DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION
 

Advisory Committee on 

Immunization Practices (ACIP) 

Summary Report

February 22-23, 2012 

Atlanta, Georgia 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Table of Contents Page 

Agenda 4-5 

Acronyms 6-7 

Wednesday: February 22, 2012 

Welcome and Introductions 8-12 

Tetanus, Diphtheria, and Acellular Pertussis (Tdap) Vaccine

 Introduction

 Update: Resurgence of Pertussis Disease in the United States

 Pertussis in Older Adults in the United States 

 Cost Effectiveness of Tdap Substitution for Td in Prevention of Pertussis in Adults 65 Years and Older

 Cost-Effectiveness Analysis for Boostrix in Adults 65 Years of Age and Older

 Safety and Immunogenicity of Tdap in Persons 65 Years of Age and Older

 Public Comment 

 Proposed Recommendation for Use of Tdap in Persons 65 Years and Older 

13-38 

Influenza 

Introduction 

Update: Influenza Activity and Vaccines 

Antiviral Medications 

Future Activities 

Recommendations (Reiteration of Recommendations for Annual Vaccination for All 6 Months of Age and Older) 

38-47 

13-Valent Pneumococcal Conjugate Vaccine (PCV13)

 Introduction

 Pneumococcal Conjugate Vaccine for Adults 50 Years of Age or Older: Background Review of Data and GRADE

 Pneumococcal Conjugate Vaccine for Adults with Immumocompromising Conditions: 

 Background, Review of Data, and GRADE 

47-64 

Hepatitis B Vaccine 

Introduction 

Ensuring Hepatitis B Protection for Remotely Vaccinated Healthcare Personnel: 

 Overview of the Issues 

 ACIP Requests for Information 

65-69 

Vaccine Supply 70 

Public Comments Day 1 70-79 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Thursday: February 23, 2012 

Agency Updates

 CDC 

 Center for Medicare and Medicaid Services (CMS) 

 Department of Defense (DoD) 

 Department of Veteran’s Affairs (DVA)

 Food and Drug Administration (FDA)

 Heath Resources and Services Administration (HRSA)

 Indian Health Services (I HS)

 National Institutes of Health (NIH)

 National Vaccine Advisory Committee (NVAC)

 National Vaccine Program Office (NVPO) 

71-74 

Meningococcal Vaccines

 Introduction

 GRADE (Grading Evidence Assessment for MenACWY-D (Menactra®) in Children 9-23 Months of Age 

 Updates to the Meningococcal Vaccine Statement 

75-84 

Measles, Mumps, Rubella (MMR) Vaccine 

Introduction 

Update: Measles / Rubella Elimination Consultation and Documentation 

Epidemiology of Measles in the United States 

Impact of a Third Dose of MMR Vaccine on the Course of a Mumps Outbreak in an Orthodox Jewish Community 

Impact of a Third Dose of MMR Vaccine on a Mumps Outbreak in Guam and the Economic Impact of the Outbreak 

Summary of Issues and Discussion 

84-102 

Public Comment Day 2 103 

Participant Roster 102-113 

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Final - February 16, 2012 

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), Kent "Oz" Nelson Auditorium
 

Atlanta, Georgia 30333 

February 22-23, 2012 

AGENDA ITEM PURPOSE 

Wednesday, February 22 2012 

8:00 Welcome & Introductions 

8:30 Tetanus, Diphtheria and Acellular Pertussis (Tdap) Vaccine 

· Introduction 

· Update: resurgence of pertussis disease in the United States 

· Pertussis in older adults in the United States 

· Cost effectiveness of Tdap substitution for Td in prevention 

of pertussis in adults 65 years and older 

Information & 

Discussion 

· Cost effectiveness analysis for Boostrix in adults 65 years of 

age and older 

· Safety and immunogenicity of Tdap in persons 65 years of 

age and older 

· Public comment 

· Proposed recommendation for use of Tdap in persons 65 

years and older 

Vote 

10:30 Break

11:00 Influenza 

· Introduction 

· Update: Influenza activity and vaccines 

· Antiviral medications Information & 

· Future activities Discussion 

· Recommendations (reiteration of recommendation for annual 

vaccination for all 6 months of age and older) 

12:00 Lunch

1:30 13-valent Pneumococcal Conjugate Vaccine (PCV13) 

· Introduction 

· Pneumococcal conjugate vaccine for adults 50 years of age or 

older: background review of data, and GRADE 

· Pneumococcal conjugate vaccine for adults with 

immunocompromising conditions: background, review of data 

and GRADE 

Information & 

Discussion 

3:30 Break

4:00 Hepatitis B Vaccine 

· Introduction 

· Ensuring hepatitis B protection for remotely vaccinated healthcare personnel; overview of issues; ACIP requests for 

information 

Information & 

Discussion 

4:30 Vaccine Supply Information 

4:45 Public Comment 

5:00 Adjourn 

PRESIDER/PRESENTER(s) 

Dr. Carol Baker (ACIP Chair)
 

Dr. Larry Pickering (ACIP Executive Secretary; 

CDC)
 

Dr. Mark Sawyer (ACIP, WG Chair)
 

Dr. Thomas Clark (CDC/NCIRD)
 

Dr. Anna Acosta (CDC/NCIRD)
 

Dr. Anna Acosta (CDC/NCIRD)
 

Ms. Shanthy Krishnarajah (Head, US Health 

Outcomes, GSK)
 

Dr. Jennifer Liang (CDC/NCIRD)
 

Dr. Jennifer Liang (CDC/NCIRD)
 

Dr. Wendy Keitel (ACIP, WG Chair)
 

Dr. Lisa Grohskopf (CDC/NCIRD)
 

Dr. Timothy Uyeki (CDC/NCIRD)
 

Dr. Lisa Grohskopf (CDC/NCIRD)
 

Dr. Lisa Grohskopf (CDC/NCIRD)
 

Dr. Nancy Bennett (ACIP, WG Chair)
 

Dr. Tamara Pilishvili (CDC/NCIRD)
 

Dr. Kathleen Dooling (CDC/NCIRD)
 

Dr. Mark Sawyer (ACIP, WG Chair)
 

Dr. Sarah Schillie (CDC/NCHHSTP)
 

Dr. Jeanne Santoli (CDC/NCIRD)
 

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Final - February 16, 2012 

Thursday, February 23, 2012 

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

8:15 Agency Updates 

CDC, CMS, DoD, DVA, FDA, HRSA, IHS, NVPO, NIH Information CDC and Ex officio members 

8:30 Meningococcal Vaccines 

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

· GRADE (Grading of Evidence) assessment for MenACWY-D 

(Menactra) in children 9-23 months of age 

Information & 

Discussion 

Dr. Elizabeth Briere (CDC/NCIRD) 

· Updates to the Meningococcal Vaccines Statement Dr. Amanda Cohn (CDC/NCIRD) 

10:00 Break

10:30 Measles, Mumps, Rubella (MMR) Vaccine 

· Introduction Dr. Jon Temte (ACIP, WG Chair) 

· Update: measles/rubella elimination consultation and 

documentation 

Dr. Mark Papania (CDC/NCIRD) 

· Impact of a third dose of MMR vaccine on the course of a 

mumps outbreak in an orthodox Jewish community 

· Epidemiology of mumps in the United States Information 

& 

Discussion 

Mr. Albert Barskey (CDC/NCIRD) 

Dr. Preeta Kutty (CDC/NCIRD) 

· Impact of a third dose of MMR vaccine on mumps outbreak 

in Guam and economic impact of the outbreak 

Ms. Amy Parker Fiebelkorn (CDC/NCIRD) 

· Summary of issues and discussion Dr. Huong McLean (CDC/NCIRD) 

12:15 Public Comment 

12:30 Adjourn 

Acronyms

GRADE Grading of Recommendations Assessment, Development and Evaluation 

MenACWY-D Meningococcal Polysaccharide (Serogroups A, C, Y and W-135) Diphtheria Toxoid Conjugate Vaccine 

NCCDPHP National Center for Chronic Disease Prevention and Health Promotion 

NCEZID National Center for Emerging and Zoonotic Infectious 

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

NCIRD National Center for Immunization and Respiratory Diseases 

TBD To be determined 

Tdap Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine 

WG Work Group 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Acronyms 

AAFP American Academy of Family Physicians 

AAP American Academy of Pediatrics 

ABCs Active Bacterial Core Surveillance 

ACCV Advisory Commission on Childhood Vaccines 

ACHA American College Health Association 

ACNM American College of Nurses and Midwives 

ACOG American College of Obstetricians and Gynecologists 

ACP American College of Physicians 

ACIP Advisory Committee on Immunization Practices 

AEs Adverse Events

AFP American Family Physicians 

AI/AN American Indians/Alaska Natives 

AIM Association of Immunization Managers 

AMA American Medical Association 

ANA American Nurses Association 

Anti-HBs Antibody to Hepatitis B Surface Antigen 

Anti-HBc Antibody to Hepatitis B Core Antigen 

ASH American Society of Hematology 

ASTHO Association of State and Territorial Health Officials 

BMI Body Mass Index 

BRFSS Behavioral Risk Factor Surveillance System 

CAP Community-Acquired Pneumonia

CBER Center for Biologics Evaluation and Research / FDA 

CDC Centers for Disease Control and Prevention 

CeNSIA National Center for Child and Adolescent Health 

CID Clinical Infectious Diseases 

CMS Centers for Medicare and Medicaid Services 

COI Conflict of Interest 

COPD Chronic Obstructive Pulmonary Disease 

CRS Congenital Rubella Syndrome 

CSTE Council of State and Territorial Epidemiologists 

DoD Department of Defense 

DSMBs Data Safety Monitoring Boards 

DTaP Diphtheria, Tetanus, and Pertussis 

DVA Department of Veterans Affairs 

EIS Epidemic Intelligence Service 

ELISA Enzyme-Linked Immunosorbent Assay 

EUA Emergency Use Authorization 

FDA Food and Drug Administration 

GAO General Accounting Office 

GMCs Geometric Mean Concentrations

GMTs Geometric Mean Titers 

GRADE Grading of Recommendation Assessment, Development and Evaluation 

GSK GlaxoSmithKline

HBIG Hepatitis B Immune Globulin 

HBsAg Hepatitis B Surface Antigen 

HBV Hepatitis B Virus 

HCMV Human Cytomegalovirus

HCP Health Care Personnel 

HepB Hepatitis B

HHS (Department of) Health and Human Services 

Hib Haemophilus influenzae B 

HPV Human Papillomavirus

HMO Health Maintenance Organization 

HRSA Health Resources and Services Administration 

IAC Immunization Action Coalition 

IDSA Infectious Disease Society of America 

IgG Immunoglobulin G

ILI Influenza-Like Illness

ILINet Influenza-Like Illness Surveillance Network 

IOM Institute of Medicine 

IPD Invasive Pneumococcal Disease 

ISD Immunization Services Division 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

JAMA Journal of the American Medical Association 

JID Journal of Infectious Diseases 

MCO Managed Care Organization 

MMR Measles, Mumps, Rubella 

MMWR Morbidity and Mortality Weekly Report 

MSM Men Who Have Sex With Men 

NACCHO National Association of County and City Health Officials 

NACI National Advisory Committee on Immunization 

NCATS National Centers for Advancing Translational Sciences 

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

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

NFID National Foundation for Infectious Diseases 

NHANES National Health and Nutrition Examination Survey 

NHIS National Health Interview Survey 

NIAID National Institute of Allergy and Infectious Diseases 

NIH National Institutes of Health 

NIS National Immunization Survey 

NMA National Medical Association 

NNDSS National Notifiable Diseases Surveillance System 

NNV Number Needed to Vaccinate 

NVAC National Vaccine Advisory Committee 

NVP National Vaccine Plan 

NVPO National Vaccine Program Office 

OGA Office of Global Affairs / HHS 

OPA Opsonophagocytic 

PAHO Pan American Health Organization 

PCR Polymerase Chain Reaction 

PCV Pneumococcal Conjugate Vaccine 

PPACA Patient Protection and Affordable Care Act 

PPE Personal Protective Equipment 

PPV23 23-Valent Polysaccharide Vaccine 

QALY Quality-Adjusted Life Year 

RCT Randomized Controlled Trial 

RSB Reparatory Diseases Branch 

SAEs Serious Adverse Events 

SARS Severe Acute Respiratory Syndrome 

SBA Serum Bactericidal Antibody 

SME Subject Matter Expert 

Tdap Tetanus and Reduced Diphtheria Toxoids 

TIV Trivalent Inactivated Influenza Vaccines 

UK United Kingdom 

US United States 

VAERS Vaccine Adverse Event Reporting System 

VFC Vaccines for Children 

VICP Vaccine Injury Compensation Program 

VNA Visiting Nurse Association 

VRBPAC Vaccine and Related Biologic Products Advisory Committee (FDA) 

VSD Vaccine Safety Datalink 

WHO World Health Organization 

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Discussion 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

February 22, 2012 

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 turned the floor over to Dr. 

