confounding would result in an overestimate of effect, Dr. Schünemann 

shared an example from the general medical literature. A drug that was used for the treatment 

of diabetes, phenformin, was highly suspected of causing the devastating complication of lactic 

acidosis. The related agent, metformin, is under suspicion for the same toxicity. This was 

widely publicized. Large observational studies have failed to demonstrate an association 

despite the over-reporting as a possible residual confounding of this association. This type of 

observations would increase the confidence in the estimate of effect. There are parallels in the 

vaccine literature. Suspicion that adverse effects may exist may be refuted by observational 

studies that assess all patients immunized that do not find these associations. Under these 

circumstances, the quality of the evidence for the existence of no association may be increased. 

To summarize the quality of evidence assessment, the body of evidence would be examined as 

illustrated by the following table: 

Study design Initial quality of a

body of evidence

Lower if Higher if Quality of a body

of evidence

Randomised

trials

High Risk of Bias

‐ 1 Serious

‐2 Very serious

Large effect

+ 1 Large

+2 Very large

A/High (four plus:

⊕⊕⊕⊕)

Inconsistency

‐ 1 Serious

‐2 Very serious

Indirectness

‐ 1 Serious

‐2 Very serious

Imprecision

‐ 1 Serious

‐2 Very serious

Publication bias

‐ 1 Likely

‐2 Very likely

Dose response

+1 Evidence of a

gradient

All plausible

residual

confounding

+1 Would reduce

a demonstrated

effect

+1 Would suggest

a spurious effect

if no effect was

observed

B/Moderate

(three plus:

⊕⊕⊕{)

C/Low (two plus:

⊕⊕{{)

Observational

studies

Low

D/Very low (one

plus: ⊕{{{)

Comprehensive evidence summaries are ultimately produced to ensure that everyone on a 

guideline panel is looking at the same type of evidence. A quality assessment is conducted for 

outcomes that are critical for a clinical question that examines the number of studies, design, 

limitations, inconsistency, indirectness, imprecision, and other considerations. The numerical 

results are presented to a guideline panel. Importantly, all of this information will be made 

available for those interested in exploring the recommendations (e.g., transparency). 

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With regard to moving to recommendations, the strength of a recommendation is defined as 

follows, “The strength of a recommendation reflects the extent to which we can, across the 

range of patients for whom the recommendations are intended, be confident that desirable 

effects of a management strategy outweigh undesirable effects.” Regarding the determinants of 

the strength of a recommendation, the factors that can strengthen a recommendation include 

the following: 

 Quality of the evidence: The higher the quality of evidence, the more likely is a strong 

recommendation. 

 Balance between desirable and undesirable effects: The larger the difference between the 

desirable and undesirable consequences, the more likely a strong recommendation is 

warranted. The smaller the net benefit and the lower certainty for that benefit, the more 

likely a weak recommendation is warranted. 

 Values and preferences: The greater the variability in values and preferences, or 

uncertainty in values and preferences, the more likely a weak recommendation is warranted. 

 Costs (resource allocation): The higher the costs of an intervention (e.g., the more 

resources consumed), the less likely is a strong recommendation warranted. 

This framework is then applied as reflected in the following illustration, which demonstrates the 

continuum from desirable effects clearly outweighing the undesirable effects to the undesirable 

effects clearly outweighing the desirable effects: 

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It is imperative to use categories in order to improve communication. In this system, strong 

recommendations are made when the balance is clear and weak or optional recommendations 

are made when the balance is less clear in favor of an intervention. When the undesirable 

effects are likely larger than the desirable effects, weak recommendations are made if the 

balance is not as clear or strong recommendations if the balance is very clear. 

Returning to the avian influenza case scenario example and what was done with WHO, a 

standard guideline development process was utilized based on the 16 cases. Group 

composition included a panel of 13 voting members of clinicians who treated influenza A(H5N1) 

patients, infectious disease experts, basic scientists, public health officers, and methodologists. 

Independent scientific reviewers identified systematic reviews, recent RCTs, case series, and 

animal studies related to H5N1 infection. There were five studies, none of which directly dealt 

with avian influenza patients. There were no clinical trials of oseltamivir for treatment of H5N1 

patients. However, there was a body of indirect evidence from cases with seasonal influenza 

infection that included four systematic reviews and health technology assessments (HTA) 

reporting on five studies of oseltamivir in seasonal influenza. The findings were that for 

hospitalizations the odds ratio was 0.22 (0.02 – 2.16), and for pneumonia the odds ratio was 

0.15 (0.03 - 0.69). This was a large effect, but it was based on very few events. For nonpandemic conditions, the cost per treatment course was approximately $40. The panel then 

assessed the strength of the evidence and made several judgments that were made 

transparent. They found that there was a very low quality of evidence. The balance between 

desirable and undesirable effects was uncertain, but the small reduction in relative risk led to a 

large absolute effect. Values and preferences were clear and there was little variability, and the 

cost was low in this non-pandemic setting. 

Dr. Schünemann pointed out that he presented this example because it was an exception to the 

rule in that very low quality evidence led to a strong recommendation that was formulated very 

clearly: “In patients with confirmed or strongly suspected infection with avian influenza A 

(H5N1) virus, clinicians should administer oseltamivir treatment as soon as possible (strong 

recommendation based on very low quality evidence).” This recommendation places a high 

value on the prevention of death in an illness with a high case fatality. It places relatively low 

values on adverse reactions, the development of resistance, and costs of treatment. 

It is important to provide users of the recommendation with information regarding what these 

strong recommendations really mean. For patients, most people in this situation would want the 

recommended course of action and only a small proportion would not. For clinicians, it means 

that most patients should receive the recommended course of action. For policy makers, the 

recommendation can be adapted as a policy in most situations. In terms of the iimplications of 

a conditional / weak recommendation, the majority of people in this situation would want the 

recommended course of action, but many would not. Clinicians will be more prepared to help 

patients to make a decision that is consistent with their own values / decision aids and shared 

decision making (e.g., pregnant women). For policy makers, there is a need for substantial 

debate and involvement of stakeholders. 

Dr. Schünemann reiterated that guideline development needs to take place in interaction with 

systematic, complete and transparent evaluation of the evidence. This begins with development 

of a clinical question, which should not debate only on what the evidence reviewers put 

together, but should also be informed by and take place in close interaction with the guideline in 

question. A guideline panel must decide what outcomes are relevant for the specific clinical 

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question, and must decide which are critical and which are not as important. Outcomes must be 

evaluated across studies. Critical and important outcomes must be assessed for their quality, 

and it may not be necessary to spend much time on non-important outcomes. Systematic and 

transparent summaries should be prepared, and quality ratings should be taking place based on 

the factors that increase or decrease the quality of the evidence. An overall assessment for all 

critical outcomes should be completed. The guideline panel must then integrate this evidence 

and formulate recommendations either for or against an intervention. These can be strong or 

weak or conditional / optional. This takes place after weighing the quality of evidence across 

outcomes based against the balance of benefits and harms, values and preferences, and 

resource use. This should result in clearly formulated recommendations. This process is 

reflected in the following illustration: 

Systematic review

Guideline development

P

I

C

O

Outcome

Outcome

Outcome

Outcome

Critical

Important

Critical

Not

Summary of findings

& estimate of effect

for each outcome

Grade

overall quality of evidence

across outcomes based on

lowest quality

of critical outcomes

Randomization

increases initial

quality

1. Risk of bias

2. Inconsistency

3. Indirectness

4. Imprecision

5. Publication

bias

Grade down Grade up

1. Large effect

2. Dose

response

3. Confounders

Very low

Low

Moderate

High

Formulate recommendations:

• For or against (direction)

• Strong or weak (strength)

By considering:

 Quality of evidence

 Balance benefits/harms

 Values and preferences

Revise if necessary by considering:

 Resource use (cost)

• “We recommend using...”

• “We suggest using...”

• “We recommend against using...”

• “We suggest against using...”

There are some specific issues related to guideline development for immunization. Dr. 

Schünemann said he wanted to stimulate some thoughts about whether demonstrating 

causation is closely related to efficacy of interventions. He believes that causation is not 

equivalent to efficacy of interventions. The Bradford Hill criteria are extremely important, but 

they are nearly half a century old. The question regards whether they should be taken as a 

“tablet from the mountain” or whether health research methodology has changed over the past 

50 years. The situation of causation is very much reflected in harms caused by medications. 

There is an assumption that not administering an immunization would lead to no exposure, 

which would lead to no adverse effects based on the strong associations observed. Another 

question regards whether to stop exposure, such as implementing policies to no longer 

administer a drug, which directly relates to stopping the outcome from occurring. An 

assessment is needed between the strength of an association and causation in relation to how 

an intervention may actually affect the exposure-outcome relation. That is, an assessment must 

be made of how confident one can be that removal of the exposure is effective in preventing 

disease. This is true whether it is drugs or environmental factors, and will depend on the 

intervention to remove exposure. 

Four considerations pertaining to GRADE and immunizations include the following: 

 Can herd immunity following immunization and indirect effects on the co-circulation of other 

pathogens typically be ascertained only through the use of observational epidemiological 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

methods? Innovative randomized controlled trials (RCTs) using cluster-randomization are 

increasingly being conducted to provide this evidence. 

 A 94% protective effect of a live, monovalent vaccine against measles is classified as 

“moderate level of scientific evidence.” GRADE’s strength of association criteria may be 

applied to increase the grade by 2 levels from “low” to “high” in this situation. 

 GRADE ratings do not give credit to “gradient of effects with scale of population level impact 

compatible with degree of coverage.” GRADE’s dose-response criterion would apply to 

such gradients. 

 Might anti-vaccination lobby groups abuse the ratings? Abuse of any system is possible. It 

is equally likely that increased transparency provided by the GRADE framework can 

strengthen, rather than undermine, the trust in vaccines and other interventions. 

In conclusion, Dr. Schünemann said he would agree with modifying the GRADE criteria if 

Bradford Hill criteria were not already considered, but they are. The emphasis in GRADE is on 

the strength of a recommendation, and the quality of evidence is only one factor. GRADE 

considers the Bradford Hill criteria to some degree, as reflected in the following table: 

Bradford Hill and GRADE Bradford Hill Criteria Consideration in GRADE

Strength Strength of association and imprecision in effect estimate

Consistency Consistency across studies, i.e. across different situations

(different researchers)

Temporality Study design, specific study limitations; RCTs fulfil this

criterion better than observational studies

Biological gradient Dose response gradient

Specificity Indirectness

Biological Plausibility Indirectness, publication bias

Coherence Indirectness

Experiment Study design, randomization

Analogy Existing association for critical outcomes will lead to not

downgrading the quality

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

WHO’s Strategic Advisory Group of Experts (SAGE): 

Approach to Evidence-Based Recommendations 

Arthur L. Reingold, MD 

Professor, Division of Epidemiology 

Associate Dean for Research, 

School of Public Health 

University of California, Berkeley 

Dr. Reingold reported that WHO’s Strategic Advisory Group of Experts (SAGE) was established 

in 1984 to serve as the principal advisory group to WHO for development of policy related to 

vaccines and immunization. Since 2005, the SAGE chair reports directly to the Director General 

of WHO. SAGE currently includes 15 members who represent a broad range of disciplines 

relating to vaccines and immunizations, with a strong emphasis on geographic 

representativeness throughout the world. Currently, there are two Americans on the committee 

(e.g., himself and Jon Abramson). SAGE currently meets twice per year in April and November, 

and meetings are three days in length. In addition, four conference calls are convened 

annually. In the past three years, SAGE has dramatically increased its activities, somewhat 

attempting to parallel the way ACIP operates, but with far fewer resources. SAGE has 

benefitted in recent years from funding from the Gates Foundation to increase its number of 

meetings and activities. As of July 2010, working groups include: Measles; Inactivated Polio; 

H5N1 Influenza; Influenza; Pertussis; Meningococcal Meningitis; Rubella; and Hepatitis A. 

Much of the work of SAGE is conducted through these working groups, which develop position 

papers that are subsequently discussed and approved by the entire SAGE committee. Staff 

support is provided by P. DuClos, who serves the same purpose that CDC serves for ACIP, 

except that he is a one-man show. He is an extraordinarily important person in helping SAGE 

with its work. 

SAGE is primarily intended to discuss and develop position papers for WHO to use to 

promulgate to regional offices and to countries which rely on WHO. SAGE develops position 

papers pertaining to new vaccines and revises and develops position papers regarding old 

vaccines and immunization schedules. The primary target audiences for these position papers 

are poor and middle income countries that do not typically have an ACIP or comparable 

organization to conduct this type of review and develop these types of papers for them. SAGE 

is particularly concerned about what occurs at the group level across large populations, and 

their work involves SAGE and outside members, and a working group typically includes two 

SAGE members and four to six subject matters experts from throughout the world who 

participate in the process. SAGE’s position papers are published in the Weekly Epidemiological 

Record and on the WHO website. The development of position papers began in 1998. SAGE 

has developed position papers for each vaccine-preventable disease, which have to be 

published in all of the WHO languages. 

In 2003, WHO decided to adopt GRADE as its approach to evaluate evidence. All of WHO’s 

advisory committees, including SAGE, are obliged to use the GRADE approach in one fashion 

or another. In 2006, WHO began to use GRADE for a series of 16 reviews. In 2007, WHO 

formed a Guideline Review Committee to implement the use of GRADE across all of WHO’s 

guidelines in vaccines and other areas. In 2008, WHO introduced the use of GRADE tables in 

its vaccine position papers. GRADE can be used to examine the quality of evidence in support 

of a decision and to assess the strength of the recommendation itself. Currently, GRADE is 

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used by SAGE to assess the quality of evidence in support of a vaccine, but SAGE does not 

use this approach in terms of making a decision about the strength of a recommendation being 

made. In 2009, a SAGE discussion group was formed concerning the use of GRADE to 

determine whether they may wish to modify the GRADE framework in some ways and to 

address challenges in applying GRADE to vaccines. This committee is currently comprised of 

Professor David Durrheim (Australia); Professor Zulfiqar Ahmed Bhutta (Pakistan); Helen Rees 

(South Africa; SAGE Chair); himself (US); P. DuClos (WHO Secretariat). Their business is 

conducted primarily by emails and conference calls. The objectives of SAGE’s GRADE 

Discussion Group are to develop a communication strategy concerning SAGE’s use of GRADE 

in its position papers; discuss possible “adjustments” to the GRADE approach; and discuss 

possible alternatives to the GRADE approach. To be perfectly honest, Dr. Reingold thought that 

the possibility of alternatives to the GRADE approach was not really “on the table” currently 

given WHO policies. 

SAGE position papers revised or created using the GRADE approach include the following: 

New Vaccines Existing Vaccines 

HPV vaccine Pneumococcal 

Polysaccharide Vaccine 

Typhoid vaccine 

Measles vaccine 

Hepatitis B vaccine 

Cholera vaccine 

When SAGE publishes a position paper, they make recommendations about the use of a 

vaccine. These recommendations have now become absolutely vital in terms of funding of 

vaccines for poor countries. For example, the Global Alliance for Vaccines and Immunisation 

(GAVI) Board, in deciding whether to utilize GAVI money to fund vaccines (e.g., pneumococcal 

conjugate, HPV, rotavirus, etc) will not do so until SAGE issues a position paper. 

SAGE’s HPV vaccine position paper states that “WHO. . . recommends that routine HPV 

vaccination should be included in national immunization programmes, . . . the primary target 

population is likely to be girls within the age range of 9 or 10 years through to 13 years” [WER 

15; 10 April 2009]. This represents the challenging fact that WHO is dealing with many 

countries in many cultural settings, so they try to be broader in the writing of position papers 

than a single country might be. The footnote in this position paper reads, “Moderate quality of 

scientific evidence to support HPV vaccination of young adolescent girls to prevent cervical 

cancer later in life” [WER 15; 10 April 2009]. Because of the use of the GRADE approach and 

the desire for transparency, the tables are presented. 

The theory is that anyone using GRADE to review this same set of papers would develop this 

identical table. The position paper then continues, stating that “Although the immunogenicity 

and efficacy of HPV vaccines may be reduced in HIV-infected females, the potential benefit of 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

vaccination in this group is particularly great. . . HIV testing should not be a prerequisite before 

routine HPV immunization.” Another footnote is included that states, “Very low quality of 

scientific evidence to support vaccination of HIV-infected young adolescent girls to prevent 

cervical cancer later in life.” Another table is then included to explain the grading of scientific 

evidence in terms of HPV and to show that only one study that has relevant data on this subject.

That is an example with a new vaccine. It is generally easier to use the GRADE system for 

newer vaccine for which there are generally well done studies. It is somewhat more challenging

to apply the system to older studies and older vaccines. 

SAGE’s pneumococcal polysaccharide vaccine 23 (PPV23) position paper includes a revised 

statement reading, “RCTs have failed to demonstrate efficacy against IPD or all-cause 

pneumonia in individuals with immune compromising conditions, regardless of age. Most 

observational studies suggest an effectiveness as high as 50 to 80% against IPD in healthy 

adults, and similar results have been reported in some high-risk populations” WER 42; 17 

October 2008. The footnote states that, “Low-quality evidence of a lack of effectiveness of 

PPV23 against IPD in high-risk groups, acknowledging the variability of high-risk groups and of 

effectiveness in these groups.” This is followed by a table showing the various studies. While 

there are people who believe that PPV23 is a great vaccine, SAGE’s assessment using the 

GRADE criteria is that the evidence is of low quality. Again, the theory is that anyone using 

GRADE to review the papers for this topic would develop this identical table. 

There are a number of perceived challenges to using GRADE when assessing vaccines, which 

include the following:

 Poor quality of many early studies of existing vaccines (e.g., tetanus toxoid) 

 Ethical inhibitions to conducting additional RCTs 

 Lack of consistency of the biological products used (e.g., BCG) 

 Inability to examine safety vis–à–vis rare AEFIs in RCTs and reliance on post-marketing 

surveillance 

 Difficulty of factoring in indirect effects (e.g., herd immunity) 

 Difficulty of factoring in effects on ecologic niches (e.g., serotype replacement) 

 Different measures of effect (immunogenicity with / without surrogates of protection; various 

clinical endpoints) 

 Duration of protection 

 Differences in age at vaccination / optimal age for immunization 

 Effects of “natural boosting” (e.g., B. pertussis) 

In conclusion, SAGE is using the GRADE approach to rate the quality of the evidence. There 

are concerns that low ratings of the quality of evidence will be misconstrued or misused. 

Possible modifications to the GRADE approach, tailored to the assessment of vaccines, are 

being considered. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Pilot of Explicit Evidence-Based Framework Based on GRADE 

Faruque Ahmed, PhD 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Ahmed reiterated that the EBRWG was proposing that ACIP adopt an explicit evidencebased framework based on the GRADE approach for new vaccines and for changes in 

recommendations for existing vaccines. 

GRADE has two components, the first of which is to assess the evidence grade for a body of 

evidence. The evidence grades are classified as high, moderate, low, or very low. The second 

component is grading a recommendation’s strength as strong or weak (for or against). 

Evidence grade is only one factor in determining the strength of a recommendation. Other 

factors include the balance of benefits and downsides, values and preferences, and resource 

use. Rather than the terms high, moderate, low, and very low quality EBRWG proposes to use 

the following letting system for ACIP evidence grades: 

A: Further research is unlikely to change the estimate of effect 

B: Further research may change the estimate of effect 

C: Further research is likely to change the estimate of effect 

D: Estimates of effect are uncertain 

EBRWG feels that the terms high or low quality may be misinterpreted or misused by persons 

who are not familiar with the GRADE method. The grades A, B, C, and D reflect the confidence 

in an estimate of effect from a body of evidence. A and B are often considered to be a good 

level of evidence. 

The GRADE approach of rating evidence begins with a study design. RCTs are initially rated as 

Grade A and observational studies as Grade B. Five factors can lower the grade: study 

limitations, inconsistency, indirectness, imprecision, and publication bias. Three factors can 

increase the grade: strength of association, dose-response, and confounding. If the relative 

risk is 2 from at least two observational studies with no possible confounders, the grade can be 

increased by one level from C to B. If the relative risk is 5 based on direct evidence with no 

major threats to validity, the grade can be increased by two levels from C to A. Expert opinion is 

graded as D, unless evidence informing opinion is graded (e.g., indirect evidence from other 

populations, vaccines, or diseases). 

Categorizing recommendations as strong or weak may not be most appropriate for vaccine 

recommendations. Therefore, the EBRWG proposed the following categories for ACIP: 

 Category I: Recommendations for or against, which apply to all persons in an age group - 

universal recommendations - or all persons in a specified high-risk group. 

 Category II: Optional use recommendations mean that clinicians should help each patient 

arrive at a decision that is consistent with their values and preferences. The optional use 

recommendation is similar to what is currently referred to as a permissive recommendation. 

It is also possible that the ACIP may decide not to make a recommendation. 

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The key elements for any ACIP recommendation include direct evidence assessment for 

vaccine safety and vaccine efficacy and indirect evidence assessment of burden of illness. 

Evidence grading would be applied to the data on vaccine safety and vaccine efficacy. Burden 

of illness information from research studies or from surveillance systems is used for calculating 

estimates of numbers needed to treat (NNT) or numbers needed to harm (NNH). Considerations 

that may result in an ACIP optional use recommendation include lower evidence grade, smaller 

net benefit, uncertainty or variability in values and preferences, or uncertainty about whether the 

net benefits are worth the costs (e.g., cost-effectiveness). For example, the ACIP 

recommendation for use of HPV vaccine in males is a permissive or optional use 

recommendation because of cost-effectiveness, burden of illness, and other factors. 

A pilot was conducted of the GRADE framework on a new vaccine, human-bovine reassortant 

pentavalent rotavirus vaccine (RotaTeq). Studies were used that were available at the time of 

the 2006 ACIP recommendation. This included Phase 3 studies of the pentavalent vaccine. 

Phase 1 and 2 studies that used a different vaccine formulation were excluded. Studies of 

rotavirus vaccines using other rotavirus strains (e.g., human-rhesus, human, lamb, bovine) were 

also excluded. Based upon the review of the studies, in terms of benefits and safety, an 

evidence grade of A was assigned for all outcomes shown, given that there were no serious 

study limitations, inconsistencies, indirectness, or imprecision. With respect to the balance 

between desirable and undesirable effects, the benefits were large compared to potential 

harms. In terms of values and preferences, parents are likely to place high value on preventing 

severe rotavirus gastroenteritis. While the vaccine is likely to be cost-saving from the societal 

perspective if the vaccine cost was $42 per dose, the vaccine price was not known at the time 

ACIP was making the recommendation. ACIP recommended universal vaccination of US 

infants with three doses of rotavirus vaccine administered orally at ages 2, 4, and 6 months 

(Recommendation Category: I, Evidence Grade: A). The key considerations behind the 

consideration are included in the remarks section of the recommendation and read as follows in 

this example, “Nearly every child in the US is infected with rotavirus by age 5 years, resulting in 

approximately 410,000 physician visits, 205,000–272,000 emergency department visits, and 

55,000–70,000 hospitalizations each year. Randomized controlled trials show that vaccination 

reduces severe rotavirus diarrhea by 97%. No increased risk of intussusception was observed.” 

Dr. Ahmed then presented evidence grades for post-licensure safety studies for Rhesus-based 

tetravalent rotavirus vaccine (Rotashield) and the combination measles, mumps, rubella, and 

varicella vaccine (MMRV). Rotashield was withdrawn from the US market because of a 

reported association with intussusception. For grading the evidence for intussusception 

associated with Rotashield vaccine, two cohort and case-control studies were included that 

were available at the time ACIP withdrew its recommendation for using the vaccine. Ecological 

studies were excluded. The initial grade was C because studies were observational. The initial 

grade was upgraded by two levels to an A because the relative risk of intussusception for 

vaccinated compared to unvaccinated infants is greater than 5. This upgrade is based on 

GRADE’s strength of association criterion. Regarding MMRV vaccination and febrile seizures 

after Dose 1, MMRV was compared to MMR+V vaccination for children ages 12-23 months. 

The initial grade for increased risk 5-12 days after vaccination was upgraded by one level 

because relative risk is ~2 based on consistent evidence from two studies. Other data support 

this finding. For decreased risk 13-30 days after vaccination, the initial grade was downgraded 

by one level because of imprecision. One study indicated a decrease, but it was not significant, 

and one study found no association. 

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In summary, the GRADE framework has two components: criteria for evidence grading and 

consideration from moving from evidence to recommendations. The framework increases 

transparency. There will usually be a high evidence grade for the primary target population for a 

new vaccine, given that the FDA requires RCTs for licensure. The evidence grade may vary for 

post-marketing observational studies. The EBRWG is proposing to use the evidence framework 

for new vaccines, and for changes in recommendations for existing vaccines. 

Discussion Points 

Dr. Baker indicated that Dr. Ahmed’s slides had been modified from the version originally 

distributed and that the revised slides would be disseminated to those present. 

Carrying Dr. Schünemann’s metaphor a little further regarding Bradford Hill, Dr. Marcy pointed 

out regarding his colleagues and their role in the hierarchy of evidence for expert opinion, the 

Ten Commandments were based solely on expert opinion. So, it depends upon the authority 

and experience of the expert. He pointed out to Dr. Poland that the Edward Jenner Society is 

perhaps misnamed. A man named Benjamin Jesty inoculated his sons with cowpox 22 years 

before Jenner did, the difference being that Jenner published. Perhaps there is a message 

there for anybody in academics. He wondered what would be done in terms of old vaccines and 

whether they would be subjected to the GRADE approach when they were re-evaluated. 

Tetanus toxoid, for example, may not stand the test of the GRADE approach. He also noted 

that Dr. Schünemann and Dr. Ahmed mentioned cost in passing. Zostavax® has told them that 

they “may build it, but no one may come if the tickets are too expensive.” With that in mind, he 

wondered what the role of cost should be in recommendations beyond all of the scientific 

evidence presented by the speakers. 

Regarding whether to revisit previous recommendations, Dr. Temte responded that the first task 

is to use the GRADE approach for new recommendations and for changes in current vaccines 

and assess the performance. At first this system needs to be piloted. There are certain vaccine 

issues for which they do not want to conduct the “RCT on parachutes.” There has to be a lot of 

wisdom used in this approach as well. 

Dr. Schünemann replied that there are many authorities in the GRADE Working Group, some of 

whom may be more accomplished than the one authority and in the context of many religions. 

That is, multidisciplinary approaches may be more appropriate and there may be many 

authorities “bringing the tablets from the mountains.” In terms of the integration of resource 

used, resource use is a very complicated matter. Examining what guideline developers have 

done throughout the world in terms of integrating resource use in the development of 

recommendations, many authorities in this field would acknowledge that there is a lot of room 

for improvement in terms of how this can actually be done to arrive at recommendations that 

truly consider resource use. A series of papers will soon be published in which this will be 

discussed in more detail. It does come down to some degree of modeling the outcomes against 

the resources that are consumed. There are different ways of doing this, one of which may be 

to take a very pragmatic approach and do this as a “back of the envelope” approach as is being 

done for many questions in several large organizations. When there is need for more detailed 

consideration, then detailed modeling should be done. 

While she thought they could have a lot more discussion, and they would not know how perfect 

this system would be until they began to use it, Dr. Neuzil endorsed moving forward with it. 

SAGE has used this approach and areas have been identified where the framework is not 

always perfect. Following a major clinical trial and an effective vaccine, it is very difficult to 

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conduct placebo-controlled trials of newer, better vaccines and placebo-controlled trials in 

subpopulations (e.g., HIV, pregnant women, specific age groups). Despite this challenge, she 

maintained that they should move forward nevertheless. 

Ms. Rosenbaum raised an additional contextual issue for discussion, the impact of the 

Affordable Care Act on ACIP’s deliberations. This is not the first time that ACIP has been 

confronted with this issue. With the 1993 addition of the Vaccines for Children Act, the impact 

of a recommendation has taken on a much greater meaning than it had previously. There have 

been observations about the impact of recommendations and its translation into vaccine safety 

discussions. The impact of a recommendation is the same whether it is for universal use or for 

selected populations in that insurers will be bound by the recommendation for those populations 

who are covered under the preventive provisions of health reform. With this in mind, she 

strongly recommended some rethinking of the terminology being used. For example, terms like 

“grading the evidence” raises problems. They are classifying certain kinds of evidence. The 

notion of “high quality” versus “low quality” evidence has the potential for significant 

ramifications because it leads to the implication that certain strong recommendations are based 

on low quality evidence though they are not. Certain very strong recommendations are based 

on certain kinds of evidence because, given the totality of the circumstances, the evidence is 

appropriate. What has occurred in the world of coverage, which ACIP should be concerned 

about in the larger context, is that there is a belief that RCT evidence is somehow always 

superior evidence. The parachute example makes complete hash out of that. Because of the 

potential to misuse and to draw the wrong conclusions from GRADE, if ACIP is going to adopt a 

formal approach to the weighing of evidence and the transparency of how evidence is 

connected to recommendations, they should discuss classes of evidence, which classes of 

evidence came into play in the weighing of the evidence and why, what classes underlie certain 

recommendations, and universal uses of vaccine versus selected use and not using the word 

“optional” because that is not an optional use for coverage at all—it is a selected use. While 

she did not have any objections to the evidence science presented, as a lawyer, Ms. 

Rosenbaum pointed out that how one uses the evidence and the larger context in which the 

evidence is being used has real ramifications. She thought they needed to be cognizant in this 

era of these ramifications and simply modify GRADE to the extent that they apply the 

terminology that would get them further in the much more complex discussions they would have 

to have about what evidence goes into a recommendation. 

Dr. Cieslak expressed concern that much of the focus was on the safety and efficacy equations, 

given that for the most part, that was not what ACIP’s deliberations tended to center on. At 

least for newer vaccines, safety and efficacy have been tested in RCTs and ACIP’s discussions 

focus more on who the risk groups are. The Hepatitis Work Group is trying to better understand 

exactly what the risk is of Hepatitis B among diabetics in the US. This number is difficult to 

determine. There are various sorts of data that allude to this, but nothing that addresses this 

directly. He wondered whether it would be possible for GRADE to assist them in grading the 

quality of evidence of the issues the ACIP discussions tend to center on, such as the quality of 

epidemiological studies evaluating risk and what the risk is in different groups or costeffectiveness studies. For HPV vaccine, he was very concerned about assessing the vaccine 

for males because there were three studies about cost-effectiveness with fairly different results, 

and it was not clear which of those was the higher quality study. The Merck study showed the 

lowest cost per quality adjusted life year (QALY) saved. This was a manufacturer-sponsored 

study, but perhaps it was the best model. He wondered how GRADE could help them to get at 

those types of questions, which seem to be the pivotal questions for ACIP’s recommendations. 

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Dr. Temte responded that on first pass, when considering a new recommendation, ACIP has 

always been asked specifically to make recommendations based on safety and efficacy first. 

Other considerations follow that. ACIP has never been asked to make a recommendation 

based solely on the cost of a vaccine. In fact, ACIP should be fairly neutral to that based upon 

its charge. That being said, as time goes on, there are numerous pieces of additional 

information that ACIP reviews, digests, and puts thoughtful consideration into in making 

recommendations. They are not proposing to use the GRADE methodology to address 

questions such as: What is the burden of illness? What is the potential herd immunity effect? 

While these issues could be approached by the GRADE methodology, Dr. Temte deferred to Dr. 

Schünemann about that. The consumers and stakeholders who are applying these 

recommendations on a daily basis are not typically lawyers, but are clinicians who are 

increasingly familiar with the GRADE approach. Within his academy, they are used to seeing 

this all of the time and are comfortable using it. He looks at this on a daily basis, especially with 

Preventive Services Task Force recommendations. They are not as concerned with the 

specifics, nor are they necessarily influenced. If there is a strong recommendation, even if it is 

based on very low quality, he will assess this carefully. For example, given the situation with 

avian influenza and oseltamivir, most physicians would not care what the evidence base was 

because they would believe it to be the right thing to do. 

Dr. Schünemann agreed that it is important to choose the right terms. For example, there are 

clear gradients involved with the term “class.” He would always like to sit in first class in an 

airplane as opposed to second or economy class. He believes the gradations that are 

associated with the term “class of evidence” are relatively similar to “grades of evidence.” He 

did not believe this made any difference. He thought there was agreement that there is 

sometimes higher and sometimes lower confidence in evidence, in particular in terms of 

estimates of effect. For example, a small RCT with 20 patients offers less confidence than an 

RCT with 2000 patients and many events. Avoiding an assessment of how much confidence 

there is in an estimate of effect is potentially problematic. That does not mean that they cannot 

make strong recommendations. They just need to express that their confidence in a strong 

recommendation may not be as good as it could be at a given time. Modifications are possible, 

but that would to some degree defeat the purpose of developing systems that can be used and 

communicated across various departments and divisions. In regard to assessing costeffectiveness studies, there are critical appraisal frameworks for such studies. Dr. Schünemann 

believes that the work that needs to be conducted in order to move to recommendations should 

be based on the systematic reviews that assess efficacy and should be based on new models. 

He would not suggest using existing cost-effectiveness studies that will not fit the purpose, 

models, or questions that the Guideline Panel has developed. A starting point is to describe a 

body of evidence with all of the outcomes believed to be important, and then to consider what 

associated resources need to be spent in order to implement a recommendations. 

Regarding Dr. Cieslak’s question, Dr. Wharton noted that when the FDA licenses vaccines, they 

are licensed based on safety and effectiveness. When they come to ACIP, they are licensed 

products. Although the safety and effectiveness information is very important for ACIP’s 

deliberations, there are a number of other factors that go into that determination that the agency 

looks to ACIP for, for example: Is it really a good idea to use this vaccine in a particular way in 

the US population? Factors that contribute to that have to do with the burden of disease and 

feasibility to use the product in a proposed way. While safety and efficacy concerns are critical, 

they are not the only issues that matter. Perhaps by the time it comes to ACIP, there are other 

important factors that must be considered as recommendations are being made. 

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Regarding the complexity of the issues, Dr. Judson was reminded of Professor Roy Anderson 

once quoting a mathematician who said that there was no problem in the world, no matter how 

complicated and how difficult to understand, which when looked at in the right way could not be 

made to seem more complicated and more difficult to understand. He thought they must be 

very careful to define the terms and then use them consistently. Additional schemes or 

approaches to evaluating evidence would probably not be helpful if they simply divided items up 

slightly differently. It would be very useful if those who work in the area of evaluating evidence 

to devise a single approach, the outline for which is generally agreed to be standard. As an 

example, the D category was added for evidence, which he thought he had seen before. 

However, from the definition “additional complexity that does not add to clarity or ability to 

discriminate problems” is not going to be helpful. C really translates into “our confidence is 

limited.” D translates to “our confidence is very little.” It would be useful to weed some of this 

out. 

Ms. Ehresmann thought it was obvious that they needed to move in the direction of evidencebased guidelines. She appreciated that they would be utilizing the GRADE approach as a pilot, 

which would give them the opportunity to determine how it works in the ACIP setting. She 

agreed with the terminology issues, and pointed out that they were discussing this in a group 

that is very familiar with the subtleties of evaluating. As they thought about moving to this 

approach, she stressed the importance of thinking about how this will be translated for the 

general public. Currently when ACIP makes a recommendation, it sounds very confident. Use 

of the GRADE approach is likely to be very complicated to translate for the public, and must be 

placed high on ACIP’s priority list in addition to evaluating how well this approach works. 

With regard to determining the strength of the recommendations, Dr. Englund expressed 

concern with the issue of cost. She believes that cost is absolutely important, although it should 

be termed “resource allocation.” Determining the strength of recommendation based on cost / 

resource allocation is a problem, given that this is really a separate issue. Cost changes over 

time and depends upon the patient population. It is very important for ACIP to not consider cost 

as just a bullet point. The HPV Work Group has spent an incredible amount of time assessing 

cost, cost analyses, cost-effectiveness, and grading cost-effectiveness such that when they are 

presenting the cost-effectiveness they show much more data than would be potentially 

allowable on the GRADE schema. She expressed hope that the cost issue could be drawn out 

and even separated as they make recommendations. She believes that decisions in the 

upcoming decade are going to be increasingly related to cost-effectiveness. 

To Dr. Baker, GRADE is an opportunity for ACIP to join together as they have with their 

important practitioner groups who actually implement recommendations so that there is a single 

common system. 

Dr. Schünemann said that he could not agree more in regard to two issues, the first of which 

was that they should speak of “resource use” versus “cost.” It is important to tease apart what 

manpower is required in order to implement a recommendation rather than stating what it costs. 

This will change over time not only across, but also within jurisdictions. Therefore, it is 

extremely important to disaggregate resource use and label it explicitly. In fact, the second 

issue relating to the consideration of resources separately was included on one of his summary 

slides that stated “if relevant, consider costs.” Sometimes, much more effort needs to be spent 

on evaluating resource use, but resource use will always be important. In a 45-minute 

presentation, it is extremely complicated to address this. Nevertheless, he thought they were in 

agreement with these comments and simply need to lay this out more clearly. 

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Dr. Chilton commented that the change in grade of evidence from high to very low to A to D 

seemed to obscure the actual meaning of those terms. With that in mind, he wondered whether 

it was necessary to have a table regarding what A to D mean, since they mean the same thing 

as high to very low. 

Dr. Temte responded that the intent, as with any recommendation, is to include a footnote 

indicating what those mean. GRADE actually provides a luxury of definitions, not to say that the 

definitions are imprecise, but for example, the Grade A high level of evidence also coincides 

with an expression of the confidence in the estimate of effect. That would be a very high 

confidence if the estimate of effect is correct. They particularly liked the way Dr. Ahmed 

presented this in one of his slides with very brief statements regarding the meaning of 

confidence in level of effect. A comment was made regarding the difference in a Grade C and 

D. He believed that ACP had utilized three levels of evidence to address that, basically 

combining C and D. He thought that had been done with the tacit approval of GRADE as well. 

They are used to seeing recommendations using a different system of evidence to some extent 

from the United States Preventive Services Task Force (USPSTF) which uses the grades A, B, 

C, D, and I. As clinician, Dr. Temte tends to lump A and B together and C and D together. That 

is the way it is laid out on the electronic tools that integrate with electronic medical record (EMR) 

systems. Because physicians are used to seeing this all of the time, they have stopped being 

concerned about the nuances and are more responsive to what this means in terms of 

operational activities during their clinical day. 

As a clinician, Dr. Baker said that she either hears “recommend” or “don’t recommend.” 

Dr. Wharton thought Dr. Reingold’s example about the strength of evidence to support the 

recommendation for use of HPV vaccine routinely and in a vulnerable subpopulation was 

particularly interesting. The evidence rating was low. The clinical trials that are available at the 

time of licensure really dictate what is included in the product labeling. There are many 

questions that are not answered by those clinical trials. One of the great values of ACIP 

statements is the helpful guidance this committee has provided to address the questions that 

the clinical trials did not address (e.g., interchangeability of vaccine products, use of vaccines in 

populations that may not have been included in the clinical trials, et cetera). While she did not 

know what the EBRWG’s considerations were pertaining to whether the GRADE criteria would 

be applied to all ACIP recommendations or simply certain key high level ones, but this is an 

area where there data are sparse or non-existent at the time recommendations are made 

sometimes. Yet, ACIP has considered the totality of knowledge about vaccines to make those 

recommendations even in the absence of explicit evidence. This is an issue that is going to 

need consideration going forward. 

Dr. Temte responded that with the GRADE methodology, one of the first tasks is to decide 

which questions are critical for decision making, which are less critical, and which are not critical 

at all. For example, the use of rotavirus in a newborn nursery is based largely on expert 

opinion. Is this a critical component of making a universal recommendation for the use of 

rotavirus vaccine? It would be on the list, but it would not rank high. Nevertheless, it can be 

considered. They must learn to live, as they already do, with the fact that a lot of information is 

going to be based on very well-informed expert opinion that will generalize from other 

experiences. 

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To crystallize her observation further, Dr. Rosenbaum said that her concern focused on the 

application of a recommendation the first time that ACIP is very transparent and makes a strong 

recommendation based on low quality evidence. Payers are bound by a recommendation and 

may potentially protest it. Also of concern is safety. It appeared to her that in this taxonomy, it 

is totally appropriate to make a strong recommendation based on low quality evidence because 

there are certain situations in which clear evidence is simply lacking and in which other 

evidence is being used because the circumstance of the situation allow them to draw major 

conclusions from low quality evidence. If they opt to utilize the GRADE terminology, she 

strongly recommended that the adoption of the GRADE system be accompanied by a lengthy 

and very accessible explanation of what they are doing, why they are doing it, how they do and 

do not intend this adoption to be used, and with the inclusion of many applications showing that 

there can be an absolute strong recommendation based on what GRADE classifies as lesser 

quality evidence. Without that, she was extremely concerned with the consequences for the 

deliberations. 

Dr. Ahmed clarified that the terms used (e.g., high quality, low quality, etc) were discussed 

within the EBRWG. The group would benefit from input regarding exactly what terms to use. 

He called upon Dr. Campos-Outcalt to discuss this further. 

Dr. Campos-Outcalt replied that some of the concerns were addressed with the EBRWG’s 

recommendation. The work group is saying that they believe ACIP should recommend or not 

and that the evidence is A, B, C, or D. The terminology being discussed was not suggested by 

this work group. They did have concerns about making a strong recommendation based on low 

quality evidence, which is why they recommended terminology that avoids this. 

Dr. Rosenbaum pointed out that every time they choose a moniker, they will have to explain 

what it means because it will take on a concept that needs to be clarified with the public in a 

way that can be addressed. 

With all ACIP vaccine recommendations, Dr. Pickering stressed that CDC has excellent 

communications staff who can help to translate meaning such that the recommendations can be 

implemented. Two other major issues to consider are the simplicity of the process and the 

support needed to implement the GRADE system. He called upon Dr. Reingold to discuss what 

support he found to be needed and what support he had received to utilize this system. 

Dr. Reingold responded that the answer depends upon the vaccine. With a new vaccine like 

HPV, there are relatively few well-done recent studies. Thus, it is not an enormous lift to apply 

the GRADE approach. However, applying the approach to all of the studies of pneumococcal 

polysaccharide vaccine is a major lift. Furthermore, the GRADE approach does not guarantee 

that the two people using it will reach the same conclusions. In fact, their assessment of those 

studies was challenged by people who had a very different view of the effectiveness of that 

vaccine. Use of the GRADE approach requires a fair amount of work and someone competent 

who has the time to work on it is needed. SAGE suffers from the fact that they basically have 

only one person who assists all of its subcommittees. 

Dr. Jim Turner (ACH) went on the USPSTF website where he found that their grading system 

differed from what was being proposed. It seemed to him that they were going to create 

additional confusion by devising another grading system. 

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Dr. Schünemann replied that there is on-going conversation with the USPSTF. With respect to 

the organizations that have adopted one of the other systems, GRADE has been adopted by 

many more groups. The criteria being used for evidence evaluation are extremely similar. In 

the end it comes down to health research methodology. He thought what had occurred with the 

revision of the USPSTF system was that there was a lot of common ground. There are perhaps 

some differences in transparency laying out how to move from research evidence to a 

recommendation. This will always be a work in progress, given that nobody has an answer 

currently. 

Dr. Poland raised a consideration for the future, born of the observation that the science moves 

quickly but adaptations of that change tends to move more slowly. That is, this discussion 

centered on a population-based approach, which for the most part is an appropriate approach. 

However, while they are doing this, the science is moving to an individualized approach. Thus, 

the caution for the future regards how to address genotypes that code for non-response to 

Hepatitis B vaccine or increasingly in the future genotypes that will predict serious adverse 

events. 

Dr. Schünemann agreed that science evolves, as will any grading system over time. It is good 

to begin with a common approach that can be evaluated on the basis of various examples. In 

terms of moving to individualized medicine, by considering patient values and preferences 

explicitly, the system addresses some of these aspects (e.g., genetic predictors). This 

information will frequently come from contextual evidence, observational study evidence, and it 

will influence a panel’s judgment about how applicable a certain body of research evidence is to 

a certain condition. This evidence needs to be included in ratings about the directness of the 

evidence, for example. 

Dr. Baker pointed out that this was similar to how they currently must deal with high risk groups 

in the face of little evidence and known high risk. 

Dr. Campos-Outcalt said he thought there was more consistency with the USPSTF framework 

than it may appear. He sees movement toward consistency in that they no longer have 

“strongly recommended.” They just have one category based on A or B level evidence. They 

also have an “optional” category which is C. Their D is “recommend against.” The category 

they use that no one else has is “insufficient evidence” to say one way or the other, or category 

I. Very few other groups are willing to do that. Regardless of what system is adopted, an 

advantage of adopting a system is to establish some consistency within the ACIP itself. 

Examining the ACIP recommendations over the years, various terms have been used to mean 

the same thing. This system was used once before in ACIP in the late 1990s for the 

pneumococcal recommendation. That statement is very clear, very easy to interpret, and it 

starkly differs from other recommendations that have been made since. He thought there was a 

lot of value in stating that a recommendation was being based on C or D level evidence, 

because if nothing else, it drives research. Of the recommendations published currently, 80% 

are C and D level evidence. That does not stop people from acting on it, but it does point 

toward where research is needed and drives the research agenda, which is very valuable. 

Dr. Samuel Katz (IDSA) pointed out that one problem practicing physicians implementing 

recommendations face is erosion of public confidence. Practicing pediatricians spend an 

inordinate amount of time answering questions from parents who have doubts and concerns 

about vaccines. While he thought GRADE was a fine system for ACIP, his concern pertained to 

the transparency with which all of their deliberations are viewed by the public. He assured them 

that within seconds of making a recommendation on evidence B or C instead of A it would be 

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quickly picked up by the doubters and the anti-vaccine groups. This will be another way for 

them to exploit the system to enhance public doubt and lack of confidence in what ACIP 

recommends. Thus, he thought the GRADE system would have to be very carefully utilized by 

ACIP and the rationale for recommendations would have to be very carefully explained to the 

public. 

Dr. Alexis Elward (HICPAC) reported that HICPAC adopted a modified GRADE system several 

years ago and had used it to produce two recent guidelines for the prevention of catheterassociated urinary tract infections and a norovirus prevention guideline, which is in draft. 

HICPAC has experienced a tremendous improvement in their efficiency, consistency, and 

transparency. They are often in the situation that ACIP may be with older vaccine studies such 

that there are no RCTs. There is a lot of variation in study designs, and HICPAC has really 

needed a systematic methodology for evaluating the strength of the epidemiologic evidence. 

That said, they do have a number of things that are strongly recommended that are not based 

on evidence. They may be based on regulatory requirements or standard of care, so HICPAC 

has made those distinctions in the grading system. Their categories include: strong 

recommendation based on evidence, strong recommendation based on standard of care, or 

strong recommendation based on a regulatory requirement. 

Dr. Sandra Fryhofer (ACP), a practicing general internist who sees patients in her office every 

day, expressed her excitement about the move toward evidence-based guidelines, 

transparency, and consistency. As a practicing doctor, with new vaccines there remain many 

things that are not explained. In the past, ACIP guidance has gone beyond the label to fill in the 

blanks for practicing physicians. She expressed her hope that ACIP would continue to provide 

clinical guidance. 

Dr. Plotkin endorsed the recommendation of the EBRWG. He thought the GRADE system 

incorporated expert opinion and public health need into the recommendation, rather than relying 

on the so-called quality of epidemiologic evidence. What is missing is the biology, which is a 

particular criticism of the Cochrane analyses. For example, in terms of HPV and the prevention 

of cancer, there is abundant evidence that the vaccine prevents infection and there is abundant 

biologic evidence that HPV incites oncogenic transformation. Therefore, it is hardly a leap of 

reason to say that HPV vaccine will prevent cancer. The same is true with respect to Hepatitis 

B and prevention of liver cancer, which was not known or proven at the time the 

recommendation was made for neonatal and other immunization, but it was known that the 

vaccine prevented infection. As another example, there were no RCTs showing that the rubella 

vaccine prevented congenital rubella syndrome, but knowledge that it prevented rubella allowed 

one to make the inference that it also will prevent CRS. Taking into account the biologic 

information as well as the epidemiologic studies allows recommendations to be made without 

using the pejorative terms. 

Dr. Zimmerman wondered what thought was given to calculating, in a routine fashion, the 

number needed to treat, or in this case to vaccinate, on a routine basis. 

Dr. Ahmed responded that while he did not state this specifically, this is the proposed format for 

presenting evidence. 

Dr. Baker said she heard fairly good consensus on several important caveats. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Meningcoccal Vaccine 

Introduction 

H. Cody Meissner, MD 

Meningococcal Work Group Chair 

Advisory Committee on Immunization Practices 

Dr. Meissner recognized the members of the Meningococcal Work Group and thanked them for 

their participation, time, and effort in working through several very complicated issues. 

The meningococcal conjugate vaccines that were the focus of discussion during this session 

were as follows: 

 Recommended for adolescents aged 11 through 18 years and others at increased risk for 

meningococcal disease: 

Æ MenACWYD (Sanofi Pasteru) licensed in January, 2005 for persons 2 through 55 

years 

Æ MenACWYCRM (Novartis) licensed 2/19/2010 for persons 11 through 55 years 

 Infant vaccines in late-stage development 

Æ HibMenCY (GSK): 2,4,6 and 12-15 months (BLA Filed) 

Æ MenACWYCRM: 2,4,6 and 12-15 months 

Æ MenACWYD (Sanofi Pasteur): 9 and 12 months 

With the increasing number of conjugated meningococcal vaccines, it is necessary to clearly 

define the abbreviations for each vaccine. The designated nomenclature for these conjugate 

vaccines is indicated above. 

The Sanofi Pastuer vaccine contains polysaccharides from meningococcal serogroups A,C,W135, and Y conjugated to a chemically detoxified diphtheria toxoid protein. This vaccine had 

been referred to as MCV4, but will now be abbreviated as MenACWYD. The Novartis vaccine 

consists of capsular polysaccharide from serogroups A,C,W-135,and Y conjugated to CRM-197, 

which is a naturally occurring mutant diphtheria toxin. CRM refers to cross reacting material. 

This vaccine will be abbreviated MenACWYCRM. Three conjugated meningococcal vaccines are 

under development for use in infants and young children. The GlaxoSmithKline HibMenCY 

vaccine includes polysaccharide from Haemophilus influenzae type b and polysaccharides from 

meningococcal serogroups C and Y,respectively, conjugated to tetanus toxoid. This vaccine 

would be administered as a 3 dose primary series followed by a booster dose. The Novartis 

vaccine also would be administered as a 3-dose primary series followed by a bosster dose. The 

SanofiPpasteur vaccine would be administered as a 2-dose series at age 9 and 12 months. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

During the meningococcal vaccine session at the February ACIP meeting, a cost-effectiveness 

analysis of an infant or toddler meningococcal vaccination program in the US was presented. 

This analysis demonstrated that the cost per quality adjusted life year saved was driven 

primarily by disease incidence and the cost of the vaccine. Based on characteristics of the 

currently available vaccines and the historically low levels of meningococcal disease in the US, 

routine immunization of infants and toddlers was felt to be difficult to justify. Major 

considerations included the following: 

 Serogroup B disease accounts for >65% of disease in children <5 years of age and 

serogroup B is not in the vaccine. 

 The peak of serogroup C and Y disease occurs at 4 to 5 months of age, too early in life to 

be prevented by doses administered at 2,4, and 6 months of age. 

 Serologic protection is unlikely to last until 11 years of age, making booster doses necessary 

in order to maintain protective immunity until the adolescent dose. However, in February 

2008, ACIP recommended against routine vaccination of children 2 through 10 years of age 

except for children at increased risk of disease. 

Thus, a general consensus was reached during the discussion that a recommendation for 

routine immunization of infants or toddlers with any meningococcal conjugate vaccine is not 

appropriate at this time. 

HibMenCY vaccine was not licensed as of the June 2010 ACIP meeting. This vaccine was 

discussed during the last ACIP meeting, and the work group continued these discussions during 

monthly conference calls. Discussion focused upon whether the HibMenCY vaccine might be 

considered as a Haemophilus influenzae type b vaccine. A persisting reservation is the concern 

that this combination vaccine will be more expensive than a monovalent Haemophilus 

influenzae type b vaccine. Even if the cost of HibMenCY were the same as monovalent 

Haemophilus influenzae type b vaccine, the benefit from the Men C and Y components will be 

low and of limited duration for the general population based on the issues already stated. 

In addition, new safety data have become available with regard to the risk of Guillain-Barre 

Syndrome (GBS) during the 6 weeks following administration of the Sanofi Pasteur vaccine 

(MenACWYD). In October 2005, the FDA and CDC issued an alert regarding a possible 

association between GBS and MenACWYD based on Vaccine Adverse Event Reporting System 

(VAERS) reports. There was insufficient evidence to conclude a causal association as the 

number of cases reported within 6 weeks of vaccine administration was not unusual. However, 

the clustering within 2 to 5 weeks raised a concern. During the next year, in April and October 

2006, updates were published in the MMWR as additional cases of GBS were reported to 

VAERS. Because the risk of meningococcal disease clearly exceeded the risk of GBS, routine 

vaccination with MenACWYD for adolescents, college freshman living in dormitories, and others 

at high risk continued to be recommended during this time. However, as a cautionary note, it 

was recommended that those with a previous history of GBS not receive and MenACWYD 

unless they were at especially high risk of meningococcal disease. 

During this session, two presentations were delivered pertaining to the risk of GBS during the 6 

weeks following administration of the Sanofi Pasteur vaccine, MenACWYD. Dr. Priscilla 

Velentgas discussed the results of a multicenter, retrospective cohort study sponsored by 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Sanofi Pasteur which estimates the risk of GBS among 11 through 18 year old vaccinees during 

the 42 day period after receipt of MenACWYD as well as during other time periods. These risks 

were compared with the risk among non-vaccinees. Eric Weintraub offered an update on 

VAERS data and Vaccine Safety Datalink (VSD) data in relation to the risk of GBS following 

MenACWYD administration. Currently, there is disparity between the package inserts for the 

sanofi pasteur and Novartis vaccines in terms of classifying the risk of GBS as a 

contraindication or as a warning. In addition, the MMWR statements presently contain various 

wording for the risk of GBS following vaccination, including those with a history of GBS. Dr. 

Amanda Cohn addressed these differences and presented the work group proposal for new 

wording in regard to the issue of GBS following vaccination with meningococcal conjugate 

vaccines and the issue regarding whether the wording should be the same for all 

meningococcal conjugate vaccines, and addressed the proposed a change in the 

recommendation for use of any conjugated meningococcal vaccine in persons with a history of 

prior GBS. 

When the Sanofi Pasteur meningococcal conjugate vaccine was licensed in January 2005, 

insufficient data were available to address the question of long-term efficacy. The expectation 

was for vaccine-induced immunity that would last through the college years. Studies now 

indicate that antibody levels decline over time and because circulating antibody, not 

immunologic memory, is most important in protection against meningococcal disease, there is 

concern about susceptibility among college students. 

One year ago in June 2009, ACIP voted to recommend a second dose of MenACWYD for 

persons at increased risk of meningococcal disease because of concern regarding waning 

immunity. College students whose only risk factor for meningococcal disease was living in oncampus housing were not included in the group for whom a second dose of conjugate vaccine 

was recommended. Because of this concern for loss of protectiom and return of susceptibility 

among college students, this topic was discussed by Dr. Cohn who outlined the various options. 

Guillain-Barré Syndrome (GBS) After Receipt of Menactra® 

Priscilla Velentgas, PhD 

Meningococcal Vaccine Study Investigator Group 

Department of Population Medicine 

Harvard Medical School and Harvard Pilgrim Health Care Institute 

Outcome Sciences 

Dr. Velentgas reported that the goal of the meningococcal vaccine study was to design and 

conduct a study with adequate power (e.g., large enough base population) to answer the 

question of increased risk of GBS following MenACYWD vaccination. The challenges were that 

GBS is a rare condition (1/100,000 PY), and prevalence of MenACYWD vaccination is <10 % 

overall in the 11 through 18 year old population, and much lower within specific 6-week time 

window (0.614% estimate). The study required combined efforts of several large health plans 

(n=10) with active health research divisions. Dr. Velentgas disclosed that funding for this study 

was provided by Sanofi pPasteur under a contract with the Coordinating Center at Harvard. 

The contract granted exclusive control over the study protocol and content of study reports and 

publications to the investigator group. The Data Coordinating Center was located at Harvard. 

Americas Health Insurance Plans (AHIP) was involved in contracting and logistics for the study. 

The five research sites included Aetna, HealthCore, Highmark Blue Cross Blue Shield, i3 Drug 

Safety, and Kaiser Permanente Center for Health Research of Hawaii. All of these sites 

provided data and analytics for the study, and each of these sites contributed one or more 

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t 

i 

i

i I

 l ti

i

i

Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

investigators to be active as part of the study steering committee. This study also had an 

external advisory board, including a pharmaco epidemiologist from Vanderbilt, a neurologist 

from Tufts Saint Elizabeth Medical Center, and various others (including Drs. Broder and 

Iskander from CDC ISO). At Brigham and Women’s Hospital, there was a panel of three 

neurologists who were responsible of adjudication of the GBS cases based on medical record 

abstractions. The study structure is reflected in the following diagram: 

Meningococcal Vaccine

Study Structure

20 Augus 2010 5 

Coordinating Center 

at Harvard 

HealthCore 

Aetna 

Highmark BCBS 

Kaiser CHR Hawaii 

External 

Adv sory 

Board 

Steer ng 

Committee (Sites 

plus CC) 

Funding Source 

Sanof Pasteur AH P 

Contracts & ogis cs 

3 Drug Safety 

Total membership ~ 50 million 

(2005-2008) 

Neurolog st 

Review Panel 

(BWH) 

The primary aims of the study were to estimate the risk of GBS among 11 through 18 year old 

vaccinees during 42 days after MenACYWD vaccination relative to the risk of GBS among 

vaccinees at other times and among non-vaccinees, and to estimate attributable risk of GBS 

following MenACYWD vaccination. The secondary aims were to identify and describe additional 

GBS cases among 19 through 21 year olds, and estimate the risk of GBS among 11 through 18 

year old vaccinees during the 42 days after administration of other vaccinations (e.g., MPSV4, 

Tdap, Td, HepB, HPV, tetanus, and influenza). The 19 through 21 year olds were designated 

as a secondary population because of the concern that the investigators might not be able to 

identify all vaccination exposures using health plan claims data in this group, given that they 

represent a largely college age population who may be receiving additional health care at their 

college health services. 

The investigators employed a cohort with nested case-control design. The study population and 

vaccinations were identified through health plan enrollment data and automated claims data. 

The primary cohort was comprised of 11 through 18 year olds, and the secondary cohort was 

comprised of 19 through 21 year olds. A distributed research network approach to data sharing 

and pooled analysis was utilized. Potential GBS cases were identified through claims data, 

confirmed through medical chart review, and adjudicated by the team of three neurologists who 

were blinded to vaccine exposure. A modified Brighton case definition was used [Registered at 

ClinicalTrials.gov (NCT00575653)]. 

The case definition that was used for the primary GBS endpoint included three possible 

categories. A case could meet any one of these categories and be included in the primary 

endpoint. Most of the cases met at least two of these. The first category was any of the levels 

1, 2, or 3 of the Brighton Collaboration GBS case definition, based on draft definition version 17, 

dated June 22, 2007. The study neurologists developed an additional set of criteria to identify 

Miller Fisher Syndrome, given that at the time the Brighton Collaboration definition did not 

include a category for Miller Fisher Syndrome, although this has since been added to the 

definition. An additional category was included that represented cases for whom a clear 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

statement regarding a diagnosis of GBS from a neurologist was identified in the medical record 

in the absence of any contradictory information. 

The characteristics of the cohort are shown in the following table: 

No. (%) of Cohort 

Total cohort N=12,589,910 

Age at study entry (yrs) 

11-13 

14-16 

17-18 

19-21 

4,552,926 (36.2) 

3,007,720 (23.9) 

2,018,042 (16.0) 

3,011,222 (23.9) 

Sex 

Male 

Female 

6,369,250 (50.6) 

6,218,810 (49.4) 

Length of enrollment (days) 

Mean (SD) 

Range (min,max) 

Total contributed time (yrs) 

524.4 (415.6) 

1279 (1, 1280) 

18,322,800 

With regard to the key results, MenACYWD vaccination level was 15% overall through May 

2008, and nearly 45% among 11 through 13 year olds in 2008. A total of 99 GBS cases were 

confirmed during the full 18,322,800 person years of observation, translating to an incidence of 

approximately 5.4/million person years. Over 1.4 million vaccinations were observed. No 

confirmed cases of GBS occurred within the 6 weeks following the 1.4 million vaccinations. The 

95% upper confidence limit for the attributable risk of GBS associated with MenACYWD was 

estimated as 1.5 cases per million doses. The investigators concluded that this study provided 

no evidence of increased risk of GBS associated with MenACYWD. The characteristics of the 

GBS cases are reflected in the following table: 

Cases (N=99) N(%) 

Age at Onset (yrs) 

Mean (SD) 

Median 

Range (min, max) 

16.7 (2.7) 

17 

10 (11, 21) 

Sex 

Male 

Female 

53 (53.5) 

46 (46.5) 

Season 

Winter 

Spring 

Summer 

Fall 

16 (16.2) 

35 (35.4) 

21 (21.2) 

27 (27.3) 

Vaccinations within 42 Days of GBS Onset 

MCV4 

MPSV4 

Tdap 

Tetanus 

Td 

Influenza 

HepB 

HPV 

0 (0.0) 

1 (1.0) 

0 (0.0) 

0 (0.0) 

0 (0.0) 

2 (2.0) 

1 (1.0) 

2 (4.3 - % of 

females) 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

With regard to GBS case identification and adjudication, 585 potential GBS cases were 

identified in claims among 11 through 21 year olds (e.g., identified as having an ICD-9 code for 

GBS in their medical claims at any time during the study period). Of these, 395 were abstracted 

and following adjudication included sufficient information to determine case status, 108 of these 

(~27%) met the primary study endpoint definition, 99 of the 108 cases had onset dates that 

were confirmed to be during the study period (72 from primary / 27 secondary), and 0 of those 

following adjudication were found to be exposed to MenACYWD within the prior 42 days. The 

investigators commented in the study report that the difference between those identified and 

those confirmed largely represents rule out diagnoses and in some cases erroneous diagnoses, 

such as Group B Streptococcus, which were evident following review of the medical record. 

In terms of the conclusions, MenACYWD uptake from initial availability in March 2005 through 

August 2008 reached as high as 44% among 11 through 13 year olds. This is consistent with 

ACIP recommendations for vaccination to occur at the 11 through 12 year old well visit. Having 

identified zero cases of GBS identified within 6 weeks following 1.4 million MenACYWD 

vaccinations, an upper bound for the one-sided 95% confidence interval for the rate of GBS in 

MenACYWD vaccine-exposed cases using the “Rule of 3” (e.g., 3 cases per 1.4 million 

vaccines). Using exact binomial confidence intervals yields the same results. Subtracting the 

expected number of MenACYWD-exposed cases (0.89), which was based on applying the 

overall confirmed rate of GBS in the rest of the study population to the total person time in the 6 

weeks following vaccination, yielded an estimate of the upper bound to the attributable risk of 

2.1 cases per 1.4 million vaccines, or about 1.5 cases per million doses. 

Regarding the interpretation of the findings and study limitations, there was incomplete retrieval 

of medical charts for 21% of potential GBS cases, which included 6 cases with MenACYWD 

immunization during preceding 42 days. Applying an overall confirmation rate of 27% that was 

applicable for the rest of the cases, there would be an expectation of having missed 1.6 true 

cases of GBS with MenACYWD-exposure in the prior 42 days. In comparison, none of the 12 

potential GBS cases with MCV4 exposure for whom charts were available were ultimately 

confirmed following the blinded neurologist adjudication, so there is some suggestion that 

surveillance bias among MCV4 exposed patients may exist. If the investigators had observed 

one rather than zero cases of GBS within 42 days of MenACYWD vaccination, the upper bound 

on the attributable risk calculated as previously described would be 2.8 excess cases per million 

doses, with a point estimate of less than one excess case per 10 million doses. 

Discussion Points 

Dr. Judson inquired as to why the investigators did not conclude that MenACYWD was 

associated with a statistically significant lower risk or incidence of GBS. The upper bound was 

far less than the actual observed non- MenACYWD recipients. 

Dr. Velentgas replied that they did not consider the hypothesis of MenACYWD being protective 

with regard to GBS given the overall biologic expectation that immunization exposures could be 

considered to promote GBS. 

Dr. Keitel wondered what the alternative diagnoses were among the cases adjudicated by the 

neurologists, given that it may be helpful for practitioners to understand potential other 

diagnoses. Dr. Velentgas responded that Dr. Amato and rest of the team felt that there were a 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

number of similar syndromes which were evaluated for possible GBS by the treating 

neurologist, but these ultimately did not meet the criteria for GBS. These included a range of 

other neuropathies and conditions which ultimately were found not to have a neurological basis. 

Dr. Cieslak asked whether vaccine efficacy was assessed. 

Dr. Velentgas indicated that the investigators did not compute vaccine efficacy. 

Menactra® and GBS: Summary of VAERS & VSD Rapid Cycle Analysis Data 

Eric Weintraub, MPH 

Immunization Safety Office 

Centers for Disease Control and Prevention 

Mr. Weintraub presented an update on Menactra® and GBS based on examination of VAERS 

and VSD Rapid Cycle Analysis (RCA) data. He apologized for using the term Menactra® in the 

presentation, but he did not want to confuse people with the acronyms. 

Within 6 weeks of receiving Menactra®, VAERS confirmed reports of GBS to date included 42 

confirmed reports for ages 11 through 19, of which 8 were ages 11 through 14 and 34 were 

ages 15 through 19 (which is one of the areas that was cause for the level of concern and the 

additional meningococcal vaccine study and the additional follow-up of the RCA VSD study). Of 

these, 17 were Brighton Level 1; 22 were Brighton Level 2; and 3 were Brighton Level 3. One of 

the MenACYWD / GBS reports had GBS twice before this incident and both diagnoses occurred 

after receiving a tetanus-containing vaccine. According to sanofi pasteur, the total number of 

Menactra® doses distributed from 2005-2009 was 25,049,486. 

Temporal clustering has been consistent since early in this investigation (2005-2006). The 

onset interval of the 42 cases was between days 2 and 37. The mean was about 16.7 days. 

When a temporal scan statistic is done, there is a significant cluster in days 10 through 15 

(p=.002). This finding, along with the slight elevation potentially in the disproportionate number 

of cases in the 15 to 19 year olds, was why the meningococcal study was done and why there 

has been continual follow-up in the VSD and continued RCA. 

The VSD was established in 1990. It is a collaborative project among CDC and 8 managed 

care organizations (MCOs) shown in the following map: 

VSD Sites: 2010 

9 

Group Health

Cooperative 

Northwest Kaiser Permanente 

No. CA Kaiser 

Permanente 

So. CA Kaiser 

Permanente 

Kaiser Permanente Colorado 

Health Partners 

Marshfield Clinic Harvard 

Pilgrim 

CDC 

AHIP 

The VSD allows for planned immunization safety studies as well as timely investigations arising 

from hypotheses from medical literature and pre-licensure; reports to VAERS; and changes in 

immunization schedules or the introduction of new vaccines. It is important to highlight that the 

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VSD now conducts what is termed RCA. The VSD population collects medical care and 

vaccination data on more than 9.2 million members annually (3% of the US population). As of 

December 31, 2008 2,239,219 children under 18 years of age were enrolled (3.0% of the US 

population) and 7,235,448 adults ≥18 years of age are enrolled (3.2% of the US population). 

The average yearly birth cohort is ~ 95,000. 

In terms of RCA, for each vaccine, specific outcomes to monitor are selected. Each week, the 

number of outcomes in vaccinated persons are evaluated and compared to the expected 

number of outcomes based on a comparison group. This is hypothesis testing, not data mining. 

To simplify this, maximized sequential probability ratio testing (maxSPRT) is utilized. 

The VSD has conducted RCA for Menactra®. The VSD lead site is Harvard Pilgrim Health 

Care, and Tracy Lieu is the principal investigator of the study. Investigators have been 

continuous monitoring predefined outcomes (e.g., GBS, Bell’s Palsy, thrombocytopenia, 

seizures) since 2005 for 11 through 19 year olds. Since mid-2008, the only outcome that has 

been continually monitored is GBS because of power and continual concern. The case 

definition for GBS for signal detection included the ICD-9 Code 357.0; the exposure window of 

interest was days 1 through 42; and the diagnosis of GBS could occur from any location (e.g., 

hospitalization, outpatient visit, or emergency room visit). The incident definition for the 

automated codes was a first event within 42 days, which allowed for the opportunity to collect a 

few more cases. Diagnoses were confirmed with chart review. 

One of the difficulties with a vaccine such as this is that it is very cyclical in its uptake. For 

example, every August there is a peak in uptake, which was an original concern from one of the 

VAERS findings in 2005-2006. As the ACIP recommendations slightly changed in 2006-2007, 

there was a shift to giving vaccine more in the older age group. The predominance of the doses 

in VSD currently are given to the younger age groups (11 through 14 year olds). 

About 889,684 doses administered at 8 sites in the VSD (538,596 in 11-14 year olds; 351,088 in 

15-19 year olds. The number of GBS cases observed in the automated data was 5, and 4 of 

the 5 had simultaneous vaccinations. After chart review, there were no true cases of new onset; 

2 had a pre-existing GBS diagnosis; 1 had a related diagnosis, not GBS (e.g., chronic 

inflammatory demyelinating polyneuropathy: CIDP); 1 had “rule out GBS” and a different 

subsequent diagnosis (numbness and tingling in lower extremities, muscle strain, was also 

reported to VAERS); and 1 had onset of symptoms on day 0, which was not within the formal 

risk window. A handful of CIDPs occur following all other vaccinations that have caused some 

confusion when evaluating GBS. 

In summary, VSD has observed 0 cases following 889,684 doses. The current plan is to stop 

monitoring routinely for GBS following Menactra®. However, surveillance may continue 

depending upon the statistical approach when monitoring the new meningococcal 

MenACYWCRM (Menveo) depending upon the uptake within the VSD sites. The RCA protocol 

for MenACYWCRM(Menveo) is currently being developed, and GBS will be included. 

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The true strength may be in combining the two very large post-licensure studies (the 

Meningococcal Vaccine Study and the VSD RCA Study). The best ascertained background rate 

of GBS in this age group is from the Meningococcal Vaccine Study with 99 GBS cases 

confirmed during 18,322,800 person years (5.4/million person years). Combining the two 

studies, there are over 2.3 million Menactra® vaccinations. Within 6 weeks (e.g., days 1-42) 

following vaccination, 0 confirmed cases of GBS occurred. Using exact statistics, the upper 

95% confidence limit for the attributable risk of GBS associated with MenACYWD is estimated 

as 1 case per million doses. The two studies provide no evidence of an increased risk of GBS 

associated with MenACYWD. 

Meningococcal Conjugate Vaccines and Guillain-Barré Syndrome 

Amanda Cohn, MD 

LCDR, US Public Health Service 

Advisory Committee on Immunization Practices 

Dr. Cohn reviewed the Meningococcal Work Group’s interpretation of the data just presented 

pertaining to GBS. GBS is an autoimmune acute inflammatory demyelinating polyneuropathy, 

which causes progressive symmetric weakness in the arms and legs. The incidence is 

approximately 1/100,000 and is even lower in children and adolescents. Therefore, the 

prevalence of adolescents with a history of GBS will be extremely low. There are case reports 

of post-vaccination GBS, but there is no estimate of incidence. Cases of GBS were detected 

after administration of Menactra® through VAERS reports in 2005-2006. These reports, as Mr. 

Weintraub described, were clustered with onset dates approximately 2 weeks after vaccination. 

One case had a prior history of two episodes of GBS post-vaccination. There were no fatalities, 

and most patients fully recovered. At the time, analyses of VAERS data using background GBS 

rates suggested a small increased risk in excess of 1-2 cases per million Menactra® 

vaccinations. 

In response to these initial VAERS reports, a contraindication for persons with a previous history 

of GBS for MenACWYD was added to the FDA package insert for Menactra®. ACIP added 

precautionary language for persons with a history of GBS. A risk-benefit decision analysis was 

initiated and the Harvard-Pilgrim Study was initiated. The decision analysis was presented at 

ACIP and strongly favored vaccination. 2397 QALYs were saved by vaccination compared to 5 

QALYs lost by excess GBS cases. The risk for meningococcal disease lasted for several years, 

while the risk for GBS pose-vaccination was time-limited to six weeks. Long-term sequelae and 

deaths were more common with meningococcal disease. Sensitivity analyses did not change 

the conclusions of this risk-benefit analysis, even at an excess risk of 10 cases of GBS / million 

doses of Menactra® vaccine [Cho et al. Vaccine, 2010: 817-822]. Data from the VSD and 

Harvard Pilgrim Studies were both large undertakings, as a large population source was needed 

to detect a small risk. Combined, over 2 million doses of meningococcal conjugate vaccine 

were given, and there were zero associated GBS cases. Of note, these studies examine the 

risk in the general population and not in persons with a history of GBS. 

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The work group has been contemplating how these new data should inform the issue of the 

precaution for persons with a history of GBS. The current ACIP language reads, “Persons with 

a history of GBS might be at increased risk for post vaccination GBS; therefore, a history of 

GBS is a relative contraindication to receiving MCV4” [CDC MMWR, August 2007]. The 

Menactra® FDA package insert states, “Known history of Guillain-Barré syndrome is a 

contraindication to vaccine administration.” The warning section of the FDA package insert for 

MenACYWCRM, Menveo®, indicates that, “Data are not available to evaluate the potential risk of 

GBS following administration of MENVEO.” 

The work group agreed that no risk for GBS after vaccination with MenACWYD was detected in 

two large studies, and extrapolated these data to conclude that persons with a history of GBS 

are not at higher risk than they are after any other vaccine. Persons with a history of GBS are 

at a higher risk for another episode of GBS than the general population. There was consensus 

that these data are sufficient to support policy change. The work group discussed that language 

around the risk for GBS should be general for both licensed vaccines. 

In the revised meningococcal vaccine ACIP statement, these new data on risk of GBS will be 

added. Proposed draft language pertaining to data interpretation would be included the 

background section to read: 

 No risk for GBS after vaccination with MenACWYD was detected in two large studies. 

There were no cases of GBS in pre-licensure clinical trials of MenACWYCRM. 

 There is no data on the risk in persons with a history of GBS. The likelihood of 

coincidentally experiencing GBS after MenACWYD is expected to be greater among 

persons with a history of GBS than among persons with no history of this syndrome. 

[Influenza ACIP statement, 2009]. 

For the recommendation itself, including the precautions section, the work group has discussed 

three options: 

1. Remove precaution for all persons with a history of GBS 

2. Maintain precaution only for persons with a history of post-vaccination GBS 

3. Make no changes to current language: “Persons with a history of GBS might be 

at increased risk for post-vaccination GBS; therefore, a history of GBS is a relative 

contraindication to receiving MenACWYD or MenACYWCRM vaccines.” 

Among the work group members there was support for Options 1 or 2. Most of the work group 

members supported Option 1 because this precaution was added based on an estimate of risk 

that the current data do not substantiate. Language should be similar for other vaccines with no 

associated risk of GBS. There was some support of Option 2, given that persons with a history 

of post-vaccination GBS may be at risk for another episode after any vaccine. Regardless of 

preference, there was strong support for ACIP to address the issue of post-vaccination GBS in 

the context of general vaccine safety rather than specifically for meningococcal vaccine. That 

is, work group members are not against Option 2, but many feel that this statement does not 

belong specifically in the meningococcal conjugate vaccine recommendations. There was 

strong consensus against Option 3. 

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In terms of language for the precaution regarding persons with a history of GBS, the work group 

requested that the full ACIP consider the following options: 

 “There is no evidence that persons with a history of GBS are at increased risk for 

GBS after vaccination with meningococcal conjugate vaccines.” 

 “A history of GBS with onset within 6 weeks after vaccination is a precaution for 

MenACWY vaccines.” 

 Make no changes to the current language: “Persons with a history of GBS might 

be at increased risk for postvaccination GBS; therefore, a history of GBS is a relative 

contraindication to receiving MenACWYD.” 

Discussion Points 

Dr. Baker congratulated the work group and investigators for a yeoman’s job of addressing a 

very concerning safety issue that arose shortly after the recommendation for this vaccine. 

Given the lack of association observed in the two large studies, Dr. Sawyer wondered 

how else the clustering seen in VAERS dada might be interpreted (e.g., reporting bias, 

some other potential explanation). 

Dr. Cohn responded that it was thought to be due to reporting bias in that more cases 

were reported during that time period. 

Regarding the two cases with pre-existing GBS diagnoses, Dr. Temte wondered 

whether they were seeing cases of another report from a case that started right before. 

Mr. Weintraub replied that he was pretty sure this was a follow-up visit for a prior 

diagnosis rather than a recurrence of GBS. He did not believe they were cases with a 

history of GBS. He thought it was a prior diagnosis closer to the time of vaccination. 

Dr. Temte reported that he had seen two cases of CIDP, both of which were associated 

with vaccines. This really jumps to the forefront for him because when it first appears, it 

looks just like GBS. It is only after appropriate treatment and recurrence that the 

diagnosis is known to be CIDP. He was curious about why this was pulled out 

separately. 

Mr. Weintraub responded that this was because of the chronic nature of CIDP, and 

because it was not believed that it was anything related to prior vaccinations. That was 

just the ultimate diagnoses. It has come up in another study the VSD is conducting in 

which a lot of CIPDs occurred and there was confusion with regard to how to treat 

CIDPs in relationship to the GBS cases. 

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Dr. Iskander pointed out that an estimated attributable risk of 1 to 2 per million is 

essentially accepted as a matter of policy for seasonal influenza vaccine. That is 

accompanied by a precaution for persons with prior GBS. Certainly, they are dealing 

with a younger population with meningococcal vaccine that is expected to have a lower 

baseline incidence. Contraindications and precautions are typically at the level of the 

individual patient. In speaking with clinical colleagues who are neurological specialists 

in GBS regarding whether there should be precaution or whether in some cases there 

might be benefits to vaccinate those populations, this can be a tricky clinical question. 

Mr. Weintraub indicated that the temporal scan statistic has been difficult to interpret 

because it has been consistent since early on. It is important to highlight that when 

clustering or aberration is observed in VAERS, the next step would be to conduct large 

epidemiological studies, which is what was done in this case. 

Dr. Wharton’s recollection of the original VAERS data was that the increase in risk, if 

there was any, appeared to be in the older adolescents (15 to 19 year olds). Given that 

there was a broad age range examined in these two large studies, and understanding 

that there were no cases observed in the 15 to 19 year olds, she wondered what the 

upper limit of the 95% confidence interval was for that population group. 

Dr. Velentgas did not calculate this. 

Mr. Weintraub also did not calculate this. He reminded everyone that Dr. Sawyer had 

suggested previously that calculations be done for the 18 to 19 year olds. Also 

interesting about the five automated VSD cases was that only one was in the older age 

group. 

Dr. Marcy noted that 40% of the doses were in 15 to 19 years, but 80% of the cases 

were 15 to 19 year olds. He wondered what the explanation was for this. 

Mr. Weintraub replied that this was in VSD and that it is difficult to interpret what 

happened in VAERS in the rest of the country in terms of where the doses are actually 

going. He could only attest to what they observed in VSD. What they witnessed in the 

Menactra® vaccine study was that no cases were observed. One of the issues is that 

this is an extremely rare outcome. To find very small risks, they would need to assess 

an even larger population than they had (2.3 million doses). The amount of doses 

would probably have to be doubled in order to find minimal risks. 

Dr. Baker noted that this showed the importance of a chart review versus just using 

ICD-9 codes in a rare disease that can be confused with other neurologic complications. 

Dr. Ben Allis was on the committee when this safety signal was first observed. Even 

though there were three cohorts (11 to 12 year olds, 15 year olds, and 18 year olds), the 

greatest uptake with the first season of the recommendations coincided with 

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Campylobacter season and was in the older adolescents (e.g., those going to college). 

There is now a much different distribution of how vaccines are being given. 

While she recognized that the package insert was not within ACIP’s purview, Dr. Keitel 

pointed out that whatever decision ACIP made would have to be reconciled by 

practitioners with the package insert. 

Dr. Cohn replied that the work group discussed this issue. Their perception was that it 

is unlikely that the package insert from the FDA can be changed. The problem was that 

she was not sure that no risk could be proven. The work group was comfortable with 

the discrepancy in the package insert. In fact, the discrepancy existed already as there 

is not a contraindication in ACIP’s current language. 

Dr. Baker added that practitioners have already been coping with this for three years. 

The information that ACIP had early on about the benefit from immunization versus the 

risk of GBS has been helpful in guiding practitioners. She wondered what “relative 

contraindication” meant and whether it was the same as a precaution. If it was a 

precaution, then she thought they should say “precaution.” A contraindication is 

consistent with the package insert. 

Dr. Cohn responded that this occurred just as she began working on this work group. 

She did not put the rest of the language in this statement, but there is an additional 

sentence that describes this somewhat better that addresses providers evaluating the 

benefits and risks of vaccination prior to making a decision. She agreed that “relative 

contraindication” was not that clear. 

To Dr. Baker, “weighing benefits and risks” suggests a precaution not a “relative 

contraindication.” Relative to what? 

Dr. Judson strongly agreed that the term “relative contraindication” would not be helpful 

to clinicians. 

Dr. Sumaya reported that the General Recommendations Work Group had a similar 

issue in that they had language for a “true contraindication” and grappled with how that 

differed from a “contraindication.” 

Dr. Messonnier indicated that the Meningococcal Work Group felt strongly that the 

language in Option 3 should be struck since it was not helpful, but he had not heard 

much discussion yet about Option 1 versus 2. 

Dr. Sawyer requested that Dr. Sumaya or others from the General Recommendations 

Work Group remind them what was included in the general recommendations about 

GBS. 

Dr. Cohn responded that there was currently no language about this issue in the 

General Recommendations. 

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Dr. Pickering added that the general recommendations will follow what ACIP stated for 

the recommendation for that vaccine. They will not develop a new recommendation. 

The wording should be similar. 

Dr. Neuzil said that she favored Option 1, given that she had not yet seen any evidence 

that supported Option 2. 

Dr. Cieslak expressed confusion by what seemed to be a slight difference between Dr. 

Cohn’s slide 11 that read, “Option 2: Persons with a history of post-vaccination GBS 

may be at risk for another episode after any vaccine” and slide 12 that read, “a history of 

GBS with onset within 6 weeks after vaccination.” 

Dr. Cohn clarified that slide 11 was not the option. It simply explained the reason why 

the work group members considered that option. Slide 10 is actually the option. 

Dr. Cieslak wondered what was the intent. Was it that people with any history of GBS 

are likely to react to vaccines in the future, or that people who have reacted with GBS 

within 6 weeks following a vaccination? 

Dr. Cohn clarified that it was within 6 weeks after a vaccination. 

Dr. Englund supported Option 1, given that the goal of ACIP is to make evidence-based 

recommendations. Option 1 is evidence-based and Option 2 is not. 

Ms. Ehresmann supported Option 1 as well. In terms of Option 2, if they really believed 

that there was an issue with regard to a history of post-vaccination GBS from any 

vaccine, this should be discussed and included in the general recommendations and not 

added to each vaccine recommendation. 

Dr. Judson noted that on the larger study, all of the other vaccines were tracked as well. 

He wondered whether the results relative to other vaccines were sufficiently powered. 

That is, aside from GBS after the 1976 swine flu vaccine, was there any conclusive 

evidence that GBS was more likely to occur after any other vaccine? 

Dr. Velentgas responded that they did not make the same calculations regarding upper 

limits of attributable risk for the other vaccines. To answer this question 

comprehensively, she would need to bring in the denominators of the number of 

vaccines observed for each of the other vaccine types assessed. This varied 

depending upon the vaccine. Nevertheless, the study is capable of further assessing 

this. 

Dr. Sumaya was unclear and unsettled about Option 1 (slide 12) because it began with 

“there is no evidence.” He wondered whether that was saying the same thing as “after 

sufficient study, there is no evidence.” His concern regarded whether this had been 

sufficiently studied. 

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Dr. Cohn replied that the work group members felt that this issue had been sufficiently 

studied, and they did discuss what constituted “sufficiently studied.” 

Dr. Offit, a work group member, pointed out that the thinking of the work group was that 

if any of the terms “contraindication” “relative contraindication” or “precaution” were 

used, people would be less likely to administer the vaccine than for a child who had a 

previous history of GBS. As always it is a matter of weighing relative risks. The 

question is: What is the risk of getting GBS following meningococcal conjugate vaccine 

in a child who has had GBS? This is arguably theoretical and, as far as is known, is 

higher than the risk of getting meningococcal disease, which is a real risk. The work 

group did not want to elevate a theoretical, non-existent risk over a real risk and, 

therefore, did not want to use the term “precaution” because they thought it would limit 

use. In terms of how many studies are enough, this has been studied enough for the 

work group to be very comfortable that the risk of GBS following meningococcal 

conjugate vaccine in a child who has had GBS is less than the risk of getting 

meningococcal disease. Thus, the majority felt comfortable with Option 1. 

In the spirit of transparency, Ms. Rosenbaum wondered whether they had to say that 

this is not a situation in which an RCT could be conducted of people with this condition 

who were and were not given the vaccine, and that given the evidence made available, 

there was no evidence of increased risk. 

Dr. Temte responded that the context for the evidence-based approach to vaccine 

recommendations was aimed primarily at the major recommendations (e.g., universally 

recommend or not). All of these small nuances do not go into a generalized 

recommendation for a vaccine. It will be nearly impossible to find evidence for the small 

things. If a study showed no effect, they could say that there was ample evidence, but 

they could not say that if they had nothing. Rather than cluttering all of the 

recommendations and statements with expert opinion, they are choosing not to do so 

and are leaving the evidence-based systems for the large recommendations that have 

effects on large populations. 

Ms. Rosenbaum stressed that they must be very clear about how they are using the 

discussion from earlier in the morning. They must be very clear with the public about 

when ACIP will not be using the GRADE system. As a layperson, she felt confused 

about this. 

Dr. Baker reminded everyone that once the FDA licenses a vaccine, ACIP is on the 

readiness path to make a recommendation or not to make a recommendation. That is 

the charge of the ACIP. When ACIP made the recommendation for the first licensed 

meningococcal conjugate vaccine, there was a safety signal and it was taken seriously. 

There was nuanced evidence for a very small number of people, and it did not sound to 

her as though the GRADE process was meant to be applied to such nuances. 

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Dr. Temte replied that it could become overly-complicated if a clinician received 20 

different instructions for any vaccine. He agreed that ACIP must be very clear about 

when GRADE would be applied. The approach is not to hobble ACIP or clinicians with 

too much information. With any recommendations ACIP makes, they can assess the 

nuances, and if they wish to address a sub-categorization of patients, they can. For 

example, dealing with genomics issues could become an impossible task. 

Dr. Marcy thought they were forgetting that people who get GBS may be different and 

that there are data to substantiate this. There are reports of people who have gotten 

GBS following tetanus vaccine who were given the vaccine two more times. Each time 

these individuals got GBS. “Unable to evaluate the risk in persons with a previous 

history of GBS” is not the same as “there is no evidence.” That is an important 

difference. The total number of people who get GBS within 6 weeks of vaccination in 

the entire country is probably a few 100 people. However, they should at least err on 

the side of conservatism for those few people in the entire country who had a prior 

reaction with vaccination. Dr. Marcy supported Option 2. 

Dr. Cieslak noted that while the statement in Option 1 that there is no evidence is a true 

statement, it is misleading in that it suggests that this has been assessed. However, 

they had no power to examine the specific issue of people who have had an episode of 

GBS previously. Therefore, his preference was either to say nothing about the issue or 

to say that the data are insufficient to comment on this. 

Dr. Messonnier referred everyone to the proposed background language that goes with 

this entire section, which reads, “No risk for GBS after vaccination with MenACWYD was 

detected in two large studies. There were no cases of GBS in pre-licensure clinical 

trials of MenACWYCRM. There is no data on the risk in persons with a history of GBS. 

The likelihood of coincidentally experiencing GBS after MenACWY is expected to be 

greater among persons with a history of GBS than among persons with no history of this 

syndrome.” 

Dr. Keitel inquired as to whether this should be included in every individual vaccine 

recommendation. 

Dr. Baker stressed that the GBS and Menactra® issue arose because of an early signal 

after licensure. In fact, the FDA almost pulled Menactra®’s license based on minimal 

information and a small cluster of GBS cases in a short period of time. RCTs are not 

likely to be conducted given the risks-benefits, nor is it probable that there will be 

motivation to conduct more very expensive studies in light of the ones that have already 

been conducted. 

Dr. Schuchat pointed out that it was worth remembering that there was a signal 

detected at the beginning of use. At pre-licensure, there would not have been sufficient 

use to detect the kind of low rate that the signal implied. The original question upon 

which the two large studies focused related to the risk in the general population. The 

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signal was detected and the issue was that some interim approach was needed that 

focused on the group considered to be at possible higher risk (e.g., those with previous 

GBS). Language was crafted (that people now do not like) but which was a 

compromise to alert clinicians that they should be cautious with those who experienced 

previous GBS following vaccine while other studies were being conducted on the 

general population. Regarding the question pertaining to whether this was needed in 

every statement, she thought that when there was a signal, it was important to say 

something about it because they are not erasing history. Three MMWRs address this 

issue. In terms of the question regarding what is known about those with previous GBS, 

vaccine trials are never going to be conducted in such people, so this is beyond the 

policy. 

If ACIP voted for Option 2, Dr. Keitel pointed out that they would then be hypothesizing 

biological plausibility that there is a subset of individuals who may be susceptible to 

developing GBS after any vaccine. Hence, if ACIP voted for Option 2, they would have 

to grapple with the issue about all other vaccines. 

Dr. Schuchat noted that the risk of GBS has been associated with preceding infections. 

Particularly in the influenza literature, there is an issue of whether a vaccine is going to 

increase or decrease the risk of antigen-related GBS. Anyone with preceding GBS still 

might be better off with prevention of a common infection that is potentially a risk. It is 

difficult to generalize from one vaccine to another in all people with GBS. 

Pertaining to Dr. Cieslak’s comments, Dr. Iskander pointed out that there is a welldocumented positive re-challenge with this vaccine. While he did not “have a dog in the 

fight” between Options 1 and 2, the wording as it stood was not in the spirit of the 

evidence discussion held earlier in the morning. While there is no controlled evidence, 

they do have a re-challenge that was part of the initial signal. Again, it may be 

suggested as evidence that supports a subset with increased risk, but if ACIP was going 

to consider Option 1, he thought they needed to tackle the precision of the wording 

because he did not think it was factually accurate as stated. 

Given that evidence was supposed to be important to them, Dr. Baker thought that 

ACIP was reassured by the data that in the general population, this vaccine is not 

associated with onset of GBS within a biologically plausible period of time. The rarity of 

immunizing people who have prior GBS with this vaccine will never allow ACIP to state 

that there is no risk, increased risk, or so forth. 

It was not clear to Dr. Campos-Outcalt in Option 2 whether the second line pertained to 

GBS following meningococcal vaccine or following any vaccine. He thought this needed 

to be clarified and noted that there is an incidence of 1 / 100,000 for GBS over a 10­

year period may be 1 / 10,000; the risk of getting meningococcal dusease is 1 / 

100,000; and there is a 1 per billion chance of not vaccinating someone and them 

getting meningococcal disease. 

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Ms. Ehresmann commented that the proposed background language was pretty explicit 

in terms of the issues, and they were debating two additional statements for a vote. 

She wondered whether it would be sufficient to include the proposed background 

language and then not use the stronger language. That seemed clearer and might 

capture the issues people were raising. 

Having heard the discussion and some discontent with the specific language in Options 

1 and 2, Dr. Baker proposed that the work group revise the wording during the lunch 

break and present it upon reconvening. 

Meningococcal Conjugate Vaccines and GBS Revised Language for Vote 

Amanda Cohn, MD 

LCDR, US Public Health Service 

Advisory Committee on Immunization Practices 

Dr. Cohn summarized the working group’s perspective on this issue. There were VAERS 

reports of GBS following receipt of Menactra®. Two large epidemiologic studies were 

conducted, and in the meantime a precaution was included in the meningococcal statement for 

persons with a prior history of GBS. Now that the two epidemiological studies have basically 

disproven that there was any evidence of increased risk after receipt of Menactra®, the work 

group essentially believed this vaccine to be the same as any other vaccine that has no 

association with GBS. The language of the ACIP recommendation was not revised. Instead, 

the actions were revised. Thus, the work group proposed the following: 

 Remove any language with precautions about persons with a history of GBS 

from the meningococcal statement 

 Include an extensive background section, including the draft language presented 

earlier. The background would discuss the history of the VAERS reports and the data 

from the subsequent studies showing no risk of GBS after MenACYWD in the general 

population. 

 The General Recommendations Work Group should address the issue of postvaccination GBS, and consider language to provide guidance for persons with a history 

of post-vaccination GBS. The meningococcal work group felt that this risk-benefit would 

differ for each vaccine, but the general recommendations could address the issue for all 

vaccines together, even though the actual risks and benefits would have to be weighed 

for each individual vaccine. 

Discussion Points 

Dr. Judson thought that in general, they should avoid providing information that neither ACIP 

nor the readers of the recommendations could understand or interpret. Since there is no 

quantitative objective risk-benefit data for people receiving any vaccine with a history of postvaccine GBS, a statement that risk-benefit will be different for each vaccine is not useful. 

Dr. Cohn clarified that the difference was that the risk for disease would be different for each 

person. Persons with a history of post-vaccination GBS are a different group of individuals and 

they very well may be at risk for another episode of post-vaccination GBS. Then consideration 

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must be given to which vaccine is being given and the risk for that particular disease. For 

example, a microbiologist working with Neisseria meningitidis in the laboratory might still be 

given meningococcal conjugate vaccine; whereas, a healthy adolescent may not be given the 

vaccine. 

Ms. Ehresmann liked the compromise language, and thought it was very appropriate to address 

vaccination in persons with a history of post-vaccination GBS in the general recommendations 

as opposed to including individual statements. She wondered whether a vote was necessary. 

Dr. Messonnier replied that the work group felt that ACIP should vote on the removal of the 

precaution from the meningococcal section. The second component outlining what will be 

included in the background and the suggestion of the actual recommendations for the General 

Recommendations work group, and if there are changes in the General Recommendations, 

those would be presented to ACIP for a vote. 

Dr. Baker inquired as to whether there would be a Notice to Readers changing the relative 

contraindication. 

Dr. Messonnier replied that they would be happy to hear input on this. Dr. Cohn is in the midst 

of preparing a revision of the statement since it has been 5 years since the last statement. 

Given that there have been so many Notices to Readers in the interim, they would not suggest 

highlighting this specifically in a Notice to Readers. Instead, they would suggest incorporating it 

into the revised statement. 

Dr. Marcy thought that because most practitioners do not read the general recommendations, 

every vaccine statement presented should include the following language, “The 

recommendation regarding persons who have previously had GBS are applicable to this 

vaccine as they are to all other vaccines.” Otherwise it would be missed. 

Ms. Rosenbaum expressed concern about changing anything in a published statement without 

an explanation of why it was changed. 

Dr. Baker clarified that there would be an explanation. 

Dr. Messonnier stressed that the background section would include the complete story of how 

this occurred and why. 

Dr. Meissner inquired as to when the next edition of the general recommendations would be 

published. 

Dr. Pickering responded that the General Recommendations were making their way through 

clearance, so if they wanted to include the statement in this edition, they would probably need a 

motion to refer it to the General Recommendations Work Group. 

Dr. Messonnier indicated that CDC would update the Vaccine Information Sheet (VIS) quickly. 

Dr. Chilton pointed out that the background statement as written was incorrect. It was not that 

there was “no risk after MenACYWD,” it was that there was “no risk of GBS due to” because 

there is a risk of GBS in the period after immunization. 

Dr. Cohn responded that “there is no increased risk,” which she would clarify. 

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Motion: Meningococcal Recommendation 

Ms. Ehresmann made a motion to remove the precaution from the meningococcal statement, 

and to submit this to the General Recommendations Work Group. Dr. Sawyer seconded the 

motion. The motion carried with 13 affirmative votes, 2 abstentions, and 0 negative votes. 

Update on the Adolescent Meningococcal Vaccination Program 

Amanda Cohn, MD 

LCDR, US Public Health Service 

Advisory Committee on Immunization Practices 

Dr. Cohn presented an update on the adolescent meningococcal vaccination program, and 

brought to the ACIP’s attention the question regarding whether the current recommendations for 

adolescents meets prevention goals. In August 2007 after initial issues with vaccine supply 

were resolved, ACIP expanded the meningococcal recommendation to all adolescents, but 

secifically, the vaccine was preferred at the 11 to 12 year-old visit as part of the adolescent 

vaccination platform. Vaccination was also recommended for adolescents 13 to 18 years of age 

who were not previously vaccinated. There are currently two licensed conjugate vaccines for 

meningococcal disease, MenACWYD and MenACWYCRM. 

The work group has continuously revisited the issue of adolescent vaccination to ensure that the 

program will prevent the majority of serogroup C and Y cases among adolescents. Five years 

after the initial recommendation, children vaccinated at 11 to 12 year olds are entering the 

period of increased risk at 16 to 18 years of age. Children initially vaccinated at 13 to 14 year 

olds are now entering or are in college. Increasing evidence of waning immunity has led the 

work group to be concerned that vaccinating 11 to 12 year olds may not protect a child through 

college. 

In terms of whether the current program meets prevention goals, these goals were to protect 

during the peak in risk during late adolescence and to protect college students, especially 

college freshmen living in dormitories who have been shown previously to be at increased risk. 

The strategy is to vaccinate prior to the period of increased risk to ensure high coverage and 

potentially induce some herd immunity during the period of risk. 

Dr. Cohn reported on coverage with MenACYWD among 13 to 17 year olds determined by the 

National Immunization Survey for Teens 2006-2008. In all age groups, steady increases have 

been observed each year in coverage. In 2009, overall coverage was approximately 40%, but 

coverage ranged by state from less than 20% to greater than 60%. The 1994 cohort was the 

first cohort eligible who turned 11 after the 2005 MenACYWD recommendations. In the 1994 

and 1995 cohort, most children who have been vaccinated received the vaccine at ages 11 to 

12. The National College Health Assessment assesses undergraduate vaccination coverage 

among participating colleges. Data from the 2009 survey show that although no colleges had 

greater than 90% coverage, a majority of colleges had coverage between 60% to 89% and very 

few had less than 30% coverage. 

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In summary, meningococcal vaccination coverage is increasing. While coverage varies by 

state, this increasing trend is expected to continue. There is also a trend toward the 2007 

recommendations in that more adolescents are being vaccinating at 11 to 12 years of age, 

which has implications for the discussion regarding duration of protection. The majority of 

surveyed colleges have achieved high coverage. 

Regarding the current epidemiology of meningococcal disease in adolescents, rates of disease 

among 11 to 14 year olds are similar to the rest of the population. Rates begin to increase 

around age 15 and remain higher until age 21 to 22 [Active Bacterial Core surveillance (ABCs); 

Rates of Meningococcal Disease (A/C/Y/W-135) by Age, United States, 1999-2008]. The 

meningococcal recommendations are focused on decreasing this period of increased risk. 

In terms of rates of serogroup C,Y,W-135 meningococcal disease among adolescents 

compared to younger and older age groups, rates of disease were cut in half in the two year 

intervals from 2006 and 2007, to 2008 and 2009. This is the first evidence of vaccine impact on 

rates of disease among adolescents. However, these same decreases were not observed in 

infants less than one year of age or adults. The same decreases were also not observed for 

serogroup B disease in adolescents. 

With respect to meningococcal conjugate vaccine effectiveness, last June a simulation model 

was presented to ACIP that modeled breakthrough disease to give a vaccine effectiveness for 

meningococcal conjugate vaccine. These data suggest the vaccine effectiveness of 

MenACWYD to be 75% to 85%. CDC is conducting a case-control study evaluation of vaccine 

effectiveness, for which preliminary data will be available in October. Results are likely to be 

similar to modeling estimates. These estimates are lower than the estimates from the MenC 

vaccination program in the UK, which was 93% to 96% effective in adolescents. However, 

some of this effectiveness in the UK may have been indirect due to herd immunity. 

Regarding the epidemiology of meningococcal disease among older adolescents ages 18 to 23, 

in 1998 and 1999, while college freshman living in dorms had a much greater attack rate than all 

18 to 23 year olds, they comprised only 10% of the total disease. Therefore, a focus on 

vaccinating only college freshman living in dorms would not necessarily prevent the additional 

90% of cases in this age group. More recent data (2006-2010) show a similar picture for cases 

of C and Y meningococcal disease among older adolescents. Among 34 cases of C and Y 

meningococcal disease in 18 to 22 year olds, only 5 (71%) were college freshman living in 

dorms and 11 were not in school at all [Preliminary data, Meningococcal Vaccine Effectiveness 

Case-Control Study]. 

Data from a multivariate analysis of cases and controls enrolled in a high school risk factor 

study show that even among high school students, there are behavioral risk factors for 

meningococcal disease such as marijuana use or attendance at a club or disco. These 

adolescents at increased risk may also be more difficult to reach for vaccination, highlighting the 

importance of vaccination prior to the onset of some of these behavioral risks [Harrison et al. 

PIDJ, 2008. 49 case-patients and 185 controls]. Disease continues to peak in late adolescence, 

but some impact of MenACWYD vaccination is being observed on disease rates. College 

freshmen living in dorms are at high risk for disease, but there is a high burden of disease in this 

entire age group. 

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The work group also considered duration of protection, with the assumption that a person needs 

an adequate level of circulating serum bactericidal antibody (SBA) to prevent invasive disease. 

Dr. Cohn pointed out that SBA was measured with different assays in each of the studies she 

was presenting, so the data were not comparable across studies. While the number tested in 

each study was low, the data are consistent. 

The adolescent recommendations were initially made with the assumption vaccine would 

protect for ≥10 years. It was initially presumed that conjugate properties in the vaccine would 

initiate a memory response that would be protective. Recent data suggest that memory alone is 

not sufficient to protect against meningococcal disease and protective levels of circulating 

antibodies are needed. 

In a study comparing MenACWYD and MPSV4 antibody persistence three years after 

vaccination in 11 to 19 year olds, using a cutoff of > 1:4 human SBA, only 35% of persons 

vaccinated at 11 to 18 years old had protective antibody levels three years after vaccination with 

either vaccine [Vu, D et al. JID 2006:193, 821-828; Granoff, D et al. PIDJ 2005:24, 132-136]. 

Another study measured the percent of subjects with titers > 1:128 (baby rabbit SBA) at 1 

month, 3 years, and 5 years post-vaccination. The 3-year subjects were initially vaccinated at 

11 to 18 years of age and the 5-year subjects at 2 to 10 years of age. Three years after 

vaccination, the subjects vaccinated with Menactra® had higher titers than those vaccinated 

with polysaccharide (MPSV4) vaccine and controls. However, at 5 years, only 54% of those 

vaccinated with Menactra® had titers at or above 1:128, which is only 12% higher than the 

proportion of the vaccine-naïve population who had naturally occurring protective antibody [data 

courtesy of Sanofi Pasteur, 3 year follow-up of MTA02 (11-18 year-olds), 5 year follow-up of 

603-02 (2-10 year-olds)]. 

In terms of the geometric mean titers (GMT) of the SBA for these same data, there is better 

persistence of SBAs in subjects vaccinated with Menactra® compared to polysaccharide 

(MPSV4) vaccine, but the absolute values of these titers are low. In a smaller study of 11 to 18 

year olds, the GMTs at 5 years in subjects vaccinated with Menactra® were lower than the 

subjects vaccinated with polysaccharide (MPSV4) vaccine [data courtesy of Sanofi Pasteur, 3 

year follow-up of MTA02 (11-18 year-olds), 5 year follow-up of 603-02 (2-10 year-olds), 5 year 

follow-up to MTA02 (11-18 year-olds). 

The concern for antibody persistence is a concern for other meningococcal conjugate vaccines 

as well. Based on recent data from the UK on persistence of antibody levels 6 to 7 years after 

vaccination with MenC vaccine, only 48% of children vaccinated at age 5 to 6 years were 

adequately protected 6 to 7 years later with an SBA titer of >1:8, and only 38% had an SBA titer 

of ≥ 1:128. 

In summary, limited data do not support that the majority of children vaccinated at age 11-12 

years will maintain protective antibody levels through college. Some additional data will be 

available on antibody persistence in the next year; however, these data are not anticipated to 

change the picture. There are also no data regarding whether herd immunity has been 

achieved in this age group which would provide some indirect protection. The sense of the work 

group is that with dropping circulating antibody levels, herd immunity cannot be relied upon with 

the current program. There is consensus among ACIP members that the current strategy (e.g., 

vaccination preferred at age 11-12 years) is not optimal for achieving program objectives. 

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Additionally, the decision-making is time-sensitive as state mandates are being implemented 

and colleges need time to incorporate any policy changes. There have also been educational 

campaigns focused on targeting vaccination at 11 to 12 years of age. 

The work group has discussed the follow two options for ACIP consideration: 

1. Booster dose at age 17 years 

Æ For those going to college / living in dorms 

Æ All adolescents 

2. Moving the first dose closer to period of risk 

ÆExpanding preferred age of vaccination 

ÆShifting from 11-12 years to 14-15 years 

A major issue with adding a booster dose at age 17 years is that these vaccines are only 

licensed as a single dose. This recommendation would be off-label, but limited data show the 

booster dose to be safe and immunogenic. This strategy would have a high cost per QALY 

saved, and the cost of the program would essentially be doubled. Vaccines for Children (VFC) 

program covers children through age 18 years, so this program could be implemented through 

VFC. The work group proposed two options for the booster dose: 

Option 1: 17 Year-Old Booster 

 Only college freshmen living in dorms 

Æ Limits off-label use 

Æ Limits additional program cost 

Æ Is an easier group to capture for vaccination 

Æ Would prevent a low proportion of disease in age group; there would be 

continued disease in adolescents outside this age group if the vaccine is truly not 

protective 

 All 17 year-olds 

Æ Would prevent more disease 

Æ Would align better with the original program goals of protecting adolescents 

through the increased period of risk 

Æ Challenging group to reach with vaccine 

Option 2: Moving the First Dose Closer to Period of Risk 

 Optimize protection with fewer total doses given 

 May not attain high coverage prior to the increase in risk 

ÆNo current vaccination visit later in adolescence 

 Impact on the adolescent platform 

 Expand age group recommended (vaccinate between age 11-15 years) 

ÆFlexible but also confusing for providers and programs to implement 

ÆChildren vaccinated at 11-12 years may still need a booster 

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 Change recommended age group (vaccinate at age 14-15 years) 

Æ Leaves 11-13 year-olds unprotected 

Æ May not achieve high coverage prior to increase in risk 

In conclusion, there has been early success of the adolescent program, including increasing 

coverage and impact on rates of disease in adolescents. However, the work group feels 

compelled to address the concern for waning immunity. The risk-benefits and programmatic 

implications of options are quite challenging. Prior to moving forward, the work group requested 

feedback from the full ACIP regarding the following questions: 

 Should current recommendations be modified to address waning immunity? 

 Does ACIP have a preference for either option? 

Æ Booster dose at age 17 years 

Æ Moving 11-12 year-old vaccination to later in adolescence 

Discussion Points 

Dr. Chilton wondered whether, among the 304 cases of meningococcal disease in 18 to 23 year 

olds, it was known what proportion were immunized at age 11 or after. 

Dr. Cohn replied that the data on the 304 cases was from 1998 to 1999, which was prior to 

vaccination. The number of cases among adolescents is substantially lower at present and 

probably ranges around 100. 

Dr. Chilton inquired as to whether there was any evidence of vaccine effectiveness other than 

serologic protection. 

Dr. Cohn responded that a year ago they presented data on breakthrough meningococcal 

disease in persons who had been previously vaccinated, and they are continuing to collect data 

on cases vaccinated. There certainly are cases vaccinated who develop disease. Part of the 

problem is that coverage was still low five years ago, so they do not have a sense of whether 

these are children who did not respond to vaccine initially or if it is due to waning immunity. It 

will probably be another year before this can be assessed. 

Dr. Sawyer did not like the option of expanding the range of first vaccination from 11 to 15, 

given that he could not imagine the language needed to make that clear to providers and it will 

be extremely difficult to implement. It is also challenging to raise the age and capture older 

populations. 

Dr. Meissner agreed based on the rising incidence of disease, which really does not begin until 

15 years of age. While this would be missing 13 and 14 year olds, this is well before the peak. 

Dr. Cohn noted that it would be leaving the group of children who are currently protected 

unprotected in the future. 

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Dr. Baker agreed that a great increase occurs at 15, but it begins to rise at 13 to 14. From the 

parents’ and providers’ perspective, moving upward would cause difficulties based on the 

information available. 

Dr. Temte inquired as to how much of the secondary peak at ages 17 to 18 was due to college 

freshman living in dorms. He also wondered whether they knew what the population of 

freshman per year living in a dorm is. 

Dr. Cohn replied that college freshmen living in dorms are ages 18 to 19. The data collection 

forms for surveillance do not specifically ask grade level in the school. Among the cases of 

meningococcal disease enrolled in the Vaccine Effectiveness Study, only about 10% of persons 

in this age group are college freshman living in dorms. 

Dr. Turner (ACHA) added that ACHA does have information on the number of freshmen living in 

dorms, though he did not readily have the information available (later someone called out 

600,000). While they were discussing recommending a booster at 17 years, he thought they 

needed to think in terms of a booster after having received the conjugate 4 to 5 years before 

because some 17 year olds may have received the vaccine when they were 14. This should be 

clarified. 

Dr. Meissner pointed out that if they were to add a booster dose only for college students that 

would address only 10% of the burden of disease in that age group. This would not address 

90% of the burden disease,which is problematic. 

Dr. Cohn clarified that in the data from the MCVE study, it could be that there is higher 

vaccination coverage among college freshmen living in dorms, which could be why the number 

is so low. The data from the 1998 to 1999 study prior to vaccination was also 10%, but it was 

10% among adolescents ages 18 to 23 years. Among just college freshmen, it was about 70% 

among those living in dorms. 

Dr. Cieslak noted that the disease rates are currently very low at .27 / 100,000. This is an 

expensive vaccine. He would have difficulty supporting basically a doubling the 

recommendation without good evidence about decreasing effectiveness of the vaccine over 

time. 

Dr. Lett expressed concern about the change in the abbreviation for meningococcal conjugate 

vaccine to the long abbreviation and a subscript to be the one in general use. She wondered 

whether the work group considered other abbreviations such as MCV2 to make it more like HPV 

and rotavirus. 