Pickering for opening remarks. 

Dr. Pickering welcomed everyone to the February 2012 Advisory Committee on Immunization 

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

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

he welcomed those who could not attend the meeting in person. 

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

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

Greene, Cindy Fowler, and Tanya Lennon. Dr. Pickering recognized that without these 

individuals it would be very difficult to conduct these meetings, and personally thanked each of 

them. Those with any questions were instructed to see him or any of these individuals. 

Dr. Pickering noted that handouts of the presentations were distributed to the ACIP members 

and were made available for others on the tables outside of the auditorium. Slides presented at 

this meeting will be posted on the ACIP website approximately one to two weeks after the 

meeting concludes, the live webcast will be posted within three weeks following the meeting, 

and meeting minutes will be available on the website three months or 90 days following this 

meeting. 

He emphasized that they had a full agenda for the next day and a half, and indicated that boxed 

lunches would be available for both days in the hallway outside the auditorium. Members of the 

press interested in conducting interviews with ACIP members were instructed to contact Tom 

Skinner, who was in attendance, for assistance in arranging the interviews. 

Dr. Pickering recognized several visitors from the World Health Organization’s (WHO’s) Pan 

American Health Organization (PAHO) office in Washington, DC, and from Ministries of Health 

of PAHO member countries, including Argentina, Chile, and Peru. He requested that they stand 

to be acknowledged. Also in attendance was a visitor from WHO headquarters in Geneva, 

Switzerland, Ms. Mikiko Kanda, BSN, RN, PHN. Ms. Kanda currently is enrolled in the 

Department of Global Health Policy, Graduate School of Medicine, University of Tokyo, Japan 

and works in the Immunization, Vaccines, and Biologicals Department of WHO. Dr. Pickering 

noted that this meeting would be translated into Spanish, and that this was the second ACIP 

meeting that was simultaneously translated into Spanish. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

He then recognized the following ex officio members and liaison representatives: 

Ex Officio Members 

 Ms. Amy Groom is the new ex officio representative for the Indian Health Service (IHS) 

replacing Dr. James Cheek who has retired. Dr. Cheek and all of the work he put into his 

service as an ex officio member are appreciated. 

Liaison Representatives 

 Dr. Laura Riley, Associate Professor, Obstetrics, Gynecology and Reproductive Medicine, 

Harvard Medical School Maternal Fetal Medicine, is the new liaison for the American 

College of Obstetricians and Gynecologists (ACOG). For many years, Dr. Stan Gall was the 

representative from ACOG, and his years of effort and wisdom are appreciated. 

 Dr. Patricia Whitley-Williams, liaison representative for the National Medical Association 

(NMA) was unable to attend, and Dr. Winston Price attended on her behalf. 

 Dr. Vesta Richardson, liaison representative for the National Immunization Council and 

Child Health Program in Mexico was unable to attend. Attending on her behalf was Dr. 

María Teresa Murguía Peniche, Infancy Branch, Director, National Center for Child and 

Adolescent Health (CeNSIA), Mexico. 

To avoid disruptions during the meeting, Dr. Pickering instructed those present to conduct all 

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

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

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

timely manner to participate in the meeting. He reminded members that the annual ACIP group 

photo would be taken in the auditorium before lunch. 

Dr. Pickering explained that 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 Stephanie Thomas record their name and provide information on the process. 

Those who registered to make public comments were instructed to state their name, 

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

With regard to disclosure, to summarize conflict of interest provisions applicable to ACIP, as 

noted in the ACIP Policies and Procedures manual, Dr. Pickering indicated that members of the 

ACIP agree to forego participation in certain activities related to vaccines during their tenure on 

the committee. For certain other interests that potentially enhance a member’s expertise while 

serving on the committee, CDC has issued limited conflict of interest waivers. Members who 

conduct vaccine clinical trials or who serve on data safety monitoring boards (DSMBs) may 

present to the committee on matters related to those specific vaccines; however, they are 

prohibited from participating in deliberations or committee votes on issues related to those 

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

participate in a discussion with a proviso that he or she abstains on all votes related to the 

vaccines of that company. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

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

process was implemented during the October 2011 ACIP meeting to formulate 

recommendations for HPV vaccine use in males and hepatitis B vaccine for use in adults with 

diabetes mellitus. Since GRADE is a new process to ACIP, educational materials have been 

placed on the ACIP website. In addition to the information shown on the slide, the GRADE 

technical document has been cleared and soon will be posted to the website. 

Applications for ACIP membership are due no later than November 16, 2012 for the term 

beginning July 2013. Requirements include: current CV, at least one recommendation letter 

from a non-federal government employee, and complete contact information. This information 

may be submitted as email attachments to Stephanie Thomas SThomas5@cdc.gov. Detailed 

instructions for submission of names of potential candidates to serve as ACIP members may be 

found on the ACIP website: 

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

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

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

recommendations. Links to these recommendations and schedules can be found on the ACIP 

web site. A listing of recommendations that have been published since the ACIP meeting of 

October 2011 follows: 

Publication of these recommendations and schedules is sometimes highly complex due to 

timeframes and would not be possible without the excellent assistance of the Morbidity and 

Mortality Weekly Report (MMWR) editors and staff, including Dr. Ron Moolenaar, Dr. John 

Moran, Dr. Chris Casey, Douglas Weatherwax, and David Johnson. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

The following resource information was shared pertaining to ACIP: 

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

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

Next ACIP meeting: Wednesday – Thursday, June 20-21, 2012 

Registration Deadline: Non-U.S. Citizens and US Citizens Wednesday, June 6, 2012 

Vaccine Safety: www.cdc.gov/vaccinesafety/ 

Immunization Schedules (2012): 

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

Childhood Vaccine Scheduler (interactive): 

https://www.vacscheduler.org 

Adolescent vaccine scheduler (interactive): 

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

Adult Vaccine Scheduler (interactive): 

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

Vaccine Toolkit: 

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

Dr. Pickering requested that William (Bill) Atkinson, MD, MPH come to the podium for 

recognition on the occasion of his retirement. He reported that following training in psychology, 

medicine, and epidemiology and receiving Board certification in internal medicine and 

preventive medicine, Dr. Atkinson arrived at CDC as an Epidemic Intelligence Service (EIS) 

Officer in 1983. During that time, he served in the Louisiana State Health Department in New 

Orleans until 1989 when he moved to CDC in Atlanta. Dr. Pickering shared 10 highlights of Dr. 

Atkinson’s CDC career. 

Dr. Atkinson’s first ACIP statement was the 1989 famous publication in the MMWR 

recommending a 2-dose measles immunization schedule. He has had major input into 

numerous other ACIP statements published over the years. Beginning in 1990, Dr. Atkinson 

assumed the lead in writing of the General Recommendations on Immunization. This document 

has been critically important as a reference and teaching guide on the techniques and concepts 

behind immunization. He helped to prepare the 1994 revision of the General Recommendations 

on Immunization and helped in the creation of the first “minimum interval” table, which appeared 

in this edition as did the 4-day rule. Dr. Atkinson was the lead author on the 2002 edition of the 

General Recommendations on Immunization, which was the first to appear in the expanded 

form published in the MMWR Recommendations and Reports series. He continued to serve as 

an author on subsequent editions, including the 2010 version. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

In 1993, Dr. Atkinson pioneered the use of satellite and broadcast technology for bringing 

immunization education to thousands of immunization providers simultaneously. Since 2001, 

over 138,000 people have registered for continuing education credit for the various courses Dr. 

Atkinson has presented. He also has been immensely helpful in initiation of the ACIP meeting 

satellite broadcasts. 

In 1995, Dr. Atkinson conceived, developed, and led the writing of one of the most widely 

sought books that CDC has ever produced: Epidemiology and Prevention of Vaccine 

Preventable Diseases, commonly known as the “Pink Book.” This book is in its 12th edition, 

requiring constant updating due to the increasing number of vaccines used in the United States 

(US). More than 320,000 copies have been distributed, with 37,000 of these being distributed in 

2011 alone. 

Dr. Atkinson is also a talented speaker who is in constant demand. From 2004 through 2011, 

he presented 199 talks to a total of 46,293 registered attendees in locations all over the US. 

The audiences were comprised of nurses, health educators, and other clinicians. He developed 

NIPINFO, a vaccine telephone and email hotline staffed by himself and other medical educators 

in CDC’s Immunization Services Division (ISD). Between 2004 and 2011, NIPINFO answered 

5000 to 10,000 queries per year. Dr. Atkinson is also the recipient of many awards, including 

CDC’s highest immunization award, the Phil Horne Award. 

Over the past 15 years, Dr. Atkinson has served as a member of almost every ACIP working 

group, of which there are generally 12 to 14 in existence at any given time. He has always 

believed that his extensive interaction with frontline clinicians provides useful input for working 

groups as they strive to formulate draft recommendations for presentation to ACIP. With only 

two or three exceptions, he has attended every ACIP meeting, which number approximately 60 

over the last 23 years. His attendance dates back to October 1989 to the days when the ACIP 

meeting was held in the Director’s Conference Room #207 in Building 1 when meeting 

participation typically included less than 30 people. 

Dr. Pickering concluded that Dr. Atkinson is a gentle giant. He is unassuming, has a dynamic 

personality, and has exceptional teaching abilities. His numerous accomplishments serve as an 

inspiration to all. As he prepares to retire, ACIP recognized the incredible career effort of Dr. 

Atkinson with a token of appreciation and a standing ovation. 

Dr. Atkinson expressed his gratitude. He said that he was very happy to be at CDC long 

enough to see universal influenza vaccine recommendations, that he was sorry not to be there 

long enough to witness the revision of the HIB statement, and that he would watch as ACIP tried 

to deal with infant meningococcal vaccination. 

Before officially beginning the meeting, Dr. Baker called for a roll call to determine whether any 

ACIP members had conflicts of interest. The following conflicts of interest were declared: 

 Dr. Tamera Coyne-Beasley: Research support is allocated to the University of North 

Carolina by Merck Pharmaceuticals. 

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

AstraZeneca for participation in multi-center clinical trials. 

 The remainder of the ACIP members declared no conflicts. 

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Discussion 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Tetanus, Diphtheria, and Acellular Pertussis (Tdap) Vaccine 

Introduction 

Dr. Mark Sawyer 

Chair, ACIP Pertussis Vaccine Working Group 

Dr. Sawyer introduced the Pertussis Vaccine Working Group, acknowledging the membership 

and noting that this working group has been convened for nearly three years. The terms of 

reference under which this working group initially was convened include the following: 

1. Review all existing statements relative to pertussis for infants and young children (1997), 

adolescents (2006), adults (2006), and pregnant and postpartum women and their infants 

(2008) and consolidate into a single statement. 