Dr. Cohn responded that the rationale for not using MCV4 versus MCV2 or 3 is that in the future 

there may be vaccines that cover 3 different serogroups. This could become very complicated. 

It is important to ensure that serogroup A is in the vaccine, for example, if it is being 

administered for a traveling vaccine. This was also to be more consistent with the way 

meningococcal conjugate vaccines are named in other countries. 

To speak to this minor issue, Dr. Baker said she thought pediatricians were pretty familiar with 

this. They are talking about the same four antigens. This is unlike HPV that has a 2-antigen 

versus a 4-antigen preparation. She agreed that it needed to have the four common antigens, 

but D is a common conjugate that is known to pediatricians as is CRM. Whether the 197 is 

needed is debatable. She suggested that the manufacturers could weigh in as well. 

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Dr. Pickering said that in the recommendations used by ACIP and in the Red Book, only CRM 

would be used. In the scientific literature, the number 197 is included. 

Dr. Meissner pointed out that college students are in a high risk category, but they were 

excluded from the recommendation a year ago to give a second dose of meningococcal 

vaccine. Thus, they may be excluding college students from optimal protection. 

Dr. Baker reminded everyone that the excellent data pertaining to college students living in 

dorms are not current data. With teen smoking down, some behaviors and risks may have 

changed. They have been waiting for more data, and Dr. Cohn rightly stated that there are 

unlikely to be more data by the time of the October ACIP meeting. 

Dr. Englund thought that the ACIP needed to think about the impact of whatever changes they 

make on the adolescent vaccine platform in the context of the practitioners. This vaccine is just 

now becoming accepted into the pediatric population. Making a change will not merely impact 

the meningococcal vaccine, but also has the potential to impact other vaccines such as Tdap, 

adolescent pertussis, and HPV. 

Dr. Baker added that state mandates vary. For example, Texas has a mandate for middle 

schoolers who are certainly not 15 years of age. 

Dr. Schuchat pointed out that much of the discussion was focused on the waning of bactericidal 

antibody. ACIP is supposed to consider many issues, including programmatic feasibility. She 

thought what they were talking about was a partially implemented recommendation with about 

40% coverage. Practitioners and state programs have been through a whipsaw of 

recommendations, as well as a shortage in the midst of all of that. She thought it would be 

beneficial to consider what contribution a second dose might have, and what the potential 

additive benefits would be to the adolescent platform. They must realize that 60% of the people 

in the entire age group were not receiving any vaccine. Of course, they would need to update 

the cost-effectiveness of the final options being considered. 

Phil Hosbach (Sanofi Pasteur) thought it was good to see that there had been some impact, 

especially given that at the last ACIP meeting, no impact was acknowledged. Regarding the 

adolescent platform and opportunities to immunize, children above the age of 12 years are 

increasingly difficult to get. There are a couple of opportunities to do so. Around ages 10 to 12, 

at the middle school entrance age, school requirements and physical exams represent a major 

opportunity. The next major opportunity after that is either high school graduation or entry into 

college. In between, this group is very hard to reach. Sanofi Pasteur has distributed more than 

30 million doses of the vaccine in the US to date, and their estimate is that about 60% of 

population has been immunized at this time. While it is good to see an impact, they should 

keep in mind the platforms where these adolescents are most likely to be reached. 

Amy Middleman (SAM) noted that SAM had changed its name to the Society for Adolescent 

Health and Medicine (SAHM). She thought it would be helpful to increase the input from 

Immunization Services in some of the work groups. A decision would be helpful for this 

particular vaccine fairly soon, and she agreed that this could potentially impact other vaccines. 

SAHM and always advocated for more than one platform during adolescents, one of which is at 

the entry point for high school at ages 14 to 15. They must also ensure that the impact for other 

vaccines is not harmed. For example, having a 15 year old platform may make it tempting for 

people to delay other needed vaccines such as HPV to the 15 year old group. VFC utilization 

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should be assessed for the 15 year old age group and as children age out at ages 17 to 18. 

Consideration should also be given to new vaccines coming down the pike, and what makes 

sense epidemiologically for those vaccines as well in order to build a platform. It is also 

important to assess other vaccines that are already recommended, where the implementation 

may be shifted by virtue of new work. Overall, SAHM supports the introduction of additional 

platforms to fully protect this age group. 

Dr. Katz (IDSA) remembered that much of the initial impetus for meningococcal vaccine came 

from the Armed Forces experience. He was interested in hearing from their colleagues at the 

DoD regarding who in the Military currently receives meningococcal vaccine. 

COL Cieslak (DoD) indicated that this is a very important vaccine for the Military. Every recruit 

receives this vaccine in basic training. An officer entering through some other route may “slip 

through the cracks,” but the vast majority of troops receive this vaccine. They have not yet had 

to address to any great degree the question of a booster dose because it has not been given to 

11 to 12 year olds long enough for that to be a factor for very many recruits. However, it soon 

will be. He and the DoD are very interested in following this story. DoD always follows ACIP 

recommendations. He expressed concern with this vaccine because it already is one of the 

more expensive vaccines. The last data he recalled was well in excess of $30 million per death 

prevented. They could easily be talking about doubling that cost by adding the booster dose. 

Obviously, this would be a major cost to the taxpayer if they had to foot the bill for the entire 

DoD. 

Dr. Baker inquired as to whether DoD had any plans to test serology in those who were 

vaccinated 5 years ago. 

COL Cieslak (DoD) responded that he was virtually certain that serology studies were being 

done, but he did not know the specific data. 

Dr. Cohn added that CDC is collaborating with the DoD in San Diego on this project to evaluate 

those who received Menactra® and polysaccharide vaccine. Every six months they have a 

group of persons whose serum they have been able to obtain from the serum repository. The 

problem is that the DoD did not implement this until about 2006 to 2007, so there really are not 

any 5 year data yet. They will have data on 3 years probably by Spring 2011. 

Reflecting on Dr. Cieslak’s comment about the rates of disease being low, Dr. Turner (ACHA) 

thought one of the reasons was because tremendous uptake had been achieved among high 

risk individuals. He hated to see them wait for breakthrough cases as a result of waning 

immunity to prove that the booster is needed. Meningococcal disease has always been rare on 

college campuses, but has become even rarer in the last 5 to 6 years. Based on a 60% uptake 

among college students, they estimate that between 2005 and 2008, 300 cases and 35 deaths 

have been prevented. That represents a lot of young people and families who have been 

spared a dreadful disease. Programmatically, from a college health standpoint, it would be 

much easier for a booster to be given at college entry for those who received their vaccine more 

than 5 years prior to that. The vaccine was licensed in January 2005 and a recommendation 

was made in June 2005, so the first cohort of vaccine recipients will likely begin college in the 

Fall of or 2011. That is why it is important to make a decision about a booster soon. 

Dr. Fryhofer (ACP) indicated that she is also a member of the American Medical Association 

(AMA) Council on Science and Public Health (CSAPH), and stated that she was speaking for 

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both organizations and on behalf of Dr. Tan to urge ACIP to consider the infrastructure for 

adolescent vaccines when choosing an option. 

Regarding the mention that 5 years might be an optimal time between immunizations, Rick 

Dosky (AHIP) pointed out that at age18, several options for insurance change and there is a 

scatter of coverage after age 18 years of age. A relatively substantial change in policy would be 

required among several self-insured employers nationwide. In addition, under age 18, there is 

almost universal acceptance across the board of almost every recommendation made by ACIP. 

Katie Brewer (ANA) mentioned in a forward thinking way that hopefully in the reformed health 

care system there would be pilot projects around school-based health centers, which may also 

factor into the decision regarding whether to expand the age recommendation for vaccination. 

There may be a better chance of capturing youth in that age range if there is a more 

comprehensive school health program. She wondered whether there would be changes when 

health plans were required to cover children to the age of 26. 

Rick Dosky (AHIP) replied that the final rules had not been published, so this remained 

unknown. 

Regarding coverage, Ms. Rosenbaum thought that in addition to age, as grandfather plans 

expired, there would be a bringing up of immunization coverage up through adulthood. Thus, 

the problem of children versus of adults, which is a rather arbitrary issue anyway, would begin to 

fall away and would be a great boon to how they think about immunizations. 

Dr. Decker (Sanofi Pasteur) expressed concern with several issues regarding the proposal to 

increase the age for initial meningococcal vaccination. In addition to having a tendency to harm 

to adolescent platform, diffusing the recommendation may actually decrease the proportion of 

adolescents who are vaccinated. Moreover, this does nothing to address the issue that brought 

this in front of ACIP, which was the question regarding whether the millions of children who are 

already vaccinated need a booster before entering college. Selecting the option to increase the 

age for initial immunization will not address the problem initially brought before the committee. 

He thought maintaining the current recommendation for initial vaccine at ages 11 to 12 and 

adding a booster pre-college, if believed to be needed, would directly address the issue that 

was presented to ACIP without risking harm to the adolescent vaccination platform. 

Human Papillomavirus (HPV) Vaccine 

Lauri Markowitz, MD 

NCHHSTP 

Centers for Disease Control and Prevention 

Dr. Markowitz indicated that the primary purpose of the HPV presentation during this meeting 

was to remind and update the ACIP members about current issues regarding HPV vaccine and 

HPV Vaccine Work Group plans. 

Regarding the current ACIP recommendations for HPV vaccine in the US, the quadrivalent 

vaccine was licensed in June 2006 and was recommended for routine immunization of females 

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11 to 12 years of age and catch-up for ages 13 through 26 years. In October 2009, the bivalent 

vaccine was licensed for use in females, and ACIP revised the recommendation to state the 

either the quadrivalent or bivalent vaccine could be used for routine vaccination in females 11 to 

12 years of age and for catch-up in females ages 13 through 26 years. The quadrivalent 

vaccine was also licensed for use in males in October 2009. ACIP stated that the vaccine may 

be given to males 9 through 26 years of age, but it was not included in the routine vaccination 

schedule. 

In terms of additional information related to quadrivalent HPV vaccine for males, as just noted, 

FDA licensed this vaccine for males 9 through 26 years of age with an indication for prevention 

of HPV 6/11-related genital warts in males [http://www.fda.gov/BiologicsBloodVaccines/ 

Vaccines/Approved Products/ucm094042.htm]. ACIP stated that HPV vaccine may be given to 

males 9 through 26 yrs [MMWR 2010; 59: 630]. ACIP also voted to include HPV vaccine for 

males in the VFC program, and the manufacturer included HPV vaccine for eligible males >19 

years in their patient assistance program. Private insurance coverage for the vaccine for males 

appears high. At the work group’s request, AHIP was asked to query a group of their health 

insurance plans. Based on the large plans queried, (although this may not represent all of the 

plans AHIP represents), AHIP estimated that approximately 90% of male beneficiaries 9 through 

26 years of age are covered for HPV vaccine, although the criteria and language of coverage 

may vary in the different plans. The HPV work group hopes to have more information on 

insurance coverage as well as data from a national survey of provider practices for presentation 

during the next ACIP meeting in October 2010. 

Data on prevention of anal intraepithelial neoplasia grade 2/3 in males became available 

following the October 2009 ACIP meeting. These data showing efficacy of about 75% (95% CI 

= 9,95) in men who have sex with men (MSM) were presented to ACIP in February 2010. A 

supplemental BLA (sBLA) has been submitted to the FDA. The FDA review is expected to be 

complete after the October 2010 ACIP meeting. The work group is continuing to discuss and 

consider issues regarding quadrivalent HPV vaccine for males. The group plans to review the 

clinical trial data, cost-effectiveness with different coverage assumptions, epidemiology and 

cost-effectiveness in MSM, and the feasibility of reaching MSM when they would benefit most 

from vaccination. As has been presented previously to ACIP, adding males to a female only 

vaccination program does not appear to be cost-effective if there is high vaccine coverage in 

females, but at lower coverage in females the program may be cost-effective. There will be 

further consideration and discussion of these issues during the October 2010 ACIP meeting. 

With respect to HPV vaccines for females, as mentioned, ACIP revised the recommendations in 

October 2009 to state that either the quadrivalent or bivalent vaccine could be used for routine 

and catch-up vaccination of females. The CDC contract for bivalent HPV vaccine was 

established in April 2010. The VFC pediatric contract price for the bivalent vaccine is $96.08 

and for the quadrivalent vaccine is $108.72 [http://www.cdc.gov/vaccines/programs/vfc/cdc-vacprice-list.htm#pediatric]. Both manufacturers have patient assistance programs for eligible 

females older than the VFC age. 

Data on coverage were presented to ACIP previously, but Dr. Markowitz presented them again 

due to the importance of coverage in models for male vaccination cost effectiveness. The 

estimated overall coverage with ≥ 1 dose of vaccine in females ages 13 through 17 was 25% in 

2007 and increased to 37% in 2008 [National Immunization Survey. MMWR 2008;57]. There 

remains wide variation in vaccine initiation across the country, with initiation being less than 

20% in some states shown in red and as high as the mid 50% range in the states shown in blue, 

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which is reflected in the following map: 

Estimated > 1 Dose HPV Vaccine 

Coverage, Females 13-17 Years 

National Immunization Survey, 2008 

National Coverage = 37% 

Source: CDC. National, state, and local area vaccination coverage among 

adolescents aged 13-17 years---United States, 2008. 

40-49%

30-39%

20-29%

50-59%

10-19%

D.C. 

NA

National and state-specific data from 2009 will be available later in the summer of 2010 and will 

be presented to ACIP during the October 2010 meeting. 

While there are no data from the NIS beyond 2008, there are data from immunization registries 

for more recent years showing that coverage has continued to increase. For example, the 

Citywide Immunization Registry in New York City includes data on coverage among females 

ages 13 through 17 years of age for 1, 2, and 3 doses from 2008-2010. Coverage increased 

during these years, such that by the first quarter of 2010, coverage with at least 1 dose was 

over 50% and coverage with all three doses was 25% [Citywide Immunization Registry, Bureau 

of Immunization, NYC Department of Health and Mental Hygiene]. 

Another issue that the work group is addressing is HPV vaccine for women over age 26 years. 

ACIP first considered this issue in 2008 when interim data from a trial in women 24 to 45 years 

of age was submitted to the FDA. Further data were requested from this trial, and Merck 

submitted a sBLA to the FDA in November 2009 with end-of-study data from that trial in women 

24 through 45 years of age. The work group had been preparing for a vote, and had an 

extensive session during the last ACIP meeting about this issue. Most work group members 

support no catch-up recommendation beyond age 26 years. The FDA has not completed 

review of the sBLA. This issue will be revisited in the future. 

The proposed agenda for the October 2010 ACIP meeting will be full. Plans are to discuss 

further data and considerations for quadrivalent HPV vaccine for males and quadrivalent HPV 

vaccine for women over 26 years; present a vaccine safety update; have a presentation from 

the Health Resources and Services Administration (HRSA) on the Vaccine Injury Compensation 

Program; and discuss any additional issues that arise prior to the next meeting. 

Hepatitis Vaccines 

Introduction 

Mark Sawyer, MD, Chairman 

ACIP Hepatitis Work Group 

Dr. Sawyer reported that the Hepatitis Work Group has been in deliberations since February 

2009 on its second term of reference, “To review data from recent hepatitis outbreaks among 

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diabetics in institutional care to determine whether vaccination is appropriate.” Considerable 

progress has been made on this topic. This term of reference originated because of an 

increasing number of reports of hepatitis B outbreaks among adults with diabetes, as depicted 

in the following diagram: 

As of June 2010, 24 outbreaks had been reported since 1990, some involving more than one 

facility. Outbreaks were initially in hospitals and nursing homes. More recently, an increasing 

number have been reported in assisted living facilities. A recurring theme found in the outbreak 

investigations is failure of infection control practice, and misuse of devices to monitor blood 

glucose or to administer insulin to adults with diabetes. 

Infection control guidelines for preventing transmission of bloodborne pathogens among adults 

with diabetes, and in long-term care, date to the 1980s and before. To highlight a few, in 1988, 

the American Association of Diabetic Educators issued a position statement on preventing 

transmission of bloodborne infections and avoiding injuries from sharps. In 2005, CDC made 

specific recommendations for glucose monitoring practices in long-term care facilities. In 2009, 

the FDA issued a health alert after learning that more than 2000 people were exposed in two 

hospitals that used the cartridge component of insulin pens intended for single patients, to 

administer insulin to multiple patients. Despite guidelines for infection control practice 

addressing the specific issues found in these outbreaks, outbreaks continue to be reported. 

There are biological reasons for the ease with which hepatitis B infection is transmitted when 

lapses in infection control practice occur. A feature of hepatitis B virus (HBV), hepatitis C virus 

(HCV) and HIV is that all three viruses cause acute and chronic infection, and a large proportion 

of the infections are asymptomatic. The estimated reservoir of chronic HBV infection is more 

than 1.25 million people. Although not as large as the reservoir of HCV, the reservoir of chronic 

HBV, provides ample opportunity for exposure to HBV in the setting where even minor breeches 

in infection control practice occur. Moreover, the titer of HBV in infection is considerably higher 

(108-9 ) than the titer of HCV (106

) or HIV (103-6) and HBV is stable in the environment for more 

than a week, and remains infectious in dried blood in amounts too small to be visible. In 

contrast, HCV and HIV are found in lower titer, and are less environmentally stable. The 

characteristics of HBV translate into high infectivity as demonstrated after a needle stick. The 

infectivity of HBV is 10-fold higher than HCV and ~100-fold higher than HIV. Given the high 

stability and infectivity of HBV, it is not surprising that transmission might take place in settings 

with poor infection control practice [Beltrami et al, Clin Microbio Reviews, 2000. MMWR 

2001;50(No. RR-11). Bond et al. Lancet 1981; 8219:550-1. Shikata et al.. J Infect Dis 

1977;136:571–76]. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

This is compounded by the fact that licensing, regulation, and inspection in long-term care 

facilities are highly variable, especially for assisted living facilities, which generally follow more 

of a “social” rather than healthcare model. Infection control practices or polices are lacking in a 

substantial proportion of these facilities, and adherence with good infection control practice is 

often suboptimal, even when polices are in place. Accumulating evidence suggests that 

outbreaks in long-term care are recognized primarily because of the clustering of cases and 

poor infection control practice is much more widespread, disproportionately affecting adults with 

diabetes [Thompson N et al. JAGS 2010; Patel AS et al. ICHE 2009; Richards CL, Jr. JAMDA 

2007;8:S18-S25]. 

Almost half of all adults with diabetes will eventually become long-term care residents. 

Progression of diabetes disease and its complications, along with aging, lead to a requirement 

for assistance in the activities of daily living, including monitoring blood glucose. Adults with 

diabetes make up a substantial proportion of residents in long-term care. The proportion of 

current long-term care residents who have diabetes has been estimated at 20% - 26% in 

nursing home, and 15% -26% in assisted living facilities, and these adults are already 

vulnerable to insults to the liver from all causes [Resnick HE et al. Diabetes Care 2008;Hendrick 

S et al. Gerontologist 2007; Travis SS et al. JAMDA 2004; Narayan KM et al. Diabetes Care 

2006; US Dept of HHS Assistant Secretary for Planning and Evaluation Office of Disability, 

Aging and Long-Term Care Policy. November 2002]. 

As reported during the February 2010 ACIP meeting, adults with diabetes are at increased risk 

of chronic liver disease and hepatocellular carcinoma. In a retrospective study of medical 

records from Veterans Administration (VA) hospitals, all patients (n=173,643) with a discharge 

diagnosis of diabetes were examined from 1985-1990. Each patient with diabetes was matched 

to 3 patients without concomitant liver disease (n= 650,620) identified any time since 1980 and 

the outcomes analyzed through 2000, excluding first year of follow-up. Using a Cox 

proportional hazard model, the incidence of chronic liver disease was higher among patients 

with diabetes than patients without diabetes at 18.3 versus 9.5 per 10,000 patient years, an 

incidence rate ratio of 1.9 for patients with diabetes. The incidence of hepatocellular carcinoma 

was also higher among patients with diabetes than among patients without diabetes at 2.4 

versus 0.9 per 10,000 patient years, an incidence rate ratio of 2.75 for patients with diabetes [ElSerag HB Gastroenterology 2004;126:460-468] 

Also reported during the February 2010 ACIP meeting were the results of a retrospective study 

suggesting that among adults with chronic hepatitis B infection, those with diabetes had 

accelerated progression to cirrhosis. In this study of 500 adults aged 42 ± 15 years with chronic 

hepatitis B attending a “liver clinic,” 71 patients with chronic hepatitis B and cirrhosis were 

compared with 102 control subjects with chronic hepatitis B without cirrhosis, matched by sex 

and age. Patients with other risk for liver disease were excluded. The most important factor 

associated with developing cirrhosis was the added presence of diabetes, with an odds ratio 4.3 

(1.5-12.1) [Huo T-L. J Clin Gastroenterol 2000]. 

This cartoon summarizes some of the potential insults to the liver among adults with diabetes: 

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Non-Alcoholic Fatty Liver Disease (NADLD) 

Non-Alcoholic Steatohepatitis (NASH) 

Hepatocellular Carcinoma 

Hepatitis C 

9 

Diabetes, Metabolic Syndrome, and

Other Potential Insults to the Liver 

Diabetes is associated with non-alcoholic fatty liver (metabolic syndrome), development of nonalcoholic steatohepatitis, and increased risk for cirrhosis and hepatocellular carcinoma (as we 

have seen). Persons with diabetes are at risk for added liver injury from medications, risk 

behaviors such as alcohol abuse, hepatitis A, and bloodborne infections including hepatitis B 

and C. They may be disproportionately at risk because of regular exposure to blood during 

glucose monitoring and diabetic care. Thus, prevention of further liver injury by preventing 

transmission of bloodborne pathogens should be a priority. 

To raise awareness of the problem of healthcare related transmission of bloodborne infections 

and to find solutions, the CDC Foundation in collaboration with CDCs Divisions of Healthcare 

Quality Promotion, Viral Hepatitis, and Diabetes Translation organized two recent meetings, the 

final reports from which will be available soon and will be part of the considerations of the work 

group in terms of other strategies that might affect this situation: 

 Sticking with Safety: Eliminating Bloodborne Pathogen Risks during Blood Glucose 

Monitoring: This meeting, convened on May 3, 2010 brought together representatives from 

CMS, industry, FDA, diabetes educators, state health departments, the VA, academia, 

infection control, and clinical practice. The purpose of the meeting was to raise awareness 

of the infectious disease risks related to blood glucose monitoring and to discuss voluntary 

strategies and opportunities for prevention in this area, including product innovation and 

improved education and marketing. 

 Safety by Design: Innovative Approaches for Safe Injection: This meeting, convened on 

May 24, 2010 assembled representatives from additional organizations with a goal to 

promote safe use and innovation in product development to eliminate transmission of 

bloodborne pathogens and other infections associated with the intravenous delivery of 

parenteral medications. 

With respect to the work group deliberations to date, the work group has had many discussions 

covering a wide range of topics including infection control and LTC, diabetes, glucose 

monitoring, risk of hepatitis B infection among adults with diabetes, vaccine coverage, and 

vaccine seroprotection. After these discussions, the majority opinion of the ACIP Hepatitis 

Working Group favored hepatitis B vaccination for adults with diabetes as an important part of a 

solution for preventing hepatitis B infections, an approach similar to the one used to prevent 

hepatitis B infections among health care personnel. This approach was characterized by 

hepatitis B vaccination for adults with diabetes; improving implementation of infection control 

practices, especially for assisted blood glucose monitoring; and encouraging innovation in 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

labeling, cleaning, and design of blood glucose monitoring devices to prevent transmission of all 

bloodborne pathogens. 

On June 18, 2010, the Division of Viral Hepatitis (DVH) presented an update on the activities 

and deliberations of the ACIP Hepatitis Working Group, to the Healthcare Infection Control 

Practices Advisory Committee (HICPAC). HICPAC members acknowledged the increasing 

evidence of widespread breeches in infection control practice and the urgent importance of 

finding solutions. The discussion reflected support for hepatitis B vaccination of adults with 

diabetes as an appropriate part of a solution for preventing bloodborne infections, including 

hepatitis B virus infection. 

Given the majority opinion in support of vaccinating adults with diabetes and the agreement of 

HICPAC, the work group faced significant challenges in defining policy options for hepatitis B 

vaccination among adults with diabetes. The number of adults with a diagnosis of diabetes has 

increased exponentially in the US during the last several decades. In 2006, the National 

Diabetes Surveillance System reported that 17.7 million adults had diagnosed diabetes [CDC’s 

Division of Diabetes Translation. National Diabetes Surveillance System available at 

http://www.cdc.gov/ diabetes/statistics from NHIS]. The life-time risk of diabetes is now greater 

than 30%, and by 2020, it is expected that 28.5 million adults will have a diagnosis of diabetes 

[Narayan KM. Diabetes Care 2006]. 

The prevalence of diagnosed diabetes in the US adult population, as determined in the 2005­

2006 National Health and Nutrition Examination Survey (NHANES), was 7.7% of the US adult 

population 20 years and older. However, the prevalence of diabetes was considerably higher 

among adults greater than 60 years than among younger adults (e.g., 17.5% of adults 60-74 

years and 14.8% of adults 75 years and older). Adults over the age of 50 or 60 years might be 

expected to show a less robust response to hepatitis B vaccine than younger adults, based on 

experience with other vaccines. The working group examined the possible advantages of 

vaccination soon after diagnosis of diabetes, or at as young an age as possible, to maximize 

seroprotection [Cowie et al., Diabetes Care 2009;32:287-94]. 

Data pertaining to the incidence of diabetes diagnosis by age group in 2008 data show that 2/3 

of adults who will ever have the diagnosis of diabetes will have the diagnosis by age 60 years. 

The proportion of new diagnoses decreases in older age groups, especially after age 65 and 

older [Adapted from: CDC. Diabetes Data and Trends. Available at: http://www.cdc.gov/ 

diabetes/statistics/age/fig1.htm; Source: Centers for Disease Control and Prevention (CDC), 

National Center for Health Statistics, Division of Health Interview Statistics, data from the 

National Health Interview Survey]. 

Data from the National Nursing Home Survey (NNHS) from 2004 show that the age distribution 

of nursing home residents by diabetes status is somewhat older overall than the age distribution 

of persons with a new diagnosis of diabetes. The age distribution of adults with diabetes in 

nursing homes peaks at 80-84 years, slightly younger than the peak age for adults without 

diabetes (85-89 years). It is important to observe that few nursing home residents are younger 

than age 65. Therefore, if hepatitis B vaccination is administered soon after diagnosis, these 

data suggest that over time, the majority of adults with new diagnosis of diabetes could be 

vaccinated before an age when they require long term care services, optimizing opportunities 

for a good response to hepatitis B vaccination. These data were taken into consideration by the 

work group during their deliberations on possible policy options [Zhang X et al. JAGS 

2010;58:724, CDC unpublished analysis]. 

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During this session of the June 2010 ACIP meeting, presentations included an update on 

national surveillance in the US for acute hepatitis B infections; information about the risk of 

hepatitis B virus infection among adults with and without diabetes; data on hepatitis B vaccine 

seroprotection and safety among older adults; and the policy options proposed by the work 

group. 

During the October 2010 ACIP meeting, the work group plans to present a cost-effectiveness 

analysis covering the proposed policy options and considerations for implementation. Following 

review and discussion during that meeting, the work group plans to call for a vote. 

Epidemiology of Acute Hepatitis B 

Ruth Jiles, MS, MPH, PhD 

Division of Viral Hepatitis 

Centers for Disease Control and Prevention 

Dr. Jiles described the incidence, trends, and associated outcomes / complications of acute 

hepatitis B disease among adults > 50 years of age. For these analyses, data were utilized 

from three sources. 

The first source was the National Notifiable Diseases Surveillance System (NNDSS). Acute 

hepatitis B is a legally mandated reportable condition in all states. Clinical laboratories and 

healthcare providers send reports of acute hepatitis B to local or state health departments. 

These reports have been submitted to CDC voluntarily using the electronic infrastructure of the 

NNDSS since 1990. The case reports include basic demographic data, but often do not include 

information about risk behaviors or exposures. States may collect information about risk 

behaviors or exposures; however, these data are not always sent to CDC. For this 

presentation, NNDSS data were used from 1980 through 2007 to describe trends. All other 

analyses used 2007 data, which is the most recently published data. 

The second data source for these analyses was the Sentinel Counties Study of Acute Viral 

Hepatitis, which was a special study for hepatitis that was conducted from 1981 through 2006 to 

supplement data from the passive NNDSS. This study included 6 counties with populations of 

approximately 4.5 million. A rigorous protocol was used to identify and characterize cases of 

acute viral hepatitis using both clinical and laboratory criteria. Follow-up interviews were 

conducted to ascertain risk behaviors and exposures, and sera were collected for serologic 

characterization. For these analyses, sentinel county data were used from 2002 through 2005. 

A demonstration project of enhanced hepatitis surveillance served as the third source of data. 

This project was initiated in 2004 and was funded through the Emerging Infections Program 

(EIP). The goal of the EIP project is to develop best practices for improving case 

ascertainment, application of case definitions, data quality and completeness of reports, 

reporting of risk factors, and serologic characterization. For these analyses, data were used 

from 2005 through 2007, which covered a population of approximately 36 million. 

NNDSS data from 1980 through 2007 show that incidence of acute hepatitis B in the US peaked 

in the mid-1980s and declined over time. The most rapid decline occurred between 1989 and 

1992. This decline coincided with the stepwise implementation of the national vaccination 

strategy to eliminate hepatitis B viral transmission. Further examination of these data show that 

the decline varied by age. From 1998 through 2007, the decline was 92% among children and 

young adults less than 20 years of age and 59% among adults 20 to 49 years of age. The 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

smallest decline, 46%, was observed among adults > 50 years of age. To describe the burden 

of disease by age group, the proportion of cases that were > 50 years of age was determined. 

Because of the small number of cases in the < 20 age group, they were combined with the 20 to 

49 age group. In 1998, 16% (n=10,108) of all acute hepatitis B viral cases reported through 

NNDSS were > 50 years of age. In 2007, 24% (n=4,499) of all cases were > 50 years of age. 

These data indicate that as the disease decreased among the younger vaccinated group, the 

burden of disease shifted to the older age group [Source: National Notifiable Diseases 

Surveillance System (NNDSS)]. 

The following table reflects acute HBV disease per 100,000 population by age group and source 

of surveillance data, and for each source, the number of cases reported during the period 

presented are also noted: 

Age group 

(years) 

NNDSS 

2007 

Sentinel Counties 

2002-2005 

EIP 

2005-2007 

n rate n rate n Rate 

< 20 83 0.1 8 NC 16 NC 

20-49 3,319 2.6 543 6.9 814 2.1 

≥ 50 1,097 1.2 102 1.9 242 0.9

 NC = rates for cells with <20 cases on average were not calculated 

There were very few cases in the group < 20 from each of the three sources. All sources 

indicate that rates were highest for the 20 to 49 age group, intermediate for those > 50 years of 

age, and lowest for the age group < 20 years. These data show that the older age group does 

experience acute hepatitis B disease. 

Hospitalization and deaths were used as outcome indicators of severity of disease. With regard 

to the frequency of reported hospitalization due to acute hepatitis B by age group and source of 

data, from 2007 NNDSS data, a similar proportion of hospitalizations were reported for cases in 

the two age groups. In the < 50 age group, there were 817 / 2008 (41%) hospitalizations and in 

the ≥ 50 group there were 258 / 655 (39%) hospitalizations. Sentinel Counties data from 2002­

2005 showed 150 / 534 (28%) hospitalizations in the < 50 age group and 32 / 101 (32%) ≥ 50 

group. EIP from 2005-2007 reported 234 / 661 (35%) hospitalizations in the < 50 age group 

and 85 / 198 (43%) in the ≥ 50 group. Reported deaths among acute HBV cases by age group 

in the three data sources were consistent. Compared to the < 50 age group, the proportion of 

deaths among cases ≥ 50 years were higher at 3% versus 1% in the NNDSS data, 2% versus 

1% in Sentinel Counties, and 4% versus < 1% in the EIP sites. 

Vital statistics data were used to determine the number of deaths attributable to acute hepatitis 

B viral infections, which showed that more deaths were reported among the older age groups as 

anticipated. The trends in these data also mirror that of the 20 to 49 year old group, which 

suggests at least consistency in reported hepatitis B as a cause of death [National Center for 

Health Statistics Mortality Files]. 

These surveillance data have several limitations. First, more than half of all cases of hepatitis B 

infections in adults may be asymptomatic. As a result, a large proportion of persons with 

incident infection will not be diagnosed or reported with this condition. A significant amount of 

under-diagnosis and / or under-reporting of acute hepatitis B is also likely if physicians who 

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diagnose cases or laboratories performing diagnostic testing do not report these findings to 

state and local health departments, or if states do not report these cases to CDC. These data 

reflect cases of acute disease, not high risk groups such as diabetics and residents of long-term 

care facilities. Unfortunately, diabetes status and residential information are not routinely 

collected in these surveillance systems. 

In summary, these data indicate that acute HBV infection occurs among adults > 50 years of 

age and older. The smallest decline in incidence was observed in this age group compared to 

the younger age group. As a result, the proportion of cases ages 50 and older has increased 

over time. Cases ages 50 and older are only slightly more likely to be hospitalized due to acute 

hepatitis B virus, but are two to four times more likely to die from hepatitis B disease. Currently, 

efforts are underway to collect information on residents in long-term care facilities, diabetes 

status, and possibly other relevant co-morbidities in the EIP demonstration sites. These data 

will be used to provide answers to relevant questions about relationships between vaccination 

status, diabetes, and hepatitis B viral infection. 

Hepatitis B Risk among Adults With and Without Diabetes 

Dale Hu, MD 

Division of Viral Hepatitis 

NCHHSTP / NCIRD / CDC 

Dr. Hu described the risk of hepatitis B among adults with and without diabetes from a variety of 

sources, and presented an overview of HBV prevalence and estimates of HBV incidence among 

adults with and without diabetes. He offered a brief update on the outbreaks of hepatitis B 

among persons with diabetes and their related morbidity; provided data showing the broader 

problem of hepatitis B transmission associated with glucose monitoring; and discussed the 

seroprevalence and estimated incidence of hepatitis B among adults with diabetes compared to 

adults without diabetes. 

Although the risk of hepatitis B has been most dramatically highlighted from reported outbreaks, 

as Dr. Sawyer illustrated earlier, these are most likely the “tip of an iceberg” of unknown size 

[Thompson, Perz. JDST, 2009; and unpublished data].. Recently, another outbreak investigation 

was initiated by CDC in Texas among persons with diabetes, which as of mid-June has yielded 

at least 14 patients with acute hepatitis B infection and 3 deaths. At this point, the outbreak has 

extended to at least 8 assisted living facilities 

With regard to the morbidity associated with such outbreaks, data from 21 outbreaks show that 

90% of persons with acute hepatitis B (e.g., persons positive for anti-HBc and anti-HBc IgM) 

were persons with diabetes monitoring blood glucose. However, 10% were other contacts who 

did not have diabetes (e.g., roommates, family members, staff at long-term care facilities). The 

morbidity from acute hepatitis B can be substantial as illustrated in additional data from 21 

outbreaks where 38% of 151 persons with acute hepatitis B were hospitalized and 18% died 

from acute hepatitis in this predominantly elderly population. Data from 13 outbreak 

investigations with complete ascertainment of hepatitis B infection and diabetes status show 

again that the percentage of adults with diabetes having acute infection is much higher (30.5%) 

than the percentage of adults without diabetes (1%). Similarly, the prevalence of chronic 

infection among adults with diabetes classified by serology at the time of the investigation was 

also higher at 6.3% versus 0.4% among adults without diabetes [CDC. Unpublished Data 2009]. 

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Although the proportion of persons developing chronic infections tends to decrease with age, 

the risk of chronic infection among older adults is higher. Among healthy adults, approximately 

5% to 10% develop chronic HBV infection. Among older adults, especially adults with comorbidities, the risk of chronic infection is much higher at 45% to 59% [Shepard CW ,Epidemiol 

Rev 2006; Polish LB. N Engl J Med 1992; Kondo K . Hepatology 1993]. 

Data from the Behavioral Risk Factor Surveillance System (BRFSS) shows that a high 

proportion of adults with diabetes have regular exposure to blood through glucose monitoring. In 

the 2006 survey, adults using insulin had the highest rates of daily glucose monitoring (84% 

using insulin and oral medication and 91% using insulin only). One-third of adults taking no 

medication monitored blood glucose daily. Overall, almost 2/3 (65%) of adults with diabetes 

monitored blood glucose at least once a day. Short-term assisted glucose monitoring is likely to 

be common during hospitalization, outpatient surgery, and in community clinics and screenings, 

even if not monitored on a daily basis. Most adults with diabetes will eventually monitor blood 

glucose [Adults 18+ yrs. Behavioral Risk Factor Surveillance System MMWR 2007;56 

(43):1133-1137]. 

In a recent study by Walter Hellinger, which was presented at the Society for Healthcare 

Epidemiology of America (SHEA) meeting in March 2010, Hellinger described an innovative 

approach for assessing the use of computerized glucose meters in a Florida hospital. The 

glucose meters recorded the time of use with different patients. The data were analyzed for one 

month in October 2008. In this facility, 38 glucose meters performed 11,665 tests on 803 

patients. Almost 80% were sequential tests on different patients. Of these, almost all were 

done within 24 hours. More than 60% were sequential tests on different patients that were done 

within one hour. In this particular facility, there were strict efforts to clean glucose meters 

between users. The study illustrates the potential for transmission of bloodborne pathogens if 

proper cleaning is not performed between patients (e.g., during periods of peak demand for 

completing testing on multiple patients) [Hellinger et al. Presented at SHEA, March 2010 

(abstract # 199)]. 

Blood contamination of glucose monitors is frequent as shown in a study by Louie and coworkers of glucose meters used in 12 hospitals represented by academic, community, urban, 

and rural settings. In this study, there was wide variation by hospital on the policy for cleaning 

the meters. Only 1 hospital policy recommended cleaning after each patient, 4 of the hospitals 

recommended cleaning the meters daily, 1 hospital recommended weekly cleaning, and 6 of the 

hospitals did not have a policy. The 608 glucose meters were examined for visible blood and 

then tested with phenolphathalein for evidence of hemoglobin. Almost a third (30%) of the 

glucose meters tested positive for blood. The presence of blood increased with the number of 

people operating the glucose meter, but interestingly was not related to the academic affiliation, 

hospital size, or the cleaning schedule. The data in this study suggest that there is a lack of 

appreciation of the significance in transmission of bloodborne pathogens for blood 

contamination of glucose meters, and suggests there might be barriers to rapid effective 

cleaning of the meters [Louie RF et al. Point of Care 2005;4:158]. 

In a study published in the Journal of the American Medical Association (JAMA) in June 2010, 

Melissa Schaefer in the Division of Healthcare Quality Promotion (DHQP) collaborated with the 

Centers for Medicare and Medicaid Services (CMS) in an assessment of the infection control 

practices at 68 ambulatory surgical centers in three states. More than 2/3 of the facilities had at 

least one lapse in infection control, 21% of facilities used single-use lancing penlets on multiple 

patients, and 32% failed to clean and disinfect glucose meters after use [Schaefer MK et al. 

JAMA 2010;303:2273]. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Data presented by Nicola Thompson to the Council of State and Territorial Epidemiologists 

(CSTE) earlier in June 2010 summarized some recent patient notifications after misuse of 

diabetes equipment (e.g., the use of equipment designed for individual use on multiple patients). 

Misuse took place in both hospitals and community settings. The problems continued for 6 

months or more in 3 of 4 of the notifications, and the misused equipment affected large numbers 

of adults with diabetes [Thompson ND. CSTE June 2010 Portland, OR]. This information, 

coupled with the data presented by Hellinger about frequent sequential use of glucose meters 

and Louie about blood contamination of glucose meters, and the finding of common infection 

control lapses in ambulatory surgical centers, highlight a significant potential risk of bloodborne 

pathogen transmission for adults with diabetes in a variety of settings that are not limited to 

long-term care. 

Given these examples of poor infection control practice, the seroprevalence of hepatitis B 

infection on a national basis among adults with diabetes compared to adults without diabetes 

using NHANES data were assessed. NHANES is a large population-based survey that seeks to 

collect data from a representative sample of the US population on a wide variety of relevant 

questions. Survey results were used from 1999 through 2008 to examine the seroprevalence of 

hepatitis B infection among adults with and without diabetes. Diabetes status was determined 

by asking respondents if they had ever been told by a doctor that they had diabetes, excluding 

diabetes during pregnancy. Hepatitis B infections were determined by positive serology for 

hepatitis B core antibody indicating past or present hepatitis B infection. A major limitation of 

this survey for determining the seroprevalence of older adults is that it excluded persons in 

institutional setting. Therefore, NHANES data do not have information for persons in long-term 

care facilities. The findings for overall seroprevalence of hepatitis B infection among noninstitutionalized adults > 18 years with and without diabetes showed that 8.3% of adults with 

diabetes had evidence of past hepatitis B infection, and that 5.2% of adults without diabetes had 

evidence of past hepatitis B infection. The odds ratio and prevalence ratios were both elevated, 

suggesting that adults with diabetes had a 60% higher prevalence of hepatitis B infection than 

adults without diabetes [CDC. Unpublished data]. 

The following graphic shows the prevalence of hepatitis B infection with and without diabetes by 

age group during the same period: 

6.8 7.0

9.6

10.5

9.3

8.6

4.4

5.5

7.3

8.5

6.5 6.6

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

11.0

12.0

35‐39 40‐44 45‐49 50‐54 55‐59 60+

Prevalence (/100)

Age group

with DM

without DM

Prevalence of HBV among Adults with/without 

Diabetes, by Age Group, NHANES 1999-2008 

Prevalence test for Adults with DM and without DM

Prevalence mean

with DM

Prevalence mean

without DM

T test for

difference

of mean

Mean (95% CI) Mean (95% CI) T value p‐Value

8.667 (7.210, 10.123) 6.467 (5.170, 7.763) 2.9 0.016

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

The point estimates of seroprevalence for each age group and the prevalence means for adults 

with and without diabetes are not statistically different, in part because the sample sizes are 

small. However, the test of the mean shows a significant difference overall, suggesting that the 

increase in hepatitis B infection is likely to be higher among adults with diabetes extending 

across ages group, even without data from the older adult age groups represented in the 

hepatitis B outbreaks in long-term care facilities. 

Turning to estimates of the incidence of hepatitis B infection, Dr. Hu reported that catalytic 

modeling using a method previously reported by Patrick Coleman in 1998 was used. Agespecific seroprevalence of diabetes was calculated from NHANES data for 2007 and 2008, and 

age-specific antibody to hepatitis B core antigen was calculated from NHANES 1999-2009. 

National surveillance reports of acute hepatitis B, adjusted for under-reporting, were used to 

estimate the force of hepatitis B infection (lambda) per 100,000 susceptible persons. A 

susceptible person was defined by having no serological markers of hepatitis B infection or 

vaccination on testing in NHANES. There were several important considerations. The Coleman 

model assumed a constant force of infection for age groups younger than 40 years [Coleman 

P. J Infect Dis 1998]. This assumption may not be accurate for older adults, who are the focus 

of this analysis. The data sources had limited numbers, even in NHANES, and did not allow for 

estimates in subgroups. In addition, the incidence was estimated of hepatitis B infection among 

adults with diabetes identified in NHANES because data were lacking for adults with diabetes in 

long-term care facilities who were not surveyed in NHANES. 

The following table shows the methodology used to arrive at the number of adults with diabetes: 

Step 1 & 2. Estimate Prevalence of 

Diagnosed Diabetes, by Age Group –

United States, 2007- 2008

Age

group

A1

Prevalence

of

diabetes

(/100)

A2

US

population

Diabetes

population

ND = Prev x US

Census

25‐59 6.19 138,109,000 8,548,947

60‐69 17.02 24,901,000 4,238,150

>=70 19.93 26,463,000 5,274,076

Overall 189,473,000 18,061,173

A1 NHANES 2007‐2008.

A2 – US population in 2007, www.census.gov/prod/1/pop/p25-1130/p251130a.pdf, 

reported by U.S. Bureau of Census. 

For 3 age groups (25-59, 60-69, and ≥70 years) the prevalence of diabetes was determined 

from NHANES. The total number of adults with diabetes was then estimated by multiplying the 

by the US Census populations in these age groups. The total number of adults with diabetes in 

2007 and 2008 was estimated at ~18 million. Given that NHANES does not include 

institutionalized adults (e.g., long-term care facilities), the prevalence of adults with diabetes in 

older adult age groups is believed to be conservative. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

The following table illustrates how the total number of hepatitis B infections among adults with 

diabetes was estimated: 

Step 3 & 4. Estimate of Total Number of Acute Hepatitis

B (HBV) Infections among Adults with Diabetes,

by Age Group - United States, 2007-2008

Age

group

A3

Incidence

of

acute HBV

(/100,000)

IT

Ratio of

prevalence

of

acute HBV

with vs

without

diabetes

k=ID/IND

Incidence

acute HBV

without

diabetes

(/100,000)

IND

d

A4

Incidence

acute HBV

with

diabetes

(/100,000)

ID=k*IND

A5

Number

acute

HBV

infection

with

diabetes

HBD=ID*ND

A6

Under‐

reporting

multi‐

plier

A7

Adjusted

for

under‐

reporting

(A5xA6)

A8

Proba‐

bility

of

jandice

(Pj)

A9

Final

multi‐

plier

(A6/A8)

Total

number

of

HBV

infections

(A5xA9)

25‐59 2.51 1.60 2.42 3.87 331 2.79 924 0.30 9.3 3,079

60‐69 0.80 1.60 0.73 1.16 49 2.79 137 0.30 9.3 458

>=70 0.80 1.60 0.71 1.14 60 2.79 168 0.30 9.3 561

Overall 441 1,229 4,097

A3 – MMWR, May 22, 2009 / Vol. 58/ No. SS‐3, page 24, report by CDC ,Division of

Viral Hepatitis.

I

T = (k*IND*ND + IND*NND) / (ND+NND)

k: k=1.6 is based on the ratio of seroprevalence of HBV with vs. without diabetes finding from NHANES

1999‐2008, manuscript in preparation

I

T*(ND+NND) / (k*ND+NND) d ‐ IND =

A6 ‐ CDC unpublished used for annual surveillance summaries

The incidence of reported acute hepatitis B cases was taken from national surveillance data 

(column A-3), which ranges from 1-4 per 100,000 population. Using approximate prevalence 

ratio of 1.6 of HBV among persons with and without diabetes from NHANES (column 3), 

calculated in column A4 is the incidence of acute hepatitis B among adults with diabetes that 

would be reported to the surveillance system. The number of adults with diabetes calculated in 

the previous table is multiplied to obtain the number of acute HBV infections among adults with 

diabetes (n=441; column A-5). 

By adjusting for under-reporting (2.79; column A-6) and the probability of symptomatic versus 

asymptomatic infection by age group (0.30; column A-8) using the same factors employed for 

national surveillance estimates, the total annual number of HBV infections among adults with 

diabetes can be estimated to be approximately 4097. Overall, it can be summarized that the 

estimated incidence of acute hepatitis B infections among adults with diabetes that are likely to 

be reported is 1-4 / 100,000, and the total incidence of acute hepatitis B infections among adults 

with diabetes is ~22.7 / 100,000. In the model, it is estimated the annual number of hepatitis B 

infections is more than 4000 per year among adults with diabetes, or about 10% of the 

estimated 40,000 total cases of hepatitis b infection among adults > 25 years of age in the US. 

The following table shows a retrospective analysis of data from 4 sites of the Emerging 

Infections Program: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Acute Hepatitis B by Diabetes Status 

Emerging Infections Program Sites 

EIP Site Years Diabetes 

No 

Diabetes 

% 

Diabetes 

New York 

City 2006-2009 32 274 10.5% 

Oregon 2009 2 20 9.1% 

Colorado 2009 0 35 0.0% 

Connecticut 

2009­

Mar 2010 2 13 13.3% 

Total 36 342 9.5% 

Unpublished analysis of retrospective data 

Each of these sites had some form of data identifying the diabetes status of persons reported 

with acute hepatitis B infection. Although an age breakout and denominator data were not 

available, these data suggested again that acute hepatitis B cases among persons with 

diabetes constitute approximately 10% of all reported acute cases. 

In conclusion, outbreaks of hepatitis B virus infection and related morbidity and mortality 

continue to occur among adults with diabetes related to poor infection control. The increased 

risk of HBV is not limited to residents of long-term care, as shown in recent data. Prevalence 

and incidence of HBV infection is higher among adults with diabetes than among adults without 

diabetes. The increased prevalence of HBV infection among adults with diabetes (8.3%) is 

comparable to the historical prevalence of HBV among certain groups of healthcare personnel 

(9% - 28%). Hepatitis B vaccine has been effective in reducing the prevalence and incidence 

among health care personnel and has potential to do the same among adults with diabetes. 

Hepatitis B Vaccine for Adults with Diabetes: Seroprotection and Safety 

Philip Spradling, MD 

Division of Viral Hepatitis 

NCHHSTP, CDC 

Dr. Spradling pointed out that many studies have documented a high proportion of 

seroprotection among children and young adults, with and without diabetes, who receive a 

standard series of hepatitis B vaccine. A special challenge for the work group was to determine 

the best way to achieve seroprotection among older adults with diabetes. Experience with other 

vaccines suggests that fewer older adults might achieve seroprotection after a standard series 

of hepatitis B vaccine, and that the proportion achieving seroprotection among older adults with 

diabetes might be even lower. In addition, although years of worldwide experience with millions 

of doses hepatitis B vaccine have established that hepatitis B vaccine is one of the safest 

vaccines, the work group wanted to be sure that no unique adverse events were associated with 

hepatitis B vaccine administered to older adults with diabetes. During this presentation, Dr. 

Spradling shared background information to help interpret the data; presented data from clinical 

trials on seroprotection after a primary series of hepatitis B vaccination and after revaccination 

among adults without and with diabetes; and summarized data on the safety of hepatitis B 

vaccine, including adverse reactions reported to VAERS for adults older than 40 years of age. 

Protection against hepatitis B virus infection is indicated by the presence of antibody to hepatitis 

B surface antigen or anti-HBs. A level > 10 international units per liter (IU/L) after vaccination 

generally is accepted as the level that predicts protection. Published data from the US and Asia 

demonstrate that a response to vaccination of at least 10 IU/L predicts at least 22 years of 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

protection from symptomatic illness and chronic infection among health adults [McMahon et al. J 

Infect Dis 2009]. 

Other historical data have shown that seroprotection among persons less than 40 years is 

greater than 90% after a standard series of hepatitis B vaccination. This includes younger 

adults and children with diabetes. With aging, however, the proportion of adults who are 

seroprotected declines. Similarly, the GMTs are substantially lower among older adults, 

especially adults with co-morbidities. The significance of lower titers is unknown as long as the 

seroprotected titer of 10 anti-HBs is achieved. For that reason, in this presentation, Dr. 

Spradling showed seroprotection proportionsrather than GMTs. Among healthy younger adults 

who do not respond to the primary series of hepatitis B vaccine, seroprotection improves after 

additional doses of hepatitis B vaccine. A small proportion of adults do not achieve a 

seroprotective titer regardless of the number of primary and revaccination doses. From 

experience with younger recipients, it is known that additional doses of hepatitis B vaccine after 

the primary series do not increase adverse reactions [Data summarized in MMWR 2006; 55 

(RR-16)]. 

The work group reviewed the literature for hepatitis B vaccination among adults. The 

populations studied in most hepatitis B vaccine trials in adults were healthcare workers, HIV 

infected adults, and adults with end stage renal disease. A large number of clinical trials of 

healthcare workers included hepatitis B vaccination of adults 60 years and older, and a few 

trials focused exclusively on persons with diabetes. However, the number and depth of these 

data were not optimal, particularly for revaccination studies. These trials, the trials among 

adults with diabetes, and sub-analyses of published and unpublished trials conducted by the 

manufacturers contributed to the data shown during this session. No data were found on the 

duration of vaccine protection among older vaccine recipients for adults with or without diabetes. 

These are areas that would benefit from additional research. 

The following graph depicts seroprotection point estimates (y-axis) after hepatitis B vaccine by 

age group (x-axis) from multiple studies in total depicts the effect of increasing age on 

seroprotection after vaccination: 

8 

Seroprotection Point Estimates After Hepatitis 

B Vaccine, by Age Group, from Multiple Studies 

0

10

20

30

40

50

60

70

80

90

100

10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90

Percent anti HBs > 10 IU/L

Age (Years)

Each white point on the graph represents the midpoint age of the various age groups included in 

each of the studies. Each point is neither a single patient nor pooled data from a single study, 

but rather a midpoint for an age range for seroprotection in a given study. Each study has 

several points, determined by the number of age groups included. Combined in single graph, it 

is easy to see the effect of advancing age on seroprotection. Based on data from these studies, 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

seroprotection is found to be high among younger adults (> 90%) and remains relatively high 

until the age of approximately 55 to 60, after which it decreases quite noticeably to the 10th 

decade of life, where seroprotection is the lowest. 

Some of the data in the previous graph are from a study which was conducted in a long-term 

care facility in France that was published in 1984. Residents up the age of 96 were vaccinated 

with 5μg IM of plasma-derived hepatitis B vaccine, the first generation hepatitis B vaccine that is 

no longer available. A dose was given every month for 3 months and an anti-HBs level was 

drawn at 4 months, 1 month after the 3rd dose. Although the outcome of this study was 

seroconversion (any measurable anti-HBs) rather than seroprotection, it demonstrates 

decreasing response with increasing age. It also shows that even adults in their 90s may 

respond to vaccine. Overall, the response among those over age 60 was 46%, keeping in mind 

that most subjects vaccinated were in their 80s [Denis et al. J Infect Dis 1984]. 

Data from a study published in 1998 that compared seroprotection after administration of two 

FDA-approved vaccines, Engerix-B and Recombivax HB, show seroprotection in a large 

number of adults. With both formulations, seroprotection was lower among adults age 40 to 65 

years compared with those younger than 40 [Averhoff F et al. Am J Prev Med 1998]. 

In a study comparing seroprotection after GSK’s Twinrix (combined formulation hepatitis 

A/hepatitis B vaccine) with Engerix-B (single antigen hepatitis B formulation simultaneously 

administered at a separate site with hepatitis A vaccine, Havrix) vaccine was given at 0, 1, and 

6 months and antiHBs levels were obtained at month 7. Seroprotection after each vaccine 

formulation was compared for adults 41 to 60 years and adults 61 to 81 years. These data, 

from an unpublished sub-analysis that is a post-hoc exploratory analysis that included small 

numbers of subjects provided by GSK, show roughly that overall response among adults 41 to 

60 years was on the order of 85-90% and among those 61 to 81 was about 65-70% [Van der 

Wielen M et al. Unpublished subanalysis provided by GSK. In a similar type of comparison of 

results by age in a trial conducted in the 1990s to determine the response to Merck’s 

Recombivax HB hepatitis B vaccine among older adults (with vaccine was administered at 0, 1, 

and 6 months) a decrease was shown in seroprotection from 84% among adults 50-64 years to 

75% among adults 65-80 years of age [Unpublished subanalysis by age of unpublished data on 

file; Provided by Merck, Data on File, Protocol 048 Used with Permission]. 

More recent data were presented at IDSA in 2009 pertaining to seroprotection for Merck 

Recombivax HB and a modified process vaccine available only in Europe. Both vaccines were 

administered on a 0, 1, 6 schedule. Again, there was a substantial decrease in seroprotection 

from adults 50-64 years of age to 65-89 years of age [Gilbert et al. IDSA 2009 Abstract # 1171. 