2. Review new data on Tdap including 

• Effectiveness of ACIP recommendations 

• Interval between Td booster and Tdap 

• Use of Tdap in adults 65 years of age and older (to be concluded during this session) 

• Vaccinated health-care personnel and need for post-exposure prophylaxis 

• Pregnant and breastfeeding women 

o	 Use of Tdap 

o Cocooning strategies 

• Revaccination (this is the next topic the working group will consider) 

3. Review updated epidemiology of tetanus and diphtheria 

This session included the following topics: 

 Update and discussion on the resurgence of pertussis in the United States 

 Pertussis in older adults in the United States 

 Cost effectiveness 

→	 Tdap substitution for Td in prevention of pertussis in adults 65 years and older (CDC) 

→	 Boostrix® in adults 65 years of age and older (GSK) 

 Safety and immunogenicity of Boostrix® in adults aged 65 years and older, given that this 

vaccine has now been FDA-approved for use in this age group 

 ACIP recommendation for vote 

 Guidance for use of AdacelTM in adults aged 65 years and older (not yet approved for use at 

age 65 and older) 

Boostrix® is licensed for those aged 10 years and older and AdacelTM is licensed for those 11 

through 64 years of age. Both vaccines are recommended as an active booster immunization 

for prevention of tetanus, diphtheria, and pertussis as a single dose. Tdap vaccine is covered 

by Medicare Part D, which is relevant to use in those aged 65 years and older 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

The current ACIP recommendations for adults are as follows: 

Adults aged 19 through 64 years 

 For adults aged 19 through 64 years who previously have not received a dose of 

Tdap, a single dose of Tdap should replace a single decennial Td booster dose. 

Adults aged 65 years and older 

 Adults aged 65 years and older (e.g., grandparents, child-care providers, and 

health care practitioners) who have or who anticipate having close contact with 

an infant less than 12 months of age and who previously have not received Tdap 

should receive a single dose of Tdap. 

 For other adults aged 65 years and older, a single dose of Tdap vaccine may be 

given instead of Td vaccine, in persons who previously have not received Tdap. 

 Either Tdap vaccine product may be used. 

The working group plans to update / consolidate the ACIP Pertussis Vaccines statement, which 

it hopes to have completed by the end of 2012; the WG will then address Tdap revaccination 

and the revaccination interval that might be recommended. 

Update: Resurgence of Pertussis Disease in the United States 

Thomas Clark, MD, MPH 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Clark reminded everyone that pertussis is nationally notifiable. The case definition 

combines a clinical case (cough ≥2 weeks AND one or more of the following: paroxysms, 

whoop, post-tussive vomiting) and a confirmed case (culture OR clinical case and PCR positive 

OR clinical case and epidemiology-linked to confirmed case). Since its incorporation into the 

case definition in 1997, PCR has become the primary method of confirmation and surveillance 

reporting. The schedule of vaccination in the US included 5 doses by school entry for children. 

In 1992, there was a move to acelluar vaccination doses for boosters and in 1997 an allacellular schedule was introduced. In 2005, Tdap was preferred for adolescents with a catch-up 

for adults. For many years there has been high vaccination coverage with the childhood series 

of DTaP. At 19 through 35 months, 95% or more children have received 3 doses and about 

85% have received 4 doses, with some catch-up by school entry. 

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 introduction of whole cell vaccine, DP, in the 

late 1940s, the number of reported pertussis cases has decreased 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. The most recent peak years were 2004 and 2005 in which 25,000 cases were reported in 

each year [CDC, National Notifiable Diseases Surveillance System and Supplemental Pertussis 

Surveillance System and 1922-1949, passive reports to the Public Health Service]. 

Infants are most impacted by pertussis. They experience the highest rates of disease 

nationwide. All other age groups tended to group closely together during the 1990s. During the 

mid-2000s, however, incidence among adolescents and adults began to increase. Interestingly, 

2009 and 2010 have yielded another emerging trend. In children aged 7 through 10 years, 

rates have been increasing since 2007. There also has been emergence of disease in 1 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

through 6 year olds [CDC, National Notifiable Diseases Surveillance System and Supplemental 

Pertussis Surveillance System]. 

There is variability of pertussis from state-to-state. The 2009 incidence was 5.5 per hundred 

thousand (n=16,858 cases reported). In that year, California was in the lowest quartile of 

incidence [CDC National Notifiable Disease Surveillance System, 2009 CDC Wonder 

Population Estimates (Vintage 2009)]. In 2010, California moved into the highest quartile of 

incidence (19.47/100,000). There were 27,555 cases reported overall nationwide. A significant 

amount of attention was paid to the outbreak in California in which there were about 10,000 

cases. However, Iowa and Minnesota had higher incidence rates at 23.17/100,000 and 

21.65/100,000, respectively [CDC National Notifiable Disease Surveillance System, 2010 data 

accessed July 22, 2011; CDC Wonder Population Estimates (Vintage 2009)]. In 2011, there 

was an incidence of 5.0/100,000 (n=15,216 cases). However, these data are preliminary. Once 

datasets are finalized, there typically are 20% to 25% more cases. 

Between the late 1990s and early 2000s, the increase in pertussis overall largely was driven by 

an increase in adolescents and young adults. Tdap products became available in 2005. Prelicensure evaluation suggested that effectiveness would be approximately 90%. Post-licensure 

evaluation suggested approximately 65% to 80%. By 2010, there was almost 70% coverage 

among adolescents. Thus, the program gradually is achieving good coverage in that age 

group. The program was implemented at the end of the last cyclic epidemic or peak in disease, 

so it is somewhat difficult to evaluate. To assess the impact of Tdap in adolescents, rate ratios 

of pertussis incidence among adolescents 11 through 18 years of age were calculated for 1990­

2008 (e.g., the rate in adolescents relative to all other age groups. For the 1990s, there was a 

steady increase in adolescent disease relative to other age groups. With the implementation of 

the adolescent program in 2005-2006, there was not just a statistically significant change in 

slope, but there was a decreasing slope. This suggests that Tdap is working in reducing the 

burden of adolescent disease [Skoff et al. Arch Pediatr Adolesc Med. 2012 Jan 11. [ePub 

ahead of print]. 

Indirect effects also were assessed. While the Tdap program was recommended to reduce the 

burden of adolescent disease, it was hoped that there would be a herd effect in reducing 

transmission and disease in infants. Comparing the rate of infant pertussis prior to 2004-2005 

and subsequently, the rates are unchanged. Thus, there does not appear to be a substantial 

herd effect in that age group. While the increase in adolescent disease recently has been 

tamped by the Tdap program, the second highest incidence group that has taken over is 

children 7 through 10 years of age. The proportion of pertussis cases contributed by this age 

group over time was 5% to 10%, but this quickly became 20% to 25%. 

In terms of the number of reported cases by year of life over time, in general the number of 

cases decline from infancy to around 9 years of age when they gradually started to increase. In 

2005, an increase occurred in 7 year olds. In 2006, this increase progressed with an increasing 

number of cases over time with increasing year of life. A stair step pattern developed until there 

was a substantial increase in 2009 in number of cases by year of life, and then declined in 11 

year olds consistent with receipt of Tdap in 2009. This is the first cohort of children who largely 

are exclusive recipients of acellular vaccines. 

Given the concern in observing the data in national surveillance as well as in the California 

outbreak, attention quickly turned to performance of the DTaP vaccination program and the 

effectiveness of DTaP vaccines. A case-control study was implemented in California. All 4 

through 10 year old children with pertussis in 2010 were eligible in the 15 counties in California 

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that chose to participate. An unmatched design was used with 3 controls per case, and 

vaccination receipt was verified from provider medical records. In terms of the vaccination 

characteristics of the subjects, just under 1% of the controls had zero vaccination confirmed for 

pertussis, suggesting that under-vaccination or vaccine refusal was not a substantial problem in 

this outbreak or a substantial finding in the study. About two-thirds of the children in California 

received their 5th dose at age 4, with fewer at age 5 and 6. Comparing receipt of 5 doses 

overall to zero doses, vaccine effectiveness was 88.7%. The goal of the study was really to 

assess time since vaccination and yearly vaccine effectiveness. It was very high at 98% within 

a year of receipt of the 5th dose and declined to about 71% 5 or more years after the 5th dose. 

To identify the magnitude of waning immunity from the acellular vaccines, which previously had 

not been done, in two states registry data were combined for receipt of 5 doses in children and 

surveillance data for pertussis cases to assess risk of pertussis by time since 5th dose. From 

Minnesota there were 224,378 subjects and 521 cases, and from Oregon there were 179,011 

subjects and 99 cases. The comparison was rates of disease by time since 5th dose and 

relative risk. There was some variability of rates of disease by increasing age between 

Minnesota and Oregon, but the relative risks were similar. Rates were higher in Minnesota at 

about 7 for pertussis by year 5 or more after vaccination, but the confidence intervals overlap. 

In summary, the Tdap program has reduced the burden of pertussis in adolescents. 

Unfortunately, there is no evidence for herd protection of infants. The initial DTaP vaccine 

effectiveness is excellent, but there is a modest but essentially immediate waning of immunity 

from DTaP following receipt of vaccination. Pertussis burden in children under age 10 years 

appears to be a “cohort effect” from change to all acellular pertussis vaccines (e.g., a problem of 

susceptibility despite vaccination). 

Dr. Clark’s group is working to maximize the benefits of the current vaccination program and to 

look to the future of pertussis control. Efforts are underway to reduce barriers to Tdap uptake, 

expand Tdap recommendations, and evaluate and refining current vaccination policy. The trend 

of increasing incidence of pertussis likely will continue, with disease in children aged 7through10 

years being more a symptom of the problem. It is unlikely that changes to the timing of 

vaccination will result in substantial changes in the burden of disease. Chemoprophylaxis works 

to prevent exposed persons from developing pertussis, but it is an ineffective strategy to reduce 

transmission in outbreaks, including the staggering number of doses that must be given. 

Current and future activities include enhancing diagnostic testing to improve surveillance; 

enhancing the 6 pertussis surveillance sites (e.g., enhanced case ascertainment and improved 

data quality; platform for analyses and studies); evaluating cocooning / maternal vaccination 

effectiveness; evaluating Tdap duration of protection; assessing temporal trends in 

susceptibility/infection (serosurvey; modeling); and increasing the evidence base for new 

vaccines or strategies. 

Discussion Points 

Dr. Duchin inquired as to whether the investigators were able to assess differences according to 

the vaccine formulation a child received. 

Dr. Clark responded that they did try to collect vaccine formulation, but it has proven difficult to 

confirm product brand and formulation for every child for every dose. They are still collecting 

these data, and this is an important future analysis for the case-control study in California. 

Other ways to determine this information also are being explored. For example, they might be 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

better able to assess this question if they evaluated a managed care organization (MCO) that 

has used one product longitudinally over time. However, there is not a sense that this is a 

problem with a product, brand, or vaccine type. 

Dr. Duchin wondered whether the differential in the risk ratio studies in Minnesota and Oregon 

could be related to the difference in the incidence of disease occurring at the time in those 

states. 

Dr. Clark replied that an attempt was made to enroll a cohort of children over time, so they 

would have moved through some cycles of disease. However, the cycles differed in different 

places. Minnesota was also one of the enhanced sites over time, so they have engaged in 

better case ascertainment and testing. In general, this results in additional cases identified in 

adolescents and older age groups more so than younger children. That may account for the 

absolute differences. 

Dr. Marcy noted that 15,000 to 27,000 cases is really an extremely small tip of a very large 

iceberg. The estimate of 1 million to 3 million cases annually in the US is far more realistic and 

puts whatever ACIP may decide into perspective. 

Dr. Clark agreed that there are problems in testing and confirmation of pertussis and even in 

suspecting pertussis. Inquiries have been posed about what is occurring in other countries with 

similar programs. Some countries have similar programs, but very few have similar programs 

with similar surveillance. The age-specific incidence in Australia is 10 to 100 times what it is in 

the US, but in Canada not so much. More must be done globally to assess the burden of 

pertussis. 

Dr. Keitel noted that the duration of protection following a case of pertussis is estimated to be 

approximately 10 to 12 years, though data shown suggested waning after 7 years. She 

wondered whether there were any differences observed with respect to race / ethnicity, status of 

medical care, and other criteria that differed from that which was observed with whole cell 

vaccines. 

Dr. Clark responded that this is the key question. There are considerable data on effectiveness 

of whole cell vaccines, but very few were conducted with vaccines that were used just before 

shifting to acellular, which probably were different from the original vaccines. Very few studies 

included the same kind of case finding, ascertainment, confirmation and the same kind of 

design. Therefore, it is difficult to know whether this is different. However, even small 

differences in the initial effectiveness or waning over time can result in large differences in 

susceptibility. Very small attack rates among susceptibles drive large outbreaks. The 12-year 

duration of protection came from the observance from the increase in disease, not from vaccine 

effectiveness studies. There are differences in the immune response from acelluar and whole 

cell vaccines. There are many unanswered questions pertaining to immunology and 

vaccinology regarding pertussis vaccines. The proportion of cases and controls did not really 

differ in terms of coverage of VFC. The analysis was done to account for potential clustering in 

the individual provider offices, so that it is considered in the analysis. There was some 

ethnicity/race difference in Hispanics, but that difference resolves with increase age. The 

highest incidence overall is in whites, and females are somewhat more likely to get disease. 

However, it is not clear why. It does not appear that individual risk factors, even non-modifiable 

ones, are driving this observation. 

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Dr. Baker added that pertussis requires a major uptake of vaccine to result in any herd 

immunity. She wondered whether there were any plans to evaluate this point, and whether 

there was a strategy to increase immunization among the recommended groups above 90%. 

Dr. Clark responded that this pertained to the concept of non-transmissibility of infection 

requiring high levels of protection. With modeling susceptibility can be changed, so analyses 

are being done to assess whether susceptibility predicts the burden of disease. The 

investigators will continue to assess the impact in infant disease with increasing pertussis 

vaccine coverage. Some countries would say they have good pertussis control with some 

degree of adolescent or adult coverage, but it is not clear this is accurate. This observation may 

be a surveillance bias in many cases. 

Dr. Baker emphasized that there would be continuing challenges for adult programs. 

Dr. Schaffner (NFID) noted that investigators in Europe, particularly investigators at the Institut 

Pasteur have been interested in changes in the organism. He wondered whether Dr. Clark 

could comment on this from the US perspective. 

Dr. Clark responded that they have assessed molecular typing of isolates to determine whether 

the vaccine-related antigens are matched to the vaccine strains. The majority of isolates are 

mismatched on the vaccine antigens. That is true in most countries that have evaluated this. 

The changes over time seem to be antigenic drift rather than vaccine pressure, because the 

changes do not correlate with any changes in the epidemiology. There are no data linking the 

presence of different antigens or increased production of different antigens to any clinical 

outcomes. Some authors have posed that as a risk, but others are not convinced about this. In 

general, it would be beneficial to have broad protection across the variability in antigens. 

Denmark uses a Pertussis Toxin only vaccine, and the epidemiology in Denmark has not 

changed substantially. One might expect a region that uses one antigen to be the “canary in the 

coal mine,” but that does not seem to have occurred. It is difficult to acquire strains, and the 

CDC group does not have a population-based sample of isolates—they have a collection. 

Pertussis In Older Adults in the United States 

Anna Acosta, MD 

Epidemic Intelligence Service Officer 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Acosta provided an overview on pertussis disease in adults 65 years of age or older. The 

literature and surveillance focused on this population are lacking. Therefore, where possible, 

she focused on adults 65 and older and otherwise focused on literature from the general adult 

population. She discussed the under-recognition of adult disease, clinical presentation and 

disease severity, and incidence and disease burden. 

There are challenges in recognizing pertussis across all age groups. In adults, particularly 

problematic factors include atypical symptoms and a low index of suspicion among providers. 

Clinical presentation in adults may not include the typical pediatric symptoms, such as 

inspiratory whoop or post-tussive emesis, which are most easily recognized as pertussis. 

Among providers, there is a low suspicion for pertussis in adults given its often non-specific 

presentation. 

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The Council of State and Territorial Epidemiologists (CSTE) pertussis clinical case definitions 

used by the National Notifiable Disease Surveillance System (NNDSS) includes “cough illness 

lasting ≥2 weeks AND paroxysms, inspiratory whoop, or post-tussive vomiting.” The case 

definition is complex and, as mentioned, the non-specific an atypical presentation of pertussis in 

adults may result in unreported cases because they are not captured by the case definition. 

With regard to the demographics of reported pertussis cases in adults, across the three age 

ranges (18-39 years, 40-64 years, and ≥65 years) sex and race are similar. About one-third of 

the cases occur in males and almost 75% are white. The symptoms that have been reported in 

adults include cough, paroxysm, whoop, apnea, post-tussive emesis, and cyanosis. Cough and 

paroxysm are common across all age groups. Whoop, apnea, and post-tussive emesis are 

reported less frequently in adults 65 years of age and older than in infants and children. This 

suggests that there is a difference in presentation between children and older adults [CDC, 

National Notifiable Diseases Surveillance System]. 

In a review of the literature focusing on characteristic symptoms of adult pertussis, the most 

commonly investigated symptoms included cough, paroxysm, inspiratory whoop, and posttussive vomiting. Paroxysm is commonly reported. Inspiratory whoop and post-tussive vomiting 

were reported less frequently, but results varied. This review of the literature of adult pertussis 

symptoms reflects what is reported by surveillance [Lasserre A et al. Euro Surveill 2011;16(5):1­

5; de Serres G et al. JID 2000;182:174–9; Strebel P et al. JID 2001;183:1353–9; Schmitt-Grohe 

S et al. CID 1995;21:860-6; Wirsing von Konig CH et al. Lancet 1995; 1326-29]. 

Several proxies for disease severity include encephalopathy, seizure, pneumonia, 

hospitalization, and death. Most sequelae are rare across all ages. However, the rates of 

pneumonia and hospitalization increase with age, with 10% of the 65 and older group requiring 

hospitalization. This suggests that serious pertussis disease does occur in this population 

[CDC, National Notifiable Diseases Surveillance System 2000-2010]. 

In summary, the clinical presentation of pertussis in adults ages 65 years and older may lack 

typical symptoms such as inspiratory whoop and post-tussive vomiting. Pertussis disease 

severity in adults increases with age, demonstrated by rising rates of hospitalization and 

pneumonia. 

Regarding incidence of reported pertussis in adults from 2000-2010 separated in three age 

groups (18-39, 40-64, ≥65), there is a peak of incidence from 2004 to 2006 as well as an 

emerging peak in 2009 to 2010. All age groups followed the same curve, but the ≥65 age group 

had substantially lower reported incidence rates. There are several limitations to the 

surveillance. NNMDS is a passive surveillance system with incomplete data retrieval from 

source sites. These factors may result in under-reporting of pertussis disease in a population of 

adults ≥ age 65. 

Pertussis is one of the few bacterial diseases for which reported incidence does not increase 

substantially with age, such as Haemophilus influenzae and Streptococcus pneumoniae. This is 

another indication that pertussis disease burden may be under-reported in older adults [CDC, 

National Notifiable Diseases Surveillance System; CDC Active Bacterial Core Surveillance]. 

To explore the extent of under-reporting, data were examined from other countries with similar 

vaccine schedules and surveillance systems. Reported disease incidence in the US for adults 

age 65 and older is comparable to Canada; however, reported incidence in Australia is 

substantially higher. Incidence there is 60 to 85 times higher than reported in the US. Reasons 

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for this large difference are unclear, but may be related to Australia’s improved reporting 

practices and the inclusion of serology in the case definition. These data suggest again that 

pertussis incidence in the US may be higher than reported [Centre for Infectious Disease 

Prevention and Control, Public Health Agency of Canada; CDC, National Notifiable Diseases 

Surveillance System; National Notifiable Diseases Surveillance System; Department of Health 

and Aging, Australian Government]. 

A review of the current literature of pertussis disease burden found a range in incidence. The 4 

prospective studies presented by Dr. Acosta included a broad age range of subjects and were 

not powered to determine estimates of disease incidence for adults aged ≥65 years. Although 

inclusion criteria varied among the investigations, all were reflective of current CSTE case 

definitions and included cough duration or cough symptom criteria. Diagnostic testing also 

varied across the studies, but most incorporated tests currently included in the case definition. 

Calculated incidence ranged from 66 to 500 cases per 100,000. For comparison, NNDSS 

reported pertussis incidence as 1 case per 100,000 for the same timeframe and age group as 

that of the APERT study, which estimated an incidence of 370 to 450 per 100,000. Reported 

incidence is at least 70- to 100-fold less than found in the literature, suggesting that true 

incidence is much higher than reported [Lasserre A et al. Euro Surveill 2011;16(5):1-5; Strebel P 

et al. JID 2001;183:1353–9; Ward (APERT) JI et al. NEJM 2005;353:1555-63; Nennig ME et al. 

JAMA 1996;275:1672-167]. 

To summarize, pertussis disease is under-recognized as a cause of cough illness. The 

epidemiology of adult pertussis is not well-understood. Surveillance data in the US and abroad 

have identified a range of incidence. There are few prospective studies focused on adults. 

Instead, subject age ranges also include older children and adolescents. There are no 

prospective studies focused specifically on adults ≥65 years of age. Available literature that 

includes adult populations demonstrates a very wide incidence range between 66 to 500 per 

100,000 population. 

In conclusion, the literature and surveillance data presented suggest that pertussis disease in 

the US is higher than reported. Based on this review, the ACIP working group’s interpretation is 

that the true burden of disease in the population of adults aged ≥65 years is likely at least 100­

fold higher than reported. 

Cost-Effectiveness of Tdap Substitution for Td in 

Prevention of Pertussis in Adults 65 Years and Older 

Anna Acosta, MD 

Epidemic Intelligence Service Officer 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Acosta indicated that the objective of her study was to evaluate the cost-effectiveness of a 

one-time substitution of Tdap for Td in healthy adults 65 years of age and older to prevent adult 

disease and complications. The analysis was completed from both a health system (medical 

cost) and societal (productivity loss) perspective. The cost-effectiveness model compared a 

one-time Tdap substitution for Td versus no substitution at 65 years of age 65. One cohort 

population was examined in the model that was comprised of healthy 65 year olds. An analytic 

time frame of 10 years was chosen given age-related mortality and probable duration of 

protection offered by Tdap. The health outcomes examined included number of cases, 

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outpatient illnesses, hospitalizations, pneumonias, and deaths. The economic outcomes 

examined included cost per case averted and cost per quality adjusted life year (QALY) saved. 

In terms of the decision analytic model, the cohort was divided into two groups. One group 

received Tdap and the other did not. The health outcomes were measured in each group in 

those who experienced pertussis. The general parameters of the model incorporated disease 

incidence and disease outcomes. Base case estimates and ranges for sensitivity analyses 

were determined. Based on a literature review, surveillance data, and ACIP workgroup input, a 

disease incidence for the base case was chosen of 100 times the reported mean surveillance 

incidence over the last 10 years, which was approximately 104 cases per 100,000. One healthy 

cohort population 65 years of age and older was examined. A healthy cohort was chosen given 

the difficulty of including comorbidities in the model. The population size was based on the 

2010 US Census and incorporated current age-based mortality rates. The four main outcomes 

of the model included outpatient illness, hospitalization, pneumonia, and death. The 

probabilities of these outcomes were based on the main percentage of cases with these 

outcomes. Because not all adults with moderate pertussis may seek medical care, it was 

assumed that only 50% of non-hospitalized cases or outpatient cases would seek care. 

Important parameters of the model related to vaccination include efficacy, waning immunity, 

immunosenescence, coverage, and adverse events. Base case estimates and ranges for 

sensitivity analyses were determined. Vaccine efficacy in adults 65 years of age and older is 

unknown. The 70% efficacy used in the model was based on efficacy rates of adolescents from 

field studies, as well as immunogenicity data across pediatric and adult populations. Waning of 

vaccine induced immunity affects efficacy in an unclear fashion in this population. Based on the 

literature and ACIP working group input, waning of immunity was accounted for by incorporating 

a 5% reduction of efficacy each year post vaccination in a base case. Because the age of the 

population in this model is older, immunosenescence is another factor for consideration. 