Merck- Unpublished sub-analysis, Protocol – 059; Used with Permission]. Each of these 

studies indicates an effect of age and lower seroprotection. 

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Regarding the effect of diabetes and older age on seroprotection, in an analysis of 

seroprotection among adults with and without diabetes by type of vaccine (Twinrix hepatitis A/B 

vaccine and Engerix-B) simultaneously administered at a separate site with hepatitis A vaccine 

in the 2 groups (at 0, 1, and 6 months), the response among persons without diabetes was 

roughly 85% and among persons with diabetes was about 68%. There were no pooled data 

from each group to provide an overall comparison. The mean age for adults with no diabetes 

was younger than for adults with diabetes, and these data were not adjusted for age. From the 

same unpublished sub-analysis provided by GSK, seroprotection was compared by age 41 to 

60 years and 61 to 80 years among subjects with diabetes. Although the number of subjects 

available for comparison became quite small (on the order of 5 to 10 subjects per group) and 

the confidence intervals became quite wide, there appears to be a sizable reduction in 

seroprotection for adults with diabetes over age 60 [Van der Wielen M et al. Unpublished 

subanalysis provided by GSK, and is the result of a post-hoc, exploratory analysis including 

small numbers of subjects]. 

Additional data are available for adults with diabetes. A study by Douvin et al shows 

seroprotection of 53% after 3 doses of hepatitis B (Engerix-B) given at 0, 1, and 2 months. 

Seroprotection was measured at month 3. The age range was somewhat younger in this study 

[Douvin et al. Diabetes Care 1997]. 

Better seroprotection of 75% was achieved among 32 subjects with diabetes vaccinated at 0, 1, 

and 6 months in a study conducted by Wismans et al. The age range of participants in this 

study was broad, with some subjects as young 22 years of age. Seroprotection among these 

adults with diabetes, albeit relatively higher, was significantly lower than among controls in the 

same study without diabetes, which was 97% [Wismans et al. J Med Virol 1991]. 

The following graph summarizes the results of studies that report separate results for adults with 

diabetes shown in yellow on the background of the studies of adult seroprotection graph shown 

earlier: 

19

Seroprotection Point Estimates After Hepatitis B 

Vaccine, by Age Group, from Multiple Studies – 

Includes Adults with Diabetes (in Yellow) 

0

10

20

30

40

50

60

70

80

90

100

10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90

Percent anti HBs > 10 IU/L

Age (Years)

Again, the points represent the mid-range age among age groups from multiple studies. 

The horizontal bars in yellow show the midpoint and age range of adults with diabetes. 

It can be observed in this graph that for a particular age or age group, seroprotection is 

generally lower among persons with diabetes than among persons without diabetes. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

In summary, published studies and unpublished data demonstrate that approximately 2 of 3 

adults over age 60, and a smaller proportion of persons with diabetes on the order of 55%, will 

achieve seroprotection after a primary series. ACIP currently recommends post-vaccination 

testing for seroprotection after a hepatitis B vaccine series in groups with low seroprotection 

rates (e.g., persons with HIV infection) and / or groups who have increased risk of exposure 

(e.g., healthcare personnel). Additional doses in the primary series may improve seroprotective 

rates. With that in mind, it is important to consider the response to revaccination among nonresponding older adults. Possible revaccination options for hepatitis B vaccine non-responders 

include the following: 

 Revaccinate (1 - 3 doses) with the same vaccine in standard dosage used in the primary 

series 

 Revaccinate (1 - 3 doses) with a higher dosage (e.g., dialysis dose 40μg) versus standard 

dosage used in the primary series 

 Revaccinate with a different vaccine formulation 

Dr. Spradling then shared data pertaining to seroprotection as a result of administering 

additional doses of hepatitis B vaccine to persons with and without diabetes who did not 

responded to the primary series with ≥10 IU/L anti-HBs (termed “non-responders”). He noted 

that non-responders were defined as having an anti-HBs level less than 2 IU/L. This is 

important because this likely includes the few adults who will not respond to vaccine regardless 

of the number of doses—sometimes referred to as “complete non-responders.” 

In terms of the results of studies that assessed the response to one additional dose of hepatitis 

B vaccine strictly among non-responders to the primary series, overall the proportion of nonresponders who achieved seroprotection after a single dose was approximately 55%. However, 

the mean age of participants was low, although the studies included a number of adults over 

age 60. None of these studies included adults with diabetes [Goldwater et al.; Struve et al.; 

Wolters et al]. 

In studies of the response of non-responders to an 2 to 3 additional doses of hepatitis B 

vaccine, the responses ranged from 60% to 100% after three doses. The 5 adult nonresponders with diabetes had an 80% response. Of interest, the overall response was ~88% 

among the 32 adults with diabetes in this study combining primary and revaccination [Bertino et 

al. (Excluded hypo-responders [2-9.9 mIU/ml]); Averhoff et al.; Clemens et al.; and Wismans et 

al). 

In a study of seroprotection after additional doses of hepatitis B vaccine among 

non-responders with diabetes, non-responders at month 3 received a 4th dose at month 4, 

resulting in 88% seroprotection. All subjects received a dose at 12 months, with overall 

seroprotection of 94%. Seroprotection was 77% among adults ages 60-66 years [Douvin et al. 

Diabetes Care 1997]. 

In four studies of seroprotection after high dosage hepatitis B vaccine among non-responders, 

none of which broke out results for subjects with diabetes, the study pertaining to response to a 

single high dose of Engerix (44% response) included only complete non-responders [Goldwater 

et al (only antiHBs negative)]. In the other three studies, 3 doses of high dosage vaccine were 

used. Seroprotection for the 3-dose studies ranged from 55% to 95% [Kim et al; Bertino et al 

(excluded hypo-responders [2-9.9 mIU/ml]); and Cardell et al]. The best results were with high 

dosage vaccine, but overall seroprotection overlapped those in studies of standard dosages. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

In summary, older adults have an increase in seroprotection with each additional revaccination 

dose using a 0, 1, 6, or 0, 2, 4 month schedule. Limited data suggest similar increases in 

seroprotection after revaccination among older adults with and without diabetes. Available data 

do not confirm a clear advantage to higher dosage (40ug) or by type of vaccine. 

In terms of the safety of hepatitis B vaccine in older adults with and without diabetes, although 

multiple studies have examined seroprotection among older adults with and without diabetes, 

few report any adverse events. Product safety information from vaccine manufacturers 

[Package inserts Engerix-B®, Twinrix®, Recombivax HB®] indicate that local adverse events 

including soreness are reported in up to 22%, and swelling or redness at the injection site is 

reported in 1%-10% of doses. Systemic events include fatigue (14% of doses) and fever, 

headache, dizziness, nausea (1% to 10% of doses). During clinical trials and post-licensure 

surveillance, no deaths were attributed to hepatitis B vaccine. Anaphylaxis is rare and occurred 

in only ~ 1 per 1.1 million doses. Although reported clinical and surveillance data are limited in 

studies of older adults, none suggests a difference in overall safety compared with younger 

adults. 

The data for adverse all events reports to VAERS for hepatitis B vaccine among adults with 

diabetes for the age groups 40-59 years and 60 years and older span more than 10 years from 

January 2000 through May 2010. Although this information cannot be put into perspective 

without denominator data, the number of reports over this period was small in both age groups, 

and no deaths were reported. 

Non-fatal serious adverse event reports to VAERS after Hepatitis B vaccine among Adults with 

diabetes, age ≥ 40 Years included the following: 

57 M Pancreatitis 

55 M Respiratory Infection, Injection site reaction, "CHF related to vaccine“ 

69 F Elevated liver function test results 

56 F Right upper extremity swelling, decrease ROM, paresthesia 

48 M 

63 M 

55 M 

70 F 

Chest Pain, Back pain 

Increase in diffuse body pains, septicemia, acute 

Arthralgias, joint stiffness 

GBS-Miller Fisher Variant 

respiratory distress 

51 M 

50 F 

Allergic reaction 

Epistaxis 

Of these reports, 6 of 10 had available medical records for review. From the available records, 

it was not apparent that any of the events was related to hepatitis B vaccine. 

In conclusion, hepatitis B vaccination of older adults with and without diabetes is safe. The 

proportion of adults seroprotected by a primary series of hepatitis B vaccine varies with age and 

co-morbidity. Approximately 90% or more are young adults, about 2/3 (67%) are healthy older 

adults, and about 50% are adults with diabetes. Revaccination of non-responding older adults 

improves seroprotection. Although data are lacking on long-term immunity among persons 

vaccinated at older ages or with diabetes, published data suggest achieving anti-HBs > 10 IU/L 

in healthy adults protects against symptomatic acute hepatitis B and chronic infection for 22 

years or more. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Discussion Points 

Dr. Chilton noted that New Mexico has a “Done by One” campaign. This is an 11-year old 

immunization platform. Perhaps a 61-year old platform is needed as well. He wondered 

whether immunization against hepatitis B would be covered under Medicare Part B or D, which 

plagues practitioners with respect to zoster vaccine. 

Dr. Baker said she did not believe Medicare covered this. 

Ms. Rosenbaum indicated that, unless someone had Medicare because of a disability, Medicare 

would not begin until age 65. Therefore, there are two issues. First, there is the B / D question 

in terms of the limitations on hepatitis vaccine and then age. In the future, some of the age 

issues may begin to fall away. 

Dr. Linda Murphy (CMS) said that she was from Medicaid not Medicare, but suggested emailing 

the question to her so that she could direct it to the right contact person. 

Dr. Schuchat added that Medicare Part B covers influenza, pneumococcal, and hepatitis B 

vaccine for high risk individuals only for anyone who is Medicare Part B-eligible. All other 

vaccines are covered under Medicare Part D, if anywhere. 

Ms. Rosenbaum said this raised the question regarding whether this would be a high risk group. 

Dr. Keitel noted that they seemed to be making a move toward stating that diabetes is a high 

risk group. 

Dr. Judson indicated that he had been working on hepatitis vaccines and epidemiology for most 

of his career. With that in mind, he suggested that the first priority on the list should be to 

ensure that nursing homes and long-term care facilities follow accepted infection control 

procedures. He did not believe they should be discussing vaccine if the lack of such practices 

continued. The first issue to be dealt with is proper use of blood glucose monitoring devices 

and injection materials. Once that is dealt with, the explanation for hepatitis B being more 

common in diabetics than non-diabetics must be broken down epidemiologically into whether 

there are covariates that lead to higher rates of exposure. One of those would certainly be risk. 

Then they must deal with whether, once someone is exposed as a diabetic, they are more likely 

to become infected and if infected they are more likely to become chronically infected. There is 

some evidence that individuals with obesity and metabolic syndrome are less likely to clear and 

handle a number of infections. The rate of seroconversion in diabetics can also be a function of 

the length of the needle used in diabetics, given that most of them are obese. All of this must 

be sorted out. 

Dr. Baker noted that Dr. Middleman had conducted a needle length study in adolescents. She 

wondered whether there were studies about needle length in Type 2 diabetic adults. 

Dr. Spradling responded that he was not aware of any. 

Dr. Neuzil pointed out that since there were a number of adjuvanted hepatitis B vaccines in 

various stages of development, it would be beneficial to hear a review of those and know 

whether any were close to licensure. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Ms. Rosenbaum inquired as to whether there was any information about those under age 65 

regarding the heightened risk by income. One of the major issues that will remain even after 

health reform is the state of immunization policy coverage under Medicaid for the poorest 

adults. 

Dr. Hu replied that with the NHANES data, subgroup analysis is very difficult. People often think 

of NHANES as very large, but when broken down into smaller groups, subgroup analyses are 

generally not recommended for cells of less than 30. Especially when assessing persons with 

diabetes, that small group becomes even smaller. Regarding a comment made earlier, it is true 

that a number of population groups who are at risk for diabetes are also at risk for hepatitis B 

infection (e.g., American Indians, Asians, Hispanics). Thus, a lot of this is difficult to tease out. 

Dr. Stephen Foster (APhA) agreed with Dr. Judson. The Needlestick Safety and Prevention Act 

stated that multiple use lancets could not be used in nursing home settings. Thus, multiple use 

of a single use devise is breaking the law. This must be resolved, especially since this pertains 

to about 150 versus 18 million people for whom a recommendation is being made for vaccines. 

One of the conclusions that states that “compared to the historical prevalence of hepatitis B 

among certain groups of healthcare personnel” the term “certain groups” is confusing. 

According to CDC statistics in 2001, fewer than 400 healthcare workers actually acquired 

hepatitis and it was not specified whether this was due to needle sticks. He agreed that before 

ACIP made a recommendation for expenditures for 18 million people, they should find out what 

other potential high risk behaviors may be. 

Dr. Temte wondered what specifically the risk factor was and whether there was any estimate of 

incidence for diabetics in long-term care versus diabetics alone. It seemed to him that at least 

the entry was all in terms of long-term care facilities. There is a major and growing population 

moving into assisted living. What is not clear whether a diabetic living in the community on their 

own with their own supplies is a risk factor, or the risk arises when entering a long-term care 

facility. 

Dr. Hu responded that despite a number of recommendations that have been in place for close 

to 20 years, there continue to be breeches of infection control. ACIP’s argument could go both 

ways. They could argue that before vaccination is recommended, the problem of breeches 

should be solved. They could also argue the importance of vaccination due to the very fact that 

these breeches continue to occur. CDC has had a number of consultations with several other 

federal agencies to assess how to approach the problem of healthcare transmission in three 

ways. The first is to strengthen existing recommendations and improve oversight. The second 

would be to improve technology and labeling of devices (e.g., glucose meters, medication vials, 

et cetera) to stress that these are for single use only. The third would be the use of hepatitis B 

vaccine. Regarding how to determine the risk for diabetes within various age groups, just as for 

the general population, this list can come from a variety of risks (e.g., MSM, IDU, et cetera). It is 

very difficult to determine whether high risk is due to the increased blood exposure that 

diabetics encounter. Unfortunately, so far there are no data on the incidence in long-term care 

facilities. However, from very small studies (some from outbreak studies and some from 

general long-term care studies) the prevalence of HBV appears to be much more elevated than 

the general prevalence. This suggests that there may be a much higher incidence in these 

facilities. Regarding healthcare workers, there were a variety of healthcare settings. He 

assessed vaccination data. There was a very nice set of studies, one of which was conducted 

by CDC’s former director, Dr. Julie Gerberding. A survey was conducted of different classes of 

healthcare workers in the UCSF system, and enrolled healthcare workers who were 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

seronegative for HBV and followed them over time. By doing so, they were able to measure the 

incidence. The success of not only hepatitis B vaccine, but also universal precautions in 

improving infection control, have dramatically reduces the incidence and prevalence of HBV 

among healthcare workers. 

To illustrate the discussion around improving infection control, Dr. Sawyer pointed out that 

everyone must keep in mind that the level of training of people working in these facilities, 

particularly assisted living facilities, is much lower than in a typical healthcare setting in which 

they are used to trying to improve infection control. There is also a great deal of turnover of 

those staff, so this requires continuous retraining. Thus, he thought they needed to be careful in 

assuming that they could achieve the same level of success in implementing infection control 

policies in long-term and assisted living settings that they do in more organized healthcare 

settings. 

Dr. Baker added that skilled nursing facilities all have rules, laws, inspections, et cetera. They 

may lose their certification. Assisted living is increasingly becoming populated by people who 

need skilled nursing who are at greater risk, yet there is no regulation at most of these facilities. 

Robert Malone (Independent consultant for a variety of vaccine developers and supporting 

companies) said he was struck by the analogy in transition in the understanding of influenza 

vaccine effectiveness in the elderly. Reasoning by analogy suggests that one co-morbidity on 

which they may wish to have data would be the incidence of chronic cytomegalovirus infection 

in these populations because of the hypotheses for why a decreased effectiveness of influenza 

vaccines is observed in elderly populations. 

Focusing on her experience in a State of Maine public health agency, Kathleen Gensheimer 

(Sanofi Pasteur) said she was clearly delighted to see the emphasis placed on enhanced 

patient safety. Regarding the residential care population over the age of 50, she followed a 

cluster of men over the age of 50 for a few years many of whom were obese, had diabetes, and 

were at home doing their own glucose monitoring. After a lot of careful questioning, it turned out 

that they were closeted MSMs who were going to a truck stop in central Maine. She wondered 

whether they were missing what could still be an unrecognized factor for transmission of 

hepatitis B, whether healthcare providers were still thinking about targeting that cohort that 

really needs vaccine, and whether there was any information on men over the age of 50 with 

other potential risk factors on a national level. 

Dr. Hu said he thought one piece of data that supported that there may be under-recognized 

MSM. If the reporting of hepatitis B cases by age group are divided by sex, the rates for men, 

even in the older age groups, are higher. 

Regarding Dr. Neuzil’s earlier question, Dr. Plotkin reported that there was an adjuvanted 

hepatitis B vaccine currently in Phase 3. The defect may be exacerbated in diabetes, but as Dr. 

Spradling emphasized, this is a defect that is inherent to immunosenescence and involves at 

least antigen processing and lack of naïve lymphocytes. Thus, it has to be remedied. Repeat 

dosing is not really a practical answer. If a recommendation is made, he would wager than 

more than one company would manufacture adjuvanted hepatitis B vaccines not only for 

diabetes, but also for hemodialysis patients, others who do not respond as well, and all people 

over a certain age. 

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Georges Peter (Warren Alpert Medical School, Brown University) agreed with Dr. Judson’s very 

important comment about obesity. Obesity is a risk factor for diabetes and there is an epidemic 

of obesity. He wondered to what extent body mass had been taken into account in the studies 

of adults over the age of 40 in terms of seroresponse to vaccination. 

Dr. Spradling responded that ironically, the data from the GSK sub-analysis of the 41 to 81 age 

groups, which broke the data down even further into diabetes and no diabetes, suggested that 

patients with lower body mass had a poorer seroprotective response to vaccine than those with 

a higher body mass. However, there is plenty of evidence to suggest the contrary. In terms of 

the analyses CDC / NCHSTP dealt with, they focused purely on diabetes and tried to stay away 

from additional factors such as body mass. Assuming that these populations who have Type 2 

diabetes are an older age group, a certain proportion of them by nature are going have high 

body masses. 

Dr. Deborah Wexler (Immunization Action Coalition) resonated with Dr. Hu’s comment about the 

“tip of the iceberg” in that these cases are being identified because diabetics get so many finger 

sticks. However, every day in every medical practice in the country, glucose meters are being 

used. They are being used on pregnant women in their one-hour glucose challenge test in 

every pregnancy. She wondered whether any cases had been seen in practice setting, 

because she thought that the same problems being observed in assisted living settings were 

also occurring in primary care settings. 

Dr. Hu replied that this pointed out that even though the focus is on persons with diabetes, once 

someone becomes infected, they can transmit as a source patient to other susceptible people. 

There is frequent glucose meter use in hospitals. In speaking with nurses and doctors, he often 

inquires as to why they use a glucose meter to determine blood glucose if they are obtaining 

daily blood chemistries. One response he has heard is that nurses like to use glucose meters 

because they are able to get blood data right away instead of going to a lab or accessing it from 

a computer. 

Dr. Catherine Counard (Public Health Physician from Northern Illinois and the NACCHO liaison 

to the ACIP Hepatitis Vaccine Work Group) thanked ACIP for taking on this very concerning 

issue. She investigated two of the hepatitis B outbreaks in assisted living facilities that were 

presented, both of which were caused by nurses transmitting infection from resident to resident 

as they performed finger stick blood glucose monitoring. The published retrospective cohort 

study revealed a relative risk of 28.5 associated with finger stick blood glucose testing. Nursing 

staff at both of these facilities were not aware, despite multiple trainings, that they could transmit 

infection from person to person. From being in the halls during an outbreak, she could attest to 

the fact that the toll at the two facilities of infected individuals was substantial. There were 14 ill, 

6 who required hospitalization, and at least 3 have not cleared their infection and have chronic 

disease as a result. Additionally, the outbreaks required significant resources from the health 

department and the medical community to determine the scope and cause of the outbreaks. 

She drew blood on 109 residents at this facility because they were unsure of the cause of the 

outbreak initially. She was there at 6 am, she processed the specimens, and she drove them to 

the state laboratory so they could be sent to CDC for further analysis. Although it is known that 

the outbreaks could have been prevented by adhering to standard infection prevention 

measures, the lack of appropriate training and oversight for personnel and rapid turnover of staff 

in these facilities provide formidable barriers. In response to the first case at one of the facilities 

investigated, an on-site investigation was done, all of the staff was interviewed, and training and 

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guidance were provided for nursing staff. When the second case surfaced 15 months later, they 

revisited this site and were amazed to find out that every nurse had turned over, including the 

director of nursing. There was no institutional memory that there had been a case at this facility, 

nor did anyone remember any of the training that was delivered previously. Thus, she regretted 

to report that hepatitis B transmission continued to occur in this facility. When they returned for 

the second case, they found 7 other cases. Unfortunately, she did not believe this was unusual. 

She has visited many of these sorts of institutions for various outbreaks. These are not rogue 

facilities. On the surface, they look like a nice place for someone to be. With all of this in mind, 

she encouraged ACIP to give serious consideration to broadening vaccination to protecting 

diabetics. She also extended her gratitude to CDC staff who have been very supportive of her 

in these outbreak situations. 

Dr. Leonard Friedland (GSK) indicated that in the subanalysis of the data Dr. Spradling 

presented, indeed, individuals with large body mass did not have a decline in response. It is 

important to note that these were very small numbers of subjects, and the majority of the 

subjects in the trials were obese. Regarding adjuvanted vaccines, GSK has a licensed 

adjuvanted vaccine licensed in the European Union for people above the age of 15 that is 

indicated for renal insufficiency. 

Policy Considerations: Hepatitis B Vaccination for Adults with Diabetes 

Dr. Trudy Murphy 

CDC / NCHHSTP 

Dr. Murphy reviewed the policy options considered by the Hepatitis Work Group for hepatitis B 

vaccination of adults with diabetes. Some of the options included vaccinating all previously 

unvaccinated adults with diabetes, or vaccinating a subgroup of adults with diabetes, for 

example only residents of long-term care with diabetes, or only adults with diabetes who monitor 

blood glucose, or only adults with a new diagnosis of diabetes. The work group considered 

hepatitis B vaccine-induced seroprotection by age, type of vaccine, and dosage. They 

considered pre-vaccination screening for susceptibility and issues related to revaccination such 

as post-vaccination testing, and they considered whether to give a booster dose to previously 

vaccinated adults with diabetes. The work group also considered hepatitis B vaccination for a 

variety of contacts of adults with diabetes in long-term care facilities (e.g., roommates, family 

contacts, and even vaccinating all residents in these facilities). 

The guiding principle in these discussions was that any proposal should be consistent with 

current recommendations for hepatitis B vaccination. The priority was to maximize 

seroprotection in all age groups by vaccinating adults with diabetes as soon as feasible after 

diagnosis and by post-vaccination testing and revaccination, if necessary, for older adults with 

diabetes who are most likely to be non-responders to the primary series. The work group did 

not favor booster dosing for previously vaccinated adults with diabetes, consistent with current 

recommendations, and did not feel that vaccinating contacts of adults with diabetes in long-term 

care facilities was practical, unless the contact met criteria for vaccination already specified by 

ACIP (for example, the sexual partner of an adult with diabetes known to have chronic hepatitis 

B infection). The wording proposed by the work group was as follows: 

 Hepatitis B vaccination is recommended for (all) unvaccinated adults with diabetes. The 

vaccination series should be completed as soon as feasible after diagnosis. 

 Available data do not confirm an advantage to any specific hepatitis B vaccine or dosage 

for adults with diabetes. 

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 For adults with diabetes ≥ 60 years, post-vaccination serology for antibody to hepatitis B 

surface antigen (anti-HBs) is recommended 1–2 months after completion of the hepatitis 

B vaccination series. 

 Adults with diabetes who do not achieve a seroprotective level of ≥10 mIU/mL anti-HBs 

should be revaccinated with 3 additional doses of hepatitis B vaccine and postvaccination serology should be repeated. 

 Additional guidance on revaccination can be found in Appendix A of the 

recommendations (MMWR 2006;55 [RR-16]). 

 No additional hepatitis B vaccination is recommended for adults with diabetes who 

received a complete series of hepatitis B vaccine at any time in the past. 

The Working Group proposed repeating the wording in current recommendations as a reminder 

for hepatitis B vaccination of employees in long-term care facilities: 

Reminder for Healthcare Workers 

 Hepatitis B vaccination is recommended for healthcare workers with reasonably 

anticipated risk for exposure to blood or blood-contaminated body fluids. (MMWR 2006; 

55 [RR-16]) 

 Facilities should provide a full hepatitis B vaccination series to all previously 

unvaccinated staff members with exposure to blood or body fluids. (MMWR 2005; 

54:220-223) 

Reminder for Medical Management, Training, and Oversight 

 Guidelines for preventing patient-to-patient transmission of hepatitis viruses from 

diabetes-care procedures in long-term care settings are available (MMWR 2005; 54:220­

223) 

Discussion Points 

Dr. Pickering noted that several of the slides Dr. Murphy shared showed an improved 

seroresponse utilizing the combined hepatitis A / B vaccine. As a follow-up to what Dr. Neuzil 

alluded to, he wondered whether it was potentially an option to utilize the combined vaccine 

rather than single antigen, knowing that even though diabetes is not on the high risk group for 

hepatitis A, people with chronic liver disease are. Perhaps a more thorough review could be 

presented during the October 2010 ACIP meeting of the responses of people with the combined 

A / B vaccine. 

Dr. Murphy said this could be provided and she could offer a preview as they had tried to do this 

to some extent. In younger age groups, there does appear to be a slight increase in 

seroprotection with the combined vaccine (ages 50 to 60 years and younger). It is a marginal 

difference. In the older age groups, the data that are available are limited and there does not 

appear to be any advantage. 

Regarding the infection control issues, Dr. Elward (HICPAC) reported that historically they had 

had a lot of success with infection prevention when addressed at multiple levels (e.g., regulatory 

oversight, reimbursement, educating the public, industry / technology, et cetera). CDC has 

done an excellent job of bringing this problem to light, measuring the problem, and beginning 

the process of communicating this information with CSTE, HICPAC, industry partners, 

stakeholders, et cetera and publishing information quickly (including in the popular press). 

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Thus, there is a lot of good foundation for a lot of these deeper, more complex fixes to be 

implemented. Vaccination could certainly be done with relatively ease and more quickly than 

some of the big infrastructure fixes that are starting to be addressed. 

Dr. Gall (ACOG) pointed out that with the addition of diabetes as a risk group who would bring 

the number of risk groups for hepatitis B to 27. One of the risk groups to be included is if a 

patient is screened for a sexually transmitted disease (STD). For obstetricians, every patient is 

screened for 5 STDs and for gynecologists, 1 to 3 STDs are screened at every visit. The 

recommendation is universal to age 19, and now there are 27 risk groups. He wondered what 

percent of the general population is covered to universal to 19 and 27 risk groups, and whether 

it was time to say that this vaccine should be universal. Or were they going to do the same 

thing that was done with influenza and chisel at it before eventually reaching the universal 

stage? 

Dr. Judson agreed. He also thought that with hepatitis being universal with youth through high 

school they would get to a universal recommendation before too long anyway. He also pointed 

out that it had not been conclusively shown that diabetics, because they are diabetics, are at 

greater risk of being exposed to and infected with hepatitis B. As everyone knows who works in 

that area, there are many potential methodological problems. Their higher risk is probably due 

to something other than the diabetes. One issue could be the misidentification of acute infection 

and other problems (e.g., obesity, metabolic syndrome, steatohepatitis, elevated enzymes). 

In the interest of transparency, Dr. Schaffner (NFID) disclosed that he was much more 

interested in promoting more widespread use of hepatitis B vaccine in adult populations. If they 

were not ready for a universal recommendation, he would take any additional “bit of the apple” 

he could. He encouraged ACIP to recommend immunization of all diabetics. However, he 

stressed that recommendations do not implement themselves. On the basis of local experience 

with the diabetic community and influenza and pneumococcal vaccine, long recommended for 

that community, neither of those vaccines have been on the quality assurance list for 

appropriate diabetes care for such patients. Therefore, if a recommendation is made, he 

expressed hope that the hepatitis folks would reach out to the diabetes community to get these 

vaccines introduced into the quality assurance activities. He also emphasized that 

recommendations are cheap, but the implementation comes with a cost. When last this 

committee considered hepatitis B vaccine in adults, they chose to stick with high risk groups. 

However, they were told then that efforts were made and resources would be found to be 

directed toward enhanced immunization of at least some people in some high risk groups (e.g., 

those being evaluated for STDs, prisoners, MSM); however, he did not believe ACIP had ever 

been given a report about whether this occurred. If they were going to recommend that adults 

in the US with diabetes be immunized, he expressed his hope that this came with good will and 

determination and resources to effect that good result. 

Dr. Baker emphasized that ACIP’s job as a committee is recommendations. While they should 

be aware of implementation issues as they make recommendations, there is a next step of 

action beyond ACIP. 

Dr. Schuchat reported that over the last several years, substantial resources from the Section 

317 vaccine purchase funds have been directed to hepatitis B vaccine for adults. The state 

health departments have been able to work in collaboration with STD, correctional facility, and 

HIV programs to try to promote greater uptake. Evaluation of this is in the early stages, and a 

recent MMWR summarized some of this work. 

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Discussion

Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Dr. Judson requested a report on the cost-effectiveness data in view of the declining trend of 

hepatitis B, with incidence down 85% to 90% and still dropping. Cost-effectiveness must look 

forward, and with those trends, the estimates will become increasingly less favorable. 

Dr. Baker agreed that ACIP needed to hear cost-effectiveness data in light of current 

epidemiology. 

Dr. Plotkin thought that the recommendation that people who have been previously vaccinated 

do not need to be revaccinated was reasonable at present, but there are some data suggesting 

that the anamnestic response to vaccines does not last forever. It begins to diminish. He 

thought this recommendation should be revisited after more data have accumulated showing 

that adults who were vaccinated when they were younger actually still have immune memory. 

Dr. Murphy responded that this is the next term of reference for the Hepatitis Vaccine Work 

Group. 

Dr. Whitley-Williams (NMA) proposed that there be improved surveillance for hepatitis B. This 

certainly is under-reported and, in fact, cases do not come to light until they become 

symptomatic. There are segments of the population, particularly Asian Pacific Islanders, who 

come to the US as adults and either know they have hepatitis and do not seek care until they 

are symptomatic, or do not even realize that they are infected having grown up in an HBVendemic country. She also echoed support for universal immunization, given that there are 

many risk factors. Surveillance does not always capture ethnicity, country of origin, how long 

someone has been in the US, et cetera. Regarding Dr. Plotkin’s suggestion, the DoD has a 

wonderful database that would permit assessment of youth who have been immunized to 

examine their duration of immunogenicity. 

Pertussis 

Introduction 

Mark Sawyer, MD 

University of California – San Diego 

Chair, ACIP, Pertussis Vaccines Working Group 

Dr. Sawyer indicated that the terms of reference for the Pertussis Working Group, and its 

primary charge, was to review existing statements on infants and young children (1997), 

adolescence (2006), adults (2006), and pregnant and postpartum women and their infants 

(2008) and consolidate those into a single statement. In the process of doing so, the group 

plans to review new data that may speak to the effectiveness of the current Tdap (Tetanus, 

Diphtheria, Pertussis) program including uptake of current recommendations and barriers to 

uptake; the interval between Td booster and Tdap with respect to safety and reactogenicity; use 

of Tdap in those ≥65 years of age and pregnant and breastfeeding women, use of Tdap; 

cocooning strategies, Tdap in healthcare workers and the need for post-exposure prophylaxis. 

The updated epidemiology of tetanus and diphtheria are also being reviewed. 

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To date, the activities of the Pertussis Working Group have included the following: 

 April 2009 

Æ Introduction and overview of pertussis epidemiology in the United States 

Æ Explored the potential early impact of Tdap vaccination 

 May 2009 

Æ Review current ACIP Tdap recommendations 

 June 2009 

Æ Safety and reactogenicity of Tdap 

Æ Interval between Td and Tdap 

Æ Pertussis diagnostics 

 July 2009 

Æ Impact of pertussis vaccination of health-care personnel on post-exposure 

prophylaxis 

 August 2009-February 2010 (hiatus) 

 March 2010 (reconvene) 

Æ Review/update Terms of Reference 

Æ Reassess where WG is regarding topics and data 

 April 2010 

Æ Use of Tdap in persons >65 years of age 

 May 2010 

Æ Epidemiology of diphtheria and tetanus 

 June 2010 

Æ Improving Tdap coverage 

The work group has carefully examined available data pertaining to the interval between Td and 

Tdap, and is anxiously awaiting data from on-going studies regarding the use of Tdap during 

pregnancy. As soon as that information is available and the working group has an opportunity 

to complete its review, an update will be presented to the full ACIP. 

The presentations during this session focused on an overview of pertussis epidemiology in the 

US, an evaluation of the current pertussis vaccine program, and a review of the current ACIP 

recommendations for use of DTaP and Tdap in the US. Those recommendations, at least with 

regard to adolescents, still have not been fully implemented. Recent coverage rates estimate 

Tdapuptake of approximately 40% in adolescents. Middle school entry requirements have been 

implemented for Tdap booster administration, which are hoped to increase coverage rates. The 

following map reflects the states for which mandatory booster requirements are in place: 

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Courtesy of the California Department of Public Heath 

Design by Justin McNiff and Natalie Nakahara

Dr. Sawyer requested that everyone consider the following questions as they listened to the 

presentation: 

 Are we using our vaccines as well as possible? 

Æ Coverage 

 Are there barriers to vaccination that can be removed? 

 What else can we do to optimize each of these components of the program? 

Æ Infant/Children 

Æ Adolescent 

Æ Adult 

Program Update on Pertussis Vaccine 

Jennifer L. Liang 

Meningitis and Vaccine Preventable Diseases Branch 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention (CDC) 

Dr. Liang presented a program update on pertussis-containing vaccines since the 2005 

recommendations. She explained that pertussis (e.g., whooping cough) is a highly contagious 

respiratory disease caused by the gram negative bacillus, Bordetella pertussis. Clinically 

recognized to cause severe debilitating cough illness, the highest morbidity and mortality occurs 

among infants. Pertussis is the most poorly controlled bacterial disease despite high childhood 

vaccine coverage. The first US pertussis vaccine for adolescents and adults, Tdap, was 

licensed in 2005. Among the other reportable vaccine preventable diseases, pertussis is still 

the least well-controlled. 

Regarding the impact of pertussis from 1922 through 2009, during the pre-vaccine era, the 

number of pertussis cases culminated to about 270,000 in the mid 1930s, with more than 

10,000 deaths. Since the introduction of whole cell vaccine, DTP, in the late 1940s, the number 

of reported pertussis cases has fallen dramatically. Despite this decrease, pertussis continues 

to be endemic. Since 1980, there has been an increase in the number of reported cases from 

approximately 2,000 cases per year to over 10,000 cases per year. Between 1990 and 2009, 

more than 190,000 pertussis cases were reported to CDC. Over time, cases less than 1 year of 

age and cases 1 through 6 years of age contributed less to the overall burden of disease, while 

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-

 l

i t l. t I f . 

ti l tifi i t , 

l i

Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

cases in adolescents and adults contributed to an increasing proportion of cases. Around 2007, 

there appears to have been a shift in the distribution, with an increasing contribution from 7 to 

10 year olds. By 2009, this age group accounted over 23% of cases [2009 Data are provisional 

Source: CDC, National Notifiable Diseases Surveillance System and Supplemental Pertussis 

Surveillance System and 1922-1949, passive reports to the Public Health Service]. 

In terms of the reported pertussis incidence by age group from 1990 to 2009, infants have 

substantially higher rates of disease compared to other age groups. The use of polymerase 

chain reaction (PCR) has become more common since PCR was approved in 1997 by the 

Council of State and Territorial Epidemiologists (CSTE) for use in confirming pertussis cases. 

Laboratories have increasingly used PCR instead of culture and there are fewer cultureconfirmed cases. Changes in laboratory diagnostics remain a concern and do impact 

interpretation of surveillance data. In general, it is believed that culture, PCR, and serology 

should be used in a complementary way to diagnose pertussis. CDC and its partners have 

multiple activities aimed at optimizing use of these tests [2009 data are provisional; source: 

CDC, National Notifiable Diseases Surveillance System and Supplemental Pertussis 

Surveillance System; data collection for PCR and epi-link began in 1995]. 

During this presentation, ACIP members were asked to reflect on vaccine coverage among 

infants, children, adolescents and adults; Tdap vaccine effectiveness and duration of protection; 

and the feasibility and effectiveness of cocooning. 

Young infants have the highest rates of disease and pertussis-related complications. From 

2000 to 2009, among infants aged less than 1 year (n=25,179), reported complications included 

apnea (n=10127; 58.0%), pneumonia (n=1875; 19.2%), seizures (n=202; 1.2%), and death 

(n=182; 1.1%). More than half (n=11571; 66.3%) of these reported cases required 

hospitalization [Source: CDC, National Notifiable Diseases Surveillance System and 

Supplemental Pertussis; Surveillance System, 2000-2009; 2009 data are provisional; 

percentages are based on total number with information; for 19% of infant cases, no information 

was available on hospitalization or apnea; for 21% no information was available on seizure; and 

for 34%, no information was available on pneumonia; pneumonia was radiographically 

confirmed]. 

The following table shows a breakdown in age groups of reported pertussis-related deaths over 

the past 30 years. The majority of deaths occurred in infants 0 to 1 month of age, before they 

were eligible to receive the first dose of DTaP: 

Reported pertussis-related deaths 

by age-groups, U.S., 1980-2009* 

Age-Group 1980 19891 1990-19991 2000-20092 

0-1 month 38 68 119 

2-3 month 11 16 56 

4-5 month 5 5 6 

6-11 month 7 4 1 

1-4 years 13 2 2 

5-10 years 1 6 2 

11-18 years 0 0 2 

>18 years 1 2 6 

Total 77† 103 195* 

*2009 Data are provisiona 

1 V tek CR e a Pedia r n ect Dis J 2003; 22(7):628-34 

2 Na ona No able D seases Surveillance Sys em CDC, 2009* † Inc udes one case w th unknown age 13 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Infant vaccine coverage for DTaP remains high. Current coverage for children 19 to 35 months 

of age who have received 4 or more doses of DTaP/DTP/DT is 85% [CDC. National 

Immunization Survey. Q3/2008-Q2/2009]. Among children entering kindergarten for the 2008­

2009 school year, DTaP coverage was 93% [CDC. National Immunization Program. School and 

Childcare Vaccination Surveys & Reports]. Estimates of DTaP efficacy vary by study, but based 

on vaccine trial studies, efficacy ranges from 85.2% to 88.7% [* Gustafsson LH et al. A 

controlled trial of a two-component acellular, a five component acellular and a whole-cell 

pertussis vaccine. NEJM 1996;334:349-355; and Schmitt HJ et al. Efficacy of acellular pertussis 

vaccine in early childhood after household exposure JAMA 1996;275:37-41, respectively]. 

For adolescents and adults with pertussis, there is a wide spectrum of clinical presentation 

which can range from being quite severe with classic presentation of pertussis to being 

asymptomatic. However, disease is often milder in adolescents and adults. Pertussis is 

clinically difficult to distinguish from other causes of cough illness, and persons with mild 

disease can transmit infection. Several studies have provided evidence that household 

members were primarily responsible for transmission of pertussis to infants (75%–83%). More 

specifically, parents and siblings were the most commonly identified source of pertussis: 

parents (55%), siblings (16%-20%), aunts / uncles (10%), friends / cousins / others (10%-24%), 

grandparents (6%), and caretakers (2%) [Wendelboe AM., et al. Transmission of Bordetella 

pertussis to Young Infants. Pediatr Infect Dis J 2007;26: 293–299; and Bisgard KM, Pascual FB, 

Ehresmann KR, Miller CA, Cianfrini C, Jennings CE et al. Infant pertussis: who was the source? 

Pediatr Infect Dis J 2004; 23(11):985-989]. 

Coverage for Tdap among adolescents aged 13-17 years was 10.8% in 2006, 20.4% in 2007, 

and over 40% in 2008. Obtaining 40% coverage 5 years after a new program might be judged 

as a success, but it falls short of the goals. Compared to adolescents, coverage of Tdap among 

adults was reported to be less than 6% in 2008 [CDC. National, State, and Local Area 

Vaccination Coverage Among Adolescents Aged 33-17 Years, United States, 2008. MMWR 

2008;58(36);997-1001. CDC. Vaccination Coverage Among Adolescents Aged 13-17 Years – 

United States, 2007. MMWR 2008;57(40)1100-1103; CDC. Vaccination Coverage Among 

Adolescents Aged 13-17 Years– United States, 2006. MMWR 2007;56(34) 885-888]. 

Although adolescents should be receiving Tdap not Td, in 2008 10% of adolescents who were 

vaccinated received Td [Vaccine type by year of first tetanus booster among vaccinated 

adolescents aged 13-17 years*, NIS-Teen 2008; slide courtesy of Shannon Stokley, CDC]. 

At the time of licensure, 85% to 89% of Tdap efficacy was based on bridging studies from infant 

vaccine efficacy studies (ADACEL and BOOSTRIX)1

; APERT study2 (1997) VE = 92% (95%CI: 

32.0-92.0); Australia3

 (2005) VE = 78.0% (95%CI: 60.7-87.6); and St. Croix outbreak4 (2007) 

VE = 65.6% (95%CI: -

35.8-91.3). Immune response to Tdap was non-inferior to the immune 

response of infants receiving DTaP. From the adult pertussis trial, overall vaccine efficacy of an 

acellular pertussis vaccine was 92%. Recent post-licensure studies of Tdap show vaccine 

effectiveness at 78% and 66%. Although not statistically significant due to limited sample size, 

the effectiveness from the St. Croix outbreak is comparable to the Australian study [[1 Schmitt 

HJ et al. JAMA 1996;275:37-41; Gustafsson LH et al. NEJM 1996;334:349-355; 2 Ward JI et al. 

Efficacy of an acellular pertussis vaccine among adolescents and adults. N Engl J Med. 2005 

Oct 13;353(15):1555-63; 3

 Rank C, et al. Pertussis vaccine effectiveness after mass 

immunization of high school students in Australia. Pediatr Infect Dis J. 2009 Feb;28(2):152-3; 4 

Wei SC, et al. Effectiveness of adolescent and adult tetanus, reduced diphtheria, and acellular 

pertussis vaccine (Tdap) against pertussis. Manuscript accepted to Clin Infect Dis]. 

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Before reporting on the potential impact of Tdap, Dr. Liang reminded everyone that the rates of 

pertussis increased gradually in the US between 1990 and 2003, before reaching a peak of 8.8 

cases per 100,000 population in 2004. The introduction of Tdap in 2005 occurred at the height 

of this peak when rates of disease in the US were significantly elevated. Since 2005, there has 

been almost a 50% decline in incidence. By 2008, rates of disease were 4.3 per 100,000. 

To determine the impact of Tdap in adolescents, the rate ratios were calculated by dividing the 

incidence of pertussis among adolescents, by the incidence of disease in all other age groups 

combined. The rate ratios were used because this allowed evaluation of how trends changed in 

one age group (adolescents) relative to all other ages. A significant, steady increase was 

observed in rate ratios prior to Tdap, followed by a reversal in the direction of the slope to a 

significant decrease post-Tdap. This suggests that the rate of disease among 11-18 year olds 

in the pre-Tdap period was increasing at a faster rate than disease in all other ages combined. 

In the post-Tdap period, rates of disease among adolescents declined at a faster rate than other 

age groups. It is believed that this reversal in the direction of the slope is being driven, at least 

in part, by the introduction of Tdap. 

Another program component is the cocoon strategy. The concept of vaccinating close contacts 

of newborns to interrupt transmission of disease to the infant has been termed “cocooning.” 

New mothers who have not previously received Tdap should receive a dose during the 

immediate postpartum period. New fathers and other close contacts should ideally receive 

Tdap at least 2 weeks before close contact with the infant. There are known to be a number of 

uptake challenges to implementation of postpartum immunization. Cocooning is a new 

immunization platform with little infrastructure to ensure effective implementation, pertussis 

awareness varies, two populations require vaccination (postpartum women and their families), 

vaccine history is difficult to determine (date of last Td booster), new immunization providers 

(postpartum vaccine is not typically administered in these settings), and reimbursement issues 

[Healy CM, Rench MA, Castagnini LA, Baker CJ. Pertussis immunization in a high-risk 

postpartum population. Vaccine. 2009 Sep 18;27(41):5599-602]. 

Several small demonstration projects designed to overcome barriers have been successful in 

vaccinating mothers, but no other family members received Tdap. However, these have not 

gone beyond small projects or demonstrated sustainability. In addition, the impact of this 

strategy is not well-assessed. There are on-going efforts to measure the effectiveness of the 

cocoon strategy. There are no studies of impact on infant disease. 

Many of the challenges regarding control and prevention of pertussis are highlighted in an ongoing outbreak in California. From January 1, 2010 to June 15, 2010, California has observed a 

4-fold increase in pertussis cases compared to the same period in 2009 (219 cases in 2009 and 

910 cases in 2010). Five deaths, all in infants less than 3 months of age, have been reported. 

From January to May 2010, two counties in California (Fresno and Madera) reported 99 

pertussis case patients. The highest number of cases was in 11 to 17 year olds, all of whom 

received the full primary series. However, only 25% of these received a booster vaccine. There 

has also been a troubling increase among 7 to 10 year olds who are too young to receive Tdap 

based upon the current recommendations. There were 12 cases in infants less than 2 months 

of age whose only protection is from cocooning [courtesy of Michael L. Jackson, CDC]. 

ACIP Pertussis Working Group aligns with WHO / SAGE Pertussis Working Group efforts to 

update their global pertussis vaccine recommendations. The WHO / SAGE Pertussis Working 

Group’s terms of reference are to review the impact of current pertussis vaccination strategy 

and surveillance efforts in support of current control efforts; propose necessary adjustments of 

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current control goals and surveillance strategies and efforts; and provide updated 

recommendations on vaccine use with a view to update the 2005 vaccine position paper on 

pertussis and identify important information gaps [courtesy of Stacey Martin, CDC]. 

Based on discussions with the ACIP Pertussis Working Group, the draft pertussis vaccine 

program evaluation of the overall US pertussis vaccination program suggests that vaccine 

coverage for infants and children is good, adolescent vaccine coverage is on track and is 

improving, and coverage for adults is suboptimal. Short-term vaccine effectiveness for Tdap is 

okay, but the duration of protection is not yet known. The feasibility of cocooning has been 

shown to be challenging, and the impact and effectiveness of this strategy needs evaluation. 

In closing, Dr. Liang reminded everyone of the questions that needed to be considered: Are we 

using our vaccines as well as possible? Are there barriers to vaccination that can be removed? 

What else can we do to optimize each of these components of the program? 

Discussion Points 

Dr. Keitel inquired as to whether Dr. Liang could give them any indication of the ethnicity / race 

distribution of cases in the California outbreak, and whether she could elaborate on what was 

known about adult coverage. 

Dr. Liang responded that she thought the majority of reported cases in the California outbreak 

were in Hispanics. Based on several NIS surveys, adult coverage is thought to be less than 

6%. 

Dr. Neuzil stressed that pregnant women are among those who should be considered as the 

group contemplates optimizing coverage and reconsidering the recommendation. Persons 65 

years of age and older were also absent from the previous recommendations, and should be 

considered as well. 

Ms. Rosenbaum pointed out that coverage for adult vaccines should be addressed. In terms of 

vaccines for children, an on-going issue is and will continue to be the lag time in the addition of 

coverage recommendations. For example, insurers desire to have sufficient notice that a 

recommendation is going to change because it affects their contracts and coverage terms. 

There is already a precedent for immunizations as part of a maternity package, so perhaps this 

can be leveraged to help speed changes in coverage. 

Dr. Baker noted that post-partum immunization is the recommended strategy for pregnant 

women. This is not part of the maternity package, which is one of the major barriers to 

implementation. 

Dr. Lett reported that a nurse in her program recently examined post-partum vaccination as part 

of her doctoral thesis, and found that Tdap and other vaccines are not part of the maternity 

package. The challenge in terms of health care reform is that there is no insurance coverage 

for vaccinating the father or any other family members visiting the hospital. Hospitals that 

overcame the barrier of having standing orders for vaccine faced major reimbursement 

problems for the mother and other family members. 

Dr. Stephan Foster (APhA) noted that information had not been presented lately regarding 

revaccination with Tdap and immunity waning after 10 years. Given it was approaching the 10­

year time period, it would be beneficial to hear input about this issue. 

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Dr. Messonnier responded that two major points of concern regard whether a single dose in 

adolescents will protect them through adulthood and how long a single dose will protect an 

adult. CDC and manufacturers are interested in pursuing this issue. The increase in reported 

cases among 7 through 10 year olds raises the issue of duration of protection, so CDC is trying 

to determine how to use the surveillance data and imperfect correlates of protection to asses 

this immunologically. 

Dr. Baker requested input regarding the number of real cases versus the number of reported 

cases. 

Dr. Messonnier responded that they are convinced that the number of real cases is dramatically 

higher than the number of reported cases for multiple reasons. For instance, people with mild 

cough illness do not typically seek medical care. If they do seek medical care, adult or pediatric 

physicians do not necessarily think of pertussis. If they do think of pertussis, they have to know 

which test to order when, and they have know whether the laboratory performing the testing is 

actually doing it right. While it is known that these are major barriers and that there is likely to 

be significant underreporting, how much is unknown. 

Dr. Stinchfield wondered about vaccine hesitancy and the role it may be playing, especially in 

the two California counties. 

Dr. Messonnier replied that this is believed to be an issue in some California counties. 

However, this does not seem to be the primary driving force in the Central Valley. 

Dr. Sawyer added that with regard to the San Diego experience, the majority of cases had 

received the recommended immunizations. Some of them were adolescents who were fully 

immunized as infants and who either had or had not yet received Tdap. He did not believe that 

the predominance of the cases was related to under vaccination. 

With respect to the question of boosting, Dr. Decker (Sanofi Pasteur) pointed out that the two 

manufacturers did not expect that no booster would be required. This is a regulatory issue in 

that FDA is not going to license a booster dose until they determine what occurs when a booster 

has been administered. A booster cannot be administered until they wait enough time to 

determine whether a booster is actually needed. Antibody kinetic studies suggest that the 10­

year re-dosing interval would be appropriate with respect to the pertussis components as well 

as the T and D components. In addition, from a programmatic point of view, since the country 

or FDA are unlikely to prefer Td to be given every 5 or 7 or 8.3 years, it is likely that booster 

doses of Adacel® or Boostrix® would be administered on a 10-year cycle. The general 

population will not reach 10 years from their initial vaccinations until about 2015; however, the 

study populations have reached the 10-year mark. Thus, both companies are conducting 

studies in their original study populations of re-boosting, and both companies likely hope a 

booster dose, if needed, will be licensed before 2015. Regarding pregnancy, Dr. Decker 

reminded everyone that the question of whether intra-pregnancy administration of Tdap has any 

effect of the immune response of the newborn thereafter remains an unsettled question. Three 

studies are underway to address this, one of which is sponsored by NIH; one of which is in 

Canada with Scott Halpern’s group, and a natural experiment of a major pertussis outbreak in a 

large healthcare institution that prompted wide use of Tdap in healthcare workers. A number of 

pregnant women were vaccinated during that outbreak, so follow-up data on their offspring will 

be available in a few months, which will be provided to the working group. The NIH and 

Canadian studies are moving very slowly because it is incredibly difficult to convince a pregnant 

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woman to enroll in a study that will involve many visits, extra blood draws, and extra diagnostic 

tests. Until there are additional data, he thought they would have to adhere to the current 

recommendation to vaccinate before pregnancy or post-partum, but not during pregnancy. 

Dr. Plotkin recommended following the international experience on the cocooning strategy, 

which is accumulating. Costa Rica and countries in Europe are using that strategy. One study 

showed that Tdap within a month or two after Td did not increase the reaction rate. 

Regarding barriers to vaccinating adolescents, Sandra Fryhofer (ACP) indicated that she was 

often involved in the handoff from the pediatrician to the internist, and sees a number of 

adolescents for a check-up prior to them entering college. The parents typically have a state 

form that list immunizations. The form says “last Td or Tdap” but does not specify which one. 

Thus, her office has to contact the pediatrician’s office to find out which one they actually 

received. Pediatricians are busy, so it is difficult to get an answer sometimes. If they do not 

receive an answer, a vaccination opportunity is missed. She wondered whether there were any 

data to address this issue, particularly with respect to interval. 

Dr. Messonnier responded that this is a point of reference the Pertussis Working Group is 

currently assessing. 

Dr. Baker commented that the interval stated in the document for post-partum immunization 

basically indicates approximately 2 years, although some people prefer 5 years. Often, adults 

have no clue what immunizations they have received. There is a routine post-partum program 

in one of the Houston hospitals. The women in this program are largely Hispanic, medically 

underserved, and under-insured. These women usually have no idea whether or when they 

have received a tetanus-containing vaccine. If they received an immunization intramuscularly in 

the arm during the fall and winter, it was probably influenza vaccine. The physicians leading the 

program decided not to consider the interval because of the high risk of pertussis to the young 

infant; they have not observed any safety issuesThe to date. This program basically considers 

the risk / benefit. For the post-partum woman, the risk to the baby is substantial, so Tdap is 

given. The requirement for a specific interval is a major barrier so many hospitals and / or their 

attorneys are not comfortable following a no interval protocol. 

Dr. Brewer (ANA) stressed that this is a major problem “on the ground” because it is extremely 

difficult to interpret what that recommendation really means, especially in local health 

departments where nurses run immunization clinics and may not be confident in making such 

decisions without advice. If extremely high risk was being observed in infants, perhaps it is time 

to do away with the interval. 

Dr. Baker noted that the working group is considering this possibility. 

Dr. Friedland (GSK) reported that in addition to assessing boosting, GSK is examining antibody 

persistence at certain intervals following vaccination. They have been reporting these data to 

the working group and will continue to do so. In addition, GSK has been studying the acellular 

pertussis vaccine (Pa) components of the vaccine in newborns. These data have been reported 

in the scientific literature and they will be happy to discuss them with the working group. 

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Dr. Pickering reminded everyone that CDC and Georgia Tech have developed an immunization 

scheduler which is a downloadable, computerized program that is free of charge. In this 

system, adults can store their vaccine records and their records can be forwarded to their 

physicians. If this system becomes widely used, it will help everyone remember what vaccines 

they have received and when. There is a link to this program on CDC’s website. 

Dr. Temte reported that in his state, he has the luxury of a very good statewide registry that is 

tied into his electronic medical record and is something that he uses on a daily basis. All of his 

adult patients are routinely assessed for Tdap. This infrastructure is needed in all states, and 

vendors need to make EMR fully compatible with registries. 

Dr. Gall (ACOG) strongly recommended that the committee revisit the recommendation to give 

this vaccine to moms during pregnancy in order to get antibodies into babies. They have been 

doing this at his place for the last 5 years. It is well-tolerated and they have unpublished data 

on significantly elevated cord levels to the antigens. The cocoon strategy has never really been 

tried in the field, and it really does not work. It was “rammed in” at the last minute after a year 

and a half of discussion on the pregnancy statement. He also suggested reading the previous 

week’s lead editorial in the New England Journal of Medicine (NEJM) written by a few members 

from the FDA stating that pregnant women should be included in the studies. 

Dr. Baker replied that the FDA needed to change some of their current regulations. She 

requested that someone address the comment that the cocoon strategy had not been proven to 

work, and whether anybody had tested this strategy for efficacy. 