Immunosenescence is the gradual deterioration of the immune system brought about by the 

natural aging process. Given the relative uncertainty of its effect on vaccine efficacy, 

immunosenescence was not incorporated into the base case. It indirectly was incorporated into 

the sensitivity analyses by comparing a range of efficacy rates and waning. Vaccine coverage 

in the base case was assumed to be 50% based on current Td coverage in this population. In 

the sensitivity analyses, coverage varied from 10% to 70%, reflecting current zoster and 

influenza coverage levels. A probability of vaccine adverse event was included in the model, 

including local, systemic, and anaphylaxis reactions. 

Important parameters in the model related to cost include disease and vaccine cost presented in 

2010 US dollars. Direct costs or medical costs encompassed outpatient, hospitalization, and 

pneumonia costs. These were based on a Thomson Reuters MarketScan dataset for average 

pertussis reimbursement costs from 2000-2009 for adults 60 through 64 years of age. It was 

assumed that pneumonia would require hospitalization. Adverse event costs were weighted by 

probability of occurrence. Program costs included incremental cost increase of Tdap vaccine 

relative to Td, and were estimated at $17.00. The administration fee was not included in the 

base case analysis because it was assumed that Tdap and Td would have similar fees. The 

discount rate in the base case was 3%. 

Health utilities or values representing preferences for different health outcomes used to estimate 

QALYs were derived from the literature. Because there are no studies addressing utilities for 

pertussis in the population of adults 65 years of age and older, it was assumed that the younger 

adult utilities for pertussis would be applicable to this model, that the utility for moderate cough 

was the equivalent to outpatient illness, and that the utility for severe cough would be the 

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equivalent to hospitalization. The estimate of pertussis disease duration of 56 days was based 

upon current literature. 

One-way sensitivity analyses were performed to examine the effect of incidence, efficacy, 

immune waning, and coverage on model outcomes. Multi-way sensitivity analyses were 

performed to examine most cost-effective and least cost-effective scenarios. Each scenario 

reflected the highest or lowest values for key model inputs, including incidence, efficacy, and 

waning immunity. 

With regard to results, following vaccination at age 65 years, there was a substantial decline in 

cases. However, with time, the difference between the two groups decreased due to immune 

waning. In terms of the reduction in the number and percentage of outcomes following a onetime Tdap substitution over a 10-year time period, of note, there was a reduction of 

approximately 5000 (25%) pertussis cases with the Tdap substitution at age 65. With all 

outcomes, there was a moderate decline of about 25%. Regarding the cost-effectiveness ratios 

associated with Tdap substitution in the 65 year old cohort, of note, the cost per QALY averted 

in the base case scenario was approximately $3,200 and the cost per QALY saved was 

$31,000. 

In one-way sensitivity analyses, when single parameters are changed from that of the base 

case, all parameters except the one change remained at base case levels. As incidence rose 

from 10 times the NNDSS value to 200, cost per QALY decreased substantially. Raising 

efficacy from 60% to 90% also decreased cost per QALY saved. Changing the degree of 

waning immunity from 5% points per year post-vaccination to 20% increased cost per QALY 

saved, but not to such a dramatic extent as incidence. Other variables examined in the oneway sensitivity analyses included coverage and percentage of non-hospitalized cases treated. 

Variation of either of these parameters did not substantially affect the cost per QALY saved. 

Data regarding pertussis incidence in adults 65 years and older are limited. However, the 

working group strongly feels that the true incidence is substantially higher than reported. Cost 

per QALY saved does vary greatly as incidence changes. Therefore, the range of incidences in 

the model was presented. As incidence increases, the cost per QALY saved declines. 

Although presented with a range of incidence levels, the working group feels that the true 

incidence is closer to 100 times rather than 10 times the reported level, consistent with the 

literature presented earlier. The following graph illustrates the importance of incidence as a key 

model input: 

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Multi-way sensitivity analyses were also performed to evaluate most and least cost-effective 

scenarios. The most cost-effective scenario showed a significant decline in the number of 

cases, hospitalizations, pneumonias, and deaths following immunization at age 65 years. The 

cost per QALY saved was $5,000. In the least cost-effective scenario, there was minimal 

reduction in a number of outcomes following immunization. The intervention was somewhat 

costly in this scenario, with the cost per case averted of about $70,000 more than that of Td 

intervention. The cost per QALY saved was $650,000 in this scenario. 

Regarding the assumptions of the analyses (e.g., incidence and under-reporting, efficacy and 

immune-waning, health utilities, costs, and comorbidities), the over-riding factor is the lack of 

empiric data for each of these variables in the model. These assumptions were addressed with 

the available literature and expert opinion from the working group, and the estimation for these 

parameters is believed to be reasonable. 

The main conclusions that can be drawn from this analysis are that substituting Tdap for Td in 

an age 65 year old cohort results in a moderate decrease in the number of cases and other 

outcomes. This may represent a cost-effective intervention robust to a range of assumptions. 

Incidence level is the primary driver of cost-effectiveness. As incidence level increases, the 

cost-effectiveness of Tdap vaccination increases. 

Cost-Effectiveness Analysis for Boostrix® In Adults 65 Years of Age and Older 

Ms. Shanthy Krishnarahah 

Head, US Health Outcomes 

GlaxoSmithKline 

On behalf of GSK, Ms. Krishnarajah thanked the Pertussis Working Group, ACIP, and CDC for 

the opportunity to present the cost-effectiveness data for BOOSTRIX® in adults aged 65 years 

and older. This work was done in collaboration with GSK, OptumInsight colleagues, Dr. 

Stephen Phelton from Boston University, and Dr. Milton Weinstien from Harvard School of 

public Health. 

The cost-effectiveness model was built to assess the public health and cost implications of 

administering GSK’s Tdap vaccine, BOOSTRIX®, to adults age 65 years and older. This study 

evaluated the incremental cost of vaccinating adults 65 years and older and the health 

outcomes. Direct vaccine effects of preventing pertussis only in the individual vaccinated are 

considered in these analyses. Indirect benefits of preventing transmission of pertussis from 

infected adults were not considered. Therefore, this direct effect model is a conservative 

assessment of the benefits of BOOSTRIX® in vaccinating adults age 65 years and older. The 

model compares a baseline strategy to an intervention strategy. The baseline strategy is the 

vaccination practice recommendations of vaccinating those aged 65 and older with Td. The 

intervention strategy is vaccination of eligible adults age 65 years and older with BOOSTRIX®. 

Other specifics of this model are that a time horizon of 35 years is considered, and the 

incidence is adjusted for age-specific mortality rate for this population. Given the uncertainty in 

the incidence of pertussis in this age group, a range of incidences was used varying from 25 to 

200 cases per 100,000. The cases of pertussis were stratified by their severity of symptoms 

into severe, moderate, or mild. A societal perspective was considered for the analysis. Results 

were presented in terms of total costs / savings, which included direct medical costs and direct 

non-medical cost of patient and caregiver productivity losses due to acute illness. Also shown 

were results for cost per case averted and cost per quality adjusted life-year (QALY) gained. 

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The probability tree describes the possible pertussis case pathways. A case reported or 

unreported can vary by severity. The conservative assumption was made that death and 

encephalopathy were possible only among severe hospitalized cases. It was assumed that all 

moderate cases were treated and that only a proportion of mild cases are treated. In the 

baseline scenario, vaccine coverage of 10% was used. A number of sensitivity analyses were 

done varying vaccine coverage from 5% to 50%. Tdap efficacy was not directly measured, but 

was estimated via immunobridging to an infant DTaP efficacy study. In the study used for 

efficacy bridging, vaccine efficacy was shown to be 89%, which was used in the baseline 

scenario. Additionally in this study, the lower limit of the 95% confidence interval for vaccine 

efficacy was 77%. Sensitivity analyses were performed based on this number. 

In the baseline analysis, the proportion of severity of cases was constant at different levels of 

incidence. However, in the sensitivity analyses, the proportion of severity of cases was varied 

at different incidence levels. At low levels of incidence, there will be more reporting of severe 

and moderate cases via passive surveillance. However, as the incidence of the disease 

increases, the proportion of mild cases reported will increase and the proportion of severe cases 

would decrease. Duration of protection was assumed to be 8 years, but this parameter value 

was varied from 6 to 10 years in the sensitivity analyses. The waning of protective efficacy 

during this time frame is exponential each year. 

In terms of the cost and utilities used in the model, incremental vaccine cost included the cost of 

the incremental price of Tdap and Td and adverse event. In the baseline analysis, the 

incremental price difference of Tdap versus Td in the private market is $18.10. Sensitivity 

analyses were done using public price increments, as well as a mix of public and private prices. 

QALY values are attached to each health status. On a scale of 0-1, by convention, 0 represents 

death and 1 represents perfect health. The source of the pertussis utility data used to calculate 

the disutility data comes from a 2010 publication by Devires et al. Sensitivity analyses were 

done reducing this disutility by 10% and 20% among those 65 years of age and older. 

With regard to the model-predicted costs and cost savings for Tdap vaccination of adults 65 

years of age and older stratified by incidence, the net societal cost of the vaccination program is 

estimated to range from $1.37 million to $4.3 million depending on the incidence level. Costs 

include $4.7 million in vaccination cost. The following table illustrates the various costs and cost 

savings predicted by the model: 

Cost Item Incidence 

25/100,000 

Incidence 

50/100,000 

Incidence 

100/100,000 

Incidence 

150/100,000 

Incidence 

200/100,000 

Total Direct Medical ($362,639) ($725,277) ($1,450,554) ($2,175,832) ($2,901,109) 

Direct Non-Medical 

Cost ($53,173) ($106,346) ($212,693) ($319,039) ($425,385) 

Direct Medical and 

Non-Medical ($415,812) ($831,624) ($1,663,247) ($2,494,871) ($3,326,494) 

Vaccination Cost $4,691,839 $4,691,839 $4,691,839 $4,691,839 $4,691,839 

Net Costs 

Net Costs including 

Lost Productivity $4,276,027 $3,860,215 $3,028,591 $2,196,968 $1,365,344 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

The model predicts that by vaccinating 10% of those age 65 years and older, when the 

pertussis incidence is 100 cases per 100,000, the cost per case averted is approximately 

$1,800. The incremental cost-effectiveness ratio is about $58,000 per QALY at an assumed 

incidence of 100 cases per 100,000, and is about $13,000 per QALY at an incidence of 200 

cases per 100,000. When vaccination efficacy is set at 77% in the sensitivity analysis, the cost 

per cases averted varies from to $638 to $12,000 depending upon the incidence level. At an 

assumed incidence of 100 cases per 100,000 the incremental cost-effectiveness ratio is about 

$73,000 per QALY. 

A comparison of results from the two BOOSTRIX® efficacy assumptions shows that the results 

of the analyses in adults age 65 years and older, and the Lee results in adults age 20 to 64 

years, are similar in cost per case averted and in cost per QALY gained. For example, at an 

incidence of 100 per 100,000 cases, the GSK model predicts a cost per QALY of $58,000 at 

89% efficacy and $73,000 at 77% efficacy. The published cost-effective analysis of Tdap 

vaccination among those 20 to 64 years of age at the same incidence shows a cost per QALY 

of $65,000 [Lee GM, Murphy TV, Lett S, Cortese MM, Kretsinger K, Schauer S, Lieu TA. Cost 

effectiveness of pertussis vaccination in adults. Am J Prev Med. 2007 Mar;32(3):186-193]. 

As the Tdap coverage rate increases, the number of cases averted increases and 

proportionately, the discounted incremental cost increases. The cost per QALY gained does not 

change when varying the vaccination coverage rate. This is because transmission of disease is 

not taken into account in the GSK model. For example, at an incidence of 100 pertussis cases 

per 100,000, the GSK model predicts a cost-effectiveness ratio of $58,000 per QALY. At an 

incidence of 200 cases per 100,000, the GSK model predicts a cost-effectiveness ratio of 

$13,000 per QALY. 