Dr. Messonnier responded that there were two parts regarding what is considered to be 

efficacy. The individuals can be vaccinated effectively, and several studies assess feasibility. 

In small populations, moms have been vaccinated. However, vaccinating the rest of the family 

members has been difficult. These are small, focused studies that are not scalable. The 

second piece is that are some early data on the effectiveness of cocooning in preventing 

disease among infants. There is a pilot study in California and some work in Texas. Thus, 

there may be some data available within the next 6 months on the effectiveness of the 

cocooning strategy. 

Dr. Turner (ACHA) urged everyone to consider how to convince emergency departments and 

urgent care centers to administer Tdap. This is a missed opportunity. 

Dr. Baker agreed. For adult immunization, this is a very difficult transition. If someone has 

tetanus prone wound, most practitioners are very comfortable giving a tetanus immunization at 

a 5-year. Administering Tdap as part of that protocol would be quite appropriate based on 

emerging data. While trials of the vaccine died due to lack of interest, they are using an interval 

for their tetanus protein conjugate in intervals as short as a year. The increased reactogenicity 

from the tetanus-containing component is approximately the same amount of tetanus antigen as 

is in Tdap. 

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13-Valent Pneumococcal Conjugate Vaccine (PCV13) 

Lance E Rodewald, MD 

Director, Immunization Services Division 

National Center for Immunization and Respiratory Diseases 

Dr. Rodewald reported that on February 24, 2010, 13-valent pneumococcal conjugate vaccine 

(PCV13; Prevnar13®) was licensed by FDA. That morning, ACIP recommended the vaccine 

and included it in the VFC program. Part of the recommendation for the PCV13 vaccine was a 

new eligibility group: children 6 through 18 years of age with sickle cell disease, HIV infection, or 

other immunocompromising conditions. On March 12, 2010, the work group and CDC 

published the final recommendation for the vaccine. That was refined to include four other 

groups of children in the highest risk group for invasive pneumococcal disease (e.g., children 

with anatomic or functional asplenia, recipients of cochlear implant, and children with 

cerebrospinal fluid leak) in the 6 through 18 year old age range. This created a situation in 

which the ACIP recommendation was out of synch with the ACIP resolution for the VFC 

program. Parenthetically, the AAP recently published a recommendation that aligns with the 

new ACIP / CDC recommendation for these four additional groups. The purpose of this 

resolution is to update the eligible groups of children ages 6 through 18 years of age to be 

consistent with the ACIP recommendation for PCV13. The proposed language to rectify the 

difference in the current resolution was as follows, with the updated groups underlined: 

Eligible Groups 

Children 6 through 18 years of age who are at increased risk of invasive pneumococcal disease 

because of anatomic or functional asplenia, including sickle cell disease, HIV infection, or other 

immunocompromising condition, cochlear implant, or cerebrospinal fluid leak. 

Schedule and Dosage Intervals 

Children 6 through 18 years of age: A single dose of PCV13 may be administered for children 6 

through 18 years of age who are at increased risk for invasive pneumococcal disease because 

of anatomic or functional asplenia, including sickle cell disease, HIV-infection or other 

immunocompromising condition, cochlear implant, or cerebrospinal fluid leak, regardless of 

whether they have previously received PCV7 or PPSV23.® 

Motion: VFC Vote 

Dr. Keitel made a motion to accept the rewording of the recommendation for the VFC as 

proposed. Dr. Marcy seconded the motion. The motion carried unanimously with 15 affirmative 

votes, 0 abstentions, and 0 negative votes. 

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Vaccine Supply 

Lance E Rodewald, MD 

Director, Immunization Services Division 

National Center for Immunization and Respiratory Diseases 

During this session, Dr. Rodewald reported on the following: 

Adult Hepatitis B Vaccine 

Merck is not currently distributing its adult / dialysis hepatitis B vaccines. Dialysis formulation is 

anticipated to return in the 3rd Quarter of 2010. The adult formulation will not be available for the 

rest of 2010. GSK has monovalent and combination product available. GSK expects to have at 

least one presentation of monovalent product continuously available to be able to meet national 

demand during the remainder of 2010. The combination product, Hep A-Hep B vaccine, is 

available as an alternative. 

Adult Hepatitis A Vaccine 

Merck will not be distributing adult hepatitis vaccine for the rest of 2010. GSK is currently out of 

stock on both presentations of its adult hepatitis A vaccine (Adult Havrix®), but anticipates that 

sufficient supply of at least one presentation will be available to meet demand for routine adult 

usage of this product by the end of June 2010. GSK’s adult hepatitis A / hepatitis B combination 

vaccine (Twinrix®) is available as an alternative product. 

MMR-V Vaccine 

Merck began taking orders for MMRV (ProQuad®) on May 10, 2010. A limited number of doses 

are available for distribution. Merck has adequate supply of both their MMR and varicella 

vaccines to meet current demand. Dr. David Bach reported that Merck has about 1 million 

doses of ProQuad® remaining in their inventory that are available for distribution. 

Zoster Vaccine 

Merck continues to accept new orders for ZOSTAVAX®; however, the product is currently 

backordered. Orders placed through mid-May are expected to be filled by the end of July. 

Orders received after mid-May are expected to be filled in November / December of 2010. 

Backorders may continue into 2011. 

Hib / Hep B Vaccine 

Merck anticipates availability of its combination Hib / Hepatitis B vaccine, COMVAX®, in the 3rd 

Quarter of 2010. 

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Discussion

Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Supply Constraints Related to Specific Presentations 

GSK anticipates intermittent supply constraints for individual presentations during the second 

half of 2010 for Kinrix vials, Kinrix syringes, Havrix ®Pediatric syringes, Engerix® B Adult 

syringes. Alternative products, presentations, and brands are available. 

CDC’s Vaccine Supply / Shortage Webpage 

This and further information is available at: http://www.cdc.gov/vaccines/vacgen/shortages/default.htm 

Day 1: Public Comments 

No public comments were offered during the first day of the meeting. 

Agency Updates 

Centers for Disease Control and Prevention (CDC) 

Dr. Schuchat reported that CDC is actively involved in upgrading its information technology 

system, the Vaccine Tracking System (VTrckS), that manages and distributes vaccines and 

helps the states with their vaccine ordering and allocations. This system is in a very active 

phase this summer, and Dr. Schuchat plans to offer updates during future ACIP meetings. 

To address the challenges that providers are having with vaccine hesitancy, CDC has been 

working with AAP and other partners to develop research-based materials that will aid in the 

physician / patient conversation. As this suite of materials is developed, they are being posted 

on a new site: http://www.cdc.gov/vaccines/spec-grps/hcp/conversations.htm. There are tools 

for providers and updated materials that can be given to patients, which is particularly beneficial 

in the case of hesitant patients. There is a new healthcare worker portal on the website that 

includes items such as the adult vaccine scheduler. 

Related to Dr. Temte’s comments, the American Recovery and Reinvestment Act (ARRA) also 

referred to as the “stimulus funding” recently permitted CDC to announce a funding opportunity 

for which over 30 states are eligible. The purpose of these funds is to facilitate the improvement 

of the interoperability of immunization information systems and electronic health records. 

Approximately $25 million dollars are available for this one-time funding to make these 

connections more sustainable and effective. 

On Friday, WHO launched a new strategic plan for the next two years for the Global Polio 

Eradication Initiative. It is a very important and both promising and difficult time currently, with 

major progress in Nigeria and India and for the new outbreak in Tajikistan. The purpose of this 

strategic plan is to address the difficult last 1% of disease. 

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Centers for Medicare and Medicaid Services (CMS) 

Linda Murphy indicated that in October 2010 when the permissive VFC resolution was voted on 

to make HPV permissive for boys, potential problems were anticipated by CMS. CMS and CDC 

have developed and submitted a response to one of the states with which a problem was 

encountered. As a result of that joint agency letter, once the state has acknowledged that the 

vaccine is permissive with respect to whether the provider and parent opt to utilize the vaccine 

versus it being permissive for the state to cover it or not, the content of letter will be posted on 

CMS’s website and will be distributed to ACIP members. 

Ms. Murphy also reported that administration rates are currently in final clearance. The goal is 

to make the administration rates readily updatable based upon when Medicare updates their 

rates so that an extensive clearance process will no longer be necessary. 

Food & Drug Administration (FDA) 

Dr. Sun reported that FDA is working very closely with many of its colleagues and other 

regulatory agencies and manufacturers with respect to some of the issues being discussed 

during this ACIP meeting (e.g., influenza and rotavirus). Since the last ACIP meeting, there 

have been approvals on some concomitant administrations of vaccines. 

Department of Defense (DoD) 

No report. 

Department of Veterans Affairs (DVA) 

Dr. Kinsinger reported that an update was published in May 2010 in the Annals of Internal 

Medicine by the VA research group who conducted the Shingles Prevention Study pertaining to 

the longer term safety of Zoster vaccine showing that it continues to be safe and effective. 

The VA is very interested in the safety and effectiveness of pertussis vaccine in those 65 years 

of age and older. The issue was raised a few months ago, and the VA determined that a 

number of veterans have received that vaccine who are > 65 and older. VA is interested in 

knowing how effective pertussis vaccine is in this population. 

Also of interest to the VA is guidance for high dose influenza vaccine for those 65 years of age 

and older, and whether the vaccine information statement will offer information regarding how to 

decide which vaccine to administer. 

Heath Resources and Services Administration (HRSA) 

Rosemary Johann-Liang, filling in for Geoff Evans from the National Vaccine Injury 

Compensation Program (VICP), reminded everyone that 5,600 claims alleging vaccine-related 

autism were filed with the program, with peak numbers in the thousands in 2003 and 2004. 

Claims are currently much less, with only 12 autism claims filed thus far in fiscal year 2010 

versus over 100 in fiscal year 2009. Regarding the Omnibus Autism Trials, in February 2009, 

the Special Masters of the US Court of Federal Claims ruled in favor of HHS in all three test 

cases. In July and August of 2009, all of these cases were affirmed by the Judge of the Court of 

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Federal Claims upon appeal. In May 2010, one of the three test cases, Hazlehurst, was 

affirmed by the next level of appeal, the Federal Circuit Court. The Hazlehurst family may next 

seek review by the Supreme Court. The second test case, Cedillo, has been appealed to the 

Federal Circuit and a decision is expected later in 2010. The last test case was not appealed. 

In March 2010, the Special Masters ruled in favor of HHS on the general causation of the three 

test cases for Theory 2. None of these three test cases was appealed by the petitioners. The 

petitioners are also no longer pursuing the third theory that Measles, Mumps, Rubella (MMR) 

alone causes autism or autism spectrum disorder. 

In terms of non-autism claims, the program is on pace for its largest number of submitted claims 

filed since 1999. Approximately half of these claims alleged injury from influenza vaccines, and 

nearly 60% of the filings were on behalf of adults. The total compensation as of June 2010 was 

$1.987 billion from the program. The trust fund currently totals $3.3 billion. 

Indian Health Services (IHS) 

Jim Cheek indicated that IHS’s collaboration with FDA to monitor potential adverse events 

following the H1N1 influenza vaccine continued to go well, and IHS is utilizing their electronic 

health record to look for possible signals. They plan to expand this work to cover additional 

vaccines over the next few months. 

National Institutes of Health (NIH) 

Dr. Gorman indicated that he was the newly appointed NIH liaison for ACIP, and that Francis 

Collins is NIH’s new director. Dr. Collins has recommitted to translational research, so NIH will 

continue to focus on engaging in work that has an immediate impact on the health of 

Americans. NIH hopes to provide some of the information that ACIP would like in order to move 

to evidenced-based recommendations. 

National Vaccine Advisory Committee (NVAC) 

Dr. Birkhead reported that during NVAC’s June 2010 meeting, Assistant Secretary for Health, 

Howard Koh, charged NVAC with three new priority requests to address. Regarding Healthy 

People 2020 goals, which should be announced formally in Fall 2010, Dr. Koh asked NVAC to 

help identify implementation barriers and challenges to establishing and reaching the Healthy 

People 2010 goals and to give him an annual report on the status toward reaching those goals. 

Second, Dr. Koh requested an evaluation of the racial and ethnic disparities in influenza and 

pneumococcal vaccination. This activity will be moved to the Adult Immunizations Work Group. 

Third, Dr. Koh asked NVAC to be involved in the Viral Hepatitis Interagency Workgroup that has 

been formed at HHS. John Ward from CDC attended the meeting. NVAC’s role will be to 

review documents prepared by the Interagency Working Group as they relate to hepatitis 

vaccination. 

During the NVAC meeting in early June, presentations were delivered regarding healthcare 

reform, and NVAC passed a resolution that was forwarded to the Assistant Secretary 

recommending that prior NVAC resolutions, particularly the extensive set of vaccine finance 

recommendations that were published in 2008, be used by HHS as a guide in developing and 

implementing healthcare reform, particularly in terms of reimbursement activities. Presentations 

were also offered about the development and finalization of the National Vaccine Plan (NVP) 

since 1994. The current timetable for that is to have a final plan ready for public comment by 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Fall 2010, which will be completed shortly thereafter. The HHS and the National Vaccine 

Program will develop an implementation plan for the NVP, which is expected in early 2011. It is 

hoped that the NVP will be the blueprint for on-going coordination of federal agency activities 

regarding all vaccination issues (e.g., development, implementation, and evaluation). NVAC 

has two very active working groups: Vaccine Safety and Adult Immunization Working Groups. 

The Vaccine Safety Working Group is moving toward recommendations pertaining to the broad 

federal vaccine safety system by NVAC’s February 2011 meeting. The Adult Immunization 

Working Group is focusing on the many sets of recommendations for adult immunization, trying 

to hone in on barriers to implementation of a comprehensive adult vaccination program in the 

US and commitment at the federal level to support such an effort. They hope to have final 

recommendations from that group by the June 2011 meeting. 

The H1N1 Influenza Vaccine Safety Risk Assessment Working Group was part of the 

unprecedented effort by HHS and NVAC to provide oversight to the coordinated efforts 

pertaining to H1N1 vaccine safety. Dr. Marie McCormick, an NVAC member, chaired the group. 

This working group was comprised of members from all of the federal vaccine committees. 

They met bi-weekly to oversee all vaccine safety efforts related to H1N1. The basic findings to 

date are that the data have been adequate to detect a signal. There have been weak signals 

detected for three conditions: Guillain Barré Syndrome (GBS), Bell’s Palsy, and 

thrombocytopenia / idiopathic thrombocytopenicpurpura. On-going studies are needed to 

determine whether there is an actual causal relationship. Vaccine monitoring should continue 

as more data are accumulated. 

The H1N1 Influenza Vaccine Safety Risk Assessment Working Group is an on-going working 

group. Two additional reports to NVAC are planned. Since last summer, two off-schedule 

NVAC meetings were convened by teleconference to assess the vaccine safety of H1N1. Two 

additional meetings were scheduled for July 27, 2010 and August 25, 2010. These are public 

teleconferences. By that time, NCAC hopes to have an end of season analysis regarding the 

safety of the H1N1 vaccine and a final report to address the issue of the weak signals. 

National Vaccine Program Office (NVPO) 

Dr. Gellin noted that everything Dr. Birkhead mentioned for NVAC represented a large part of 

the work stream and themes of NVPO. In addition, Dr. Gellin highlighted three efforts. He 

expressed his hope that the NVP would be completed by the time of the next ACIP meeting in 

October 2010, and that this could be further discussed at that time. 

Regarding coming attractions from Washington, there was a review by the President’s Council 

on Science and Technology, which was their second review related to influenza. The second 

review was inspired by how late the vaccine was this year. A report from this review will soon 

be disseminated, the focus of which will regard what can be done in terms of technology and the 

regulatory stream to shorten timeframes. 

Related to that, a medical countermeasures review was conducted by the Office of the Assistant 

Secretary for Preparedness and Response, which has some of the same themes. A report will 

soon be distributed on that review as well, which will focus on emerging threats and bioterrorism 

issues, and nimble technology. 

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Discussion

Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Influenza 

Introduction 

Kathy Neuzil, MD, MPH 

Chair, Influenza Vaccine Workgroup 

Dr. Neuzil began by acknowledging some history. In addition to being the year that ACIP made 

the historic universal influenza vaccine recommendation, 2010 also marks the 50th anniversary 

of the first influenza vaccine recommendation. A publication from 1960 in Public Health Reports 

by the Surgeon General, Dr. Burney, illustrates the beginning of influenza recommendations for 

high risk groups [Burney LE. Public Health Rep. 1960 Oct;75(10):944]. The three high risk 

groups contributing most to the excess deaths and who the Public Health Service then believed 

should be routinely immunized each year included: 1) Persons of all ages who suffer from 

chronic debilitating disease (e.g., rheumatic heart disease, other cardiovascular diseases, 

chronic bronchopulmonary disease, diabetes, and Addison’s disease); 2) Pregnant women; and 

3) All persons 65 years or older. 

Noting that those first Surgeon General recommendations predated the ACIP, the second piece 

of history Dr. Neuzil shared was the agenda, provided by Dr. Jean Smith, of the first meeting of 

the ACIP convened on May 25-26, 1964. A description of the committee’s purpose and function 

and the initial charter topped the agenda. In 1964 as in 2010, influenza took up more than its 

fair share of the agenda. 

Also important to acknowledge is the history of the past year. It was a busy and unusual year 

with many surprises, and a tremendous amount of work was done by the people in the room. It 

was certainly historical that it was the first year in which two influenza vaccine recommendations 

were made within a month of each other. 

Dr. Neuzil acknowledged that this would be her last ACIP meeting, stressing that the Influenza 

Vaccine Work Group would be in excellent hands with Dr. Wendy Keitel taking over as the 

chairperson. Dr. Keitel is an internationally recognized influenza expert. Her positive impact on 

this committee was immediate. She has made significant contributions already and everyone is 

very pleased that she agreed to chair this committee beginning July 1, 2010. 

In addition, Dr. Neuzil acknowledged that this would be Dr. Tony Fiore’s last ACIP meeting as 

the CDC lead for the Influenza Vaccine Work Group. Dr. Fiore will be the Associate Director for 

Science in the Division of Parasitic Diseases, National Center for Zoonotic, Vector-Borne, and 

Enteric Diseases (NCZVED) at CDC. On behalf of the group, Dr. Neuzil thanked him and 

wished him all the best. 

To begin the session, Dr. Neuzil stressed that public policy is always difficult, but is particularly 

difficult with regard to influenza. To quote Drs. Neustadt and Fineberg, “Policy decisions 

regarding influenza rest on judgments about the behavior of the virus, the impact of the disease 

and our ability to interdict its course. But the virus is capricious, the disease elusive, and our 

remedies imperfect” [Neustadt R, Fineberg H. The Swine Flu Affair: Decision-making on a 

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slippery slope. http://www.iom.edu/?id=65926]. She thought the past year very nicely 

demonstrated the sentiments of this quotation. 

Influenza Season Update and Summary 

Anthony Fiore, MD, MPH 

Influenza Division, NCIRD, CDC 

Dr. Fiore acknowledged again that they were losing two key Influenza Vaccine Work Group 

members who were rotating off of ACIP. The first was Dr. Susan Lett, who had been the voice 

of immunization programmatic reason, informing the work group about what programs could, 

could not, and perhaps would not do. That has been an important reality check on some of the 

ideas the work group has had over the past several years. Dr. Kathy Neuzil has been 

absolutely the right person, in the right place, at the right time during all of the turmoil over the 

last three years. On behalf of all members and CDC, Dr. Fiore extended a heartfelt thanks to 

Dr. Neuzil for all of her hard work and leadership. 

With that, Dr. Fiore turned to the epidemiology of influenza over the past few months. The 

Influenza-like Illness (ILI) Surveillance Network (ILINet) shows that over the past few months, 

there has been very little influenza-like illness observed in providers’ offices. ILI has been well 

below baseline over the past several months in contrast to the very sharp peak last fall with the 

pandemic [Percentage of Visits for Influenza-like Illness (ILI) Reported by the U.S. Outpatient 

Influenza-like Illness Surveillance Network (ILINet), Weekly National Summary, October 1, 2006 

– June 12, 2010]. 

Regarding notifiable deaths among children, a reporting system has been in place since 2004. 

These reports tend to lag somewhat, so they reflect higher numbers than in February. The key 

points are that during the 2007-08 influenza season, 88 deaths were reported. In the fairly mild 

season of April 2008-2009 season, 68 deaths were reported. During the pandemic, 341 deaths 

were reported. Of course, that far exceeds anything that has been observed in this system thus 

far. These are laboratory-confirmed reported deaths. This does not account for children whose 

deaths were not reported. The estimate of the real number could be expected to be higher 

[Number of Influenza-Associated Pediatric Deaths by Week of Death: 2007-08 season to 29 

May 2010]. 

The viral surveillance system, through the WHO / NREVSS labs, also shows very few viruses 

reported since February 2010. The viruses that are reported are either influenza A and not 

subtypes, or 2009 H1N1. In the US, very few other viruses are being isolated. Over 99% of 

viruses have been 2009 H1N1. When these are sub-typed, there does not appear to be a 

substantial antigenic drift in the US or elsewhere in the world at this point. Over 99% of these 

viruses are susceptible to oseltamivir and all are susceptible to zanamivir. Over 99% are 

resistant to adamantine drugs [Influenza Positive Tests Reported to CDC from U.S. 

WHO/NREVSS Collaborating Laboratories, National Summary, 2009-10]. 

This world map depicts the type and subtype distribution of viruses isolated from around the 

world in recent weeks. The Southern hemisphere season is beginning, although there has been 

relatively little activity in most countries thus far. On this map, 2009 H1N1 viruses are the yellow 

slice, H3N2 viruses are the blue slice, and influenza B viruses (mostly B Victoria) are the 

maroon slice. In Africa, there have been a number of H3N2 viruses. There are a variety of 

viruses types, with Asia in particular reporting B viruses. There is still 2009 H1N1 in every 

region: 

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Source: World Health Organization June 18, 2010 

http://www.who.int/csr/don/2010_06_18/en/index.html 

The manufacturers are usually asked in June about supply projections, and they always caution 

CDC that this is going to be subject to change based upon issues such as regulatory approvals, 

production yields, demand for the product, et cetera. Therefore, these are merely projections. 

Together, it appears that manufacturers plan to provide approximately 170 million doses, and all 

manufacturers report likely availability of at least half of the projected supply by the end of 

September: 

Manufacturer Projected Production 

CSL 12.5-12.7 M doses (reduced by 1.5 M from prior 

estimates due to unavailability of 0.25mL 

product) 

GSK ~36 M doses 

MedImmune ~16 M doses 

Novartis 35-40 M doses 

Sanofi ~70 M doses 

TOTAL 169.5-174.7 M doses 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Effectiveness of U.S. influenza A(H1N1) 2009 

Monovalent Vaccines in Preventing Health Care 

Visits Associated with RT-PCR-Confirmed 2009 H1N1 Infections 

David Shay MD, MPH 

Prevention and Modeling Team 

Epidemiology and Prevention Branch 

Influenza Division, NCIRD, CDC 

Dr. Shay reported preliminary estimates of pandemic vaccine effectiveness. The outcome that 

this group studied was prevention of RT-PCR confirmed medically attended 2009 H1N1 

influenza. The setting was 4 communities located near the Marshfield Clinic in Southeast 

Michigan; University of Michigan and Henry Ford Health Systems; Rochester, New York; and 

Nashville, Tennessee. This was a case-control study conducted from October 2009 through 

January 2010. The enrollees were patients evaluated for acute respiratory symptoms in 

outpatient or inpatient settings who were prospectively enrolled and tested for influenza viruses 

by real time RT-PCR methods. Cases were those who tested positive for 2009 H1N1, and 

controls were those who tested negative for influenza. 

Vaccination status was based on data collected by self-report and confirmed by record review. 

Immunization was defined by receipt of at least one dose of 2009 H1N1 vaccine greater than 7 

or greater than 14 days before the onset of respiratory symptoms. The analysis was conducted 

in the usual way with VE=(1-adjusted OR)x100, estimated with logistic regression models and 

assessment for potential confounding by age, date of symptom onset, days between symptom 

onset and enrolling in testing, insurance status, and the presence of high risk medical 

conditions. The most important confounder was date of symptom onset. 

The descriptive data are reflected in the following two tables: 

Results – Descriptive data Pandemic nf uenza cases Influenza-negative controls 

Characteristic N 897 % of total N=3,259 % of tota 

Sex 

Female 476 53.1% 1,831 56.2% 

Age groups 

6 mo-9 years 338 37.7% 989 30.3% 

10-18 years 200 22.3% 303 9.3% 

19-29 years 149 16.6% 346 10.6% 

30-39 years 58 6.5% 327 10.0% 

40-49 years 66 7.4% 329 10.1% 

50-64 years 71 7.9% 529 16.2% 

65+ years 15 1.7% 436 13.4% 

H gh-risk cond t on 

No 617 68.8% 1,805 55.4% 

Yes 280 31.2% 1,454 44.6% 

Insurance status 

Not insured 74 8.2% 167 5.1% 

Pr vate insurance 590 65.8% 1,914 58.7% 

Pub ic nsurance 233 26.0% 1,178 36.1% 

Enrollment s te 

Outpatient 740 82.5% 1,932 59.3% 

Emergency dept 87 9.7% 446 13.7% 5 

Inpatient 70 7.8% 881 27.0% 

Results – Immunization status* 

Enrollees Seasona vacc ne H1N1 vaccine Both vaccines 

Character st c No. No. % No. % No. % 

To a 4,156 1,371 33.0% 408 9.8% 315 7.6% 

Study community 

Marshf e d, WI 1,932 643 33.3% 251 13.0% 189 9.8%

Rochester, NY 282 75 26.6% 15 5.3% 11 3.9%

Southeast, MI 760 208 27.4% 29 3.8% 23 3.0%

Nashv lle, TN 1,182 445 37.6% 113 9.6% 92 7.8%

Age groups 

6 months 9 years

1 dose on y 1,327 106 8.0% 157 11.8% 118 8.9%

2 doses 1,327 361 27.2% 55 4.1% 39 2.9%

10 18 years 503 117 23.3% 28 5.6% 19 3.8%

19 49 years 1,275 312 24.5% 93 7.3% 73 5.7%

50 64 years 600 240 40.0% 53 8.8% 49 8.2%

65+ years 451 235 52.1% 22 4.9% 17 3.8%

H gh-risk cond t on 

No 2,422 680 28.1% 241 10.0% 175 7.2% 

Yes 1,734 691 39.9% 167 9.6% 140 8.1% 

Case status 

Controls 3,259 1,183 36.3% 400 12.3% 308 9.5% 

Cases 897 188 21.0% 8 0.9% 7 0.8% 6 * mmun zat on defined by receipt of at leas 1 dose of vacc ne >14 days before symp om onset 

Note that the cases were more likely to be age 6 months through 9 years or 10 to 18 years, with 

more than half of the cases and relatively few of the controls being in that age group. The 

attack rate for this particular virus in older individuals was low. For example, 1.9% of the cases 

versus 13% of the controls were age 65 and greater. Similar proportions of people had high risk 

conditions. Most of the cases and controls were enrolled in outpatient settings, with a larger 

proportion of cases than controls enrolled as outpatients. 

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Regarding immunization status, 33% of the enrollees in the time period studied had received the 

seasonal vaccine, 9.8% had received H1N1 vaccine, and 7.6% had received both. There were 

some differences by the study community, particularly when contrasting receipt of seasonal 

vaccine with H1N1 vaccine. The greatest difference was among the younger group in which 

27% received two doses of seasonal vaccine versus 8% who received only one dose. For 

H1N1, only 12% of youth received one dose of vaccine and only 4% received 2 doses. 

Therefore, the investigators were unable to make an assessment of the effect of two doses 

versus one dose vaccine in this age group. Based on the crude data, 12.3% of controls versus 

only 0.9% of cases received H1N1 vaccine, but the time component must be taken into account. 

During the peak of disease, there were relatively few vaccinated cases or controls. The 

availability of vaccine varied from available before the peak of disease or only available after the 

peak of disease in some of the sites. 

In all ages, there were 897 cases and 3259 controls. After adjusting for site, age, and onset 

date, vaccine effectiveness was 62% (95% CI, 30% to 79%) if vaccination occurred greater than 

7 days prior to symptom onset, and 62% (95% CI, -4% to 86%) if vaccination occurred 8 to 14 

days prior to symptom onset. The investigators were unable to stratify vaccine effectiveness 

estimates by vaccine type, high-risk status, or by 1 or 2 doses among children aged <10 years 

because of small sample sizes. There was no effect of seasonal vaccine against pandemic 

outcomes, as might be expected. 

In conclusion, receipt of US monovalent, non-adjuvanted pandemic vaccine was associated with 

substantial protection against medically attended 2009 H1N1 illness. This is the highest 

estimate for vaccine effectiveness that has been observed in this system in several years of 

operation. Vaccine estimates were similar if vaccine was received greater than 7 or greater 

than 14 days prior to symptom onset. These estimates of vaccine effectiveness are similar to 

those obtained by studies in Europe, where a variety of vaccines were used, but where 

adjuvanted vaccines were predominantly used. No effect was observed of the seasonal 2009­

10 vaccine on 2009 H1N1 illness. 

ACIP Influenza Vaccine Workgroup Discussions and Recommendations 

Anthony Fiore, MD, MPH 

Influenza Division, NCIRD, CDC 

Dr. Fiore reminded everyone that Wendy Keitel would become the Chair Apparent of the 

Influenza Vaccine Work Group beginning July 1, 2010. Tim Uyeki will be taking Dr. Fiore’s 

place as Acting CDC Liaison to Influenza Vaccine Work Group. Dr. Uyeki has a 10-year history 

in the Influenza Division, so this transition should be relatively smooth. 

Dr. Fiore reminded everyone that the Influenza Vaccine Work Group convenes teleconferences 

every two weeks, engages in on-going email and telephone discussions, and scans the horizon 

for upcoming influenza issues and brings them to the attention of the full ACIP during public 

meetings, including proposals for votes on new recommendations for use of vaccines and 

antivirals. Major topics discussed by the group from February 2010 to June 2010 have 

included, but have not been limited to, the following: 1) antiviral recommendations; 2) 

vaccination recommendations for children <9 years old who did not receive any doses of 2009 

H1N1 monovalent vaccine; and 3) vaccine safety monitoring, including data from the H1N1 

2009 monovalent vaccine program, plans for the 2010-11 season, and fever and febrile seizures 

among young Australian children who received an inactivated 2010 southern hemisphere 

trivalent seasonal vaccine. 

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In February 2009 before the pandemic, the major concern for the Influenza Vaccine Work Group 

was the development of antiviral resistance among the seasonal H1N1s. For that reason, the 

vote for the antiviral recommendations was tabled during the February 2009 meeting and the 

antiviral recommendations were separated from the vaccine recommendations. 

Antiviral recommendations were discussed during the June 2009 ACIP meeting. The antiviral 

recommendations were changed very little from the usual recommendations that had appeared 

in 2006, 2007, and 2008. The important changes to the recommendations included greater 

emphasis on empiric treatment pending diagnostic testing results when influenza is suspected 

for hospitalized or severely ill patients; outpatients with medical conditions that confer higher risk 

of influenza complications (e.g., chronic illness, pregnancy, immunosuppression); persons ages 

65 or older; and young children. This was driven by the relatively low sensitivity of rapid 

influenza diagnostic testing and the concern that clinicians were waiting until they received 

definitive results or were placing too much faith in negative results. There was also an 

emphasis on using local epidemiology and viral surveillance when available in choice of antiviral 

(e.g., when circulating viruses are >99% 2009 H1N1, use oseltamivir or zanamivir but not 

adamantanes). Emphasis was also placed on judicious use of chemoprophylaxis in selected 

circumstances based on epidemiologic setting, patient risk, and clinical judgment. During that 

public meeting, ACIP encouraged consultation with local public health authorities and seeking 

guidance from the CDC website to learn about the latest antiviral recommendations versus 

codifying a blanket set of recommendations for chemoprophylaxis. 

Based upon these variations, the antiviral recommendations text was finalized and updated 

through September 2009. However, submission for publication in the MMWR was delayed 

because this was the peak of the pandemic. Treatment and chemoprophylaxis 

recommendations are consistent with CDC (Last updated December 7, 2009), IDSA (April 2009; 

updated FAQs October 2009), AAP (Update planned summer 2010), and WHO (May 2010). 

The Influenza Vaccine Work Group resumed work on the antiviral recommendations over the 

past few months to determine whether they were still useful. The group concluded that the 

current epidemiologic situation is unchanged in that >99% of viruses are sensitive to oseltamivir, 

and the majority are 2009 H1N1. Groups at higher risk who are recommended for empiric 

treatment remain unchanged from the 2009 H1N1 pandemic period. There are continued 

concerns about inappropriate use of chemoprophylaxis with respect to the potential for 

increasing risk of antiviral resistance and adverse events. Watchful waiting, with early treatment 

when indicated, is often a better approach. The work group’s recommendations were approved 

during the June 2009 ACIP meeting. It was agreed that the recommendations should be 

submitted for MMWR publication as the 2010 antiviral recommendation after updating the 

references. 

The second topic discussed by the work group was the 2010-2011 influenza vaccine 

recommendations for the number of vaccine doses for children ages 6 months through 8 years. 

The current recommendations are as follows: 

 Previous immunogenicity and vaccine effectiveness studies indicate that children ages 6 

months through 8 years old should receive 2 doses in current season: 

Æ If they have never received trivalent vaccine before 

Æ If they only received 1 dose last season and it was the first time they had ever been 

vaccinated 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

 Children ages 6 months through 8 years old who have been vaccinated in a year before last 

season (i.e., 2008-09 or before) are currently recommended to receive 1 seasonal influenza 

vaccine dose annually 

 Need for two doses in children who have not previously been vaccinated is believed to be 

due to need for a priming dose followed by a booster 

Æ Many children ages 6 months through 8 years old lack previous immunologic 

experience with influenza or influenza vaccine 

Data from the Immunization Information System Sentinel Sites, 2007-08 and 2008-09 influenza 

seasons, suggests that full vaccination (e.g., 2 doses) in children aged 6 through 23 months and 

2 through 4 years is hovering around 20% to 30%. Vaccination coverage is low among children 

<9. Most young children are due to be given 2 doses of seasonal vaccine each season 

according to current recommendations [Source: CDC MMWR 2009]. 

Data presented by Jim Singleton at the National Immunization Conference a few months ago 

show that slightly over 50% of children received at least one influenza vaccine of some sort by 

March 2010. There has not been much vaccination since then. H1N1 coverage was 

approximately 40%. Some children received one or the other or both types of vaccine [J 

Singleton, National H1N1 Flu Survey. National Immunization Conference April 2010]. 

Key Influenza Vaccine Work Group considerations have been that <10% of children <9 years 

old had antibodies to the 2009 H1N1 virus before the pandemic. The presence of antibodies 

before the pandemic is not associated with previous seasonal influenza vaccination. The 

dosing schedule recommended for 2009 H1N1 monovalent vaccine was that children ages 6 

months through 9 years should receive 2 doses, and that older children and adults should 

receive 1 dose. Pandemic 2009 influenza A(H1N1)-like viruses are expected to circulate during 

the 2010-2011 season. Epidemiologic evidence indicates that unvaccinated young children had 

little or no protection against the antigenically distinct pandemic 2009 influenza A(H1N1) 

viruses. 

Children entering the 2010-2011 season have a variety of immunologic profiles: 

 Susceptible: Those who were not infected, were not vaccinated, or did not respond to 

vaccine. 

 Naturally Immune: Those who are immune following natural infection. Seroprevalance data 

just coming out more or less agrees across studies conducted throughout the world that 

there is a fairly high prevalence of antibody to the H1N1 antigen among young children, 

especially school aged children. For example, the Miller et al studies conducted in the 

London area published in Lancet in early 2010 showed approximately 21.3% seropositvity 

among children less than 5 years of age and 42% among school aged children after the fall 

pandemic wave, compared to studies that showed <5% seropositivity in this age group 

before the pandemic. Ross et al published a study conducted in the Pittsburgh area (PLoS 

Currents 2010) that showed 28% seropositivity among 0 to 9 year olds, including some 

children who had relatively little or perhaps no symptoms. 

 Immune after receiving 2 doses of monovalent vaccine: Those who are immune after 2 

doses of the monovalent vaccine. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

 Monovalent Immune / 1 Dose: Those who are immune after 1 dose of the monovalent 

vaccine. However, the proportion of young children who develop immunity after 1 dose is 

much less certain. 

The following tables summarize a number of study arms that assessed immunogenicity data in 

older children and adults: 

2009 influenza A(H1N1) monovalent vaccine immunogenicity 

summary: Older children or adults, day 21 post dose 1 (15 mcg) 

Manufacturer 

(Dose) 

% Baseline 

anti-HA≥ 1:40 

(95% CI) 

% Post dose 1 

anti-HA≥ 1:40 

(95% CI) 

Seroconversion 

% 

(95% CI) 

GMT 

(95% CI) 

GMT fold 

increase 

(95% CI) 

Novartis 

(9y-17y) 1 

29 

(21-37) 

96 

(88-98) 

NR 883 NR 

CSL 

(18y-64y) 2 

33 

(26-42) 

97 

(92-99) 

71 

(63-78) 

217 

(177-266) 

11 

Sanofi 

(10y-17y)3 

11 

(6-19) 

93 

(86-97) 

90 

(82-95) 

390 

(289-528) 

49 

(35-69) 

Sanofi 

(18y-64y)4 

26 

(19-34) 

98 

(94-100) 

96 

(91-99) 

1405 

(1120-1763) 

64 

(51-82) 

Sanofi 

(65y+)4 

25 

(17-35) 

93 

(86-97) 

89 

(81-94) 

390 

(283-537) 

21 

(16-29) 

1Arguedas et al NEJM 2010 

2Greenberg et al N Engl J Med 2009 

3NIH/VTEU investigators, unpublished 

4Plennevaux et al Lancet 2009 14 

The second data column shows the percentage of persons who are 10 years of age or older 

who responded with an anti-HA titer ≥ 1:40, which is believed to be the protective level. This 

ranges from 93% to 98% after just one dose, which is a very high rate of seropositivity after just 

a single dose for these older children and adults. 

In younger children, this is somewhat different. The following table includes data from the 

published studies and also data provided by the National Institute of Health / Vaccine Treatment 

Evaluation Unit (NIH/VTEU) investigators that is not yet published: 

Manufacturer 

(Dose) 

% Baseline 

anti-HA≥ 1:40 

(95% CI) 

% Post dose 1 

anti-HA≥ 1:40 

(95% CI) 

Seroconversion 

% 

(95% CI) 

GMT 

(95% CI) 

GMT fold 

increase 

(95% CI) 

Novartis 

(15 mcg)1 

26 

(17-37) 

72 

(60-82) 

NR 147 

(90-200) 

12 

CSL2 

(15 mcg)2 

28 

(20-37) 

93 

(86-97) 

86 

(77-91) 

201 

(156-260) 

13 

(11-16) 

Sanofi 

(15 mcg)3 

4 

(1-9) 

75 

(66-83) 

75 

(66-83) 

111 

(84-147) 

10 

(8-14) 

Sanofi 

(15 mcg)4 

6 

(2-13) 

48 

(35-60) 

48 

(35-60) 

35 

(22-58) 

5 

(3-9) 

Sanofi 

(15 mcg)4 

10 

(3-21) 

44 

(30-59) 

40 

(26-55) 

28 

(16-49) 

4 

(3-6) 

2009 influenza A(H1N1) monovalent vaccine immunogenicity 

summary: Children ages 3y to 8-9y, day 21 post dose 1 (15 mcg) 

1Arguedas et al NEJM 2010 

2Nolan et al N Engl J Med 2009 

3Plennevaux et al Lancet 2009 

4NIH/VTEU investigators, unpublished (NIH trial 09-0054 and DMID 09-0047) 

15 

The above data are for children 3 years to roughly 8 to 9 years, depending upon the study arm. 

These data show that approximately 44% to 93% of these children responded to with an anti-HA 

titer ≥ 1:40 to a single dose of 15 micrograms (μg) by 21 days after the dosing. The last two 

columns show the antibody levels that were reached. The GMTs ranged from nearly 400 to 

over 1000 in the older children and adults in the first table. In the younger children, GMTs range 

from 28 to about 200. 

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The following table includes children ages 6 months through 36 months: 

2009 influenza A(H1N1) monovalent vaccine immunogenicity 

summary: Children ages 6 months--36 months, day 21 post 

dose 1 (7.5-15 mcg) 

Manufacturer 

(Dose) 

% Baseline 

anti-HA≥ 1:40 

(95% CI) 

% Post dose 1 

anti-HA≥ 1:40 

(95% CI) 

Seroconversion % 

(95% CI) 

GMT 

(95% CI) 

GMT fold 

increase 

(95% CI) 

CSL 

(15 mcg)1 

9 

(5-18) 

92 

(84-96) 

88 

(79-94) 

113 

(87-147) 

14 

(11-17) 

Sanofi 

(7.5 mcg)2 

5 

(2-11) 

45 

(35-55) 

44 

(34-54) 

31 

(23-43) 

3 

(2-4) 

Sanofi 

(15 mcg)3 

4 

(1-10) 

21 

(12-32) 

21 

(12-32) 

12 

(8-19) 

2 

(1.5-2.8) 

Sanofi 

(15 mcg)3 

0 

(0-12) 

19 

(7-39) 

19 

(7-39) 

13 

(8-22) 

2.7 

(2-4) 

1Nolan JAMA 2010 

2Plennevaux et al Lancet 2009 

3NIH/VTEU investigators, unpublished (NIH trial 09-0054 and DMID 09-0047) 

16 

Some of these children received the 7.5 μg dose that is currently recommended. Some of them 

also received a 15 μg dose, or double what they would receive in the seasonal vaccine. Again, 

looking at that second column, from 19% to 92% of children in this age group responded to one 

dose. That is even lower than for the somewhat older children, the 3 to 9 year olds. Again, the 

GMTs are a lot lower than they were for older children and adults and somewhat lower that they 

are for 3 to 9 year olds. 

One of the NIH studies compared the response after one dose and after two doses. 

Approximately 20% of the 6 to 35 month olds responded to one dose. Close to 80% responded 

to two doses. Approximately 50% to 80% of 3 through 9 year olds and 90% of 10 to 17 year 

olds responded to just one dose. This is a fairly marked difference by age in response to the 

first dose. The good news is that two doses brings a large majority of children to an antibody 

level that is thought to be protective [Source: NIH VTEUs, preliminary data]. 

The work group’s conclusions regarding immunogenicity of influenza A(H1N1) 2009 monovalent 

vaccines were as follows: 

 After 1 dose of 2009 pandemic H1N1 monovalent vaccine, hemagglutinin inhibition (HI) 

titers considered to be protective (≥40) develop in: 

Æ 81% of adults 65 years and older

Æ 90%-97% of older children and adults

Æ 44%-93% of children 3 years through 9 years 

Æ 19%-92% of children ages 6 months through 35 months 

 Responses after 1 dose of children < 9 years old vary across studies: 

Æ Some children who are currently recommended to receive 1 seasonal 2010-11 dose, 

and who received no monovalent vaccine doses, might benefit from 2 doses of 2009 

H1N1 antigen 

Æ After 2 doses, 73% to 100% of infants and young children develop HI titers 

considered to be protective 

Æ There appears to be no increase in reactogenicity with the second dose 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

 Previous studies of seasonal influenza vaccine demonstrate that 2 doses separated in time 

(Spring-Fall) are immunologically equivalent to 2 Fall doses when vaccine virus antigen 

does not change [Walter et al. Pediatrics 2006] 

The final piece of information that may arise in the discussions regards what is known about 

separating the doses. In other words, the child who received one monovalent dose in the spring 

and receives a single dose of trivalent inactivated vaccine (TIV) in the fall, receives the two total 

2009 H1N1 antigen doses. What are the implications for that for achievable protection? The 

work group considered two options with regard to this issue: 

Option 1: Continue current recommendations for determining which children ages 6 months 

through 8 years should receive 2 doses of seasonal vaccine based on previous receipt of 

seasonal influenza vaccine: 

 All children ages 6 months through 8 years who receive a seasonal influenza vaccine for 

the first time should be given 2 doses. 

 Children who receive only one dose of a seasonal influenza vaccine in the first influenza 

season they receive vaccine should receive two doses, rather than one, in the following 

influenza season. 

Option 1 is consistent with the current recommendations, so no new communication message 

would be required. This option is consistent with actions when B lineage changes or drifted 

H3N2 appears (no recommendation for 2 doses). Most children ages 6 months through 8 years 

old will still be recommended for 2 doses because they have never been fully vaccinated with 

seasonal vaccine before. However, some children who did not receive any monovalent vaccine 

doses would receive only 1 dose of the 2009 H1N1 antigen (with the 2010-11 seasonal dose), 

and some young children who receive only 1 dose might not develop an immune response 

considered to be protective. 

Option 2: Change the recommendation for determining which children ages 6 months through 8 

years should receive 2 doses of seasonal vaccine, taking both seasonal and 2009 H1N1 

monovalent doses received into account: 

 All children ages 6 months through 8 years who receive a seasonal influenza vaccine for 

the first time should be given 2 doses. 

 Children who receive only one dose of a seasonal influenza vaccine in the first influenza 

season they receive vaccine should receive two doses, rather than one, in the following 

influenza season. 

 In addition, for the 2010-11 influenza season, children ages 6 months through 8 years 

who did not receive at least 1 dose of an influenza A(H1N1) 2009 monovalent vaccine 

should receive 2 doses of a 2010-11 seasonal influenza vaccine, regardless of previous 

seasonal influenza vaccination history. 

Considerations for Option 2 are that it is consistent with the monovalent vaccine 

recommendations to give 2 doses of 2009 H1N1 vaccine antigen to all children ages 6 months 

through 9 years old. As expected, most young children receiving a vaccine to protect against a 

virus with a major antigenic change require 2 doses. This option is likely to increase the number 

of children who develop an immune response. However, this differs from previous seasonal 

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influenza vaccine recommendations. Some children who would normally receive one seasonal 

vaccine dose will be recommended for two doses. More total vaccine doses will be required for 

this age group. The added public health benefit of two dose recommendation might be small, 

given that many children’s immunity is based on natural infection, relatively low coverage might 

persist, and many will be recommended for 2 doses anyway based upon lack of previous 

seasonal vaccine. 

Discussion Points 

Dr. Temte inquired as to what the best guess would be (if summing what is known about natural 

seropositivity from exposure to the virus, the amount of vaccine distributed, and number of 

people immunized) of current immunity for the US population and what modeling suggests 

about the likelihood that H1N1 will ever recur. 

Dr. Fiore replied that he did not think he could answer this unless they continued to see virus 

around the world. In previous pandemics, with many susceptibles presumably, there is not as 

much pressure for the virus to change. There could be considerable overlap between children 

who are naturally infected, especially among those who were asymptomatic and those who 

were vaccinated. One cannot simply add together the seropositivity data with the vaccination 

data because there are serologic studies, many of which were conducted before the vaccination 

campaigns were finished. Accounting for that overlap, there might be in the neighborhood of 

50% of children who are seropositive in the school aged group, and it is probably lower for 

children less than 5 years of age. That is at least what the seropositivity data would suggest. 

CDC’s interpretation of that is that there is still plenty of fuel for continued transmission for that 

particular virus. There are plenty of susceptible children, even with that degree of seropositivity, 

among whom continued community outbreaks could occur with this particular virus. 

Dr. Marcy asked whether Dr. Fiore could account for the difference in immunogenicity in 

children 6 months to 8 to 9 years between the CSL Biotherapies vaccine and the Sanofi Pasteur 

vaccine. There seemed to be striking differences in the immunogenicity data presented. He 

also wondered whether there were any data showing that use of oseltamivir, or patterns of 

oseltamivir or zanamivir use in communities or in countries, has in any way affected the 

resistance patterns of the H1N1 to those antivirals. 

Dr. Fiore responded that to answer the question about differences across the studies in 

response to the vaccines was that they were conducted at somewhat different times in the 

epidemiology of the country in which the study was conducted. The CSL study was conducted 

in Australia in the midst of their winter pandemic wave, which was different from the other 

studies. The implication of that is that many more children were seropositive going into that 

study than in some of the other studies. For the younger age group, this was in the 

neighborhood of 10% to 15%. Over 20% of the 3 through 9 year olds were seropositive at the 

time they were enrolled. The vaccine for those children might have acted more as a booster 

than as a priming dose if they had already been infected. The testing itself also varied across 

studies. The test is not fully standardized across labs and identical specimens might test 

differently in different laboratories. In addition, there may be more immunogenicity differences 

amongst the vaccines that is not fully understand even though they are made in essentially the 

same way. With regard to whether use of oseltamivir drives resistance, there has been 

relatively little resistance in the 2009 H1N1 viruses. Resistance has typically been observed in 

one of two circumstances: immunocompromised persons who are being treated for a long time 

because they are having trouble clearing the virus; and in situations where a lot of people 

receive chemoprophylaxis (e.g., camp situation). Community wide transmission of resistant 

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viruses according to how much oseltamivir is used in that community has not been observed. 

During the 2007-08 season, Norway was the first country to see widespread resistance. They 

had almost no oseltamivir use. 

Ms. Ehresmann asked what the sample size was for the immunogenicity studies, and requested 

clarification with respect to whether they were going to include 9 year olds in the new 

recommendations. 

Dr. Fiore replied that for most of these studies, the sample sizes were on the order of several 

hundred children per arm. Though fairly small, the sizes were enough that statistical 

significance was achieved in terms of showing immunogenicity. In terms of the new 

recommendations, he said it was difficult to draw and exact line between the point at which one 

needs 1 or 2 doses. Clearly, the need appears to be more acute in the younger side of the age 

range. At 8 to 9 years of age, the rate of being seropositive to the viruses increases. There is 

some arbitrariness to the cutoff in terms of whether it is 9 or 10, but the work group thought it 

was reasonable to go back to the standard age cutoff for two doses, i.e., 2 doses for children < 

9 years old. 

Ms. Ehresmann noted that there had been no comments regarding the length of time between 

having received an H1N1 vaccine and receiving a seasonal vaccine that contains H1N1. 

Minnesota providers who have been administering vaccines very late into the season are 

wondering if there needs to be any time delay. 

Dr. Fiore responded that they should follow the interval currently being used for the two doses of 

seasonal vaccine of at least 28 days apart; however, he did not believe the time interval of two 

or three months would pose a problem. 

Dr. Sumaya noted that while enhanced immunogenicity is the goal, coverage is glaringly poor. 

He wondered whether there were any new strategies to increase immunogenicity procedurally 

versus increasing the coverage of children in particular. 

Dr. Fiore responded that for children approaching school age, there has been an increased 

emphasis on the use of school-based vaccination. This is probably a very nice way to increase 

coverage in that age group. This was a sign of great success in several states during the 

pandemic in which the achieved coverage rates in school-aged children reached 60% to 70%. 

CDC supports developing these programs, evaluating how well they work, and assessing best 

practices. For the younger age group, most children are vaccinated in the medical home. As 

pediatricians and family practitioners become more accustomed to gearing up for influenza 

season by vaccinating everyone in their practices, the hope is that they will get better at it. 

Dr. Sawyer expressed concern about the added complexity of Option 2 and the ability of 

physicians to determine whether children received vaccine in the past year, particularly with 

regard to school-located clinics in which communication back to the medical home may not 

have been ideal. In trying to understand what percentage of young children this extra dose will 

ultimately apply to, he wondered whether there was any information about children who did not 

receive H1N1 in the past season, but who had previously received two doses of seasonal 

vaccine or received one dose in years past. 

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Dr. Fiore responded that there are no longitudinal data in the coverage surveys that indicate a 

child’s immunization history going back more than one year, because it just became too difficult 

to ask the question. It remains unknown how many children this affects. The bottom line is that 

that most children, regardless of whether Option 1 or 2 is selected, are probably going to be 

recommended for two doses of seasonal vaccine this year because they have never been 

vaccinated before. 

With regard to the 9 year old group, Dr. Neuzil reassured everyone that the work group asked 

for data breakdowns from NIH by age. While the numbers were small, there was a clear 

relationship with increasing seroprotection after one dose with increasing age. The work group 

felt comfortable looking at the cumulative evidence that children 9 and over would be protected 

with one dose. 

Returning to the coverage issue and the pertussis discussion, Ms. Rosenbaum said she thought 

they were in a “chicken / egg” problem. They are ramping up the practice, and ramping up 

alternative practice sites as associated with ramping up the financial basis for ramping up the 

practice. She wondered whether there had been any discussion between CDC and the public 

and private insurers about rethinking the structure of coverage agreements so that 

contingencies are built into the agreements to allow for an adjustment of the coverage in the 

event of an epidemic where suddenly there is a change in practice standard and a second dose 

and second administration have to be administered. This is not an insurmountable problem, 

and it would create some certainly on the part of everybody in the system that if suddenly the 

professional standard changes, the payment system essentially will rise to the standard of care. 

Trying to get a pivot going in the practice system means financing that pivot to occur. She 

strongly recommended that they try to develop for further discussion within the ACIP this 

constant problem, which is going to be a problem for any condition for which a change in 

practice standard is needed. They really cannot afford lag times of one to two years while old 

contracts expire and new contracts have to be developed when, in fact, a professional body is 

saying they need to ramp up immediately because it would be safer. 

Dr. Englund commented that as a pediatrician, one of the major reasons for the low pediatric 

coverage was the delay in receipt of vaccine. No fault intended, but it was a fact that there was 

no vaccine available. For the pediatric practices and health clinics to have vaccine available 

earlier, which is going to occur this year, is expected to make a big difference in availability of 

the children having the potential to receive vaccine. Granted, there is still the problem of time. 

There are ample data on reactogenicity showing that multiple doses of inactivated influenza 

vaccine or live attenuated vaccine are safe and non-reactogenic in this patient population. She 

thought ACIP, as a committee, needed to acknowledge that there are data both in concomitant 

and simultaneous administration of old TIV, the new H1N1, and in the past years. It should be 

safe and is an important cornerstone of what the work group recommended. There are also 

ample data about spreading the time between vaccines as much as one year. She voiced her 

support for Option 2, which is slightly complicated, but addresses the need for two doses of 

pandemic H1N1 vaccine in younger children under the age of 9. 

Dr. Baker added that the vaccine was not only late, but also it was allocated state-by-state and 

distribution evenness and equity were issues in some states. 

Regarding coverage issues moving forward, Dr. Schuchat pointed out that the next season 

would be of unprecedented complexity. In terms of comments about the vaccine being late last 

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year, the disease was early. It is not clear what is going to happen this fall with regard to 

whether the disease will be early and when the vaccine will arrive. Parents, providers, and 

adults have many questions because there were two different vaccines last year. CDC’s 

communication team has been working with partners and conducting a lot of formative research 

to understand what the issues are and to create communication strategies that will address 

some of the barriers. They are trying to anticipate some of the challenges, but are learning from 

last year that they must be very careful with expectations, realize that there is a lot of 

complexity, and that they must work incrementally. She does not think that influenza pediatric 

coverage is principally a financing issue. The VFC program and good insurance have been 

covering influenza vaccine for children for a long time. It is more likely practitioner and parent 

attitudes that are driving this. During the pandemic, there were emergency circumstances such 

that vaccine was free but the administration was covered in unusual circumstances. The lag 

that Ms. Rosenbaum mentioned is really important for routine vaccines, but the low coverage of 

influenza vaccine is different from other pediatric vaccines and is something they have to work 

on seriously over time. 