Various sensitivity analyses were performed for cost per QALY, varying the proportion of 

encephalopathy cases, proportion of severity of cases depending on incidence, duration of 

protection, incremental price of the vaccine, and QALY decrement. For example, when the 

incidence is 100 per 100,000, the cost per QALY gained ranges between $76,000 per QALY to 

$48,000 per QALY when varying various input assumptions. These results indicate that not one 

particular input is driving the model results, as the results are quite stable given the variation in 

inputs. 

As with any cost-effectiveness model, this model has some limitation and model assumptions. 

Given the uncertainty regarding the pertussis incidence level, five different scenarios were 

assessed by varying incidence from 25 to 200 cases per 100,000. BOOSTRIX® vaccine 

efficacy in persons 65 and older has not been directly assessed. The estimates of efficacy in 

persons 65 and older are based on bridging to infant DTaP efficacy results via immunogenicity 

data. Data used to estimate vaccine effectiveness and outcomes were derived and synthesized 

from a variety of sources. Given the underlying methodological assumptions of the static model, 

the model does not account for long-term medical costs associated with disease outcomes, 

family or household dynamics, or transmission of disease. A model that captures these factors 

will result in a lower cost per QALY gained. 

In conclusion, the GSK model shows that BOOSTRIX®, a Tdap vaccine licensed for individuals 

65 years of age and older, is cost-effective at an incremental cost-effectiveness ratio of $50,000 

per QALY when pertussis incidence is greater than 110 cases per 100000. Cost-effectiveness 

ratios in this age group are of similar magnitude as those that have been modeled in adults age 

20 through 64 years. Additionally, the GSK results align with the CDC results presented by Dr. 

Acosta. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Working Group’s Conclusions About the Cost-Effectiveness Analyses 

Dr. Jennifer Liang 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Liang reported that the working group’s interpretation of the cost-effectiveness of Tdap in 

adults aged 65 years and older was that there is a modest cost per case averted and cost per 

QALY saved. The incidence estimates accounting for under-reporting are reasonable based on 

limited data and expert opinion. There is reassuring concordance between the two different 

cost-effectiveness models. 

Discussion Points 

Dr. Keitel corrected a statement she made earlier regarding duration of protection being 12 

years, which was after whole cell vaccination. Regarding the comparison of the efficacy in older 

adults with that in younger adults, she wondered what percent efficacy was estimated in the Lee 

article. She also inquired as to whether, since no serologic correlates of protection against 

pertussis have been established, it would be a more direct calculation to use observed levels of 

efficacy in younger adults and then test lower levels, assuming that there is waning, in the older 

population. 

Dr. Krishnarajah replied that for the Lee model of ages 20 through 64 years, the vaccine efficacy 

used was in the 80% range. Several internal discussions have occurred about what the correct 

efficacy estimate is for the adult population aged 65 years and older. After lengthy discussion, 

the decision was made to use efficacy values that were consistent with all prescribing 

information. Several sensitivity analyses were performed and noted that this specific parameter 

is not very specific in the model. The cost-effectiveness ratio was $58,000 per QALY when 89% 

efficacy was used; $73,000 per QALY when 77% efficacy was used; and $83,000 per QALY 

when 70% efficacy was used. 

Dr. Temte reported that the previous week, his department saw about 4000 patients, of whom 

about 15% had a respiratory infection coded. It is known from surveillance being conducted in 

their clinics that for about 50% of those illnesses, a viral cause can be confirmed by multiplex 

PCR. Of people who present, about 86% have a cough illness. There is a huge sea of patients 

for whom there is no confirmation to identify cause. In fact, there is really no surveillance 

system to identify bacterial causes of acute respiratory tract infections and cough illness. 

Dr. Duchin said he was deeply troubled by the efficacy estimates in the cost-effectiveness 

models, which he found to be extremely high. With a generalization of efficacy from 70% to 

90% in a cohort of patients 65 years of age and older, he did not find the outcomes to be 

convincing. 

Dr. Acosta replied that in their sensitivity analyses, they examined a rate as low as 60%. 

However, this was not the key input in the model. When efficacy was varied from 60% to 90%, 

the cost per QALY saved ranged from $19,000 to only $40,000. It is true that this is an 

unknown factor. The investigators made the best estimation possible with the data available. 

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Dr. Bennett expressed similar concerns. While the investigators pointed out that efficacy was 

not a key element in the models, she would submit that this was because it had not been varied 

that much. She wondered whether any effort was made to vary efficacy to a much lower rate. 

There certainly have been vaccines that do not work in the elderly, so she was concerned that 

the same may be true with Tdap. 

Dr. Clark responded that these points were well-taken. Initial effectiveness was based on field 

evaluations, and immune waning of at least 5% per year was built in over the horizon of the 

vaccination to as much as 20% waning. While the model is somewhat robust to that, incidence 

is really the primary driver. 

Ms. Ehresmann requested further clarification about the immune waning that was built in. 

Dr. Acosta clarified that each year post-vaccination, the initial effectiveness value used would 

decrease by 5%. In the sensitivity analysis, each year post-vaccination waned by 20%. 

Dr. Clark added that GSK’s input is based on their antibody responses bridged to infant trials. 

There are data suggesting higher effectiveness, at least very short-term after vaccination. 

Dr. Sawyer pointed out that they would hear immunogenicity data in this age group by antibody 

measure, which may help everyone digest how likely these vaccines are to be effective in the 

age 65 years and older population. 

Dr. Duchin requested further clarity about the GSK model. 

Dr. Krishnarajah responded that the GSK model evaluated 10% of vaccinating a single cohort of 

adults aged 65 and older. 

Dr. Acosta indicated that their model included waning each year and followed a 10-year 

timeframe. At 75 years of age, vaccine efficacy was 20% in the base case. 

Dr. Keitel noted that current policy was targeted at recommending that adults 65 and older be 

vaccinated if they have close contact with young infants. She wondered if it was known what 

proportion of that population actually has close contact with young infants. 

Dr. Liang responded that there is not an accurate estimate of this. 

Safety and Immunogenicty of BOOSTRIX® in Persons 65 Years of Age and Older 

Dr. Jennifer Liang 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Liang reminded everyone that two Tdap products are licensed for use in the US: AdacelTM 

(sanofi pasteur) and Boostrix® (GSK). The vaccines differ in composition and approved age for 

use. BOOSTRIX® currently is licensed for people aged 10 years and older and AdacelTM is 

licensed for those 11 through 64 years of age. Both are for use as an active booster 

immunization for prevention of tetanus, diphtheria, and pertussis as a single dose. Tdap 

vaccine is covered by Medicare Part D, which is relevant to use in people aged 65 and above. 

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As previously mentioned, in October 2010 ACIP reviewed the safety and immunogenicity data 

of both AdacelTM and BOOSTRIX® in adults aged 65 years and older. At that time, both 

vaccine products were not approved for use in this population. In July 2011, the FDA approved 

the expanded age indication for BOOSTRIX® to include adults aged 65 years and older. With 

the availability of an approved Tdap product in this age group, the working group reviewed the 

data again and considered revising the current Tdap recommendation. 

GSK provided information and allowed Dr. Liang to present data on their behalf to expedite the 

presentation and allow for more time for discussion. Because these data were presented during 

the October 2010 ACIP meeting, Dr. Liang summarized only the major points. 

Data from subjects aged 65 and older are from two clinical trials that are primarily from the 

pivotal study 011 comparing BOOSTRIX® to Td vaccine in which 887 subjects received 

BOOSTRIX®. The mean age was 72 years, with a range from 65 to 93 years. There were no 

apparent differences in the subject characteristics between vaccine groups. With respect to 

local reaction, BOOSTRIX® appears to be similar to Td vaccine. For reported general 

symptoms, BOOSTRIX® also is comparable to Td vaccine. Few serious adverse events were 

report, and none were attributed to receipt of BOOSTRIX®. 

For any Tdap vaccine, pertussis immunogenicity has been determined by bridging to a 3-dose 

DTaP infant series. BOOSTRIX® was bridged to three doses of Infanrix®. Comparing the 

GMT concentrations of the 3-dose Infanrix® series to BOOSTRIX® in adults aged 65 years and 

older, BOOSTRIX® met the pre-defined non-inferior criteria. The immune responses to 

diphtheria and tetanus toxoids were similar to BOOSTRIX® and Td, and also satisfied noninferiority criteria. For the three pertussis antigens contained in BOOSTRIX®, increases were 

observed the GMT concentrations for PT, FHA, PRN. As previously stated, this satisfied noninferiority criteria. Post-marketing safety data from the Vaccine Adverse Event Reporting 

System (VAERS) was also previously reviewed by the working group. During 2005 through 

2010, there were 243 reports in adults 65 years of age and older given Tdap vaccine. Of these, 

95.5% were non-serious reports. The most frequent adverse events after Tdap were local 

reactions. There were 11 serious reports, included 2 deaths among individuals with multiple 

underlying conditions. Clinical descriptions of the two deaths made it unlikely to attribute to 

receipt of Tdap. Post-marketing data suggest that the safety profile of Tdap vaccine in adults 65 

years of age and older is as safe as Td vaccine [Moro PL, et al. Adverse events after Tetanus 

Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis (Tdap) Vaccine administered to 

adults 65 years of age and older reported to the Vaccine Adverse Event Reporting System 

(VAERS), 2005–2010. Vaccine 29 (2011) 9404– 9408]. 

After a review of the data, the working group conclusions were that BOOSTRIX® for adults 

aged 65 years and older is safe and immunogenic. Older adults boost, which likely provides 

protection, but the absolute efficacy is unknown for Tdap for all ages. Also unknown is what 

proportion of people are protected and for how long. 

Discussion Points 

Dr. Baker noted that this immunogenicity data like most data ACIP sees are one month postimmunization, and she assumed at this point there was no further follow-up information for 

further duration of protection. 

Dr. Liang requested that GSK respond to this question. 

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Dr. Wayde Weston (GSK) replied that in the 65 years of age and older population, GSK does 

not have any follow-up data and is not conducting any follow-up studies. They do have followup data on younger adults aged 19 to 64, some of which has been published, and they are 

continuing to collect those data. 

Dr. Temte asked for clarification regarding whether the individuals 65 years of age and older 

had multiple morbidities or were considered to be healthy. Increasingly, the patients he sees 

tend to have multiple conditions that all may affect immunogenicity. 

Dr. Liang replied that for the clinical trial, the population was comprised of healthy people. 

Dr. Weston confirmed that they were generally healthy subjects 65 years of age and older. 

Some co-morbidities were expected, and subject were excluded who had any 

immunosuppressant conditions or who were taking any type of immunosuppressive therapy, 

such as those with rheumatoid arthritis. 

Dr. Marcy inquired as to why data were not being collected on those 65 years of age and older. 

It seemed to him that they had been circling this question repeatedly. 

Dr. Weston responded that he would take this back to GSK as a topic for discussion. 

Dr. Marcy emphasized that this should be taken back as a topic for action. GSK seems to be 

the only group that can give ACIP this answer. 

Proposed Recommendation for Use of Tdap in Persons 65 Years and Older 

Dr. Jennifer Liang 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Liang reminded everyone that as presented to ACIP, the working group has interpreted data 

on disease burden, safety and immunogenicity, and cost-effectiveness of the one Tdap product 

approved for use in persons aged 65 and older. As outlined by Dr. Sawyer at the beginning of 

the session, if ACIP approved of the proposed recommendation, the working group would 

provide guidance on the use of the other Tdap product not approved for use in this age group. 

The current Tdap ACIP recommendations for adults are as follows: 

 Adults aged 19 through 64 years 

 For adults aged 19 through 64 years who previously have not received a dose of 

Tdap, a single dose of Tdap should replace a single decennial Td booster dose. 

 Adults aged 65 years and older 

 Adults aged 65 years and older (e.g., grandparents, child-care providers, and 

health care practitioners) who have or who anticipate having close contact with 

an infant less than 12 months of age and who previously have not received Tdap 

should receive a single dose of Tdap. 