Ms. Rosenbaum clarified that it is the administration fee not simply the dosage. It is ramping up 

of the contractual obligation to pay the second administration fee, which should be unequivocal. 

In her area, the administration fee was nearly $50 and became a tremendous problem for 

privately insured children who were not from high income families. This is a problem that can 

and should be addressed. It is simply a minor blip in otherwise complex contracts that can be 

clarified. 

Dr. Baker agreed that disease was early and it certainly was not CDC’s fault. The vaccine was 

late, given the promise date that was spread throughout the media. 

Dr. Meissner added that even though the vaccine was late, it was manufactured and distributed 

in a record amount of time nevertheless. Although the disease was very early, the system 

worked very well to a certain extent. At this point, he thought he favored Option 2. He 

wondered whether Dr. Fiore had any sense of the number of people who would be able to 

remember accurately whether they received the 2009 H1N1 vaccine last year. 

Dr. Fiore did not have any sense of this, but agreed that it would be a challenge. 

Dr. Keitel thought it was very unfortunate that they had to devise a very complicated strategy. 

One simple way to think about it is that children are unprimed to the three antigens in the 

vaccine and it may require that they receive two doses to cover each of the antigens in the 

vaccine. That is consistent with ACIP’s prior thinking about influenza vaccination. The number 

of doses being suggested is to optimize the immunogenicity to provide protection. Some of 

these studies were actually conducted with simultaneous administration and some were 

conducted with the three week interval, which shorter than usually preferred. At least with a 

three week interval, there should be absolutely no concern about matching these types of 

results. The questions about distribution, uptake, and availability of vaccine simply need work. 

The on-going need for two doses of vaccine in a single season for young children and the 

difficultly in achieving or accomplishing that goal really lays out a research agenda in terms of 

develop ways to immunize infants and young children successfully with a single dose of 

vaccine, particularly since they are recommending this on an annual basis. Until they have the 

marvelous universal vaccines that will protect everyone for years on end, she thought there 

were existing vaccines that needed to be explored for their ability to confer protection after a 

single dose. There are limited data suggesting that live attenuated vaccines can do this in 

contrast to the limited data showing that inactivated vaccines cannot. 

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Dr. Cieslak said he had always understood the need for two doses of vaccine in younger 

children as being a result of their not having been exposed to previous seasonal influenza 

strains. Over age 10, it is not that the immune system matures, but rather that this age group 

has probably been exposed to influenza previously and will respond to one dose of vaccine 

even though the strain may differ. For example, a child who had two doses of influenza vaccine 

and seasonal influenza vaccine two years ago, did not receive monovalent H1N1 vaccine in the 

past season, in the coming season receives a seasonal vaccine, and responds to one dose of 

monovalent H1N1 may be precisely the child who has been exposed to influenza before or 

vaccinated with previous influenza strains. With that in mind, he wondered whether the 

additional recommendation was needed. That is, are there data that suggest that children who 

have received seasonal vaccine before do not respond to even one dose of monovalent H1N1? 

Dr. Fiore responded that the immunogenicity studies did not characterize very well the previous 

receipt of seasonal vaccine. Data are usually collected on the current season or the previous 

season, but they do not go backwards to determine whether a child might have received a 

couple of seasonal doses two or three years ago and whether that increased the response rate. 

Dr. Marcy did not think they were giving enough credence to what Dr. Meissner said. He 

thought the confusion would be significant. He suggested an Option 3: Give two doses to all 

children 6 months to 9 years of age. 

Dr. Baker agreed with Dr. Schuchat that for parents, there would be a great deal of confusion 

and many questions. Therefore, communicating to them is very important. She also thought 

the message for practitioners must be straightforward, and should provide them with the ability 

to answer all of the complex questions patients and parents would have. 

Dr. Judson asked what the overall attack rate was in the US population for H1N1 last year. 

Dr. Fiore replied that this is unknown in terms of immunologic data. The estimate from modeling 

data is over 60 million persons are thought to have been cases some of whom did not develop 

symptoms. That would be over 20% and would be much higher in younger age groups. Those 

over 65 years of age are largely unaffected, which represents a large part of the population. 

Regarding the spacing of doses, Dr. Judson said he had tracked this for quite a while. There 

are often three doses vaccines such as hepatitis. There is probably significant leeway with the 

third dose in that a booster dose is being used. He wondered whether any studies had been 

conducted to give the booster dose at 2, 3, 4, 5, 6, 7, 8, 9 months to clarify whether (if using the 

same influenza antigen, the same vaccine) there really is a major recall difference with a 

booster given at 2 months versus a year later. Is the immunologic memory thought to be 

completely lost in an 8 year old from the first prime? 

Dr. Keitel pointed out that when middle aged, 30 to 60 year old people, were vaccinated 

repeatedly year after year, there is not a huge immunologic booster. She thought some of the 

data shown were pretty clear that in people who were primed, those people over age 10 years, 

the GMTs were much higher. Similar observations were made in adults who were given 

pandemic vaccines in past pandemics. They would respond after two doses of vaccine and 

would have low GMTs; whereas, older people who had been primed would have much higher 

GMTs of antibody. 

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Dr. Chilton thought in the previous season there had been a higher than ever immunization rate 

among school aged children at about 40% across the country. Part of that was a result of 

school-located clinics and part of it was spill over of anxiety on the part of parents that came 

about because of the H1N1 scare. However, this was misplaced to the seasonal vaccine which 

did not have much effect this year. With respect to Dr. Rosenbaum’s question, it has been 

demonstrated in a couple of projects that have been carried out with CDC support in Rochester, 

Denver, and Arizona that health plans have responded quite well to billing for administration 

fees for influenza vaccine. New Mexico is hoping for this as well. With regard to Dr. Marcy’s 

comment, he thought that given the choice between the complexities of Option 3 and the need 

to immunize every child under the age of 9 with two doses, he would choose Option 2. 

Following up on Dr. Marcy’s comment, Dr. Pickering wondered whether there would be a 

statement in the recommendations, regardless of which option was voted for, that it would be 

crystal clear that if a practitioner is not certain which vaccine or the number of vaccines a child 

has received, children ages 6 months through 8 years should receive two doses of seasonal 

immunization. He thought this was a great Category 1, Grade B comment. 

Dr. Campos-Outcalt (AAFP) advocated in favor of simplicity. They must keep in mind that this 

decision is not the only one that would probably be made during that visit. The vaccine 

schedule is getting more complicated, so this will be one of a multitude of decisions that are 

going to be made. For a single decision, which is one or two doses, if there are more than one 

or two decision points, this will be done incorrectly a high proportion of the time. 

Dr. Joe Bocchini (AAP) thanked Drs. Fiore and Neuzil for allowing the Committee on Infectious 

Diseases (COID) to participate in the work group, and stated that COID favors Option 2. This 

has been discussed in detail, and although a number of people were in favor of Option 1 

because of its simplicity, the majority of the COID members were in favor of Option 2 because 

of the epidemiologic and serologic data. He thought Option 1 would cover more children 

effectively than Option 2. It actually adds just one additional decision and, in fact, the 

practitioner does have to go through for the first two parts of Option 2 with the same review of 

immunization history to determine if the child has received two doses of seasonal, et cetera. 

Although it will add some complexity and it may be more difficult for this year, it is appropriate to 

deal with that difficulty. 

Dr. Stan Grogg (AOA) said that as a pediatrician who liked to keep it simple, he liked Option 2. 

Dr. Whitley-Williams (NMA) asked whether the group examined any data on children who had 

proven real time PCR H1N1 and perhaps two doses of seasonal vaccine. 

Dr. Fiore said the short answer was that there is not anything known about long-term protection 

after natural infection with the 2009 H1N1. It presumably would be for at least several years, so 

in that sense perhaps there are children who had true laboratory confirmed 2009 H1N1 who will 

not have to worry so much about that particular virus. They might have to worry about a drifted 

H1N1. It is difficult to determine whether a child received influenza vaccine doses in the 

previous year, and it will be more difficult to figure out whether they truly had lab confirmed, 

PCR confirmed, H1N1. The advise would be to err on the side of vaccine according to the 

dosage received rather than a laboratory test, which is probably not going to be available to 

most immunizers. 

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Ms. Stinchfield (NAPNAP) said that as a working group member, she also tried to share the 

voice of simplicity. Last year, vaccines were given in medical homes, schools, malls, tents, and 

all sorts of strange places. Given the data, she thought Option 2 seemed the most reasonable. 

(e.g., if unsure what was received, give 2 doses). 

Paul Etkind (NACCHO) would hardily endorse the simpler, the better. In terms of Ms. 

Rosenbaum’s comments, any barriers that can be eliminated in terms of billing would be of 

extraordinary help. 

Dr. Katie Brewer (ANA) favored Option 1 pointing out that if they continued to create 

complexities in terms of the schedule, they would also continue to alienate people who are 

trying hard to immunize. 

Following up on Ms. Rosenbaum’s comments, Dr. Birkhead (NVAC) noted that in 2008, NVAC 

adopted a comprehensive set of finance recommendations for pediatrics and adolescents that 

included a recommendation that managed care plans in particular be flexible in the mid-contract 

cycle to adopt new changes. With H1N1, a number of the large plans did at least send letters 

indicating that they were going to cover the administration fee for 2 doses. Clearly, that was not 

universally adopted. Those recommendations were a consensus set of recommendations that 

included support from AHIP, so he thought the challenge now was to disseminate those 

recommendations in order to bring them to the attention of the various plans so that they can be 

implemented across the board. He also inquired as to what the evidence basis was for the 

current recommendation that children who receive one dose of seasonal vaccine in their first 

season should receive two doses again in the next season versus a single dose. 

Dr. Fiore responded that the recommendation was largely based on a study conducted during 

the 2003-2004 season and published in the Journal of Pediatrics, which used a managed care 

database to assess differences in the effectiveness of ILI for children who had those two 

scenarios (e.g., those who received a single dose in their first year and a single dose in their 

second year, versus those who received two doses in their first year. There was a significant 

difference in the rates of ILI in those two groups, but it is a fairly limited database. 

Dr. Baker reminded the committee members ACIP is a policy committee, not a implementation 

committee. She then called for a motion. 

Dr. Cieslak pointed out that they had not seen any data to suggest that people who met the 

criterion of having had two doses in a previous season do not respond to one dose of H1N1 

vaccine. Where is the burden of proof? He thought the burden of proof was on those who 

would add complexity to the recommendation, so he supported Option 1. 

Dr. Neuzil said they must remember that this is an antigenically distinct virus and it caused a 

pandemic. Going into a pandemic situation, it was fully expected that the whole population 

would need two doses. The idea is that this virus is so antigenically distinct that priming for the 

seasonal viruses would not boost a response. That is substantiated by the tremendous 

differences in the responses in the younger age groups versus the older age groups who were 

exposed to H1N1 50 years ago. 

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Dr. Temte said he had looked at Option 2 a number of times prior to the meeting and he still had 

difficulty understanding exactly how he would implement this in his practice. He loved Dr. 

Marcy’s suggestion because in the coming year, he is more concerned about the H3 virus than 

H1N1. Therefore, he would opt for simplicity in relationship to clinicians who have to implement 

this. 

Dr. Cieslak said his response to Dr. Neuzil was that those who did not see H1N1 50 years ago 

did respond to a single dose of H1N1 vaccine this year. 

Dr. Keitel indicated that in at least one of the NIH studies, the history was obtained of prior 

priming and the children were supposed to have been primed based on a verbal history from the 

parents. She thought it was very interesting that they fully understood the immunologic reasons 

for the 10 years of age plus, but her way of thinking about that would be that those people had 

more opportunity for naturally occurring H1N1 infections as opposed to trying to prime them with 

an inactivated H1N1 vaccine antigen. 

Dr. Englund indicated that some data would soon be available. 

Dr. Gorman (NIH) indicated that the studies conducted for the H1N1 vaccine were designed to 

answer the question regarding how many doses it took to generate an immune response. Data 

were collected about the previous vaccination status of individuals. This was done by recall, 

and the numbers of that particular data field did not prove to be very predictive in any way of 

response. In addition, the numbers were small. While he would love to offer this committee 

data, the only data he could provided would be data based on recall, which would not be useful 

and would not contribute in any realistic way to the discussion they were having. 

Dr. Englund added that certainly data from that trial indicated that, regardless of receipt of 

vaccine, children under 3 responded poorly. Based on this it is obvious that the youngest age 

group, those under 3, absolutely need two doses regardless of previous vaccines. 

Dr. Ehresmann requested a reminder of Dr. Marcy’s Option 3. 

Dr. Meissner agreed that the default should be 2 doses for any child for whom previous doses 

are unclear. However, some practices will keep very clear records and some families will know 

that their child received 2009 H1N1 vaccine in the previous year. Therefore, he did not think 

they needed to recommend it for everybody. 

Motion: Influenza Vaccine 

Dr. Chilton moved that ACIP adopt Option 2 with the addition that children who have not 

received one previous dose of H1N1 vaccine have to receive 2 doses in the coming season if 

they are under the age of 9. Dr. Meissner seconded the motion. The motion carried with 10 

affirmative votes, 5 negative votes, and 0 abstentions. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Vaccines for Children (VFC) Program Resolution Update: Influenza Vaccine 

Lance E Rodewald, MD 

Director, Immunization Services Division 

National Center for Immunization and Respiratory Diseases (NCIRD) 

Dr. Rodewald indicated that with this vote, there became an inconsistency with what ACIP 

recommended for all children and what was allowable under the VFC program. The purpose of 

this session was to update the recommendation for the 2 doses of vaccine in children ages 6 

months through 8 years based on receipt of the influenza A(H1N1) monovalent vaccine, and to 

streamline the resolution through the use of links to published documents. In addition, an 

additional phrase would have to be added to the resolution to state something to the effect that 

children with uncertain status could be receiving two doses of the vaccine. 

Additions are underlined in the following recommended schedule: 

Recommended Vaccination Schedule (TIV) 

 6 months through 8 years: 1 or 2* doses

 9 through 18 years: 1 dose 

 *All children ages 6 months through 8 years who receive a seasonal influenza vaccine 

for the first time should be given 2 doses. Children who receive only one dose of a 

seasonal influenza vaccine in the first influenza season they receive vaccine should 

receive two doses, rather than one, in the following influenza season. In addition, for the 

2010-11 influenza season, children ages 6 months through 8 years who did not receive 

at least 1 dose of an influenza A(H1N1) 2009 monovalent vaccine should receive 2 

doses of a 2010-11 seasonal influenza vaccine, regardless of previous influenza 

vaccination history. 

Recommended Vaccination Schedule (LAIV) 

 2 years through 8 years of age: 1 or 2* doses 

 9 through 18 years of age: 1 dose 

 *All children ages 6 months through 8 years who receive a seasonal influenza vaccine 

for the first time should be given 2 doses. Children who receive only one dose of a 

seasonal influenza vaccine in the first influenza season they receive vaccine should 

receive two doses, rather than one, in the following influenza season. In addition, for the 

2010-11 influenza season, children ages 6 months through 8 years who did not receive 

at least 1 dose of an influenza A(H1N1) 2009 monovalent vaccine should receive 2 

doses of a 2010-11 seasonal influenza vaccine, regardless of previous influenza 

vaccination history. 

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Contraindications (LAIV) 

 If an ACIP recommendation regarding influenza vaccination is published within 6 months 

following this resolution, the relevant language above (except in the eligible groups 

sections) will be replaced with the language in the recommendation and incorporated by 

reference to the URL. 

 Contraindications and precautions can be found at: 

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5808a1.htm?s_cid=rr5808a1_e 

There is a statement in all the resolutions that if an ACIP recommendation regarding influenza 

vaccination is published within 6 months following a resolution, the role of the language except 

the eligibility groups, will be replaced by the language in the recommendations and incorporated 

by a reference to the link, which is shown above. 

Discussion Points 

Dr. Chilton did not believe the Recommended Vaccination Schedule (TIV) language was entirely 

consistent on the strange question of whether a child received the first dose in a year prior to 

the year under consideration. For example, if a child received a single dose in 2007-2008 and it 

is 2010, then that child would need only one dose in the current year. That was in the 

recommendation, but not in the VFC recommendation. 

Dr. Fiore responded that the intent was that a child who only received a single dose in a 

previous season that was not the last season would only be getting one dose for the upcoming 

season. However, with the addition of taking the monovalent vaccine into account, some of 

those children will fall into the two dose requirement. In other words, they got a dose at 6, 7, 

and nothing since then, so they would receive two doses of the seasonal this year because they 

need two doses of the 2009 H1N1 antigen. 

Dr. Campos-Outcalt (AAFP) noted that if a child received H1N1 last year, that was not a 

question. However, if they received no seasonal vaccine last year, and the year before that was 

their first time and they only got one dose, it would be unclear whether they should received 1 or 

2 seasonal shots this year. It still says “in the following year” and that makes in unclear. If they 

were out two years from that first dose, that terminology (the following year) makes it unclear 

whether it is two doses this year or one dose this year. 

Dr. Fiore replied that this is in harmonization with AAP recommendations a couple of years ago 

when it was decided that the data supported giving two doses to a child who had only had one 

dose in their first season, and extended to that following season. He welcomed suggestions 

about how to make this clearer. 

Motion: VFC Resolution for Influenza Vaccine 

Dr. Neuzil moved that ACIP approve the language as stated with the addition of the “default of 

two doses” language. Dr. Meissner seconded the motion. The motion carried unanimously with 

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

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Monitoring Influenza A (H1N1) 2009 Monovalent Vaccine 

Safety: Preliminary Findings from Three Systems 

Frank DeStefano, MD, MPH 

Immunization Safety Office 

Division of Healthcare Quality Promotion, 

National Center for Emerging and Zoonotic Infectious Diseases 

Centers for Disease Control and Prevention (CDC) 

Dr. DeStefano presented an update on the safety of H1N1 vaccine from several systems that 

have been used for monitoring. His presentation covered VAERS, the Real Time Immunization 

Monitoring System (RTIMS), and the Emerging Infections Program (EIP) GBS Surveillance 

Project. 

The routine systems that have been in place for several years include VAERS, the Vaccine 

Safety Data Link (VSDL), and the Clinical Immunization Safety Assessment Network (CISA) for 

case reviews. The following diagram shows the systems used: 

The right side of the screen shows either enhancements primarily to VAERS and some of the 

new systems that were presented during this session. The top half indicates systems that are 

primarily used to detect signals, while the lower half shows the systems that can be used to 

follow up signals. 

Dr. DeStefano explained that VAERS is a spontaneous reporting system that is used primarily 

for signal detection. The system is subject to the well-known limitations of spontaneous 

reporting systems, such as various reporting biases (e.g., underreporting, differential reporting, 

stimulated reporting; inconsistent data quality and completeness; and lack of an unvaccinated 

comparison group to conduct causality assessments). Various methods are used to evaluate 

VAERS reports. One of the first is to look at the safety profile, which is usually done in 

comparison with vaccines that have an established vaccine safety profile. For the 2009–2010 

H1N1 vaccine, the main comparator was seasonal vaccine used either during the current 

season or in past season. This is felt to be a valid comparator because seasonal influenza 

vaccines have a well-established safety record. The total reports for H1N1 are considerably 

more than received from past seasons or even a current season (n=7241). It is believed that 

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this is due to stimulated reporting. Serious reports include such things as hospitalization or 

long-term disability. H1N1 has had a similar serious proportion as previous seasonal vaccines. 

These results are based on an estimated 65 million vaccinated people. This was as of January 

31, 2010. The number of reports is similar for live attenuated vaccines, based on an estimated 

17 million vaccines (n=2068). 

Another method that was used to evaluate VAERS reports was formal data mining. This 

basically asseses all types of symptoms and conditions that have been reported for a particular 

vaccine and compares those to other vaccines. This has been done through this season by the 

FDA. They rely on a method called Empirical Bayes. The analyses exclude non-US reports, 

there is adjustment for age and gender, and the comparison groups are an appropriate 

comparative vaccine (e.g., the inactivated vaccine is compared with other inactivated vaccines, 

and the live attenuated vaccines as compared to other live vaccines). With regard to the data 

mining results for the inactivated vaccine, there was only one adverse event signal, which was 

for incorrect dose administration in the age group 0-1. The cutoff is the EB05, which stands for 

the Empirical Bayes measure that indicates a cutoff of the lower 5th percentile of the confidence 

interval. The FDA uses a cutoff EB05 of 2 or higher for an indication of possible signal. This 

particular signal was 2.7 and was in the infants who received an inappropriate dose for their 

age. The data mining results for the live attenuated vaccine found the expected results from the 

clinical trials from the vaccine (e.g., cough and oropharyngeal pain, and contraindication to 

vaccination). This represented a vaccination of a live attenuated vaccine of pregnant women, 

individuals with asthma, or immunosupressed individuals. 

The other main approach to evaluating VAERS reports is to conduct extensive clinical case 

reviews of the reports and supplementary medical record review by medical officers, 

supplemented as needed by CISA experts. 

VAERS reports of deaths following inactivated H1N1 vaccine by body system in 42 vaccinees 

included: 20 cardiac (includes 1 pregnant), 8 infectious (1 with GBS), 5 multiple systems, 4 

neurologic (includes 1 with GBS), 1 respiratory, 1 trauma, 1 pregnancy complication, and 2 

unknown. The 6 VAERS reports of death following live H1N1 vaccine by body system included: 

2 cardiac (myocardial infarction, hypertrophic cardiomyopathy*), 2 infectious (pneumococcal 

pneumonia* with pandemic influenza, pneumococcal sepsis*), 1 neurologic 1 (sequelae of spina 

bifida), and 1 respiratory (aspiration from choking on food). * Lung tissue from 3 death reports 

was tested at CDC for molecular evidence of vaccine strain H1N1 and was found to be 

negative. 

Clinical case reviews were conducted of selected adverse events, including GBS. Reviews of 

those cases identified 99 confirmed reports of GBS and 117 reports of anaphylaxis. When 

reporting rates were calculated using estimates of vaccine coverage from immunization surveys, 

the reporting rates for GBS were 1.1 per million and for anaphylaxis were 1.4 per million. Both 

of those were right at or less than would be expected from background rates. 

In summary of VAERS, the H1N1 reported adverse event pattern was consistent with 

expectations in that there were no new signals, the most common non-fatal serious reports after 

inactivated vaccine were neurologic (results not presented), the most common non-fatal serious 

event after the live attenuated vaccine were respiratory / influenza type conditions. GBS and 

anaphylaxis reports after H1N1 vaccination were rare, each occurring less than 2 per million 

doses administered. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Dr. DeStefano explained that the RTIMS was conceived and operated at John’s Hopkins 

University by Dr. Neal Halsey, who is the principal investigator. This is automated web-based 

active surveillance targeting health care workers, pregnant women, and children. This was a 

collaboration between CDC and Johns Hopkins School of Public Health. There were two 

methods of enrollment of participants: 1) active capture (permission to contact at time of 

vaccination); and 2) passive capture (enter via websites maintained by Johns Hopkins, CDC, 

states). Individuals were followed up periodically post-vaccination up to 42 days. There were a 

total of over 14,000 enrollees, of which 10,700 were enrolled through the active capture method. 

The following table summarizes the results from this system: 

Policy/Health Services or ProgramEvaluation

Rates of Adverse Events Adjudicated Diagnoses 

After Influenza Vaccines Active Capture as of 4/15/10

Don’t know or Seasonal Only H1N1 Only Both Tota Missing (N=3046) (N=6,264) (N=1096) (N 10,743) Reported Symptoms (N 337) 

n Rate* n Rate* n Rate* n Rate* n Rate*

Sought Medical Care 138 45.3 266 42.5 35 31.9 6 17.8 445 41.4

Hospita ization 7 2 3 15 2.4 0 0.0 1 3.0 23 2.1

mmed ate Hyper 0 0.0 6 1.0 0 0.0 0 0.0 6 0 6 sensitivity (<48 hours)

Delayed Hyper 0 0.0 3 0.5 0 0.0 0 0.0 3 0 3 sensitivity (>48 hours)

Neurologic: 11 3.6 17 2.7 2 1.8 0 0.0 30 2 8 Non seizure 

Se zures 0 0.0 1 0.2 0 0.0 0 0.0 1 0 1

nfluenza like Illness 55 18.1 70 11.2 11 10.0 4 11.9 140 13.0

All other complaints 147 48.3 295 47.1 54 49.3 3 8.9 499 46.4

. 18 

*Rates per 1000 

These results are from about 10,000 active capture of participants. The main comparison to 

focus on would be the left most columns that indicate the results for seasonal only and H1N1 

only. The results are very similar suggesting that the adverse event patterns for the H1N1 

vaccine is quite similar to the seasonal vaccine. 

During this session, Dr. DeStefano also described the EIP program for GBS. This was recently 

published in the MMWR [MMWR June 4, 2010 vol 59 (21): 657-661]. This system is a 

collaboration between CDC, state health departments, and academic centers. The population 

covered is about 45 million people in 10 catchment areas. Active case finding is conducted by 

surveillance officers using neurologist networks and hospital discharge diagnoses. Case 

vaccination status has been determined by telephone interview and physician records. The 

population vaccinated was determined from telephone surveys (BRFSS). Brighton case 

definitions were used to define GBS. The timeframe was October 1, 2009-March 31, 2010. 

The preliminary results are that 326 cases met the Brighton case definition, of whom 27 

received H1N1 vaccination during the 42 days before GBS onset. Of note, antecedent 

respiratory or gastrointestinal illness had occurred in about 59% of the vaccinated versus 78% 

of the unvaccinated cases. Calculating the rate of GBS per 100,000 person years, it was 1.92 

in the vaccinated versus 1.21 in the unvaccinated. This translated into an age-adjusted rate 

ratio of 1.77. The confidence interval does not overlap 1, indicating that this was a statistically 

significant result at P of less than .05. It is estimated that this would account for 0.8 excess 

cases of GBS per million vaccinated, which is similar to what has been observed for seasonal 

vaccines in some years. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Planned additional analyses in the EIP project will be a self-controlled case series. This is a 

fairly established method in vaccine safety research. This method avoids potential biases 

introduced by survey estimation of vaccinated population and comparing vaccinated to 

unvaccinated, and uses only vaccinated cases to estimate the relative risk of vaccine (cases 

serve as their own controls). This method is commonly used in vaccine safety studies, and 

results correlate well with cohort studies. A final sweep of hospital records is important to 

ensure that all cases found. The results from these analyses will be available in the early fall. 

H1N1 Vaccine Safety Findings from the Vaccine Safety Datalink (VSD) Project 

and the Post-Licensure Rapid Immunization Safety Monitoring (PRISM) Network 

Tracy Lieu, MD, MPH, and Grace Lee, MD, MPH 

Department of Population Medicine 

Harvard Pilgrim Health Care Institute and Harvard Medical School 

Dr. Lieu reported the findings from the VSD project and the PRISM Network, focusing on 

findings pertaining to GBS, Bell’s palsy, and seizures. VSD and PRISM are two of the largest 

active surveillance systems that participated in H1N1 safety monitoring this past season. VSD 

is organized by CDC and includes 9 million people in managed care settings. The PRISM 

system is a completely new system that has been organized by FDA, NVPO, and CDC. It 

includes 35 million persons. DoD, CMS, VA, and IHS also have participated in monitoring. The 

VSD project includes 8 health plans. It is sponsored and coordinated by CDC, and includes 

data on 9 million persons (3% of the US population) and has an annual birth cohort of 95,000. 

This system has very good geographic diversity and an amazing set of collaborators. 

In the VSD study, vaccination records are linked with hospital and emergency department (ED) 

diagnosis codes, as well as outpatient visit diagnosis codes. The data are linked by study IDs, 

they are kept at each site, and the data sets are actually never sent to CDC. This was one of 

the earliest distributed data networks in the country. Rapid cycle analysis is conducted for 

influenza vaccine and for most newly introduced vaccines. Data are updated on all vaccines 

and all outcomes every week, and data are analyzed every week. Pre-specified outcomes are 

monitored that are selected for each vaccine based on the literature as well as VAERS and 

other reports. The number of outcomes is evaluated in vaccinated persons, and these numbers 

are compared to an expected number of outcomes from a comparison group. 

In weekly monitoring of H1N1 vaccines, the risk or exposure window is assessed. That is the 

period after H1N1 vaccination. The length of the risk window depends on the outcome and can 

be up to 42 days or shorter in the case of certain outcomes like seizures that would biologically 

not be expected to last that long. Comparisons are made using historical rates after seasonal 

influenza vaccination and the self-controlled case series comparison, which uses unexposed 

time periods from the same person. Sequential analytic methods must be used, given that data 

are being analyzed every week, so they must adjust for the false positives that could result from 

repeated testing of this accumulating data. For this evaluation, the maximized sequential 

probability ratio test was used. 

For H1N1 vaccine, there are several analytic challenges. The priority groups for H1N1 

vaccination differ from the historical comparison groups who received TIV vaccine. Influenza 

vaccines are given over a relatively short period of time. The data, especially hospital claims 

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data from health plans, can take about three months to fully settle and be reliable. Finally, there 

may be confounding by seasonality if the outcomes of interest themselves are seasonal. 

With regard to the VSDs results, the total number of H1N1 doses under surveillance in the VSD 

project totals 1.6 million including 1.3 million doses of inactivated and 267,000 doses of live 

vaccine. The inactivated vaccine includes 37,000 doses that were given to pregnant women. 

The overall vaccine coverage rate was 20%, which varied a great deal by age group. The lull is 

about 10% in the 18-24 year old age group. The high was 54% in the 6-23 month age group. 

The VSD is monitoring 10 outcomes in all persons plus three additional outcomes that are 

pregnancy-related. All of the outcomes are monitored using computerized ICD-9 codes. For 

GBS, in addition to the ICD-9 codes, chart reviews have been done for the cases and a 

comparison group of all of the historical cases. These are being adjudicated by an expert 

neurologist. 

Regarding the findings for GBS after inactivated H1N1 vaccine, there were 15 cases observed. 

The expected number of cases based on historical computerized data is 9.2 for a relative risk of 

1.6, and this was not significant. Of these 15 cases, 8 were confirmed after chart review. 

These 8 cases were compared to the historical cases that also had been chart reviewed. Based 

on that historical chart review data, there would have been 3.4 cases expected for a relative risk 

of 2.3. This also was not statistically significant, although the test statistic did move in the 

direction of significance. It is possible that the relative risk of 2.3 is due to an increase case 

identification in the current year compared with historical years. 

All of these cases were adjudicated by a team of expert neurologists, and the level of certainty 

about these cases was based on the Brighton collaboration criteria. People usually look at 

Brighton levels 1, 2, and 3 as being probable GBS cases. In terms of the percentage of cases 

that are in these categories, the pattern for the cases after H1N1 in the current season does not 

look different from the pattern for historical cases after TIV in past seasons. There is really no 

support for the hypothesis that this elevated relative risk is simply due to a lower bar for case 

identification in the current year compared with in the past. 

A one-time interim analysis was also conducted, partly because of the finding of relative risk that 

was reported by the EIP. In this type of analysis, the investigators were able to adjust for more 

confounders. This model was adjusted for age group, sex, and VSD site. This analysis used 

Poisson regression, using an exact method to deal with the low numbers of cases, and found a 

relative risk of 2.44. This relative risk is relative to the TIV vaccinees in historical data. The 

95% CI from this analysis was 0.96 to 5.42. This CI includes 1, so it is not statistically 

significant, but it is close, which is a cause for some concern. GBS is rare, so this relative risk is 

going to translate into a very small attributable risk. 

The team is currently evaluating the attributable or excess risk of GBS that could be associated 

with inactivated H1N1 vaccine. There are several important issues being considered. The rapid 

cycle and interim analyses compare H1N1 in the current season to trivalent influenza vaccine in 

historical years, and the estimate of attributable risk is going to depend on what is chosen as the 

most appropriate background rate. It is preferable to use a background rate that is most 

comparable to the analyses in terms of the population and the case definition being used. In 

other words, they would like a background rate that is based on chart reviewed and adjudicated 

GBS cases in vaccinated persons. The interim analysis findings are very new, and the team 

and the Vaccine Safety Risk Assessment Working Group (VSRAWG) need to discuss what the 

appropriate background rate to use for the attributable risk would be. 

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An end of season analysis of GBS after H1N1 vaccine is planned. Also planned is a selfcontrolled case series design. Because of the need for the risk windows to lapse and the 

comparison windows to lapse, and another three months for the data to settle, it will not be 

possible to conduct an accurate end of season analyses until August. These analyses are 

expected to shed more light on whether the increase in risk observed in the interim analysis 

represents a true association, or whether it is due to other explanations, such as unmeasured 

confounding or other issues with the analysis. 

Turning to the other outcomes of greatest interest, in the rapid cycle analysis, the relative risk of 

Bell’s Palsy in adults 25 years or older was 1.7. This was statistically significant using the selfcontrolled case series method. Statistical signals do not necessarily represent true 

associations. When a signal like this is observed, an effort is made to try to confirm or exclude it 

based on additional analysis and, if needed, additional data collection. The initial signal was a 

relative risk of 1.7 in the self-controlled case series analysis. An alternative analysis was 

conducted using a historical TIV group as a comparison, and no signal was found. A temporal 

scan of these cases was done and no clustering of cases was found. A case-centered analysis 

was done that adjusted for seasonality, age group, gender, and site that found an odds ratio of 

1.2 and 95% CI that was .093 to 1.57, and was not significant. 

Several additional analyses are in progress. Most of the team members involved with working 

up this signal do not believe that this statistical signal represents a true increase in risk. There 

are several possible explanations for the Bell’s Palsy signal. From least to most likely, there 

could be a true excess risk. The additional analyses being conducted are starting to provide 

evidence against this being a true excess risk. There could be confounding by indication, 

meaning that the vaccinees differ from the comparison groups. This seems somewhat unlikely 

for clinical reasons, and such an effect is not observed for TIV in the historical data. There 

could be some seasonality effect, which seems like a potential partial explanation given that the 

seasonal distribution of H1N1 inactivated vaccine was different from the current and prior TIV 

vaccines. Finally, chance is actually the most likely primary cause of the signal, because even 

though the statistical methods attempt to adjust for this, surveillance is being conducted for so 

many outcomes, sometimes age-stratified, and 4 different influenza vaccine types are being 

assessed (e.g., live and attenuated H1N1 and seasonal influenza vaccines). 

There have been concerns raised in Australia that influenza vaccines cause seizures in 

children. In the initial VSD analysis of seizures after H1N1 vaccine, a relative risk of 1.9 was 

observed in persons who were less than 24 years old. This was not statistically significant, but 

because of the Australian data, the team opted to take a closer look. This age group was 

stratified into those who were less than 4 years old and those who are 5 to 24 years old. A 

historical comparison approach was used because the numbers became too small for the initial 

self-controlled case series approach to be reliable. The relative risks on this closer look at the 

youngest age groups were not significantly elevated. 

Other outcomes being monitored include encephalomyelitis, demyelinating disease, ataxia, 

anaphylaxis, and allergic reactions. The relative risks are all close to 1, and none are 

statistically significant. 

There are some general lessons with respect to the VSD project. The VSD’s success has 

depended on very robust relationships among the collaborators, as well as endless pursuit of 

data quality. The intense public health interest this past season has led to higher demands and 

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higher accountability, and the team is quite thankful to have VSRAWG to discuss these findings 

with. However, even the VSD project has limited power to detect signals for extremely rare 

outcomes. The VSD operated through much of the H1N1 season with a sense of crisis due to 

the high levels of public concern, the media coverage, the websites, and the expressed 

concerns about this H1N1 vaccine. Dr. Lieu reminded everyone that the Chinese word for crisis 

combines characters from danger and opportunity. The sense of crisis over H1N1 vaccine 

safety has opened a chance to strengthen the national vaccine safety monitoring infrastructure 

for the long-term. 

The major new effort Dr. Lieu was involved in was the PRISM network, which includes four 

national health plans and 9 state immunization registries. There were two reasons that PRISM 

was started. The impetus was to assess larger populations to help monitor GBS and other rare 

events. Having larger populations should shorten the time to identifying problems. It was also 

anticipated during H1N1 season that much of the H1N1 vaccine would be distributed through 

public providers who would not necessarily be captured in traditional health plan claims. The 

PRISM network was formed to help capture vaccine exposure from these settings. The four 

health plans that participated were selected on the basis of their ability to rapidly assemble data 

to update it every one to two weeks. The participants were Aetna, CIGNA, Humana, and 

HealthCore, which represented Blue Cross Blue Shield plans in four states. From among these 

health plans, PRISM included a total of 35 million persons. The state immunization registries 

were selected based on having timely H1N1 vaccine data and having experience in matching 

these data with health plans on the basis of size. There were 9 participating states including 

Arizona, Florida, Georgia, Michigan, Minnesota, New York, New York City, Pennsylvania, and 

Wisconsin. There were a total of 12 million persons in the participating health plans who lived in 

these 9 states. 

PRISM is a very large collaboration that involves HHS, AHIP, Population Medicine at Harvard 

Medical School and Harvard Pilgrim Health Care, Computer Sciences Corporation which is 

providing technical support, states, health plans, and the Public Health Informatics Institute. 

More than 100 people have been involved, and special credit goes to Daniel Salmon, who 

spearheaded this entire effort and stood by and pushed. To be honest, it was a strenuous 

scramble to put all of this together in the late summer and the early fall. The participants 

deserve tons of credit. The leadership team of PRISM also includes Bob Ball of FDA and Jerry 

Tokars and Eric Weintraub of CDC who participate in the leadership calls. 

Comparing VSD and PRISM, VSD is nearly 20 years old and it has the strong advantages of 

experience, stable data, the ability to launch major new efforts like H1N1 monitoring in a timely 

way, and rapid access to the charts of the people who may have the ICD-9 coded cases. 

PRISM has the advantage of a larger size and it includes much more extensive state 

immunizations registry data. PRISM has also an additional few novel features. There is a full 

population linkage between the health plans and state registries. The freshest possible claims 

from the health plans are being used and it is not classified as research. Interestingly, VSD has 

always been classified as research. In PRISM, part of the reason the team was able to get 

these systems going within a few months is that they had a letter from the Office for Human 

Research Protections (OHRP) that it is not research. They did not have to go through IRB 

oversight, which has really sped some of the HIPAA and other arrangements that the health 

plans and states needed to make. In PRISM, the current season surveillance takes all of the 

current health plan members, obtains their H1N1 vaccine exposure data from both the health 

plan claims and the immunization registries, and then the outcome data on all the vaccinated 

persons come from health plan claims. Historical data are gathered in the same way, but all of 

the data are from health plan claims in the historical seasons after seasonal influenza vaccine. 

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Data confidentiality is maintained by keeping all of the personal level data behind health plan 

firewalls. Standardized programs are written that aggregate these data into counts of 

immunizations in outcomes. Then these counts can be sent beyond the health plan firewalls 

and analyzed by Harvard and at Computer Sciences Corporation. 

PRISM monitors a total of 2.7 million vaccine doses. About 112 of these are known to be live 

vaccine and the rest are either inactivated or of unknown vaccine type. In PRISM, the overall 

coverage rate is about 15% and the pattern by age group is very similar to VSD’s registries. Of 

the H1N1 vaccine doses being monitored in PRISM, state registry data alone contributed 57% 

of those doses. Thus, all of the work put into making these matches between the 9 state 

registries and the 4 health plans strengthened the diversity of data that were captured by this 

system. For seasonal TIV, the percent that are captured in state registry data alone is actually 

lower at 26%, so the patterns here are quite different. In terms of the findings from PRISM, for 

GBS, the analysis of computerized data from PRISM actually did not find an increase in the 

relative risk of GBS. The relative risk was 0.8, which is quite different from the VSD finding. At 

this point, an extensive review is being conducted of the PRISM data, and a chart review is 

being initiated of the GBS cases in the current and historical groups in PRISM. The rest of the 

findings from PRISM are quite reassuring. For Bell’s Palsy and seizures, the relative risk is 

under 1, and they are not significant. In terms of the rest of the outcomes, the relative risks are 

not also marketedly elevated and they are not statistically significant. 

In summary, 1.6 million doses of H1N1 have been monitored in VSD and 2.7 million doses have 

been monitored in PRISM. For GBS, there is a relative risk of 2.4 from chart-confirmed data in 

VSD, with a 95% CI that ranges from 0.96 to 5.4. The attributable risk of GBS is being 

discussed and is being worked out. There is a weak signal for Bell’s palsy after inactivated 

H1N1 in VSD, but not in PRISM. It seems unlikely that this represents a true increase in risk. 

The next steps are to conduct end-of-season analyses after the data settle in August. 

Comparisons will be done with those post-vaccination windows. Additional outcomes will be 

evaluated. Overlapping H1N1 and seasonal influenza vaccination will be assessed because 

that is what the coming vaccine will look like. Analyses of pregnancy-related outcomes will be 

refined, and Daniel Salmon is leading a plan to combine chart review data from VSD, PRISM, 

and several other systems for the purpose of gaining more power to do a clean evaluation of 

GBS. 

H1N1 VACCINE SAFETY MONITORING Medicare Population 

Frank DeStefano, MD, MPH 

Immunization Safety Office 

Division of Healthcare Quality Promotion, 

National Center for Emerging and Zoonotic Infectious Diseases 

Centers for Disease Control and Prevention (CDC) 

Dr. DeStefano presented on behalf of Dr. Hector Izurieta. For H1N1 monitoring, FDA 

coordinated bringing some other large healthcare databases into the monitoring system. In this 

presentation, Dr. DeStefano covered the primary results from three systems: Medicare, VA, 

and IHS. 

Medicare covers data on 38 million people 65 years or older and an additional 8 million people 

under 65 with disabilities. This particular system was used to monitor for GBS. The main risk 

interval used was 0 to 42 days post-vaccination. A couple of different risk intervals were used 

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for secondary analyses. The expected adverse event rate was obtained from the occurrence 

after in five prior influenza seasons among seasonal influenza vaccinated individuals. Basically, 

as with the other systems, they have been conducting sequential testing throughout the 

vaccination season and have adapted methods to account for multiple testing. Also, they have 

adjusted delays in claims accrual. So the expected adverse event rate is modified by the delay 

in adverse events derived from historical distribution of delay times. 

Regarding the main result from the Medicare data for GBS monitoring, for the 0 to 42 window 

among all vaccinees (n=over 3 million vaccines), 14 cases of GBS were observed with an 

expected 14.67. The relative risk was 0.95, which was not statistically significant. In the other 

risk windows, the relative risk still remains close to 1 and none were statistically significant. 

The VA has an integrated electronic database for which data on vaccination, outpatient visits, 

and hospitalizations are considered complete and available in real time for rapid cycle analysis. 

This database includes an approximate total of 2.1 million veterans and over 300,000 H1N1 

vaccine doses administered. They also have been able to integrate prescription databases, the 

National Patient Care Databases, mortality data, and other disease registries. The rapid cycle 

analysis for the VA is a pilot integrated database and immunization tracking system. It is 

focused on the inactivated H1N1 vaccine, abbreviated MIV. Two analyses have been 

conducted with VA data, and the comparison is based on historical background rates from 

previous seasonal influenza seasons. Regarding the two analyses, the first version uses 

currently available data whereas the second version allows a full week data delay in the 

analyses. 

Regarding the primary findings from those analyses, the preliminary results for a total of over 

350,000 people vaccinated with inactivated H1N1 vaccine showed no signals for any of the prespecified outcomes, with the exception of thrombocytopenia. Results for the outcome TP II are 

stratified, and TP I is the broader category of conditions. TP II restricts the thrombocytopenia 

cases to those coded as 287.31, which is ITP or idiopathic thrombocytopenic purpura. This is a 

highly specific code that did not signal. Moreover, in this on-going investigation, out of 70 

thrombocytopenia cases already reviewed by VA researchers, only 4 (6%) were confirmed as 

ITP. Although there was no signal for GBS, the number of cases (n=5) was too small to be 

conclusive. The results for version 2, allowing the 4-week delay, are very similar to the version 

1 results. Regarding limitations, prevalent TP diagnoses remain with an adjusted wash-out of 

24 versus 6 months. The diagnosis is not always picked up as previous ICD-9 codes in the 

database because many patients have multiple co-morbidities exceeding the max of 10 

diagnoses in the administrative databases. Many veterans are ill and can have up to 15 or 

more co-morbid conditions. 

There is a proposed end-of-season analysis plan to evaluate risk of pre-specified diagnoses 

following inactivated H1N1 vaccine. Indirect adjustment will be to assess standardized 

incidence ratios of pre-specified adverse events (GBS, encephalitis / myelitis, optic neuritis, 

thrombocytopenia, Bell’s Palsy, and anaphylaxis) following inactivated H1N1 vaccine using 

background data as the source of reference rates, adjusting for seasonal influenza vaccine 

exposure and / or other potential confounding factors among the VA population. Self-controlled 

case series will assess the associations between inactivated H1N1 vaccine and Bell’s Palsy or 

other outcomes, if the sample size is sufficient, occurring in the VA population. 

IHS H1N1 coverage was over 20%. Most (77%) of the vaccine doses administered were 

inactivated H1N1 vaccines. The analysis to follow all H1N1 vaccines was combined. The 

standardized incidence ratio provides the summary results from their analyses. It compares 

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expected number of cases using background rates generated from a previous influenza season, 

2007-2008. The observed cases are from the H1N1 surveillance system. There were no GBS 

cases among the vaccines; therefore, GBS was not included in this table. The overall 

thrombocytopenia events observed (adding 287.31, 287.4, and 287.5) were significantly higher 

than expected, but the individual code was less for the specific code of 287.31 for which there 

were only 4 observed cases. The code 351 for Bell’s Palsy also had a statistically significant 

signal, but for a very low relative risk 1.24. 

Some of the limitations were that the expected number of cases from the IHS National Data 

Repository is limited. 100% of the facilities are included for the current analysis, as for the 

expected number; whereas, the observed number was obtained from 60% of facilities. 

Future steps include case verification for background cases. For signal detection, stratified 

analysis will include age, gender, and temporal and geographic analyses. Rapid cycle analysis 

using MaxSPRT methods will be conducted. End-of-season studies include a self-controlled 

case series study of confirmed cases. 

In summary, the findings were not consistent across the system. There were possible signals 

identified and some data sources for GBS, thrombocytopenia, and Bell’s Palsy. The rates for 

GBS were higher than expected in some analyses, but they did not achieve statistical 

significance. Further analyses are planned of confirmed cases using self-controlled case series 

and other methodologies, and these will be implemented at the end of the season. There are 

enough integrated data for most partners for end-of-season analyses, particularly for the GBS 

analyses. 

Discussion Points 

Dr. Marcy was under the impression in the conversation they had with the VSD that there was 

attributable risk for GBS. 

Dr. Lieu replied that it was certainly possible to make estimates of what the attributable risk 

would be if there was a particular background rate. This can be done, but these are back of the 

envelope estimates. She suggested that they had to be confident about it and wait until there is 

some consensus on what background rate ought to be used. If the background risk per million 

TIV doses is believed to be around 1, the attributable risk per million H1N1 doses would be 1.5. 

If the background risk is thought to be higher than 1, then the attributable risk of H1N1 would be 

higher. However, the CI are very wide. They include 0 and they include higher numbers. 

There needs to be better consensus on what should be used as the background risk. Larger 

numbers and more systems need to be involved as well so that the confidence intervals are 

more reliable. 

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Febrile Seizures in Australia and CDC Monitoring 

Plan for 2010-2011 Seasonal Influenza Vaccine 

Michael McNeil, MD MPH 

Immunization Safety Office 

Division of Healthcare Quality Promotion 

National Center for Emerging and Zoonotic Infectious Diseases (proposed) 

Dr. McNeil presented information to familiarize ACIP with a situation in Australia with febrile 

seizures, and the CDC seasonal influenza vaccine monitoring plan for 2010–2011. 

Febrile seizures are seizures that occur with fever, usually in younger age groups between 6 

months and 5 years. The peak age group is 14 to 18 months, and typically affects 

approximately 2% to 5% of young children in the US. It has an excellent prognosis, although 

one third of children who have a first febrile seizure will have a recurrence. Importantly, febrile 

seizures have not been associated with seasonal trivalent influenza vaccines in past seasons. 

There are three VSD studies. Safety monitoring during the recent H1N1 monovalent 

vaccination program did not show any signal for febrile seizures in the US [AAP. Pediatrics. 

2008; Johnston M. Nelson Textbook of Pediatrics. 2007; Baulac. Lancet Neurology. 2004; 

Hambidge et al. JAMA 2006; France et al. Arch Pediatr Adolesc Med 2004; and Greene et al. 

Am J Epidemiol 2010]. 

Regarding the Australian situation, the recommendation for the entire country prior to April 2010 

was that seasonal vaccination was recommended for children with chronic medical conditions 

ages 6 months to 18 years with unadjuvanted inactivated trivalent vaccine. There was a funded 

program in the State of Western Australia, and the recommendation was for vaccination of all 

children ages 6 months through 5 years. This followed some deaths that occurred in 2007 and 

has been in place for the last two years at least. 

For seasonal inactivated trivalent influenza vaccine (TIV) in Australia, trivalent Fluvax® Junior 

(CSL) dominates market. Vaxigrip® (sanofi pasteur) and Influvac® (Solvay) are also available. 

The 2010 Southern Hemisphere formulation includes pandemic 2009 H1N1 antigen, and is the 

same as recommended for 2010-2011 Northern Hemisphere vaccine. Nearly all TIV distributed 

by late April 2010 was Fluvax® Junior (CSL). 

On April 23, 2010, Australia’s Chief Medical Officer suspended the 2010 seasonal trivalent 

vaccinations for all children less than 5 years old. This followed reports of febrile seizures 

following vaccination. The suspension included all 2010 TIV manufacturers, but not monovalent 

2009 pandemic H1N1 vaccine. There was an investigation by authorities in Australia, including 

the Therapeutic Goods Administration (TGA), which is the Australian equivalent of the FDA. 

The preliminary investigation revealed that there was a signal suggesting an increase in febrile 

seizures, primarily in children less than 5 within 24 hours, approximately 7 hours, after 

vaccination with the 2010 seasonal TIV. There was no increased febrile seizure risk 

documented with non-CSL TIV products. It was estimated that up to 9 per 1000, compared with 

an estimate less than 1 per 1000 risk for febrile seizures, was identified. The Chief Medical 

Officer is quoted as saying that “No biological, clinical, or epidemiological factors have been 

identified to explain these higher than expected rates of febrile convulsions. Vaccine testing has 

shown no abnormalities.” 

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The updated recommendations from the Chief Medical Officer were made on June 1, 2010. 

The update reiterated suspension of use of trivalent vaccines for healthy children less than 5 

years of age. Again, the Panvax® (monovalent 2009 H1N1 vaccine) was available for use. For 

children with chronic medical conditions, there were options. They could use the Panvax® 

monovalent 2009 H1N1 vaccine or TIV. The recommendation was to prefer the other 

manufacturers’ preparations (Influvac® or Vaxigrip®). Also, Fluvax® Junior manufactured by 

CSL could be used, but there was a warning label added about the increased risk of fever and 

febrile convulsions. There was also a statement by the TGA that had considered overall the 

balance of the benefits and risks of Fluvax® and Fluvax® Junior, manufactured by CSL, 

continued to be positive and that these were available still for older age children. 

The manufacturer, CSL Biotherapies in Australia, also posted on its website that it had noted a 

significant increase in reports of fever and febrile seizures in children less than 5 years of age 

after receiving the 2010 CSL preparation compared to the earlier seasons. It also commented 

that the extensive investigations had not established an explanation. It ceased distribution of its 

pediatric influenza vaccine and collaborated on investigations with the government authorities. 

It also updated prescribing information for influenza vaccine and sent a letter to providers 

informing them; moreover, it commenced a retrieval program for its remaining 2010 pediatric 

influenza vaccine obtaining back unused supplies from suppliers and medical offices. 

Other countries in the Southern Hemisphere are using 2010 seasonal influenza vaccine. CDC 

has been in contact with WHO and some of these countries. New Zealand also experienced a 

few cases of febrile seizures following use of CSL pediatric influenza vaccine, and as a 

precautionary measure, had also suspended its use. South America and South Africa have 

typically received the same CSL product in the past, and CDC has been in contact with officials 

in both countries. There are no reports to WHO of febrile seizures associated with the 2010 

influenza vaccines. 

With regard to the use of CSL vaccines in the US, CSL vaccines have been licensed for use in 

persons aged 18 years and older since 2007. The CSL influenza vaccine, Afluria®, was 

licensed for use in persons aged 6 months and older in November 2009. Very few doses were 

distributed during 2009-2010 influenza season. CSL pandemic H1N1 monovalent vaccine was 

licensed for use in November 2009 for ages 6 months and older. A review of the current 

monitoring systems for all manufacturers of trivalent seasonal influenza vaccine for the last 

season showed that there were 162 seizure reports, none of which followed receipt of CSL TIV, 

Afluria®. For the 2009 H1N1 monovalent influenza vaccine, there were 211 seizure reports, 4 

of which were after receipt of CSL MIV preparation. All of these were in adults aged 18, 30, 32, 

and 59 years old. There was adequate information on the first two to confirm that these were 

seizures without fever. It is important to note that a report to VAERS does not indicate the 

adverse event was caused by the vaccine. 

These reports were reviewed in more detail. Of the seasonal influenza vaccine, 39 of the 162 

were classified using only metric codes as febrile seizures, and 40 of the 211 following the 

monovalent were classed as febrile seizures. Again, these are from the automated data. The 

other method of assessing VAERS data is data mining. This method looks for patterns of 

disproportionate reporting for adverse events, and has not detected any signal for seizure 

following either the seasonal trivalent flu vaccines, including the CSL preparation, or the live 

preparation by MedImmune. VAERS will be in the front line for monitoring for adverse events 

with the coming influenza season. 

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The other major system for monitoring safety of the vaccines is the VSD. Its data has also been 

assessed in terms of febrile seizures. For all ages, a total of 47,824 doses of seasonal vaccine 

were monitored. Of these doses, 6 seizure cases were detected in Days 0 to 7, and 5 were on 

Day 0, vaccination day. They were adults. There was one Day 2 case in an adult. There were 

only 11,175 doses of the monovalent in the VSD. No seizure cases were detected within days 

0-7. In the age group 6 months to less than 5, there were 23 doses of TIV and 347 doses of 

MIV. 

Future plans with the VSD are to monitor for seizures in three age groups (6 m/o–4 y/o, 5-24 

y/o, and >25 y/o). If signals are detected, charts are reviewed to confirm a seizure and whether 

it is associated with fever or not. The current seizure definition includes ICD-9 codes 345.0*, 

345.9*, 780.3* (generalized non convulsive epilepsy: convulsions). Seizures are looked for in 

in-patient settings and in the emergency room. The exposure window is days 0 to 7. There is a 

lot of power in the VSD to detect a relative risk. The estimates of relative risk from Australia 

have ranged between 5 and 10, so there is greater than 99% power to detect a relative risk of 3 

or more, and 76% power to detect a relative risk of 2. This would be looking at seizures day 0 – 

1 in the age groups 6 months to less than 5 years, and a background rate calculated from 

previous seasons of 5 per 100,000 doses. This also assumes that there would be similar 

vaccine uptake and coverage to what was observed in the 2008-2009 season, the last regular 

influenza season. 

The next steps are to maintain close collaboration with international scientists, partners, and 

regulatory authorities, including FDA; collaborate on laboratory (animal pyrogenicity) studies 

using CSL vaccine at CDC; monitor for seizures / febrile seizures following 2010-2011 TIV using 

existing vaccine safety data systems (VAERS, VSD) currently in place for 2009 H1N1 vaccine; 

and communicate with ACIP and other stakeholders. 

Discussion Points 

Dr. Baker observed that the safety monitoring appears to be robust and in place to look for this 

potential safety issue. 

Dr. Pickering thought it was interesting that in the NIH studies they just heard about, the CSL 

seroconversions or antibody levels were much higher than they were with the other vaccine 

manufacturers. Although enough patients may not have been enrolled to look for febrile 

seizures, he wondered if the rates of fever or local reactions were higher in those age groups, 

and extrapolating that on to what occurred in Australia, whether there was a connection, 

particularly if these are the same vaccines. 

Dr. Englund noted that the data that Dr. Fiore showed about the CSL vaccines was Australian 

data and not NIH data, so she thought it was really important to realize that the CSL data shown 

earlier in this session with the very high antibody titers was done in a different population, with 

disease on-going, in a totally different study, with a different laboratory. 

Dr. Neuzil added that as discussed in the work group, no signal was observed for increased 

seizures after use of the monovalent H1N1 in Australia. 

Dr. McNeil replied that there was not, and they have not suspended its use. In fact, it is the 

major option and they anticipate that H1N1 will be the dominant strain this season in Australia. 

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Discussion

Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Respiratory Syncytial Virus (RSV) 

Introduction 

Lance Chilton, M.D.

Chair, RSV Immunoprophylaxis Workgroup

Dr. Chilton reported that the RSV Immunoprophylaxis Work Group is moving inexorably and 

methodically toward developing recommendations for RSV immunoprophylaxis products. The 

RSV Immunoprophylaxis Work Group was assembled for several reasons. RSV causes a large 

amount of morbidity, although rather low mortality, every year. Pediatricians know the winter 

and spring months as bronchiolitis season, even though others think of it as influenza season. 

Attempts to develop a vaccine against RSV have thus far not been successful, but would 

change the face of pediatrics perhaps even more than HIB vaccine changed pediatric practice in 

the past. Aside from oxygen, nasal suction, and fluids, little can be done to help children who 

are affected by RSV. An effective, but expensive product for passive immunoprophylaxis exists. 

Current plans for replacement of palivizumab by a newer product, motavizumab, remain on hold 

given the negative vote on licensing by an FDA advisory board earlier this June. ACIP has 

ability to bring together individuals from different backgrounds (e.g., infectious disease, 

pediatrics, epidemiology, economics, pulmonology, neonatology, evidence-based medicine) to 

develop recommendations for prophylaxis based on disease burden, safety, efficacy, and 

economics. 

Beyond safety and efficacy, the work group believes that special consideration must be given to 

economics because the cost for a current product, palivizumab, is very high at estimated drug 

cost of $6,674 per patient per year (4-5 monthly injections; depends on infant weight at 15 

mg/kg/dose). A single monthly dose costs more than all of the other vaccines that are given to 

children in a lifetime. These costs are largely dictated by the cost of the product itself, though 

the cost of administration can also be high depending upon where it is given. Even though 

bronchiolitis and pneumonia caused by RSV are common and expensive to care for in hospitals, 

previous economic evaluations have not shown that providing prophylaxis to be cost-saving, 

though it may be cost-saving in certain restricted populations. Most cost studies have not found 

cost savings, and have varying estimates of cost-effectiveness. 

Work group economist, Ismael Ortega Sanchez, helped to determine examples of cost 

estimates. The assumptions for these examples included the following: no wastage, use of 100 

mg vials, private sector cost of $2,253 = $22.53/mg, public sector cost of $1,495 = $14.95/mg, 

weights at the 50th percentile for age for males born at 1.5 kg or 3.5 kg, no administration costs. 

The following table reflects the results for this example: 

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Weight at birth 1.5 kg 

premature 

infant 

3.5 kg infant 

with CHD 

1 mo. weight 1.7 kg 4.5 kg 

2 mo. weight 2.4 kg 5.4 kg 

3 mo. weight 2.8 kg 6.0 kg 

4 month weight 3.3 kg 6.5 kg 

5 mo. weight 3.9 kg 7.4 kg 

Total cost of 

palivizumab 

$3172- $4759 $6705-$10,058 

Current and future RSV workgroup activities are to review the epidemiology of RSV infections, 

including seasonality and host and environmental risk factors for severe disease; review the 

safety and efficacy of prophylaxis; assess the costs and benefits of prophylaxis; identify areas in 

need of further research for informing recommendations; draft recommendations for ACIP 

consideration and decision making. The work group has begun to examine areas where future 

research would be beneficial in formulating recommendations in the use of this drug, for 

example, for children with cystic fibrosis or immune deficiency disorders. The group plans to 

update the full ACIP membership over the next several meetings, and to have draft 

recommendations for ACIP approval perhaps as early as June 2011. That means frequent 

meetings over the next year to review data from a number of standpoints. 

One June 2, 2010, the FDA advisory committee voted 14 to 3 not to recommend licensure of 

motavizumab at this time. FDA action has not yet taken place. With that in mind, the RSV 

Immunoprophylaxis Work Group has decided to continue to work toward a set of 

recommendations for use of available products for prophylaxis, including recommendations for 

motavizumab if and when it is licensed and available. 

This informational session included presentations regarding the epidemiology of RSV infections 

and the history of immunoprophylaxis. 

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Epidemiology of Respiratory Syncytial Virus (RSV) 

Infections in Infants and Young Children 

Gayle Fischer Langley, MD, MPH 

Centers for Disease Control and Prevention 

Division of Viral Diseases 

Dr. Langley reported on the epidemiology of RSV infections in infants and young children. RSV 

is an enveloped, single stranded RNA virus. It is part of the paramyxovirus family, which also 

includes parainfluenza, mumps, and measles viruses. There are two surface proteins that are 

related protective immunity, the F and G proteins. The F protein promotes fusion of the virus, 

and host cell membranes. This is the target of the immunoprophylaxis under consideration by 

the work group. The G protein promotes attachment of the virus to the cell and determines the 

major genetic groups, of which there are two, A and B. 

Upon exposure, RSV enters the upper respiratory tract and replicates in the nasopharynx. It 

then may spread to the lower respiratory tract (LRT) in about 1 to 3 days and causes 

inflammation of the small airways, leading to obstruction. Persons who are infected are usually 

symptomatic 2 to 8 days after exposure to the virus. Recovery generally occurs within 1 to 2 

weeks, but symptoms may persist for several weeks. Most often, children infected with RSV 

present with upper respiratory tract infections (e.g., rhinitis, otitis media) and about 20% of 

young children present with lower respiratory tract infections (LRTI). The majority of these 

LRTIs are bronchiolitis. Bronchiolitis is inflammation of the small airways or bronchioles. 

Patients present with the hallmark signs of wheezing on expiration. Pneumonia is also relatively 

common. Apnea, or the absence of breathing, without other respiratory symptoms, may also 

occur in young infants. 

Severe RSV in early infancy is also associated with recurrent wheezing. However, there are no 

data establishing a causal link. Recurrent wheezing may be a direct consequence of having 

RSV infection. Alternatively, children who wheeze with RSV may have an underlying 

predisposition or susceptibility to reactive airway disease or asthma. Whether RSV infection 

predisposes children to recurrent wheezing, and whether it can be prevented by 

immunoprophylaxis, are important considerations when assessing the potential benefits of 

immunoprophylaxis. 

Primary RSV infection occurs early in life. Approximately 70% of children are infected with RSV 

in the first year of life. Almost all of these infections are symptomatic, with about 20% resulting 

in LRTI. Primary infection does not confer complete protective immunity and is not long-lasting 

so re-infection is common. Subsequent infections tend to more mild, but severe infection can 

occur in any age group. The risk is of severe infection upon re-infection is greatest in persons 

65 years and older and in adults with underlying immunodeficiencies or pulmonary or cardiac 

disease [Glezen, AJDC (1986)]. 

The symptoms of RSV infections in children and adults are non-specific, so laboratory tests are 

needed to confirm the diagnosis. Detection of the virus is generally made from respiratory 

secretions. There are rapid antigen and molecular assays that are used in clinical settings to 

diagnose RSV. Antigen assays have a sensitivity of 80% to 90% in children and a lower 

sensitivity in adults. Molecular assays have higher sensitivities, which is particularly important 

for testing adults who tend to shed less virus. Both assays have high specificities. Results from 

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cell culture take 3 to 5 days and are used primarily to analyze strains and new mutations. 

Serology is primarily used for seroprevalence studies [Henrickson, PIDJ (2007)]. 

The following graph shows the distinct seasonality of RSV infections using antigen detection 

data from the National Respiratory and Enteric Virus Surveillance System between 2004 and 

2008: 

RSV Antigen Detections: National Respiratory and

Enteric Virus Surveillance System (2004‐2008)

Location Duration

National 21 weeks

Florida 31 weeks

South* 22 weeks

Northeast 14 weeks

Midwest 19 weeks

West 16 weeks

Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun 8 

*Excludes Florida CDC, unpublished

The x axis represents the month. The y axis, on the left, represents the geographic location of 

the detections. The duration of the season is on the right side. The first hash line indicates the 

season onset, the middle line indicates the season peak, and the end line indicates the season 

offset. Most laboratory detections of RSV during this time period in the US occurred between 

early November and the middle of March, with a peak in January. However, there was variation 

in the timing and the duration of detections by US region or states within regions. In Florida, for 

instance, season onset occurred in mid-July, peaked in mid-October, and ended in midFebruary. Even when Florida is excluded, the Southern states had the earliest onset, peak, and 

offset, followed in time by the Northeast, Midwest, and West regions. The longest duration 

occurred in Florida, followed by other states in the Southern region, and then states in the 

Midwest, West, and Northeast regions. 

Within these national and regional patterns, during a given season, outbreaks are generally 

localized within communities. Evidence for this includes the recognized differences in onset, 

peak and offset of detections between laboratories located within short distances. Also, 

molecular studies show that circulating strains may vary between adjacent communities during 

the same season. Despite outbreaks being localized in communities, approximately 80% of all 

RSV hospitalizations in the US occur between November and April [Mullins, PIDJ (2003), 

Panozzo, PIDJ (2007), and Anderson, JID (1991)]. 

RSV is the most common cause of LRTI in children under 5 years of age in the US. While 

deaths are rare, it causes a significant number of hospitalizations, ER visits, and outpatient 

visits. In children under 5 years of age, RSV has been associated with approximately 200 to 

500 deaths and between 57,000 and 125,000 hospitalizations per year. The highest annual 

rates of RSV hospitalizations occur in infancy, with an estimated 16.9 per 1000 infants 0 to 5 

months old and 5.1 per 1000 infants 6 to 11 months old hospitalized each year with RSV 

infection. Additionally, there are over 500,000 ER visits and over 1.5 million outpatient visits for 

RSV infections each year. In fact, the burden of RSV disease in young infants is more than 2 to 

3 times greater than the burden resulting from influenza infections [Shay, JID (2001), Hall, 

NEJM (2009), Shay, JAMA (1999)]. 

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In terms of absolute numbers, most RSV hospitalizations occur in healthy infants born at full 

term, but the relative risk is greater in infants and young children with certain underlying medical 

conditions. These conditions include chronic lung disease (CLD), prematurity, and congenital 

heart disease (CHD). Other medical conditions, such as neuromuscular disorders and 

immunodeficiencies, may also place a child at increased risk of RSV hospitalization. Children 

with CLD, CHD, or prematurity have been the main high risk groups targeted for 

immunoprophylaxis, which has been shown to reduce the incidence of RSV hospitalizations in 

these groups. 

CLD, which was formerly known as bronchopulmonary dysplasia (BPD), is a condition of 

immature lung development and lung injury that results from premature birth and medical 

interventions. As a result, these infants require oxygen and other medical therapies. Even in 

the absence of CLD, infants born prematurely are more likely to be hospitalized with RSV 

compared children born at term. This has been attributed to their immature immune system, 

incomplete transfer of maternal antibodies, and an underdeveloped lung system. Additionally, 

select infants born with a structural heart defects, referred to as CHD, have an increased risk of 

RSV hospitalizations. This is particularly true for conditions associated with pulmonary 

hypertension. The increased risk is due to their inability to increase cardiac output when 

infected with RSV and their increased exposure to healthcare settings where RSV may circulate 

during the season. For healthy infants born at full term, the incidence of RSV hospitalization is 

about 1 to 3 percent per year. For children with CLD, the incidence ranges from 8 to 39% per 

year. For children with CHD, the incidence ranges from 2 to 15% per year. For children born 

prematurely, the yearly incidence ranges from 2 to 8%. 

Despite the large burden of disease, there are few options for RSV prevention. In healthcare 

settings, RSV may be prevented by adhering to standard and contact precautions, which 

includes cohorting of persons with RSV infection. In the community, hand hygiene and avoiding 

settings where there is a high risk of exposure to RSV, such as crowds and daycare centers, is 

recommended during the RSV season. For now, immunoprophylaxis remains the main mode of 

prevention. However, because of costs and other considerations, immunoprophylaxis is 

generally recommended for select infants and children with CLD, CHD, or prematurity. Because 

hospitalizations are so common, even in healthy infants and children, providing prophylaxis has 

limited impact on the overall disease burden. A vaccine is needed to better address this large 

burden. There are vaccines in early development and testing, but safety and efficacy studies 

have not yet been done in young infants. 

History of RSV Immunoprophylaxis 

H. Cody Meissner, MD 

Tufts Medical Center 

Boston, MA 

Dr. Meissner pointed out that there are three basic approaches to the control of an infectious 

disease: vaccines, antimicrobial therapy, and passive immunoprophylaxis. Development of a 

safe and effective RSV vaccine has proven to be a difficult challenge. After 5 decades of 

research, no RSV vaccine approach has been fully successful at conferring protection among 

high risk persons. Ribavirin was licensed in 1986 for aerosol treatment of serious RSV 

infections in hospitalized children, and this drug remains the only FDA licensed drug for 

treatment of this disease. Ribavirin is seldom used today in non-compromised patients because 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

of limited efficacy, requirement for a cumbersome delivery system, and high cost. Investigational 

drugs under development fall into several categories and include fusion inhibitors, antisense 

drugs, and small interfering RNA. However, none of these are likely to be licensed in the near 

future. Passive immunization is the third option. Over the past 20 years, progress in the field of 

immunoprophylaxis for protection of high risk infants and children against RSV infection has 

achieved considerable success. 

RSV causes a primary infection as well as re-infection during infancy and throughout life. Reinfection occurs despite the presence of maternal antibody, and despite the presence of 

immunity from previous infections. Unlike influenza, re-infection occurs without the need for 

significant antigenic change. Initially, these observations caused skepticism regarding a 

protective role for passively administered antibody; however, the observation of a correlation 

between high maternal antibody levels and less severe RSV infection in the first months of life 

among certain infants suggested that neutralizing antibody to RSV might afford some measure 

of protection. 

Early studies in cotton rats and owl monkeys by Chanock, Prince, and Hemming suggested that 

exogenous antibody might indeed be safe and efficacious for preventing RSV lower respiratory 

tract disease in humans. In the early 1990s, two prophylaxis trials with monthly infusions of 

standard intravenous immunoglobulin were conducted in high risk infants. These two small 

trials demonstrated safety, but efficacy was not demonstrated. This was most likely because a 

sufficient peak seroconcentration of RSV neutralizing antibody was not achieved. In an effort to 

achieve higher serum antibody concentrations, a hyperimmune globulin was developed at the 

Massachusetts State Laboratory by George Siber and Jean Leszczynski. This hyperimmune 

globulin was later called RespiGam® and possessed about 5-fold greater neutralizing activity 

than standard intravenous immunoglobulin. Three multi-centered randomized control trials were 

then conducted using monthly infusions of the hyperimmune globulin. Based on results from 

two of the three trials, the hyperimmune globulin was licensed by FDA in January of 1996 for 

protection of preterm infants with or without bronchopulmonary dysplasia (BPD), but was 

contraindicated for children with severe CHD. Because the nasal mucosal represents the portal 

of entry for RSV, it was reasonable to expect that topically administered immunoglobulin (IgA) 

might be protective; however, a Phase III trial of once daily intranasal nose drops on monoclonal 

IgA versus placebo failed to reach the primary endpoint of reduced RSV hospitalization, and no 

further trials were conducted with this product. 

Next, efforts focused on monoclonal antibody development in an effort to avoid several 

problems associated with the hyperimmune globulins. Two humanized monoclonal antibodies 

directed against different epitopes on the F protein were developed. F protein appeared to be 

the most suitable target because this protein mediates a key component of the life cycle of the 

virus; that is, fusion of the lipid envelope with the plasma membrane of the respiratory epithelial 

cell. Certain sequences of the F protein are highly conserved. A trial sponsored by SmithKline 

Beecham with a humanized murine monoclonal antibody failed to demonstrate a statistically 

significant difference in RSV hospitalization rates between infants who received monthly 

prophylaxis, every other month prophylaxis, or a control group. Subsequent analysis suggested 

this particular monoclonal antibody was directed against an epitope on the F glycoprotein, which 

was less effective at viral neutralization and had less fusion inhibitory activity than monoclonal 

antibody directed against other epitopes on the F protein. 

A trial sponsored by MedImmune evaluated a second murine monoclonal antibody against the F 

protein in a Phase III trial and this monoclonal antibody demonstrated efficacy. Palivizumab has 

50 to 100 times the activity of hyperimmune globulin against RSV in micro neutralization and 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

fusion inhibition assays and an enabled reduction in dosage from 750 mg per kg per dose of the 

hyperimmune globulin to 15 mg per kg dose of palivizumab. This enabled administration of a 

smaller volume by intramuscular root. Results from the IMpact trial of this RSV prophylaxis 

product demonstrated the efficacy of Palivizumab. This study involved 139 sites in the US, 

Canada, and the UK and was conducted over one year during the 1996 / 1997 RSV season. A 

total of 1500 preterm infants with or without chronic lung disease were randomized 2:1 to 

receive either 5 intramuscular injections of palivizumab or 5 injections of a placebo administered 

at 30 day intervals. The primary endpoint was efficacy of prophylaxis in reducing the incidence 

of RSV hospitalization. Overall, monthly prophylaxis with palivizumab was associated with a 

55% reduction in hospitalization due to RSV and the primary endpoint was met. In the 

subgroup analysis, significant reductions were observed in preterm infants without chronic lung 

disease, as well as those infants with chronic lung disease [Study Group, Pediatr 

1998;102:531]. 

In June 1998, the FDA licensed this monoclonal antibody, establishing palivizumab as the first 

monoclonal antibody introduced into clinical practice for prevention of an infectious disease. 

The IMpact RSV trial was the only Phase III data generated at the time of licensure. A second 

randomized, double-blind, placebo controlled trial with palivizumab was conducted during the 4 

years between 1998 and 2002 and involved almost 1300 infants and children with 

hemodynamically significant CHD. Subjects were randomized 1:1 to receive 5 monthly 

intramuscular injections of palivizumab or placebo and were stratified at entry by cardiac lesion 

to a cyanotic or a non-cyanotic group. Palivizumab recipients had a statistically significant 45% 

decrease in the rate of RSV related hospitalization relative to placebo recipients [Feltes et al. J 

Pediatr 2003;143:532]. 

The palivizumab package insert from March 2009 states the following: 

INDICATIONS AND USAGE: Synagis is indicated for the prevention of serious lower 

respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients 

at high risk of RSV disease. Safety and efficacy were established in infants with 

bronchopulmonary dysplasia (BPD), infants with a history of premature birth (≤ 35 weeks 

gestational age), and children with hemodynamically significant congenital heart disease 

(CHD) (see CLINICAL STUDIES ). 

The number of infants and young children who qualify for prophylaxis using these indications is 

large. Approximately 8.5% of the 4.1 million births per year in the US are born at or before 35 

weeks gestation, which is about 350,000 infants. If all infants in just this one high risk group 

receive prophylaxis, the annual cost would exceed $2 billion for the drug alone; therefore, in an 

effort to optimize the benefit cost ratio, the COID generated a series of recommendations 

starting with the availability of hyperimmune globulin in 1996. 

Palivizumab was licensed in 1998, 2.5 years after the licensure of the hyperimmune globulin. 

Since the first AAP recommendation, these recommendations have been revised and updated 

several times as new data have become available, principally in regard to the seasonality of 

RSV disease in different areas of the US and in regard to the new understanding of risk factors 

for severe RSV disease. During the June 2, 2010 FDA Antiviral Advisory Committee meeting, 

the Biologic License Application (BLA) was reviewed for motavizumab, a second generation 

monoclonal antibody which differs from palivizumab by 13 amino acids. The potential 

advantages of a more potent second generation molecule include fewer breakthrough 

infections, and because of increased anti-RSV activity in the upper airways, perhaps a role in 

the treatment of active infection. In cell culture, motavizumab has about 18-fold greater 

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neutralization activity than palivizumab. At equivalent serum levels in the model, this drug 

produces 50- to 100-fold greater production in RSV titer over palivizumab in the lungs and a 2 

log reduction in nasal RSV titers. However, three weeks ago, the FDA Antiviral Advisory 

Committee voted 14 to 3 against licensure of motavizumab. Several issues were raised by the 

advisory committee. One of the overriding concerns was a higher rate of hypersensitivity 

adverse events in the motavizumab arm relative to the palivizumab arm. Furthermore, because 

of issues regarding motavizumab’s efficacy relative to that of palivizumab, the advisory 

committee expressed concern that the risk-benefit assessment did not favor licensure of 

motavizumab. 

The results of a head-to-head, non-inferiority comparative trial of palivizumab and motavizumab 

were published in January 2010. Because palivizumab is the standard of care, no placebo 

group was included in the design of this trial. Results of this trial demonstrated low rates of RSV 

hospitalization in both groups. In addition, motavizumab recipients experienced a 26% relative 

reduction in RSV hospitalization compared with palivizumab recipients. This figure of 26% 

achieved the predetermined threshold for non-inferiority, but did not reach the superiority 

threshold. Sub-group analysis by gestational age and chronic lung disease status were 

consistent with overall non-inferiority. Surprisingly, in comparison with the IMpact trial 

conducted in 1996, the RSV hospitalization rates were 1.5 to 2.5 times lower among 

palivizumab recipients for all subgroups in this trial. Possible explanation for this large 

difference in RSV hospitalization rates among palivizumab recipients in the two trials are first 

that the trials were conducted in different RSV seasons and it is possible there were different 

virulence patterns among circulating strains of RSV. Second, the threshold for admission of 

RSV infected children may have changed between 1996 and 2004 with infected children now 

more likely to be managed as outpatients. Third, the infants enrolled in the non-inferiority trial 

had less severe underlying disease than infants in the impact RSV trial. This makes data 

comparison between the two trials difficult [Pediatrics 2010;125:e35]. 

Several challenges are encountered when preparing recommendations for RSV prophylaxis 

with palivizumab. First, only two randomized placebo controlled trials with palivizumab are 

available. Second, the true RSV hospitalization rate in various groups of infants and children 

with different risk factors is difficult to establish from the available literature. More than 20 risk 

factors have been reported, but most of these risk factors have only a modest impact on RSV 

hospitalization rate. Risk factors to identify those infants most likely to require admission to the 

ICU or to have a fatal outcome are not easily established. In addition, many of the published 

studies which attempt to address risk factors for hospitalization were conducted in countries 

other than the US with different health care systems and different practice patterns, or the 

studies used historical controls or they were retrospective in nature. 

Because of these issues, the goal of establishing evidenced-based recommendations for 

selection of infants and children in the US has proven to be a difficult task. In an era of limited 

resources, a responsibility of all advisory groups is the need to optimize the benefit-cost ratio 

and to exercise responsible stewardship of public funds. The conclusion of the COID is that 

palivizumab prophylaxis results in a substantial increase in cost, a small increase in quality 

adjusted life years (QALY) saved as a result of decreased hospitalization, and no measurable 

reduction in mortality rates in any of the published studies. Finally, it is important that 

recommendations provide the practitioner with a simplified approach for selection of infants for 

prophylaxis. 

What might the future hold for RSV prevention? The protective immune response to RSV 

infection is mainly directed against the two major surface viral proteins, G and F. Palivizumab 

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or antibody to F protein, is not effective in treating active RSV disease and this may be due to 

lack of control of viral induced host inflammatory response. In contrast, a series of studies 

suggest that the G protein plays a role in inducing and modulating the inflammatory response 

during RSV infection. This is in addition to the role of G in attachment of the virus to the cell. In 

studies largely conducted by Larry Anderson and his group at CDC, a specific segment of the G 

protein has been shown to modulate the inflammatory response. Treatment with a monoclonal 

antibody to G inhibits both viral replication and reduces the inflammatory response in 

experimental models. This suggests that antibody to G could have a role in both prophylaxis 

and a treatment of RSV infection, and is a promising area of research. However, the greatest 

promise for overall control of the burden of disease caused by RSV comes from a vaccine 

administered early in life or perhaps administered during gestation. Presently, passively 

administered antibody and careful attention to methods which reduce exposure to RSV offer the 

best options for control of disease among higher risk infants and children. 

Discussion Points 

As evidenced by the public comments to be delivered at the end of the meeting, Dr. Baker 

pointed out that this is a controversial area. She requested that Dr. Meissner summarize for the 

committee members and the audience what the AAP / COID recommendations are. The 

license is for children with hemodynamically significant CHD and those of less than 35 weeks 

gestation. 

Dr. Meissner replied that the COID engaged in lengthy and difficult discussions to identify the 

children who are most likely to benefit from prophylaxis, and have identified several categories. 

Preterm infants represent the largest group. Children who are less than 29 weeks of gestational 

age are clearly an important group. The groups between 29 and 32 weeks of age represent a 

second group, and the infants between 32 and 35 weeks of gestational age represent the 

largest group as mentioned (n=350,000). Risk factors and a maximum of three doses of 

monthly prophylaxis for children in that category have been suggested. Recommendations 

have also been made for children with hemodynamically significant CHD from birth through 24 

months of age; children with what used to be called bronchopulmonary dysplasia that is now 

called chronic lung disease of prematurity; and those children who still require medical 

intervention (e.g., steroids, bronchodilators, diuretics, et cetera), who are eligible up to 24 

months of age. 

Dr. Whitley-Williams (NMA) indicated that NMA has great concerns regarding the change in the 

recommendations, particularly given the lack of data with regard to ethnicity in terms of the 

impact that this might have going forward. There is ethnicity data in the IMpact trial; however, 

she did not believe there was stratification of the data by ethnicity in the 32 to 35 week age 

group. She suggested that the unpublished COID data be provided to ACIP to further inform 

the recommendation development process. The NMA convened a consensus panel meeting in 

May 2010, and a paper will published following the annual meeting. She has an executive 

summary of that paper, which she indicated she would make available to the full ACIP 

membership. The gist of NMA’s recommendations is they would like for ACIP to review the 

change in recommendations, particularly in the 32 to 35 age group, knowing that there is a 

disparity with regard to prematurity and the potential impact of not protecting those infants. She 

also requested that any data available for the 0 to 3 month group be provided to ACIP as well. 

Dr. Baker said that given the practice changes with regard to admitting patients with RSV to the 

hospital, she was not surprised that the incidence of hospital admission was lower; however, it 

would be beneficial for ACIP to review data from that trial. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Responding to Dr. Whitley-Williams, Dr. Chilton thought their approach to this would be zerobased. In other words, they would specifically assess either the 2003 or 2009 

recommendations. Instead, they will start at a zero point and move forward from there. 

Dr. Pickering requested that Dr. Sun comment on the FDA status of motavizumab. 

Dr. Sun replied that he spoke with Dr. Shapiro, who is on the ACIP work group, before he 

arrived at this ACIP meeting. His division is reviewing the product. At this time, he was not free 

to comment on the timeline of the review. 

Dr. Baker reported that in the interest of full disclosure, Dr. Pickering and she are ex-officio, 

non-voting members of the COID of the AAP. 

Dr. Whitley-Williams noted that surveillance in the 0 to 3 month age group varies from state-tostate. Often, deaths that occur at home may fall under sudden infant death syndrome (SIDS) 

and not be recorded as RSV. She thought improve surveillance of this entity. Published scores 

are used in evaluating these patients with regard to whether they should be hospitalized. She 

urged the work group to carefully review this issue, and to support increased surveillance and 

better diagnostic techniques for this entity to determine which infants should be targeted within 

the 32 to 35 month age group before making a decision to change the current 

recommendations. 

Dr. Baker added that if they really wanted to do this as a country, we should also look for an all 

bacterial sepsis agent for deaths in that cause death in that age group. 

Health Care Reform and Immunization Policy 

Sara Rosenbaum, JD 

Hirsh Professor and Chair 

GWU / SPHHS 

Department of Health Policy 

Ms. Rosenbaum reported that the fundamental aim of health care reform was to stabilize the 

private health insurance market as the principal means by which the health care system is 

financed, given the national preference for private coverage and the desire to retain the 

employer system. Moreover, coverage is intended to be accessible, affordable, and include 

reasonable coverage and investment in preventive services. There is also an emphasis on the 

introduction over time of cost controls; a fair amount of emphasis on cross-payer quality 

improvement; and an increase in the national investment in prevention, wellness, primary care, 

and better management of chronic illness. 

With respect to individual responsibility (Title I), by 2014 most individuals will be required to 

have coverage or pay a fee equal to the greater of $695 per person ($2,085 per family) or 2.5% 

of household income. This will be phased in from 2014 through 2016. Exceptions include 

financial hardship; religious objections; American Indians; people who have been uninsured <3 

months; persons for whom the lowest cost health plan exceeds 8% of income; and persons with 

incomes below the tax filing threshold ($9,350 for an individual and $18,700 for a married 

couple in 2009). Basically, the requirement is universal. There are advance refundable tax 

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credits and cost sharing assistance for those who have low to moderate income levels. There is 

Medicaid coverage for the poorest people. 

Regarding employer responsibility (Title I), there is no mandate to provide insurance; however, 

there will be a fee of $2,000 / per employee assessment of employers with 50 or more 

employees on employers that do not offer coverage and have at least one employee who 

receives a premium credit through a state exchange. There will be a similar assessment on 

employers with more than 50 employees that offer coverage but have at least one employee 

who receives a premium credit through a state exchange. Employers offering coverage must 

provide a voucher to employees with incomes below 400% FPL, if the employee share of the 

premium is between 8% to 9.8% of income, to provide their choice of an exchange plan. Large 

employers (>200 FT employees) offering coverage must automatically enroll employees into the 

employer’s lowest cost premium plan if the employee does not sign up for employer coverage or 

does not opt out of coverage. 

There are numerous private insurance reforms as illustrated in the following tables: 

11 

PRIVATE INSURANCE REFORMS (Pre-2014) (exceptions for grandfathered plans) 

DEPENDENT COVERAGE* To age 26 

PREVENTIVE BENEFITS 

EFFECTIVE: 

1st Plan Year after 09/10 

Preventive benefits with no cost-sharing: A or B (USPSTF). ACIP recommended immunizations,

Preventive care for children & additional care/screenings for women 

recommended by HRSA. 

PRE-EXISTING CONDTIONS No pre-existing condition exclusions for children <19 

TAX CREDITS AND HIGH RISK 

POOLS 

Small employer tax credit (<25 employees moderate average annual

wage, and subsidized high risk pools for individuals with pre-existing 

conditions and uninsured for 6 months or longer 

REINSURANCE For firms covering retirees 55+ and not eligible for Medicare 

RECISSIONS* Barred except in cases of intentional fraud 

LIFETIME CAPS* 

ANNUAL LIMITS 

WAITING PERIODS* 

Lifetime caps barred 

Annual limits regulated 

Waiting periods regulated 

PREMIUMS Rate reviews for unreasonable rate increases, beginning 2010 

MEDICAL LOSS RATIO Medical loss ratio reporting, rebates in 2011 for group plans not 

meeting 85% MLR & individual plans not meeting 80% MLR 

CONSUMER WEBSITE Consumer website and information improvement 

Title I 

DHHS

DHHS2

12 

PRIVATE INSURANCE REFORMS (2014) (Title I) 

Self-insured ERISA group health plans and large insured group health plans operate outside of

rules governing exchange plans 

Qualified plans sold 

in state exchanges 

Available to individual and small group markets (100 or fewer FT employees,

state option to set at 50 or fewer until 2016) 

Benefits and 

Coverage 1. Essential benefits 2. Consumer protections 

3. Waiting periods limited to 90 days 

4. No prior approvals or higher out of network cost sharing for emergency care 5. Prohibition against health status discrimination No denial based on pre-existing conditions 6. Coverage for approved clinical trials 

7. No lifetime or annual limits 

Consumer 

Protections 

1. Limits on annual cost sharing exposure 

2. Caps on annual out-of-pocket spending 

3. Prohibits discrimination against providers, individuals, employers 

4. Rescissions barred 

Insurer Practices 1. Rules on premium rating/pricing: Prohibits gender discrimination 

2. Accounting for the cost of insurance 

3. Non-discrimination in favor of highly compensated employees 

4. Review of premium increases 

Important items with regard to immunization policies include dependent coverage through age 

26; preventive benefits with no cost-sharing; ACIP-required immunization coverage levels; 

additional preventive services to be designated by the Secretary; changes in limits on coverage 

for people who are ill; lifetime are barred, annual caps are regulated; waiting periods are 

regulated; et cetera. Over time the major changes apply, which include access to coverage for 

everyone, elimination of pre-existing condition requirements for everyone, certain consumer 

protections, elimination of lifetime and annual limits, limits on cost-sharing and out-of-pocket 

spending, and a lot of regulation of the business of insurance itself (e.g., setting of premiums, 

accounting for the cost of insurance, accounting for the medical loss ratio, et cetera). 

Other private health insurance markets will remain outside the exchange. The exchanges that 

will be set up in all states are for the individual and small group markets. States can permit 

anyone into exchange purchasing, but the assumption is that these are really for individuals and 

small groups. Ultimately, a small group means under 100 people, which is the vast majority of 

people who work in the US. Self-insured employer-sponsored group plans and large fully 

insured employer-sponsored group health plans, meaning 101 people or more, stay out of the 

exchange and presumable always will. This is important in terms of the benefit design. 

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Exchange products must meet certain benefit standards, including the following benefit classes: 

 Ambulatory patient services 

 Emergency services 

 Hospitalization 

 Maternity & newborn care 

 Mental health and substance use disorder services including behavioral health treatment 

 Prescription drugs 

 Rehabilitative and habilitative services and devices 

 Laboratory services 

 Prevention and wellness services and chronic disease management 

 Pediatric services including oral and vision care 

There may be no discrimination based upon age, disability, or expected length of life. Exchange 

products must also take into account the health care needs of diverse population segments 

including women, children, persons with disabilities, and others. There must be emergency 

access rules. 

Coverage of preventive services (Title IV) requires qualified health plans to cover, without costsharing, “evidence-based items or services” rated A or B by the USPSTF; ACIP-recommended 

immunizations; preventive care for infants, children, and adolescents recommended by HRSA; 

and additional preventive care and screenings for women recommended by HRSA. This will be 

effective six months following enactment. For all USPSTF A and B recommendations, see the 

chart at http://www.ahrq.gov/clinic/pocketgd09/gcp09s1.htm. Title IV also provides 1% FMAP 

increase for states that offer Medicaid coverage of and remove cost-sharing for A and B 

USPSTF recommended services and ACIP-recommended immunizations effective January 1, 

2013. However, newly eligible beneficiaries are covered by benchmark plans, which under 

Section 1937 SSA must cover “preventive services as designated by the Secretary.” Costsharing is eliminated for Medicare-covered preventive services USPSTF recommended A or B 

services. Medicare coverage is authorized for comprehensive health plans and risk assessment 

and the deductible and coinsurance are waived for personalized prevention planning. The 

Secretary is authorized to modify Medicare coverage of preventive services based on USPSTF 

recommendations. Nothing changes about the VFC or the coverage rules for children; however, 

for the poorest adults, preventive benefits, ironically, may still be an option. 

Complex requirements apply to “Grandfathered Plans.” Rather than selecting a date by which 

all products sold in the affected markets are upgraded to the new coverage standards, the law 

provides for current plans in effect on March 23rd to remain in effect as grandfathered plans and 

essentially directed the Secretary to set standards for what it means to be a grandfathered plan. 

Standards were issued the week before this ACIP meeting. 

In the case of Medicaid, by 2014, all non-elderly persons with incomes up to 133% FPL, based 

on “modified adjusted gross income” should be covered. An adult coverage option will be 

effective July 1, 2010, and additional reforms for women (family planning) and children aging out 

of foster care are to be included. There are maintenance of effort (MOE) requirements for 

children under 19 through 2019 and for adults eligible for Medicaid until the Secretary 

determines that exchanges are fully operational. There is 100% federal funding for the costs of 

newly eligible persons (2014-2016), dropping to 90% federal funding for 2020 and subsequent 

years. There is phased in federal funding for states that already have expanded adult eligibility 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

to 100% of the poverty level. Benchmark coverage for adults includes some level of preventive 

services as designated by the Secretary. There is an increase Medicaid payments for services 

of primary care physicians to 100% of Medicare payment rates in 2013 and 2014 with 100% 

federal financing of increment, and a federal incentive for Medicaid preventive services 

coverage for all adults (1% FMAP increase). 

There are numerous quality improvement requirements (Title III) aimed at insurers, the health 

care system, and clinical practice. It can be expected, due to the link between quality and 

efficiency, that there will be numerous efforts to upgrade the quality of practice and to 

emphasize prevention practice. There is an incentive in the legislation for employee wellness 

programs, with a broad level of discretion given to employers to design employee wellness 

programs. Thus, immunization status could be an employee outcome that incentivizes a 

reduction in premium year cost-sharing. 

A considerable amount of funding and attention have gone into access (Title V). There is an 

investment of $12.5 billion to expand health centers and fund National Health Service Corps 

($9.5 billion to expand health center operations, $1.5 billion in health center capital investment, 

and $1.5 billion for Corps health professionals). A doubling of the program’s reach is expected 

by 2019 once coverage financing also begins. Immunization is a required activity of all health 

centers. Also included is authorization of school health centers programs (mandatory funding 

only for construction and development 2010-2013). 

In terms of prevention and public health (Title IV), a trust fund has been set up with an 

appropriation of $15 billion over 10 years ($2 billion a year beginning in FY 2015, $500 million in 

FY 10, $750 million in FY 11). Some of the funding has already been put into primary care 

expansion. The remaining funds are expected to be invested in community prevention 

activities. Moving forward, there is a major emphasis on community prevention activities. 

Anything that is legal under the Public Health Service Act is a community prevention activity. 

Therefore, states, localities, and the Secretary could design a lot of interventions aimed at 

boosting immunization status. 

Part of the prevention strategy includes community transformation grants. This is new grant 

authority (no mandatory appropriation) for community prevention (state, local, and NGOs 

eligible grantees). There is a requirement for detailed plans for policy, environmental, 

programmatic and infrastructure changes to promote healthy living and reduce disparities. 

Immunization status is not specifically identified in the statute as a community health outcome, 

but could be added by the Secretary. The CDC director is to oversee the program and develop 

state and local capacity to engage in community transformation activities. 

With respect to the immunization program and Medicare immunizations (Title IV), the major 

news is the use of state authority to utilize the federal contract for adult vaccines. There is a 

Section 317 demonstration program to improve immunization coverage authorized in concert 

with the Task Force on Community Preventive Services. Medicare beneficiary access to 

vaccines is to be studied formally going forward. 

In terms of what Ms. Rosenbaum would flag as major issues, she believes that because over 

time there will be a transformation of what it means to be covered in the US, within the next 10 

years the new normal will be full coverage for all ACIP-recommended vaccines across all 

insurance markets. This places ACIP recommendations into an astounding light. It means that 

to the extent that ACIP has devoted a lot of its time to children, once the way is cleared to think 

somewhat more broadly about immunization coverage, the “door will be opened” to a culture 

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shift in how financial issues are thought of in immunization coverage. She thought they would 

have to think about this in three ways: 

1) Insurer behavior: How do insurers design their benefits? For example, even in states that 

purport to regulate state-regulated insurance products, there may be public health 

emergency exceptions. There may be all sorts of limitations and exclusions on vaccine 

coverage because it does not have to meet the ACIP standard. Moving forward, it will make 

no difference whether a full or qualified recommendation ACIP recommendation is made. 

The standard is a recommendation. 

2) Provider behavior: Over the next period of time, providers will come to be certain about the 

financial backdrop for their immunization practices in their offices. The justifications for not 

being at the ready all of the time and not to have missed opportunities will begin to 

decrease, and it is assumed will also begin to affect everyone’s thinking about what good 

immunization policy looks like. 

3) Family behavior: Family immunization behavior is the product of many things, but one 

barrier is an uncovered $50 administration fee even if the vaccine itself is free. 

In terms of performance and health care quality improvement changes in medical homes, the 

law provides for a great ramping up of comparative effectiveness research (CER): How much 

does immunization practice get figured in? How much do ACIP recommendations help inform 

CER design and execution? How much expansion is there in community health centers? How 

much do pediatric and adult immunizations become a bedrock for measuring community health 

center performance? 

Discussion Points 

Dr. Sumaya inquired as to whether the $12.5 billion represented new dollars or was a 

component of current funds. 

Ms. Rosenbaum responded that the $12.5 billion was on top of the current funds. The 

assumption on the part of the advocacy world for the program is that they will hold the base as it 

stands now against inflation following the stimulus, which appropriated additional funds, and that 

the $12.5 billion ($9.5 billion of which is operating money going forward) is on top of what would 

be inflation-adjusted. Thus, it is real expansion and the prediction is a doubling in the number of 

patients served. 

Dr. Campos-Outcalt wondered what the implications would be of full coverage for the VFC. 

Ms. Rosenbaum replied that there are no changes whatsoever in the VFC, meaning that all 

children who are entitled to vaccine coverage are in the program, and the purchasing system 

through Medicaid remains in place. Backing out any children who will not qualify because of 

legal status in the US, the theory is that some 8 million children are, probably more than any 

age group, as close to the universal coverage of a population as will be observed. Even if 

children are covered through the exchange, so not Medicaid, would be entitled to all ACIPrecommended vaccines. The VFC is the delivery mode, but the basic entitlement under 

Medicaid is to ACIP-recommended vaccines. That has now become the standard for children 

and adults. In 2014, that will be the standard. The two markets that are outside are large 

insured employer plans and self-insured employer plans. Basically, the assumption is that over 

time, even those two markets will fall into place because the companies that sell to the 

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exchange market and to the larger employer market are going to want to sell a valued product 

that includes good preventive benefits. That will come to be an expectation on the people’s 

part. 

Dr. Pickering requested further information about the grandfather clause in terms of whether it 

meant that insurance companies would be permitted to function the way they are functioning 

currently for a prolonged period of time unless they make these significant changes, which 

would mean that all insurance companies would grandfather in. 

Ms. Rosenbaum reminded everyone that the mantra leading up to the passage of the law was, 

“If you like what you have, you can keep it.” The grandfather provision is designed to make 

good on that. An equally important decisions was made, which is that the grandfather status 

should not be used as a cover for eroding people’s coverage. The House bill veered more 

toward a data certain to make a shift. The Senate was more lenient. The regulations 

essentially say that as long as premiums, benefits, coverage, and cost-sharing rules remain 

stable. There is room to increase these, but the regulations set a threshold amount above 

which changes result in a loss of grandfathered status. These are cumulative rules, so the 

assumption is that over the next three years, the federal government estimates that half of all 

plans will have relinquished their grandfather status. The premium increases that are 

anticipated may be enough to set off a loss of grandfathering. 

Dr. Temte requested information on the change in administrative fees under Medicare, which 

impacts a great number of children being immunized by private clinicians through the VFC. 

Ms. Rosenbaum replied that one of the changes that was made in the law with Medicaid primary 

care reform was a requirement that Medicaid agencies set their primary care payment rates at 

the Medicare payment level. That takes effect in 2014. For several years, the federal 

government will pay the full cost of the increment in payment that would result. The hope is that 

if Medicaid primary care rates, including administration fees, are brought up to the Medicare 

level, that will be a decisive increase in compensation rates for immunization, among other 

things. It is an ironic time to be talking about Medicare as being an improvement, given the pay 

cut that Medicare-participating physicians are facing. Hopefully, that deadlock will be broken. 

Dr. Baker pointed out that currently, Medicare recipients are paying more for their Medicare 

coverage. She wondered whether this would continue as health care reform moved forward. 

Ms. Rosenbaum responded that nothing about health reform would change the premiums. 

Those with higher incomes, as the law defines higher income, will pay a higher premium. 

While Dr. Birkhead (NVAC) thought it was great that vaccines and administration would be 

covered in the preventive package, the NVAC Finance Working Group identified the question of 

the adequacy of that reimbursement and whether, in the private sector, vaccine and 

administration costs were being fully covered by the administration fee. In the public sector, the 

Medicaid programs for most states do not contribute enough state dollars to draw down the full 

federal contribution, so some states are paying $2.00 administration fees. He wondered if there 

was anything in the reform to address the adequacy of the administration fees for the public and 

private sectors. 

Ms. Rosenbaum indicated that there is the change in terms of raising the Medicaid primary care 

rate, which includes vaccine administration costs to the Medicare level that she just mentioned. 

That is a full federal contribution for the increment between the state and the Medicare fee. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Dr. Birkhead (NVAC) wondered whether the vaccine administration fee codes would reflect this 

as well. 

Ms. Rosenbaum said she assumed on implementation a major issue for NVPO and NVAC 

would pertain to how much CMS has internalized exactly what it means to reach Medicare parity 

levels with respect to vaccine administration. Regarding private coverage, she expected that 

NVPO and NVAC would want to engage in significant discussions with CMS, the new Center for 

Health Plans within HHS that is dealing with the exchanges and health plans, the Department of 

Labor to the extent that they are involved in the small employer market, and the Treasury 

Department in terms of what it means to cover immunizations recommended by ACIP. The 

statute states “ACIP-recommended immunization.” It does not say “vaccine” or include a list of 

immunizations. Therefore, the question regarding what it means is left to interpretation. 

Rotavirus 

Impact of Rotavirus Vaccination Programs 

Margaret M. Cortese, MD 

on behalf of the 

Viral Gastroenteritis Epidemiology Team 

Centers for Disease Control and Prevention 

Dr. Cortese presented an update on the impact of rotavirus vaccines, and on rotavirus vaccines 

and circovirus. She reminded everyone that in 2006, the results of the two major safety and 

efficacy studies were published on the two new rotavirus vaccines, RV5 and RV1. These were 

among the largest vaccine safety studies ever conducted, with each safety study including 

>60,000 infants. Safety and high efficacy were demonstrated for both of these vaccines. 

Efficacy of 85% to 98% was demonstrated against severe rotavirus disease [Vesikari T et al 

NEJM 2006; Ruiz-Palacios G et al, NEJM 2006]. 

ACIP recommended RV5 (RotaTeq®) in February 2006 and RV1 (Rotarix®) in June 2008. 

CDC has monitored the impact of these vaccines in various ways using simple to more 

sophisticated methods. The National Respiratory and Enteric Virus Surveillance System 

(NREVSS), a simple but very timely monitoring system, is a network of 67 laboratories 

throughout the US reporting since 2000. Weekly reporting is done on the number of stool 

specimens tested for rotavirus by EIA and the number of positive tests. Based on the number of 

absolute tests performed in these laboratories from 2000 through 2010, since these vaccines 

were recommended, there has been a dramatic reduction in the number of r of rotaviruspositive tests [Tate J et al Pediatrics 2009; CDC unpublished data]. 

For the first season following good rotavirus vaccine uptake (for the 2007/08 season, which is 

when only RV5 was available), comparing proportion of tests that were positive for that year 

compared to pre-vaccine mean, there was a dramatic reduction overall in the percentage of 

positive tests and the delay in the timing of the positive tests, suggesting delay in the onset of 

the season [Rotavirus Test Results at NREVSS Laboratories, 2008 season]. 

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CDC also assesses impact through medical claims data from various data sources. In the 

Southern US, for example, In the 2007/2008 season, there was almost complete flattening of 

gastroenteritis admissions across the age groups, compared to previous years. This occurred 

with only approximately 60% estimated 2008 coverage with ≥1 dose of rotavirus vaccine (RV5) 

among children aged <1 year. ) [Gastroenteritis Hospitalizations and RV5 Coverage; Medical 

Claims Data, Southern US; Cortese M et al PIDJ 2010]. 

The estimates of rotavirus burden reduction, can be shown in various ways. In the following 

table, substantial reductions are shown in all-cause gastroenteritis that occurred during the 

rotavirus season in ages <1 year and 2 years. This suggests an indirect benefit to older 

children who were not within the age category who could have received vaccine [Gastroenteritis 

Hospitalizations and RV5 Coverage; Medical Claims Data; 2008 vs. mean of 3 pre-vaccine 

years]: 

Average 3 US regions 

(South, Northeast, Midwest) 

Reduction in GE Hospitalizations 

Age <1 Year 

Reduction in GE Hospitalizations 

Age 2 Years 

Rotavirus Season 

• Excess GE 

• All GE 

96% 

69% 

85% 

70% 

Annual 

• Rota-coded GE 

• All GE 

81% 

30% 

69% 

41% 

Rota vaccine coverage (≥ 1 dose) 58% <1% 

In a more robust way, Dr. Curns examined complete hospitalization data for gastroenteritis and 

rotavirus-coded hospitalizations in 18 states for those aged <5 years from 2000-2008. Again in 

the 2008 season, a marked decline was observed in all gastroenteritis-coded and rotaviruscoded hospitalizations in these 18 states. The estimated reduction in US hospitalizations for 

children aged<5 years in 2008 was greater than 40,000. [Curns A et al, JID 2010]. 

The Cadillac method by which CDC monitors the impact of these vaccines is through the 

National Vaccine Surveillance Network (NVSN) with colleagues the University of Rochester, 

Cincinnati Children’s Hospital Medical Center, and Vanderbilt University where active rotavirus 

surveillance is performed. This allows for the direct estimates of rotavirus disease burden 

among children in the counties served by these hospitals. From the baseline of about 50% of 

children with acute gastroenteritis testing rotavirus positive, in 2008, only 9 children (6%) of 

children tested positive at these 3 children’s hospitals [Payne D et al PAS, 2009 and 

unpublished data]. Age-specific reductions in rotavirus hospitalization rates demonstrated an 

80%-90% reduction, including among children aged 2 who were too old to have received 

vaccine, indicating what is believed to be herd immunity... 

For the 2008-2009 season, the second season post-good uptake of rotavirus vaccine, from 

NREVSS laboratory system, the percentage of positive tests remained well below the median 

pre-vaccine percentage. However, the percentage of positive tests was slightly higher than the 

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2007-2008 season. This season was also not quite as delayed as the first very dramatic 

season [Rotavirus Test Results at NREVSS Laboratories, 2009 season]. 

Based on preliminary medical claims data from the 2008/2009 season in the Southern US, in 

children under the age of 1 there was higher rotavirus vaccine coverage than the previous year 

and continued blunting of the winter peak in gastroenteritis hospitalizations. In the older 

children, at least in the South, a resumption in the peak in the winter season was observed. 

This was still lower than pre-vaccine, but not as flat as in the first year with good coverage postintroduction of vaccine. It is believed that this could a result of disease among children who 

were neither vaccinated nor previously infected by rotavirus because of the greatly reduced 

circulation of rotavirus in the previous season [Gastroenteritis Hospitalizations and Rotavirus 

Vaccine Coverage 2009 Medical Claims Data, Southern US; CDC, unpublished data]. The 

NVSN data support this. From this active surveillance system, in 2009, there was a modest 

increase in rotavirus-positive test results among children aged < 3 years, the great majority of 

whom were, again, in the older, unvaccinated cohort [Total Acute Gastroenteritis and Rotavirus 

Hospitalizations, age <3 years, NVSN 2006-2009; Payne D et al PAS, 2009 and unpublished 

data]. 

Looking at rotavirus test results fort NREVSS laboratories for the 2010 season, it appears that 

the proportion of positive tests is even further reduced compared with the first very dramatic 

season. These data are supported by NVSN data that are just coming in, which showed a 

continued marked reduction in rotavirus circulation in the US. 

Fortunately, the US is not the only country that is benefitting from these vaccines. In El 

Salvador, for example, RV1 was recommended in October 2006. DePalma et al published a 

paper recently showing a marked reduction in all-cause gastroenteritis hospitalizations and 

rotavirus-positive hospitalizations in seven hospitals throughout the country where active 

surveillance is also performed, similar to NVSN. For 2008-2009, there was an estimated 

reduction in rotavirus hospitalizations following RV1 introduction in El Salvador of 69% to 84% 

among children aged <5 years [De Palma O et al, BMJ 2010]. 

A very exciting article was recently published titled “The Effect of Rotavirus Vaccine on Death 

from Childhood Diarrhea in Mexico.” Using their routine system of collecting data from death 

certificates in children, they were able to quickly analyze their data and demonstrate a marked 

decline in childhood diarrhea deaths after RV1 introduction in Mexico. In terms of total diarrhea 

deaths in Mexico for July 2002 to December 2008, there was a characteristic peak during the 

fall- winter months that is most prominent among children 0-11 months of age but also occurs 

among children aged12-23 months. Characteristically, rotavirus is attributed with causing these 

peaks that occur between December and May. Rotavirus vaccine introduction occurred in May 

of 2007The peak for the fall-winter months of 2008 that is typically attributed to severe rotavirus 

cases was blunted for the 0 to 11 month age group, which is the only age group exposed to the 

rotavirus vaccine [Richardson V et al NEJM 2010]. In winter 2009, there was an estimated 66% 

reduction in diarrhea-related deaths, strongly suggesting vaccine effect on mortality in Mexico. 

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The following map illustrates the global distribution of the 527,000 annual rotavirus deaths in 

young children: 

1 dot = 250 deaths 23 

Demonstrating the performance of these vaccines in low-income countries is critical to be able 

to provide benefit to these children, where mortality is greatest. 

Based on an RV1 efficacy trial conducted in Malawi and South Africa, efficacy in both countries 

was generally lower than typically observed in developed countries, as expected with oral 

vaccines. Also, as expected, there was some variation by country such that the point estimate 

for efficacy was 49% in Malawi with 6.7 rotavirus cases prevented per 100 vaccinated, and 77% 

in South Africa with 4.1 rotavirus cases prevented per 100 vaccinated. Nevertheless, even a 

vaccine with efficacy of 49% is expected to play an important in such countries, given that the 

burden of severe disease is extremely high [Madhi S et al NEJM 2010]. 

Regarding a new finding, rotavirus vaccines and circovirus, Dr. Cortese reported that in March 

22, 2010 FDA recommended temporary suspension of Rotarix® while collecting further 

information on detection of porcine circovirus DNA in Rotarix®. On May 6, 2010, FDA reported 

detection of porcine circovirus types 1 and 2 DNA in RotaTeq®. On May 7, 2010 an expert 

Vaccines and Related Biological Products Advisory Committee (VRBPAC) review panel was 

convened by FDA. On May 14, 2010, FDA lifted the temporary suspension on Rotarix® and 

recommended continuing to use RotaTeq®. CDC has revised the Rotavirus Vaccine 

Information Statement. 