 For other adults aged 65 years and older, a single dose of Tdap vaccine may be 

given instead of Td vaccine, in persons who have not previously received Tdap. 

 Either Tdap vaccine product may be used [Note: No vaccine was approved for 

use in this age group at the time of this recommendation]. 

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The rationale for the proposed changes to the recommendations is that there is now one Tdap 

product approved for use in adults aged 65 and older; data on the safety of BOOSTRIX® in this 

population are reassuring; and the proposed recommendation is consistent with existing Tdap 

recommendations. 

Before presenting the proposed language for ACIP’s consideration, Dr. Liang listed the ACIP 

Tdap recommendations that would remain unchanged: 

 General adolescent Tdap recommendation 

 Tdap administration regardless of interval since last Td 

 After receipt of Tdap, persons should continue to receive Td for routine booster 

vaccination
 

 Adolescents and adults having close contact with an infant should receive Tdap 

(cocooning)
 

The working group proposed the following changes to the general adult Tdap recommendations 

for a vote: 

 Expand the age range to include adults aged 65 years and older 

 Remove the phrase “. . . a single dose of Tdap should replace a single decennial Td 

booster dose” 

Though the working group discussions have focused on adults aged 65 and older, the members 

wanted to take the opportunity to update the entire adult Tdap recommendation. To be 

consistent with the ACIP’s past removal of language regarding minimal interval, the working 

group proposed removal of the phrase regarding replacement of a single decennial Td booster 

dose. This also would be consistent with the overall goal of removing barriers to Tdap uptake. 

The working group unanimously agreed to the following proposed language: 

 For adults aged 19 years and older who previously have not received a dose of Tdap, a 

single dose of Tdap should be given. 

The proposed change would replace the current cocooning and permissive Tdap 

recommendations for those aged 65 years and older with a universal adult Tdap 

recommendation. 

Discussion Points 

In moving forward with evidence-based recommendations, Dr. Keitel wondered whether Dr. 

Liang could reflect upon how the recommendation might look for the younger versus the older 

age group. That is, how would the working group grade the recommendation for younger adults 

versus older adults. 

Dr. Liang responded that the working group had not been approached to grade this. While she 

was aware of the grading system, she would not be able to address that without additional 

guidance. 

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As a member of the working group, Dr. Baker said that given the amount of evidence, the 

grading would be significantly different for older versus younger people because there are 

significantly more data for the younger population. 

Dr. Schuchat added that the two pieces of evidence available are immunogenicity, which does 

not look that different, and incidence, which has many unanswered questions for all age groups 

and for which there may be a particular bias for some under-detection versus substantial underdetection. It is very indirect to bridge with other bacterial and viral vaccines with poorer efficacy 

in the older population. Regarding the grading for this particular vote, it was decided that since 

most of the updated Tdap recommendations preceded the implementation of grading, that they 

would forgo moving backwards to grade everything for the new statement. In 5 years when an 

update is done, ACIP will grade everything as per protocol. Perhaps there will be even more 

data at that time. 

Dr. Baker expressed her hope that the vaccine manufacturers heard the comment that more 

evidence would be very useful in moving forward. 

Dr. Temte indicated that for his patients over the age of 65 on Medicare, he wondered what the 

implications would be in terms of coverage. 

Ms. Rosenbaum responded that the instruction is for adults who previously have not received a 

dose of Tdap to receive a dose. However, the US healthcare system is not good enough to 

indicate longitudinally whether an individual has received a previous dose of Td. This raises the 

default question. The default appears to be that if someone has not received a dose or there is 

no verification of whether they have received a dose, a dose is recommended. She thought that 

because of the coverage implications, unless they really meant only to give a vaccine when 

there was affirmative evidence of no prior receipt, ACIP should clearly state that a dose should 

be administered to those who have not received the vaccine and those for which receipt cannot 

be confirmed. That is, a clear message should be sent that this should be routine in either case. 

Regarding the over 65 year old population, any recommended vaccine would be covered as a 

Part D benefit if it is not specified as a Part B benefit, which it is not. She wondered whether 

more was known from the on-going discussion about Part D coverage of vaccine coverage how 

effective Part D has been in realizing access to the vaccine because of the rather clumsy way in 

which Part D works. Because there is not a direct payment to the provider, unless one is in an 

integrated delivery system, the vaccine has to be transported from a dispensing site to the 

provider. 

Dr. Baker indicated that the default would be to immunize if immunization status is unknown, 

which is how pediatric medicine works. She requested that Dr. Hance, the CMS liaison, 

comment on the question pertaining to Medicare coverage. 

Dr. Hance (CMS) responded that, as was noted, Tdap vaccine is part of the formulary for 

Medicare Part D, so patients with Part D will have access to the vaccine. Given that she is on 

the Medicaid side, she was unable to offer further details. However, she said she would follow 

up with her colleagues for further information. 

Dr. Poland inquired as to whether Td vaccine fell under Part B. He also wondered why in the 

recommendations they did not formally signal research that will be needed in order to make 

valid recommendations in the future. For example, they were just shown that an 

immunologically vigorous adolescent who receives a booster dose has a 30% plus drop in 

efficacy 5 years later. Now they were considering recommending a dose to 50 year olds who 

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will be exposed to children 12 months or younger 15 years later when they are beginning the 

slide into immunoscenescence. It is unknown what the efficacy is 15 years after receipt of the 

vaccine. These seemed to be significant provisos that should be signaled and incorporated into 

the recommendation to motivate the collection of the data. 

Regarding Dr. Poland’s Part B questions, Dr. Hance (CMS) responded that Td vaccine falls 

under Part B if it is indicated for a room contamination or a previously existing condition. 

Dr. Baker added that the working group would address duration in all age groups as its next 

major job. 

Dr. Schmader (AGS) echoed Dr. Poland’s comments. Because elders are often excluded from 

clinical trials, including vaccine trials, geriatricians have to act on the absence of evidence a lot 

of times. If they have to wait for the perfect randomized controlled trial, they will never do 

anything. Weighing the pros and cons, the American Geriatric Association (AGS) agreed with 

the working groups’ conclusions and completely supported this recommendation. 

Dr. Tan (AMA) indicated that in November 2011, the General Accounting Office (GAO) released 

a publication on vaccine access for Medicare Part D versus Medicare Part B, which highlights a 

lot of the concerns that were raised by ACIP that there is a dramatic decrease in access as a 

result of vaccines being included in Part D. 

Regarding implementation, Ms. Groom (IHS) reported that IHS has a high proportion of 

grandparents who are primary caregivers in the American Indian / Alaska Native populations. 

The recommendation to target those with infant contact has been very challenging for their 

providers to tease out. IHS went ahead and routinely forecast this for adults, including those 65 

years of age and older. Acceptance of the proposed recommendation would help to support 

that. 

Ms. Ehresmann made a motion to approve the recommendation as proposed, which was 

seconded by Dr. Jenkins. Further discussion ensued. 

Ms. Rosenbaum inquired as to whether the language should be amended. It was unclear to her 

whether they would have to think about this each time because of the coverage implications. 

That is, if it is common practice when information is not known or cannot be verified to immunize 

routinely, ACIP needs to be clear that this is its recommendation. With that in mind, she 

suggested the following revision to the proposed language, “For adults aged 19 years and older 

who previously have not received a dose of Tdap or for whom prior receipt of a dose cannot be 

verified, a single dose of Tdap should be given.” 

Dr. Schuchat responded that the guidance language in the draft statement says that. It is fairly 

standard for adult vaccines in addition to pediatric vaccines. The pneumococcal polysaccharide 

vaccine is the one for which an enormous amount of change was implemented in the 90s. It 

was not about provider coverage. It was just provider caution about what to do when they could 

not find a record. At this point, it is standard when vaccine history is unknown to administer it. 

Dr. Jenkins pointed out that it would be beneficial for those who had not served for very long to 

be provided with a history of how they reached this point, and whether they were waiting for 

something particular before moving forward. 

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Dr. Liang replied that when the original recommendation was approved in October 2010, neither 

Tdap product was approved for adults 65 and older. Given that no product was available at that 

time for that age group, the working group thought it was important to provide protection to 

infants through grandparents who were primary caregivers and to provide the additional 

permissive recommendation. In July 2011, BOOSTRIX® was approved for that age group. 

Now that a product has been approved in that age group, the working group wanted to revisit 

and update the language. 

Dr. Baker added that ACIP attempts to stay within the FDA label, but there are situations like 

infant pertussis in which recommendations are made without aligning with the FDA label. 

In the finessing of the language in the proposed recommendation, Dr. Temte requested that the 

working group consider adding language in terms of future data to better understand 

immunogenicity and waning of immunity over time, and efforts to improve surveillance of 

pertussis in all age groups. 

Dr. Baker said she thought that was planned for the statement. 

Vote: Recommendation for Use of Tdap in Persons 65 Years of Age and Older 

Ms. Ehresmann made a motion to approve the draft language as presented. Dr. Jenkins 

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

abstention. The motion passed by a majority vote. The disposition of the vote was as follows: 

14 Favored: Baker, Bennett, Bocchini, Campos-Outcalt, Ehresmann, Jenkins, Keitel, Marcy, 

Meissner, Rosenbaum, Sawyer, Temte, Vazquez 

1 Opposed: Duchin

0 Abstained: N/A

Guidance for Use of Tdap in Adults Aged 65 Years and Older 

Dr. Jennifer Liang 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Before providing guidance for the use of AdacelTM, which is not approved for use in adults 65 

years of age and older, Dr. Liang presented a brief summary of the safety and immunogenicity 

data for AdacelTM in this age group. She thanked sanofi pasteur for providing data and 

permitting her to present on their behalf. As a reminder, these data originally were presented to 

ACIP during the October 2010 meeting. For the past three months, the working group has 

reviewed these data in detail. 

Sanofi pasteur conducted a clinical trial, Td515, for AdacelTM in persons 65 years of age and 

older. For this study, 1170 participants were vaccinated with AdacelTM and 391 were vaccinated 

with Td. One-third of the subjects were 75 years of age and older. The safety data showed that 

the proportion of local and systemic reactions did not differ from Td. For tetanus and diphtheria 

immunogenicity, antibody responses were similar to Td and met non-inferiority criteria. 

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The major question with which the working group grappled pertained to how to interpret the 

pertussis immunogenicity data when AdacelTM is not approved for use in this age group. In a 

comparison of the GMC of infants who received either a 3- or 4-dose DAPTACEL® and adults 

aged 65 years and older who received AdacelTM, sanofi pasteur no longer had data to bridge to 

PT from the 3-dose DAPTACEL® infant series and, therefore, bridged to the 4-dose series. The 

three antibodies (e.g., PT, PRN, and FIM) have lower GMC concentrations when compared to 

infants who received DTaP and do not meet non-inferiority criteria. Although AdacelTM did not 

meet the non-inferiority criteria, it has been shown to be immunogenic in adults aged 65 and 

older. There is a 4-fold to 15-fold increase in pertussis antibodies 28 weeks post-vaccination 

depending upon the pertussis antigen. 

As mentioned previously, both Tdap products differ in antigen content and responses to each 

antigen. The working group felt that it was important to assess the pre- and post-vaccination 

GMC levels for each vaccine type side-by-side, although this assessment was not intended to 

directly compare the immunogenicity of AdacelTM and BOOSTRIX®. The gestalt of immune 

response for each vaccine is that both result in boosted antibody responses, and it is known that 

antibodies provide some level of protection. 

The ACIP WG’s conclusions were that AdacelTM has an acceptable safety profile in adults aged 

65 years and older. Regarding pertussis, AdacelTM is immunogenic in adults 65 years and older 

and would likely provide protection. Because AdacelTM is not approved for use in adults in this 

age group, the working group considered guidance for use because there are providers who 

stock this product. She reminded everyone that in the previous recommendation of cocooning 

and permissive vaccination for adults aged 65 years and older, ACIP stated that either Tdap 

product may be used. 