Update on CBER Activities on Porcine Circovirus in Rotavirus Vaccines 

Wellington Sun, MD 

FDA / CBER / OVRR 

Dr. Sun reported that in February 2010, GSK was informed by a University of California, San 

Francisco (UCSF) investigator who conducted a study of DNA sequences of live attenuated 

vaccines, that he had detected PCV-1 in 2 batches of Rotarix® [Victoria et al] GSK initiated 

experiments to confirm these results and to conduct further investigations. Tests confirmed the 

presence of PCV-1 DNA in Rotarix® at all stages of the production process. GSK informed 

FDA of the detection of PCV-1 DNA fragments in Rotarix ® and in harvests, but not in the final 

product, of inactivated poliovirus (IPV)-containing vaccines that were produced in a related cell 

bank. The Center for Biologics Evaluation and Research (CBER) testing confirmed the 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

presence of PCV-1 DNA in Rotarix® . As noted, FDA recommended temporary suspension of 

use of Rotarix® vaccine on March 22, 2010 as a precautionary measure while CBER gathered 

additional information. Although testing by Victoria et al did not find PCV1 DNA sequences in 

Merck’s rotavirus vaccine (RotaTeq®), CBER embarked on testing RotaTeq® and 

recommended that Merck do the same. The FDA was subsequently notified by Merck that 

preliminary studies identified fragments of DNA from porcine circovirus type 1 and type 2 (PCV1 

and PCV2) in RotaTeq® vaccine. 

In terms of the CBER lab response to date, CBER has confirmed the presence of PCV-1 DNA in 

Rotarix®, including complete virus genomes; showed that PCV-1 DNA in Rotarix® is particleassociated, in other words, it is not just DNA; showed that PCV1 virus in Rotarix® can infect 

swine cells in culture; and confirmed PCV1 and PCV2 DNA fragments in RotaTeq®. To date, 

there has been no detection of full length PCV genomes and no infectious virus (tested in cell 

culture) has been found in RotaTeq. These studies are on-going. 

PCV-1 and PCV-2 are small DNA viruses containing a single strand of circular DNA. PCV-1 is 

ubiquitous in pigs and is found in pork products. PCVs are not known to cause disease in 

humans. There is currently no evidence to suggest that PCV or PCV DNA in US licensed 

vaccines poses a safety risk. To date, no serious or unexpected safety signals have been 

observed in pre-licensure studies or post-marketing surveillance of Rotarix® or RotaTeq®. 

GSK’s preliminary serology studies did not show antibody response to PCV-1 among recipients 

of Rotarix, suggesting that PCV-1 did not infect vaccine recipients. However, those numbers 

are relatively small. CBER and the manufacturers’ results are reflected in the following table: 

Vaccine CBER Manufacturer 

Rotarix (GSK) PCV-1 DNA in product PCV-1 DNA in product, 

bulks, seeds, cells 

Particle-associated near full 

length PCV1 DNA in product 

Infectious PCV1 in cell culture Infectious PCV-1 in cell 

culture 

Preliminary data: No PCV-1 

seroresponse among 

vaccine recipients 

IPV containing 

vaccines 

(GSK) 

Pending PCV-1 DNA in harvest, 

seeds, cells, but not in 

bulks or final container 

Rotateq 

(Merck) 

Particle-associated PCV-2 

DNA fragments in harvest; 

PCV-1 and PCV-2 DNA 

fragments in final container 

PCV-1 and PCV-2 DNA in 

harvest, PCV DNA in final 

container 

On May 7, 2010, VRBPAC considered the substantial safety record of the vaccines known to 

contain PCV; considered the benefit of vaccines to outweigh theoretical risks from the presence 

(or potential presence) of PCV; discussed the importance of transparency and providing 

information to public; and recommended taking steps to remove PCVs from products. VRBPAC 

also discussed new genomic techniques that may increase the likelihood of finding additional 

viruses, virus-like sequences in vaccines. If found, the potential risks from such viruses or 

sequences may be difficult to assess. Introduction of these techniques in a regulatory setting 

will require standardization and development of approaches to confirm findings. 

Subsequent and on-going FDA actions include a reversal of the recommendation to suspend 

Rotarix® use; continued testing at CBER; discussions with manufacturers regarding further 

testing, labeling, and removal of PCV from products; and discussions regarding the implications 

of new genomic techniques in a regulatory setting. 

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ROTARIX® (Rotavirus Vaccine, Live 

Oral): GSK’s PCV1 Investigation 

Leonard Friedland, MD 

Vice President 

Clinical and Medical Affairs, Vaccines 

GlaxoSmithKline 

For context, Dr. Friedland recapped that GSK was notified by independent investigators of an 

unexpected finding of PCV-1 in Rotarix® (J Virol 2010;84:6033). GSK confirmed the PCV-1 

finding in a validated laboratory in mid-March and notified FDA and other regulatory agencies. 

As noted, on March 22, 2010, FDA recommended temporary suspension of use pending further 

investigation. On May 6, 2010, FDA notified the public of the presence of PCV1 and PCV2 in 

RotaTeq®. On May 7, 2010, FDA convened the VRBPAC meeting as noted. Materials and 

presentations from this meeting are posted on the FDA website at the following url: 

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOther 

Biologics/VaccinesandRelatedBiologicalProductsAdvisoryCommittee/ucm211828.htm. On May 

14, 2010, FDA “determined it is appropriate to resume the use of Rotarix® and continue the use 

of RotaTeq®.” All available data support that PCV1 in Rotarix® is a manufacturing quality issue 

not a safety issue. 

Rotarix® is licensed in over 110 countries. More than 69 million doses have been distributed 

worldwide, and 2.5 million have been distributed in the US. US licensure occurred in 2008. 

Rotarix® is manufactured in compliance with FDA regulations on adventitious agent testing, and 

in accordance with guidance in place at the time of licensure. 

PCV-1 is a non-pathogenic virus that is common and widespread in pigs. PCV-1 is not known 

to cause disease in pigs or any other animal, including humans. There is no convincing 

evidence of human infection by PCV-1. PCV-1 DNA has been detected in US pork products 

and in human stools in the US. PCV-2 has not been found in Rotarix®. PCV-2 is the causative 

agent of “postweaning multisystemic wasting syndrome” in pigs. PCV-2 not known to cause 

disease in humans. 

When GSK was notified of the unexpected finding of PCV-1 DNA in Rotarix®, the company set 

out to determine how PCV-1 originate in Rotarix®. To answer this question, they had to go 

back in time prior to the initiation of the development of Rotarix®. Vero cells were sourced from 

the biological resource center, ATCC in 1980. GSK produced the master cell bank in 1983, and 

further derived the working cell bank in 1993. The working cell bank was used to produce the 

Rotarix® viral seed in 1999 using an ancestor seed produced on an alternative cell line. Once 

screening for PCV-1 DNA was performed using quantitative PCR, the vero cell line source from 

ATCC was found to be negative. The master cell bank and the working cell bank from GSK 

were found to be positive, while the ancestor of the Rotarix® viral seed was negative. GSK 

speculates that a likely source of PVC-1 might be the use of the porcine-derived reagent trypsin, 

which is used to propagate cells in the manufacturing process. Trypsin was not irradiated 

before 1993. Manufacturing corrective actions to produce a Rotarix® free of PCV1 will be a 

complex process and will involve generation of a new bank, generation of a new Rotarix® viral 

seed, and performance of the necessary clinical trial in agreement with regulatory authorities. 

This will take several years. 

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GSK has investigated the nature of the PCV-1 signal present in Rotarix®. In this investigation, 

they followed the same testing algorithm that was used to investigate the presence of Avian 

Leukosis Virus in a commercial vaccine in the 1990s and sought to answer the following 

questions: 

1. Is this PCV-1 signal associated with presence of viral particles? 

2. Is this PCV-1 signal associated with presence of viral particles capable of infecting 

permissive cells? 

3. Is this PCV-1 signal associated with presence of viral particles capable of productive 

infection in human cells? 

4. Is this PCV-1 signal associated with presence of viral particles capable of causing infection 

in human infants? 

For the sake of time, Dr. Friedland did not go into the details of their manufacturing 

investigations which were reviewed in detail during the May 7, 2010 VRBPAC meeting. In short, 

the results of the manufacturing investigations showed that the PCV-1 signal is associated with 

very low amounts of viral particles, that the viral particles are capable of infecting permissive 

cells (e.g., cells of the natural host such as porcine kidney cells), and that the viral particles are 

not capable of productive infection in human cells (meaning the ability of the virus to infect cells 

and produce detectable, intact viral particles). GSK’s investigations indicate that there is no 

evidence that PCV-1 associated with Rotarix® can undergo productive infection in human cell 

lines. Answering the fourth question (Is PCV-1 capable of causing infection in human infants?) 

was very important in GSK’s investigation. 

GSK’s clinical investigation had two objectives, which were to: 1) evaluate if infants receiving 2 

or 3 doses of Rotarix® or placebo develop an immune response to PCV1 as assessed by the 

presence of antibodies against PCV-1; and 2) evaluate the presence of PCV1 DNA and pattern 

of detection in stool samples collected at pre-determined time points after a single dose of 

Rotarix or placebo. 

To do this, GSK performed blinded retrospective laboratory testing, using archived clinical 

samples collected in completed Rotarix® clinical trials. The studies selected were required to 

be placebo controlled, to involve the collection of pre- and post-vaccination sera, and to include 

the collection of stool samples which were obtained in a subset of subjects in the Rotarix® 

clinical studies at days 3, 7, 10, 15, 22, 30 and 45 after vaccination. Four completed studies 

were identified. In three of the studies, infants were healthy at study entry and one study 

evaluated administration of Rotarix® to HIV positive infants. The goal was to test samples from 

20 subjects in each of the four studies, for a total of 80 subjects (40 who received Rotarix® and 

40 who received placebo). For serum samples, GSK used an immunoperoxydase monolayer 

assay (IPMA) to detect anti-PCV-1 antibody response. For stool samples, Q-PCR was used to 

detect PCV DNA. This study was specifically included since it might be speculated that 

replication of PCV-1, if it were to occur, might be enhanced in an HIV+ population. There were 

300 stool samples and 160 serum samples. 

The results of these clinical investigations demonstrate lack of PCV-1 infection in infants. None 

of the infants seroconverted. PCV-1 was detected in the stools of 4 of 40 Rotarix recipients® 

(2/5 [40%] at day 3, and 2/40 [5%] at day 7. None was detected at later time points (days 10, 

15, 22, 30, 45) after vaccination. The adverse event profile in subjects with PCV-1 DNA 

detected in stools was similar to placebo recipients. Currently available data do not support 

PCV-1 infection in infants who received Rotarix® in clinical trials. The conclusion of the 

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currently available data from GSK’s clinical investigations is that the PCV-1 present in Rotarix® 

is not capable of causing infection in infants. These results are consistent with the published 

literature, which indicates that PCV-1 is not capable of causing infection in humans. 

GSK’s investigations reveal that PCV-1 has been Rotarix® from the early stages of 

development, throughout clinical trials and post-marketing to the present. As a vaccine 

manufacturer, GSK’s primary focus is always on patient safety. In parallel with the 

manufacturing and clinical investigations, when GSK first learned about the presence of PCV-1, 

they critically reviewed the scientific literature and consulted experts. The unanimous 

conclusion from all sources is that PCV-1 is not known to be infectious in humans, nor does it 

cause disease in humans or any other animal. The Rotarix® safety database is large, robust, 

and extensive. It is continuously monitored over time, and consistently demonstrates the safety 

of Rotarix®. There is no specific PCV-1 lens by which to query GSK’s database because in the 

absence of disease, there are no symptoms. 

Rotarix® has had one of the largest vaccine development programs. Supporting US licensure 

in 2008 were 11 studies, with more than 75,000 infants enrolled, 40,000 of whom received 

Rotarix®. Efficacy was evaluated through 2 years, 2 rotavirus seasons, after vaccination. 

Therefore, safety was also evaluated for many of the infants up to 2 years after vaccination. 

The development program included a large safety study in more than 60,000 infants and was 

specifically powered to assess intussusception (n=63,225). 

Recently, Rotarix® was one of multiple products reviewed by the FDA’s Pediatric Advisory 

Committee. This committee conducts routine, periodic safety reviews of pediatric drug and 

vaccine products. The Pediatric Advisory Committee unanimously agreed with FDA’s 

conclusion that no new safety concerns were identified with Rotarix®, as well as with FDA’s 

recommendations for continued routine monitoring. The Pediatric Advisory Committee did not 

specifically review the product with the knowledge of PCV-1, because the finding had just 

become available. However, as has since been learned, the product reviewed contained PCV-1 

and has since early development. 

In addition to the clinical trial database that supported licensure, a large global post-marketing 

experience supports Rotarix® safety and effectiveness. Pharmacovigilance activities are in 

place. GSK has a worldwide network of safety personnel who analyze adverse events and 

expedite reporting to worldwide regulatory agencies. For spontaneously reported 

intussusception cases, enhanced pharmacovigilance is used, comparing the number of cases 

observed to the number expected. Since the worldwide launch in 2006, over 69 million doses of 

Rotarix® have been distributed, including 2.5 million doses in the US. The company has 

received approximately 3,000 adverse event reports, approximately 1,200 of which are 

considered to be serious as defined by regulatory criteria. This represents a reporting rate of 

4.3 per 100,000 doses distributed. This rate is consistent with reporting rates expected with 

new vaccines. 

Various Phase 4 clinical trials have been conducted, including safety and immunogenicity trials 

in HIV positive infants and in premature infants. Rotarix® was found to be immunogenic and 

well-tolerated in these particularly vulnerable populations. GSK has also conducted a 

transmission study between twins, demonstrating low rates of transmission with no associated 

gastroenteritis symptoms, and is also conducting a number of observational studies worldwide 

to further monitor the safety and effectiveness of Rotarix®. One on-going study in the US will 

include 55,000 infants receiving Rotarix® to assess the risk of intussusception and other serious 

adverse events. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

GSK has previously presented results from its worldwide randomized placebo-controlled clinical 

trials to ACIP, which have demonstrated the substantial efficacy of Rotarix®. The published 

studies shown in the following table demonstrate the considerable impact and effectiveness of 

Rotarix® in preventing severe rotavirus disease in real-life settings. These data together 

demonstrate that Rotarix® is a very effective tool for significantly reducing morbidity and 

mortality due to rotavirus gastroenteritis: 

17 

Rotarix is Effective in Preventing Severe 

Rotavirus Gastroenteritis 

Effectiveness Studies 

Country Outcome Effect Journal 

Australia 

(New S Wales) 

pos. RV solates and ED vis ts 

due to GE 

lowest numbers compared to 

previous 8 RV seasons Comm D s Intell 2009 

Australia 

(Central) G9 RV hospitalized GE 85% Vaccine effectiveness CID 2009 

Brazil All-cause GE hospitalization 26-48% rate reduction PIDJ 2010 

Brazil 

(Rec fe) G2[P4] severe RV diarrhea 77% V effectiveness JID 2010 

Brazil 

(San Pao o) RV GE hospitalization 59% rate reduction ESPID 2009 

El Salvador severe RV gastroenteritis 74% V effectiveness WHO WER 2009 

Mexico All-cause diarrhea-related 

mortality 41% rate reduct on NEJM 2010 

To summarize and conclude, rotavirus infection is the leading cause of severe childhood 

diarrhea in both developed and developing countries. Prior to the development of vaccines 

against rotavirus, worldwide one child died from rotavirus every minute. Vaccination is the only 

effective preventative strategy. Globally, its use has the potential to prevent about 2 million 

deaths over the next decade. Studies in the US have shown that vaccination has resulted in at 

least a 60% reduction in rotavirus disease as compared to the pre-vaccine era. Rotarix® 

confers robust and broad protection against rotavirus gastroenteritis. Rotarix® has been 

extensively studied before and after approval, and has been found to have an excellent safety 

record. Material from PCV-1 has been present since the initial stages of the vaccine’s 

development, throughout clinical trials and post-marketing, to the present. Thus, all of the 

safety data reflect exposure to PCV-1, supporting the safety profile of Rotarix®. Overall, the 

benefit for Rotarix® remains highly favorable. 

It is now known that an adventitious agent, no matter how benign, is present in Rotarix®. GSK 

is continuing discussions with FDA and other regulatory agencies regarding additional clinical 

investigations, and is committed to manufacturing Rotarix® using PCV1-free materials. 

Developing a new manufacturing process is a complex undertaking that will require time to 

implement. GSK will continue with its comprehensive pharmacovigilance activities already in 

place worldwide. Use of Rotarix® has been resumed and Rotarix® is available for use by US 

healthcare providers. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

RotaTeq® (Rotavirus Vaccine, Live, Oral, Pentavalent) 

Update on Porcine Circovirus (PCV) 

Kim Dezura 

Global Vaccine Technology & Engineering 

Merck & Co., Inc. 

RotaTeq® was licensed in the US in February 2006. In March 2010, Merck received global 

WHO pre-qualification. Currently, RotaTeq® is licensed in over 90 countries. Over 37 million 

doses have been distributed worldwide, of which over 30 million have been distributed in the 

US. RotaTeq® has an established safety profile based on large, comprehensive pre- and postlicensure studies that have been conducted. Protection against rotavirus gastroenteritis has 

been demonstrated in developed and developing countries (e.g., North America, Europe, Latin 

America, Africa, and Asia). A substantial reduction in rotavirus disease burden has been 

observed across the globe after vaccine introduction, particularly in Australia, France, 

Nicaragua, and the US. 

It is important to note that both PCV-1 and PCV-2 commonly circulate on pig farms. There is 

frequent detection of PCVs in US pork products and US stool samples. Neither PCV-1 nor 

PCV-2 is known to cause infection or illness in humans. PCV-2, while linked to wasting 

syndrome in pigs has not been linked to any illness within humans [Li L et al. J Virol. 

2010;84:1674–1682; Victoria JG et al. J Virol. 2010; 84:6033–6040; Fraile L et al. Can J Vet 

Res. 2009;73:308–312; Food and Drug Administration,fda.gov/BiologicsBloodVaccines/ 

Vaccines/ApprovedProducts/ucm212140.htm. Accessed May 24, 2010]. 

Ms. Dezura reported that on March 22, 2010, no PCV was found in RotaTeq® by the US 

research team at UCSF. On March 23, 2010, FDA recommended that Merck conduct testing for 

PCV. Initial testing of RotaTeq® by FDA in March and April 2010 was negative for PCV. In the 

latter part of April 2010, Merck notified regulatory agencies worldwide that very low levels of 

PCV DNA had been found in RotaTeq® by PCR. On May 6, 2010, FDA preliminary testing 

revealed low levels of PCV-1 and PCV-2 DNA in RotaTeq® from its own testing. On May 14, 

2010, FDA recommended continued use of RotaTeq® and resumption of Rotarix® following the 

May 7th VRBPAC meeting. 

In developing an analytical test plan for the evaluation of RotaTeq® for PCV, Merck focused on 

the following four key questions: 

1. Is PCV DNA present in RotaTeq®? 

2. Is PCV DNA detected associated with virus particles? 

3. Are PCV virus particles infectious? 

4. What is the source of PCV DNA? 

QPCR testing of 3 lots of RotaTeq® showed very low levels of PCV DNA. PCR-based assays 

conducted on 5 rotavirus bulk lots showed very low levels of PCV DNA, with inconclusive results 

on particle-association. Infectivity assays were initiated on 5 rotavirus bulk lots, with results 

anticipated July 2010. Initial PCR testing of cell banks, virus seeds, and trypsin lots indicates 

that PCV DNA in bulk lots is introduced from irradiated trypsin. These data are consistent with 

finding of no replication of PCV-1 or PCV-2 in RotaTeq®. Although these data suggest that 

there is no infectious PCV in RotaTeq®, additional studies are ongoing to confirm these results 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

 A key challenge in the PCV investigation for RotaTeq® conducted by Merck is that there are 

very low levels of PCV DNA in RotaTeq® (1.4 to 1.7 x103

 copies / mL of PCV DNA by QPCR). 

Demonstration of lack of infectious virus in RotaTeq® requires multiple analytical approaches 

and longer testing periods of up to 28 days in duration. There is a risk of false negatives if 

assays are not qualified for low levels of PCV DNA. Merck determined that establishing 

appropriate assay conditions is critical moving forward. In terms of considerations for analytical 

methods in the PCV investigation for RotaTeq®, Merck employed a 3-fold approach to the 

assays internal to Merck. First, methods had to be developed to determine DNA particle 

association. Also important was to overcome the matrix effect (e.g., interference of host DNA in 

RotaTeq®) within the assays. In addition, they had to generate infectious PCV positive controls 

to understand the performance of assays. Merck has systematically evaluated all assays to 

ensure that current and future results are informative and meaningful. 

As noted, Merck began testing on 3 final container lots of RotaTeq® and subsequently moved 

into the bulk inputs into the final containers. In the manufacturing processing, Merck uses 5 

bulks, one for each of the 5 reassortants that compose RotaTeq® and blend them with 

stabilizer as they go into the final container. The advantage of testing bulk inputs is that allows 

for a more concentrated matrix to be able to look for PCV DNA. What the data have shown 

from the PCR testing is that there are very low levels of PCV DNA within the Merck product. 

Specifically within the bulks, f PCV-1 DNA was not detected or was below the limit of 

quantitation and PCV-2 levels were just higher than the limit of quantitation for the assay. It is 

also important to note that PCR assays act by detecting DNA fragments, so this does not 

necessarily indicate a live, intact infectious virus. 

In terms of understanding whether the PCV DNA being detected was associated with virus 

particles, for quantitative PCR Merck used short chain amplicons that look for very small 

sequences of the DNA. There were non-quanitifiable levels of PCV-1, and a signal was 

detected for PCV-2 DNA. Longer chain amplicons were investigated through the use of 

conventional endpoint PCR assays looking at an approximate 400 base pair and 842 base pair. 

Inconsistent results were observed when moving to the longer chain amplicons. These data 

indicated that there were fragments of DNA, but that they may not necessarily be associated 

with an intact virus. This has moved Merck forward into conducting direct infectivity testing 

using cell culture-based methods. 

Merck has leveraged in vitro cell culture-based assays to assess the presence of infectious 

virus particles. Infectivity testing has been initiated on 5 rotavirus bulk lots. Merck is leveraging 

susceptible cell lines (PK-15 and Vero cells) that they know will replicate PCV readily. Merck 

focused on the cell culture infectivity conditions to provide a high sensitivity for ensuring that if 

there is infectious virus, it can be seen. A QPCR detection method is being used to ensure high 

sensitivity. Infectious PCV positive controls are included, which is essential to ensure 

confidence in a negative result. Specific culture conditions have been incorporated to ensure 

viral replication. Duration of testing for a negative result is 21 to 28 days. Initial results were 

expected to be available in July 2010. 

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ti : ll t t it i t l i . 

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= t tit ti

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

With regard to the source of PCV DNA, the following diagram illustrates the manufacturing 

process for RotaTeq®: 

17 

What is the Source of PCV DNA? 

Evaluation of Process Inputs 

Vero Cell Expansion 

Rotavirus 

Virus Propagation 

Vero Working 

Cell Bank 

PCV1 DNA: ND 

PCV2 DNA: < LOQ 

Rotavirus 

Stock Seed 

PCV1 DNA: ND 

PCV2 DNA: < LOQ 

Irradiated Trypsin PCV1 DNA < LOQ 

PCV2 DNA: 2.9 x 105 copies/mL 

Vero Master 

Cell Bank 

PCV1 DNA: ND 

PCV2 DNA: ND 

Rotavirus 

Master Seed PCV1 DNA: ND, < LOQ 

PCV2 DNA: ND, < LOQ 

Process Inputs Bulk Manufacturing Process 

Filtered Virus Fluids & 

Redispense as 

Individual Virus Bulks 

PCV1 DNA < LOQ 

PCV2 DNA: 3.7 to 7.8 x 103 copies/mL 

Sample Prepara on A samples rea ed w h DNase pr or o QPCR Ana ys s 

ND No Detec ed 

LOQ Limi of Quan a on 

The approach taken to assess the source of the PCV was to map back the lineage for each of 

the inputs for the rotavirus process. The presence of PCV was not detected in the Vero master 

cell bank. For the working cell bank, no detectable levels of PCV-1 and not-quantifiable levels 

of PCV-2 were observed. Similar results were observed for the master seed and stock seed, 

again testing the seeds associated with each of the reassortants. , One lot of commercial 

irradidated trypsin was tested and a positive signal for PCV-2 DNA was observed within that 

trypsin lot. Thus, Merck focused on the use of irradiated trypsin. 

 Trypsin is irradiated at 2 stages before use in the manufacturing of RotaTeq. Irradiated trypsin 

is utilized in the cell bank, virus seed, and bulk manufacturing processes. Each irradiated 

trypsin lot is tested for a panel of adventitious agents. This trypsin lot was tested by the vendor 

at time of release and was found negative for infectious PCV-1 and PCV-2. In conclusion, PCV 

DNA in bulk lots is introduced from irradiated trypsin solutions. The data thus far are consistent 

with no replication of PCV-1 or PCV-2 virus within RotaTeq®. PCV infectivity testing of bulk lots 

and trypsin will be performed to confirm these results. 

To summarize, the PCV analytical testing for RotaTeq®, QPCR testing of 3 lots of RotaTeq® 

showed very low levels of PCV DNA. PCR-based assays conducted on 5 rotavirus bulk lots 

showed very low levels of PCV DNA, with inconclusive results on particle-association. Initial 

PCR testing of cell banks, virus seeds, and trypsin lots indicates that PCV DNA in bulk lots is 

introduced from irradiated trypsin. Data support that there is no replication of PCV-1 or PCV-2 

in RotaTeq®. Infectivity assays were initiated on 5 rotavirus bulk lots, with results anticipated 

July 2010. Results will continue to be communicated to global regulatory agencies upon 

availability. 

For the clinical evaluation of RotaTeq® for PCV, Merck has asked three key questions, which 

are as follows: 

1. Is PCV DNA present in clinical bulk lots for RotaTeq®? 

2. Is PCV DNA detected in stool samples of vaccine recipients? 

3. Are antibody responses to PCV detected in serum samples of vaccine recipients? 

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Clinical and marketed bulk lots are being evaluated for the presence of PCV-1 and PCV-2 DNA 

by QPCR. If presence of PCV DNA is confirmed for clinical lots, testing of stools and serum 

samples will proceed. Merck plans to test serum and / or stool samples from approximately 150 

vaccine recipients and 50 placebo recipients, depending upon availability of samples. Stools 

will be evaluated for PCV-1 and PCV-2 DNA by QPCR. If positive by the PCR-based method, 

samples will be assessed to determine if the PCV DNA is associated with viral particles. Serum 

will be evaluated for immune response to PCV-1 and PCV-2 by ELISA. 

With respect to the analytical test plan for RotaTeq® to date, analysis of RotaTeq® final 

containers is complete, assessment of PCV DNA in RotaTeq® and associated bulk lots is 

complete, and assessment of the source of PCV DNA via PCR is complete (confirmatory data to 

be completed in June 2010). During July and August 2010, Merck will assess rotavirus bulk lots 

and trypsin lots via in vitro PCV infectivity assays. If presence of PCV DNA is confirmed for 

clinical lots, testing of stools & serum samples will proceed . Testing of additional clinical bulks 

will be completed by July 2010. Preliminary QPCR results of clinical stool samples collected 

during clinical trials will be available in July 2010. In August 2010, preliminary results will be 

available of clinical serum samples collected during clinical trials, although timing is pending 

finalization of assay conditions. 

Merck is committed to completing PCV analytical and clinical testing of RotaTeq®. The 

company will continue to share data with regulatory agencies, the scientific community, health 

care providers, and the public upon availability and is also committed to taking appropriate 

action as necessary. Approaches will be developed to enhance screening and removal of PCV 

in RotaTeq®. Merck will partner with scientific experts and regulatory authorities to evaluate 

current and emerging analytical technologies to enhance product quality assurance. 

Discussion Points 

Dr. Meissner noted that while there do not appear to be a safety issues, the cell lines mentioned 

were porcine kidney cells and Vero cells, which are African Green Monkey kidney cells. He 

wondered whether there had been efforts to infect human line cells with this virus. 

Dr. Friedland responded that GSK has tested human cell lines. There is a report in the literature 

by Hattermann et al who tested 18 human cell lines and found that PCV-1 was not able to 

produce a productive infection in any of the 18 human cell lines tested. GSK has now tested 5 

human cell lines: MRC5 (human diploid cell line), U937 (monocytic human cell line), Hep2 

(transformed human cell line), an epithelial colorectal cell line(CaCO) and PBMCs. Again, there 

is no evidence indicating that PCV-1 associated with Rotarix® can undergo productive infection 

in human cell lines. 

Dr. Cieslak said he was persuaded that perhaps this was an orphan virus. He was more 

concerned about the pathogenic viruses that they may not even know about. With that in mind, 

he wondered what could be done to test the cell lines used to grow vaccine viruses. His guess 

would be that human viruses tend to infect humans, and he would be most concerned about the 

human cell lines. 

Dr. Baker inquired as to whether anyone knew of other human cell line information. 

Dr. Sun said he thought that was the question. Assessing adventitious agents is a progressive 

process that moves as technology moves forward. One of the issues he raised in his summary 

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Discussion

Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

pertained to how to use genomic techniques to screen cell substrates for known and unknown 

viruses. It is imperative to ensure that tests are validated as with any other assay. 

Dr. Keitel wondered whether human stools from any of the studies or in other investigations had 

been assayed for infectious virus on susceptible cell lines. 

Ms. Dezura responded that Merck had not yet initiated testing on stool samples, given that they 

first focused their efforts on the clinical bulk that went into the clinical trials, the results from 

which will be used to select the patients for which stool testing will be done. The first step is to 

determine whether PCV DNA is observed within clinical supplies. 

Dr. Friedland said it was important to mention that this finding came to light toward the end of 

March 2010 and GSK was asked to present at an FDA advisory committee 6 weeks later. Thus, 

a tremendous amount of work needed to be done in an area where PCV had not been studied 

in humans. There are no humans known to have antibody responses to PCV-1, including 

people who work in the swine industry. Therefore, GSK had to adapt an assay that was used in 

pigs for humans in a very short period of time. As noted, discussions continue with respect to 

collecting additional data. 

Ms. Stinchfield (NAPNAP) requested further information about the purpose of the trypsin 

solution in the manufacturing process. 

Ms. Dezura replied that trypsin is an enzyme that is utilized in the cell expansion part of the 

process to dissociate cells from the disposable cell culture ware. It is also used as part of the 

virus infection process. It is an incoming raw material to the product. 

Day 2: Public Comments 

Frankie Millie 

Founder / National Director 

Meningitis Angels 

Mother of Child Who Died from Meningococcemia 

Recently, I spent two weeks in Oklahoma with the meningococcal outbreak there. There were 

nine children in that outbreak over a two-week period: an infant who lost both arms, both legs; a 

toddler; six second graders, two of whom died, one of whom is still fighting who lost both arms, 

both legs, and most of his face, including his eyelids and part of his tongue; and a 17-year old. 

We now see an outbreak in Colorado in young men ages 22 to 29. My concern is that we need 

to prevent this disease in as many age groups as we possibly can. I encourage and beg this 

committee, as you move forward in looking at adolescent recommendations, that you leave 

those in place that are there already, that you add a booster, and that in the future as it comes 

to pass, that you protect as many infants, children, teens, and young adults from this deadly, 

debilitating disease as you possibly can. I also encourage manufacturers to work with ACIP to 

try to create and negotiate reasonable pricing so that more people, more children, more infants, 

more toddlers, more adults can have access to lifesaving vaccines. Thank you. Dr. Baker 

clarified that CDC, not ACIP, is responsible for price negotiation. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Keira Sorrells, President 

Zoe Rose Memorial Foundation 

The Zoe Rose Memorial Foundation is a non-profit that supports families with premature infants. 

I am here to speak on behalf of the parents across the country who are facing one of the most 

traumatic life experiences of having and raising a medically fragile child. More importantly, I am 

a mother. I am a mother of triplets born at 25 weeks, and I am a mother who has had the 

challenge of protecting and raising a medically fragile infant. I had three of them. I am also a 

mother who has lost one of my daughters at only 14 months of age because of an infectious 

disease. I am a mother who spent a week in the hospital with my two survivors watching them 

fight RSV just six months ago. My family, six months later, is still dealing with the financial 

hardships of that hospital stay because of lost time at work and medical bills. But we’re insured. 

We have good insurance. We’re the lucky ones. But what about the families that aren’t so 

lucky. The cost to these families extends well beyond the hospital stay because of medications, 

treatments, and therapies that can last a lifetime. As the parent of a medically fragile infant, I 

was repeatedly informed by our doctors about what we were going to be facing. I knew how 

fragile they were. I took precautions. I heard time and time again, “Keep your girls healthy. 

Keep them out of the hospital. Don’t let them get RSV.” But what about the babies that are 

born just a few weeks early or even full term? These are babies that you’ll read about in our 

handout. These babies have parents who are told that RSV is just a bad cold, if they are even 

told about it at all. They are automatically excluded from the possibility of prophylaxis treatment, 

and yet they contract the virus and in far too many cases have lifelong medical issues or even 

die. With a virus that is as contagious and vicious as RSV, how can we let these parents think 

that it’s just a bad cold, and how can we exclude these babies from a lifesaving prophylaxis 

treatment? If you are fortunate enough to have a healthy child, imagine that you are one of 

these parents like me that stands helplessly by your sick child’s bedside knowing that something 

exists that could have protected your child from the disease, and yet you couldn’t get it for them. 

When you look at the numbers and the statistics and the economics, realize that each of those 

numbers has a child behind it—a living, breathing child who has a right to a healthy life. The 

value of a child’s life should never be measured in dollars and cents. When you talk about 

statistical significance, you are talking about my children. You’re talking about your children or 

your grandchildren. This is not just a bad cold, and we should never think that losing even one 

child to this virus is acceptable. You are the experts. You know what RSV is, and only you hold 

the power and the influence in your hands to protect our children. Thank you. 

Dr. Mitchell Goldstein 

President, National Perinatal Association (NPA) 

Medical Director, Citrus Valley Medical Center NICU 

Associate Professor Pediatrics, Loma Linda University Children’s Hospital 

We at the NPA have published our own guidelines because of what we perceive to be a need 

for a truly objective evidence-based guideline for RSV prophylaxis, especially with regard to 

neonates at 32 to 35 weeks post-conceptual age. The COID, as we feel, is rationing health 

care. The NPA sees the 2009 COID guidelines as creating potential confusion through 

encouraging the use of a non-FDA approved dosing regimen. There is lack of medical evidence 

for the change. Endpoints other than hospitalization are not considered. A large number of 

babies born at 32 to 35 weeks post-conceptual age are placed at risk. Moreover, by 

marginalizing risk factors, the 2009 COID guidelines place the most socioeconomically 

disadvantaged at significant risk. Most importantly, this is not a vaccine. Our guidelines have 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

the endorsement of over 1500 neonatologists around the country, including representatives of 

several prominent children’s hospitals as well as Alan Spitzer, Senior Vice President and 

Director of the Center for Research and Education at the Pediatrix Medical Group. Most 

importantly, we have the support of our parent membership in the NPA whose babies are most 

at risk and who have, as we have heard, the most to lose. It seems contradictory that while the 

current data support an emphasis on an understanding of the increased risk for the pre-term or 

late pre-term infant, the COID redefines them as near-term in the management of their RSV 

risk. Thank you very much for your consideration. 

Dr. Lance Wyble 

Florida Healthy Start Coalition 

Today I am speaking on behalf of Healthy Start of Florida regarding their concern that ACIP will 

decide to simply approve the 2009 Redbook guidelines on RSV. Since 1992 in Florida, Healthy 

Start, a state funded program, has been successful in lowering infant mortality rates by offering 

wrap around services to at risk pregnant women, mothers, and babies. While the babies 

covered by Healthy Start don’t all qualify for monthly palivizumab injections, they are, we 

believe, disproportionately affected by the decisions that resulted in changes in the 2009 

Redbook. Unfortunately, this group has only a weak voice to verbalize concern. Likewise, the 

lifestyle, living conditions, and usually fractured relationships with health care providers and the 

health care system for Healthy Start families creates a formidable barrier for receiving even 

somewhat reduced and definitely more complicated to follow recommendations of the 2009 

Redbook. I hope the committee will recognize that impact when they come forward with their 

recommendation. When many of the clinicians in Florida understood the significant changes 

recommended by the 2009 Redbook, over 500 of them spoke out through a petition stating in 

essence that they did not believe these changes were prudent, whether they were more costeffective or not. Furthermore, these practitioners and the constituents of Healthy Start see the 

2009 changes as minimizing the concern about RSV in Florida. I would like to emphasize to the 

committee that the most important part of committee work on this is the human side—not the 

dollar side. As many practitioners nationally point to the aspects of the 2009 changes that Dr. 

Meissner himself referred to as “difficult to characterize as strong evidence” Healthy Start is 

concerned that a similar interpretation of the data by this committee, if that is what comes out in 

the final recommendations of ACIP, will unfortunately disproportionately affect those from a 

lower socioeconomic background. Thank you. 

Lyn Redwood 

Safe Minds 

As stated by Dr. Friedland and others, the Food and Drug Administration recently convened a 

panel of experts to review the findings that rotavirus vaccine given to infants in the US, 

RotaTeq® produced by Merck and Rotarix® produced by GSK) are contaminated with pig 

viruses. Rotarix® has been shown to contain nucleic acids from both PCV-1 and PCV-2. I want 

to point out that PCV-2 is a pathogen in pigs that is associated with wasting and 

immunodeficiency. While acknowledging that the entire short- and long-term risks from porcine 

circoviruses are yet unknown, the FDA advisory panel decided that “the benefits of the vaccine 

trumped its risks.” Safe Minds disagrees with this conclusion, and calls on the Advisory 

Committee for Immunization Practices to rescind their recommendations regarding the routine 

administration of rotavirus vaccine until adequate safety studies have been conducted. While 

the technology to detect genetic contaminants in vaccines was not available until just recently, 

the dangers of generating new viruses and bacteria that can cause disease were foreseen by 

the pioneers of genetic engineering. Horizontal gene transfer (HGT) refers to the direct uptake 

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and incorporation of genetic material, DNA fragments, into species. In this instance it is from 

viral contaminants and live viral vaccines into the human host or host-related bacteria. Unlike 

chemical pollutants which breakdown and become diluted out, nucleic acids are infectious. 

They can invade cells and genomes. They multiply, mutate, and can recombine indefinitely. 

Potential hazards of HGT and free nucleic acids include the generation of new viruses and 

bacteria that can cause disease; spread of drug- and antibiotic-resistant genes among viral and 

bacterial pathogens, making infections untreatable; random insertion into genomes of cells 

resulting in harmful effects, including cancer; and the reactivation of dormant viruses present in 

all cells and genomes, which may also cause disease. These issues have not been adequately 

investigated. Absence of evidence is not the same as absence of harm. Research 

demonstrates that the pathogenic potential of PCV-2 to cause AIDS-like disease in pigs is 

unleashed when there is a simultaneous immune system activation, for example, a current 

vaccination in the animals. Thus, the concurrent ingestion of rotavirus vaccine contaminated 

with PCV-2 DNA sequence along with DTaP, HIB, PCV, IPV, and hepatitis B, which is currently 

recommended by ACIP provides a high risk scenario for disease in humans. 

Safe Minds requests that ACIP call on the Immunization Safety Office (ISO) to immediately 

research adventitious agents in vaccines, especially live viral vaccines. PCV-2 is a 

lymphotropic virus that affects primarily lymphoid tissue. Its detection in lymphoid tissue of 

exposed vaccinated children should be the focus of urgent investigations. Such tissue is 

available in the form of intestinal biopsies from children with a variety of conditions. In addition, 

lymphatic tissue is also available from Rhesus Macaque monkeys that were exposed to the 

vaccine schedule as part of on-going safety studies. These tissues should be screened using 

the same metagenomic and panmicrobial array technology used by Victoria. Such analyses 

should be conducted by independent scientists and done immediately. If this contamination had 

been discovered prior to licensure of the rotavirus vaccine, I doubt FDA would have licensed the 

vaccine. Why should it be any different now? The charter of this committee allows for the 

alteration or withdrawal of previous recommendations regarding a particular vaccine as new 

information becomes available on the risk or the disease changes. Ideally, this vaccine should 

be suspended until such safety studies are completed. Once completed, a new risk / benefit 

analysis should be conducted based on these new findings, taking into consideration that 

rotavirus disease carries a low mortality rate in the US. In absence of this necessary research, 

the precautionary principle should dictate policy. At a minimum, accurate and transparent 

information regarding PCV contamination in the rotavirus vaccine should be included on the 

vaccine information sheet given to parents prior to vaccination highlighting the lack of research 

on health effects. That is not there right now. It’s impossible for parents to give free and 

informed consent for a vaccine containing pig viruses when the risks are unknown. To continue 

to administer these vaccines given the impossibility of informed consent is unethical. Thank 

you. 

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 hereby certify that to the best of my knowledge, the foregoing Minutes of the October 21-22, 

2009 ACIP Meeting are accurate and complete. 

 

_____________________ 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Certification 

I hereby certify that to the best of my 

knowledge, the foregoing Minutes of the 

June 23-24, 2010 ACIP Meeting are 

accurate and complete. 

Date ________________________________ Dr. Carol J. Baker, Chair 

 Advisory Committee on 

 Immunization Practices (ACIP) 

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Discussion

      

    

  

  

  

  

  

  

  

  

  

  

     

   

          

  

  

  

  

  

  

        

  

  

  

  

  

        

  

  

   

  

  

      

    

      

Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Attendees 

Last Name First Name Email Citizenship

Debrus Serge serge.e.debrus@gskbio.com Belgium

Rocha Eliseu eliseubiologia@gmail.com Brazil

Shwe Thein thein.shwe@wv.gov Burma

Ismail Shainoor shainoor.ismail@phac‐aspc.gc.ca Canada

Misurski Derek derek.a.misurski@gsk.com Canada

Seet Bruce bruce.t.seet@gsk.com Canada

Shindman Judith judy.shindman@sanofipasteur.com Canada

York Laura laura.york@pfizer.com Canada

Florez Jorge jflorezot@hotmail.com Colombia

KALUBI Congo, Democratic Republic

LUFUNGULA GILBERT gkalubi@yahoo.fr of The

El Zein Majed majed_el_zein@hotmail.com Czech Republic

Abu‐Elyazeed Remon remon.abu‐elyazeed@gsk.com Egypt

Boseila Abeer abeerboseila@gmail.com Egypt

ALLAVOINE THIERRY tallavoine@spmsd.com France

Saddier Patricia patricia.saddier@merck.com France

ANUEKATOA

JAMES PETER jamespeter20052000@yahoo.fr Ghana

DODOO HARRY winburkina@gmail.com Ghana

EKTABHARTI SIVA KUMAR sivaekta@hotmail.com India

Ebihara Keiko keiko_ebihara@merck.com Jamaica

Furuya Yoshikata yoshikata_furuya@merck.com Japan

Kamiya Hajime hakamiya@nih.go.jp Japan

Ubukata Kanako Kanako.Ubukata@pfizer.com Japan

Ba Amy amy.ba@sanofi‐aventis.com Mauritania

AJUMA MARY SULE kogistatgovt@yahoo.com Nigeria

Akolo Christopher Christopher_Akolo@sra.com Nigeria

FADAHUNSI‐ GBOLAHAN

SUNMONU MUFATIU fadahunsigbolahan@yahoo.co.uk Nigeria

MIKE UNYIME ANTHONY kogistatgovt@yahoo.com Nigeria

abbasi khurshid prof_kabbasi@hotmail.com Pakistan

Omer Saad somer@emory.edu Pakistan

Tan Litjen (L.J) litjen.tan@ama‐assn.org Singapore

Agarwal Mukul agarwalm@medimmune.com United States

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Alexa Pamela pamela.alexa@pfizer.com United States

Ambrose Karita karita.ambrose@novartis.com United States

Armstrong Jennifer jennifer.l.armstrong@gsk.com United States

Arthur Phyllis parthur@bio.org United States

Ashley Don don.ashley@pfizer.com United States

Ault Kevin kevin.ault@emory.edu United States

Baker Carol cbaker@bcm.edu United States

Bandell Allyn bandella@medimmune.com United States

Behlim Azra Azra.Behlim@walgreens.com United States

Bernbaum Judy bernbaum@mail.chop.edu United States

Berns Abby abby.berns@gmail.com United States

Birke Beth beth.birke@novartis.com United States

Birkhead Gus gsb02@health.state.ny.us United States

Blalack Gary gary.x.blalack@gsk.com United States

Bleyenburg Dawn dbleyenburg@uamail.albany.edu United States

Bobo Nichole nbobo@nasn.org United States

Bocchini, Jr Joseph jbocch@lsuhsc.edu United States

Bozof Lynn lynn.nma@gmail.com United States

Brady Michael Michael.Brady@NationwideChildrens.org United States

Bresnitz Eddy eddy_bresnitz@merck.com United States

Brewer Katherine katie.brewer@ana.org United States

Brooks Dennis dennis.brooks@pfizer.com United States

Buchanan Anna abuchanan@astho.org United States

Campos‐Outcalt Doug dougco@aafp.org United States

Canupp Charles charles_canupp@merck.com United States

Cary Donna donna.cary@sanofipasteur.com United States

Chaffee Mary Ann mchaffee@spectrumscience.com United States

Chaney Mike mchaney@gaaap.org United States

Chilton Lance lchilton@salud.unm.edu United States

Ciarlet Max max_ciarlet@merck.com United States

Cieslak Paul paul.r.cieslak@state.or.us United States

Cieslak Ted trc0@cdc.gov United States

Claxton Isabelle isabelle.5.claxton@gsk.com United States

Clover Richard rclover@louisville.edu United States

Coelingh Kathleen coelinghk@medimmune.com United States

Coit Henry rennie@igncap.com United States

Collins Tegwyn collinst@ruderfinn.com United States

Colwell Chris christopher_colwell@bd.com United States

Conner Penny phconner@dhr.state.ga.us United States

counard catherine catherine.counard@skokie.org United States

Cover Michael mcover@spectrumscience.com United States

Cullison Mark mark_cullison@merck.com United States

Curry David R david.r.curry@drcurryassociates.net United States

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Donald

Dalrymple "Dack" dackdal@rcn.com United States

Dana Adrian adrian_dana@merck.com United States

Decker Michael michael.decker@sanofipasteur.com United States

Dezura Kimberly A. kimberly_dezura@merck.com United States

Dinovitz Richard RCDVaccine@aol.com United States

Duggan Goldstein Sarah sarah.duggangoldstein@ama‐assn.org United States

Ehresmann Kristen kristen.ehresmann@state.mn.us United States

Elward Alexis Elward_A@kids.wustl.edu United States

Englund Janet janet.englund@seattlechildrens.org United States

Etkind Paul Petk United States

Evans Jim jim@sosatlanta.com United States

Feinberg Mark mark_feinberg@merck.com United States

Flores‐Martin Catherine cmartin@communitycouncil.org United States

Fortner Angela angela.edwards@nghs.com United States

Foster Stephan sfoster@uthsc.edu United States

Friedland Leonard Leonard.R.Friedland@gsk.com United States

fryhofer sandra sandra@DrSandraFryhofer.com United States

Gabor Gerald gerald.gabor@wisconsin.gov United States

Gaffoglio Diane dgaffoglio@bellsouth.net United States

Gall Stanley sagall@louisville.edu United States

Gargano Lisa lgargan@emory.edu United States

Geddes Cathy catherine.geddes@pfizer.com United States

Gellin Bruce bruce.gellin@hhs.gov United States

gensheimer kaTHLEEN kathleen.gensheimer@sanofipasteur.com United States

Goldstein Mitchell mgoldstein@nationalperinatal.org United States

Gonzales Tara Gonzalest@medimmune.com United States

Gordon‐Evans Jill jim@sosatlanta.com United States

Goveia Michelle michelle_goveia@merck.com United States

Grabenstein John john_grabenstein@merck.com United States

Greenberg David david.greenberg@sanofipasteur.com United States

Greenberg Michael michael.greenberg@csl.com.au United States

Greenspan Joel joel.greenspan@attuneinc.com United States

Grogg Stanley sgroggdo@travelmedicine.com United States

Groothuis Jessie groothuisj@medimmune.com United States

Hahn Christine hahnc@dhw.idaho.gov United States

Hall Lori levans2@cdc.gov United States

Halsey Neal jefernan@jhsph.edu United States

Hannan Claire channan@immunizationmanagers.org United States

Haupt Richard Richard_Haupt@Merck.com United States

Hemby Lisa hembyl@medimmune.com United States

Heyward William bheyward@dynavax.com United States

Hosbach Phil phil.hosbach@sanofipasteur.com United States

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Houston Marsha mhouston@cdc.gov United States

Humphrey

Franklin Donelle dhfranklin@dhr.state.ga.us United States

Hunter Paul phunte@milwaukee.gov United States

Israel Zimra zimra.israel@pfizer.com United States

James Chuntiel ccjames@dhr.state.ga.us United States

Jodhpurkar Uday uday.jodhpurkar@sanofipasteur.com United States

Johann‐Liang Rosemary rjohann‐liang@hrsa.gov United States

Johnson David dr.johnson@sanofipasteur.com United States

Johnson Erica ejohnson@apcoworldwide.com United States

Judson Franklyn franknjudson@comcast.net United States

Kagan Stephen stephen.kagan@pfizer.com United States

Kanesa‐thasan Niranjan niranjan.kanesa‐thasan@novartis.com United States

Katz Samuel katz0004@mc.duke.edu United States

Keenan Richard rkeenan@naccme.com United States

Keitel Wendy wkeitel@bcm.edu United States

Kesselman Adam debra.x.kessler@gsk.com United States

Keyserling Harry hkeyser@emory.edu United States

Kimberlin David dkimberlin@peds.uab.edu United States

Kinsinger Linda Linda.Kinsinger@va.gov United States

Kitchen Chester chet_kitchen@merck.com United States

Kuter Barbara barbara_kuter@merck.com United States

Laird Susan slaird@cdc.gov United States

Lancaster Karen lancasterk@medimmune.com United States

Lastinger Joe jlastin@mac.com United States

Lawson Herschel hw.lawson@gmail.com United States

Marie‐

Leger Michele mleger@aapa.org United States

lett susan susan.lett@state.ma.us United States

Lewin Clement clement.lewin@novartis.com United States

Lewis Randi rbeth121@yahoo.com United States

Lewis Tamara tamara.lewis@imail.org United States

Lieu Tracy tracy_lieu@harvardpilgrim.org United States

Liu Christina CHRISTINA.LIU@NOVARTIS.COM United States

Lorick Suchita slorick@cdc.gov United States

Lucey Daniel DRL23@Georgetown.edu United States

Mahadevia Parthiv mahadeviap@medimmune.com United States

Makari Anders Doris makarid@medimmune.com United States

Malinoski Frank frank.malinoski@liquidia.com United States

Malone Robert Rwmalonemd@gmail.com United States

Stephan

Marcy Michael smmarcy@LABiomed.org United States

Maroney Patrick Patrick.Maroney@sanofipasteur.com United States

Masaquel Anthony masaquela@medimmune.com United States

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Mason Dean Dean.Mason@pfizer.com United States

McKinney William mckinney@louisville.edu United States

Mclaughlin Jeffrey jeffrey.r.mclaughlin United States

Meade Bruce bruce@meadebiologics.com United States

Meigs Wendy wmwm@swbell.net United States

Meissner Cody cmeissner@tuftsmedicalcenter.org United States

Michael Stephan smmarcy@LABiomed.org United States

Middleman Amy amym@bcm.edu United States

Milewski Katie kmilewski@aap.org United States

Milley Frankie Fmilley@aol.com United States

Moore Kelly kelly.moore@tn.gov United States

Muhammad Riyadh muhammrd@dhec.sc.gov United States

Mulach Barbara bmulach@niaid.nih.gov United States

murphy linda linda.murphy@cms.hhs.gov United States

Neale Todd t.neale@medpagetoday.com United States

Neloms Stacey stacey_neloms@sra.com United States

Neuzil Kathleen kneuzil@path.org United States

Norman James jnorman3@gatech.edu United States

Offit Paul offit@email.chop.edu United States

Pacheco Henry h.pacheco@att.net United States

Paradiso Peter peter.paradiso@pfizer.com United States

Patel Renita renitap@email.unc.edu United States

Peter Georges gpeter@lifespan.org United States

Peterson Diane diane@immunize.org United States

Petrucelli Michael petrucellim@medimmune.com United States

Plotkin Stanley stanley.plotkin@vaxconsult.com United States

Poland Gregory poland.gregory@mayo.edu United States

Polino Pamela pam_polino@Merck.com United States

Quinn Jane jane.r.quinn@gsk.com United States

Rallapalli Kumar kumar.rallapalli@pfizer.com United States

Randall Lisa lisa@immunize.org United States

Redwood Lyn Lyn@autism.com United States

Reed Greg gkr0@cdc.gov United States

Reeves Cheryl creeves@albany.edu United States

Reingold Arthur reingold@berkeley.edu United States

rennels margaret margaret.b.rennels@gsk.com United States

Rest Michele michele.rest@merck.com United States

Richardson Vesta vesta.richardson@gmail.com United States

richmond heather richmondh@medimmune.com United States

Rizzo Christopher rizzoc@medimmune.com United States

Ropero Alba Maria ROPEROAL@PAHO.ORG United States

Rosen Brian rosenb@medimmune.com United States

Rosenbaum Sara sarar@gwu.edu United States

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Rosenblum Elizabeth erosenblum@ucsd.edu United States

Sawyer Mark mhsawyer@ucsd.edu United States

Schaffner William william.schaffner@vanderbilt.edu United States

Schmader Kenneth schma001@mc.duke.edu United States

Schunemann Holger schuneh@mcmaster.ca United States

Scott Laura lscott@familiesfightingflu.org United States

Seaver Kenny kenny.seaver@solvay.com United States

Shannon Ellen ellen.shannon@sanofipasteur.com United States

Shawen Elizabeth lizs@moore‐pr.com United States

Sherner Jim james.sherner@pfizer.com United States

Shoback Barbara bshoback@hrsa.gov United States

SIEVERT ALAN ajsievert@bellsouth.net United States

Skjeveland Eric eric_skjeveland@merck.com United States

Smith Stephen stephen.smith@sanofipasteur.com United States

Smith Parker megan.evans@elsevier.com United States

Sorrells Keira keira@zoerose.org United States

Spence Rosemary rosemary.spence@state.co.us United States

Steinberg Nina steinbergn@ruderfinn.com United States

Stinchfield Patsy patsy.stinchfield@childrensmn.org United States

Strikas Raymond raymond.strikas@hhs.gov United States

Strutton David david.strutton@pfizer.com United States

Stuerke Stacy stacy_stuerke@merck.com United States

Sumaya Ciro sumaya@srph.tamhsc.edu United States

Swain Chris christopher.swain@sanofipasteur.com United States

Sylvester Gregg gregg_sylvester@merck.com United States

Talkington Kathy ktalkington@astho.org United States

Temte Jonathan jon.temte@fammed.wisc.edu United States

TenEyck Carolyn teneyckc@medimmune.com United States

Thomas Lonnie lonnie.thomas@henryschein.com United States

Thompson Brad brad.thompson@pfizer.com United States

Trizzino John jtrizzino@novavax.com United States

tsai theodore theodore.tsai@novartis.com United States

Turner James jct4w@virginia.edu United States

Vaupel Christine christine.a.vaupel@gsk.com United States

Vigliarolo Peter pvigliarolo@cooneywaters.com United States

Vogt Kitty kvogt@gra.org United States

Wambold Deb deb.wambold@merck.com United States

Wexler Deborah deborah@immunize.org United States

White Tomekia twhite@ahecsa.uams.edu United States

Whitley‐Williams Patricia whitlepn@umdnj.edu United States

Worcester Sharon United States

Wyble Lance lewyble@att.net United States

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 23-24, 2010 

Yamada Eileen Eileen.Yamada@cdph.ca.gov United States

Yamauchi Terry yamauchiterry@uams.edu United States

Yarn Sandra jray@gaaap.org United States

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