Multiple other countries have a broader approved age range for AdacelTM. In Canada, licensure 

for AdacelTM recently was broadened to include older adults following a review of the same data 

that were presented to the working group and ACIP. In the European Union (EU), the German 

licensure is for those 4 years of age and up. This is also true of 28 EU member states. In 

Australia and New Zealand, licensure is for ages 10 years and up. Most Latin American and 

Asian countries follow license in the country of origin, Canada. 

As the working group prepared the language, a review of comparable language from other 

vaccines was conducted. Guidance will include the following table that notes the approved age 

indication for BOOSTRIX® and AdacelTM: 

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After several working group discussions and input from FDA, the working group favored 

practical guidance for vaccinating this population. The following specific points were agreed 

upon by the working group: 

 When feasible, the approved Tdap vaccine for adults aged 65 years and older should be 

used. 

 A dose of AdacelTM administered to a person aged 65 years and older is considered 

valid. 

 Providers should not miss an opportunity to vaccinate persons aged 65 years and older 

with Tdap, and may administer the vaccine that they have available [Phrasing from the 

General Recommendations Interchangeability language]. 

Discussion Points 

Ms. Ehresmann wondered whether there was a reason they referred to the approved Tdap 

vaccine and then specifically mentioned AdacelTM. She thought they should say the brand or 

not, but should be consistent. 

Dr. Liang indicated that the first bullet could be revised to read, “When feasible, BOOSTRIX® 

vaccine should be used for adults aged 65 years and older. 

Dr. Baker requested an interpretation of how the recommendation is considered valid in terms of 

Medicare. This seems like a subtle preference and “is considered valid” is unusual language. 

Stating the “approved vaccine” gives a preference, and suggesting a preference is always going 

to result in missed opportunities. She requested input regarding how practitioners will 

understand this in terms of the two available vaccines. 

Dr. Liang responded that with regard to the guidance, the reason for providing this in the way 

that it was presented was so that providers would not miss an opportunity to vaccinate, but 

recognizing at the same time that there is one vaccine that is approved for use in this age 

group. The goal was to provide some guidance that would permit providers to use AdacelTM if 

they had that in stock rather than defer vaccine and miss an opportunity to vaccinate. 

Dr. Baker said it should be “FDA-licensed” not “approved.” 

Dr. Fryhofer (ACP) pointed out that as a practicing physician, she found the language to be very 

confusing and thought that it would limit access to vaccines. It seems to suggest that the FDAapproved vaccine should be administered. During the last ACIP meeting, data were presented 

that addressed the safety of both vaccines and during this session, it was shown that other 

countries have safety information. Therefore, it was unclear to her why AdacelTM had not been 

FDA-approved. 

Dr. Tan (AMA) agreed with Dr. Fryhofer and suggested deleting the first two bullets and leaving 

the third to achieve the objective. 

Dr. Sawyer clarified that an attempt was made to model previous language or general 

recommendations language, including the statement that vaccination is “considered valid” if 

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used when not FDA-approved. The statement in the second bullet, “may administer the vaccine 

they have available” is taken from the general recommendations language. 

Dr. Sun (FDA) responded to the questions raised about why AdacelTM had not been FDAapproved in this age group. The basis upon which FDA approves indications is the use of 

adequate, well-controlled studies. The two studies, one on BOOSTRIX® and one on AdacelTM, 

were very similar in design and pre-specified serological endpoints. BOOSTRIX® met the 

criteria and AdacelTM did not, which was the reason the FDA did not approve both. 

Dr. Coyne-Beasley acknowledged that the working group puts a lot of thought and energy into 

formulation of recommendations. She expressed interest in hearing from working group 

members about whether they would be comfortable with the recommendation that was put forth 

by one of the liaisons regarding the inclusion of just the third bullet. 

Ms. Ehresmann commented that part of the motivation for asking the question about why the 

language “approved Tdap” was used for the first bullet and the trade name was used in the third 

bullet, was that there is significance to the fact that a vaccine is licensed. While she wanted to 

acknowledge and completely support the idea of missed opportunities, there is a situation in 

which there is a licensed vaccine and use of the other vaccine is off-label. She thought it was 

important for the recommendations to recognize that difference, and that the proposed language 

did this in a very nice way that continues to promote vaccination but acknowledges that there is 

a process for licensure. 

Dr. Sawyer agreed that part of the impetus behind the language was to address that there are 

two products, one that is approved by FDA and one that is not. Some members of the working 

group who have reviewed the immunogenicity data in detail do not believe these are equivalent 

vaccines in this population. This is how the working group arrived at this compromised position 

to avoid missed opportunities by basically stating that if AdacelTM is given, that is considered 

valid and it should be given if it is what an office has in stock. However, they wanted also to 

state a slight preference for the FDA-approved product. 

Dr. Bennett thought the language was very complex for a practitioner and actually would 

interfere with administration of these vaccines. She wondered whether it would be possible to 

make a general recommendation about Tdap and then in the description of how to give Tdap 

include the considerations, including the differences in immunogenicity. As a physician, she 

would never think about whether she gave a valid vaccine. This is not the language physicians 

use or the way they think about this. 

Dr. Liang clarified that this language is not part of the recommendation. It is guidance that 

would be included within the statement. The language of the actual recommendation would be 

what ACIP just voted on for adults. The guidance would be included within the body of the 

statement to explain the rationale behind the guidance. 

Dr. Marcy pointed out that sanofi pasteur now has 1200 immunosenescence individuals they 

could follow to assess decay. He wondered whether they planned to follow this cohort. 

Dr. Hahn (CSTE) indicated that she serves on the working group and helped to craft this 

language. She suggested reversing the sequence of the bullets to move the third bullet to the 

first bullet, possibly this might make people more comfortable that this is the main point being 

made. 

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Dr. Loehr (AAFP) said that as a practicing physician, he would like to know that BOOSTRIX® is 

approved and AdacelTM is not, but that he could use AdacelTM if necessary. That should be the 

clear point if that is what ACIP wants. If ACIP does not really care about approved or not, then 

the third bullet is all that is needed. He was also curious about the difference between 

“approved” and “licensed” and which word should be used. It was his understanding that the 

vaccine was licensed and then approved for this indication. 

Dr. Baker replied that the FDA licenses vaccines and approves drugs, and ACIP recommends. 

Dr. Clark added that the working group was directed by FDA in these discussions. He clarified 

that both vaccines are licensed; however, BOOSTRIX® is the only one approved by the FDA for 

use in those 65 years of age and older. He liked the suggestion to flip the language, and 

suggested modifying the second bullet to state that “a dose of either vaccine is immunogenic 

and valid.” 

Dr. Moore (AIM) asked for clarification regarding whether the recommendation was to 

administer Tdap at the next visit to anyone who has not yet had a Tdap, or if it was akin to the 

19 through 64 year old recommendation in that it would replace the decennial Td vaccine 

unless there is a specific need to administer Tdap earlier. 

Dr. Liang clarified that with the vote ACIP just passed, the phrase about the decennial Td 

booster for all adults was removed. 

Dr. Moore (AIM) emphasized that thinking programmatically, it is important to tell people who 

have not had it that they need it. 

Dr. Netoskie (AHIP) suggested revision of the first bullet to read, “When feasible, the approved 

Tdap vaccine or a dose of AdacelTM for adults aged 65 and older” and elimination of the second 

point. That would be clearer for physicians and payers. 

Dr. Baker assured everyone that they would try to make everyone happy with the final 

language, and make it clear to the practitioner. She thought a strong point that had been made 

was that the recommendation upon which ACIP voted was very clear, but the guidance 

language needs to take into consideration some of the issues that would confuse practitioners. 

Dr. Jenkins stressed that there are no data on the older population; however, the demographic 

curve is shifting in the sense that there are more well people in this age group. She expressed 

her hope that the discussion highlighted the point that more data should be collected in this 

population as more people shift into this age group. 

Dr. Friedland (GSK) reinforced that GSK is following immune duration and antibody persistence 

across all ages for 10 years following vaccination. Those vaccines were licensed in 2005, so 

they are approaching that timeframe. All adults from the clinical trial program who are 19 

through 64 years of age are being followed for 1-, 3-, 5-, and 10-year for antibody persistence 

studies. The over 65 group was just licensed for BOOSTRIX® in July 2011, so there has not 

yet been time for these people to age into the duration studies. Nevertheless, GSK takes these 

comments seriously and is interested in generating as must data as possible that can help guide 

policy discussions. 

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Discussion 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Influenza 

Introduction 

Wendy A. Keitel, MD 

Chair, Influenza Working Group 

Dr. Keitel reported that the activities of the Influenza Working Group over the last few months 

included discussions of vaccine products currently under development; discussion of recent 

epidemiology, including influenza A(H3N2)v; and initiation of review of the evidence base using 

GRADE. 

Influenza Activity Update 

Lisa Grohskopf, MD, MPH 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Grohskopf offered a brief update of domestic influenza surveillance for the season at this 

point. She shared the most recent available FluView data, which was for Calendar Week 6 

ending February 11, 2012. These maps depict weekly influenza activity estimates reported by 

state and territorial epidemiologists, and are intended to illustrate geographic spread over the 

course of time to provide a snapshot rather than to reflect influenza season severity or intensity. 

For the week ending February 11, 2012, virtually all reporting states and territories reported at 

least sporadic influenza activity. Notably, only California was reporting widespread activity at 

this time. Dr. Grohskopf compared this to Calendar Week 6 ending February 12, 2011 of the 

previous season which showed a fair amount of contrast in terms of widespread activity. The 

current season seems to have gotten off to a somewhat slow start. It is not possible to 

determine where the peak will occur until it has already been passed. 

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Note that the results of influenza positive tests are reported to CDC by the 80 WHO organization 

and 60 respiratory and enteric virus surveillance laboratories that are in all 50 states throughout 

the US. The WHO collaborating laboratories, all state public health laboratories, some county 

laboratories, and some tertiary center laboratories participate in this system. The NREVSS 

laboratories are primarily hospitals. In terms of the results of influenza positive tests reported to 

CDC by the WHO / NREVSS collaborating laboratories, it was only in the previous couple of 

weeks that were 10% or more positive specimens. Among specimens that have been typed 

thus for, there has been a predominance of H3. Within the sample, there is a relatively low 

number (~5%) of B isolates. 

In terms of the characteristics of recent influenza virus isolates that have been submitted to and 

tested at CDC, since the season officially started on October 1, 2011, there have been 369 US 

isolates tested. Among those, 58 (16%) were Influenza A (H1N1), 56 (97%) were 

A/California/7/2009-like; and 263 (71%) were Influenza A (H3N2), of which 257 (97%) were 

A/Perth/16/2009-like. These two strains are those represented in the current 2011-2012 

seasonal vaccine. There has been a relative dearth of Influenza B specimens. Only 48 

specimens have been received, representing 13% of the total tested. Of these, 22 (46%) were 

of Victoria lineage, 198 (99%) were B/Brisbane/60/2008-like, and 26 (54%) were of Yamagata 

lineage. This is quite a small sample of viruses. Worldwide, most isolates have been similar to 

the 2011-2012 vaccine strain. 

In terms of the percentage of outpatient visits for influenza-like illness (ILI) reported by the US 

Outpatient Influenza-like Illness Surveillance Network (ILINet), ILINet is a network of over 3000 

healthcare providers throughout the 50 states who report data to CDC on a weekly basis. The 

epidemic threshold, or national baseline, is calculated based on the mean percent of visits for 

ILI averaged over the last three years of non-influenza season weeks. The baseline is currently 

about 2.4%. The percentage of illnesses due to ILI remained below epidemic threshold at this 

time. 

In terms of the number of influenza-associated pediatric deaths reported from the 2008-2009 

influenza season to the present season. For 2010-2011 that total number of pediatric deaths 

reported was 122. This is a slight increase over the figure presented in October 2011, as there 

were some late reports for 2010-2011 that came in since then. Notably, for 2011-2012, since 

October 1, 2011, only 3 pediatric deaths have been reported. Compared to this time period last 

year, this represents quite a few fewer deaths. It is important to keep in mind that the season is 

not over, the peak will not be known until it has occurred, and there is a reporting lag. 

Dr. Grohskopf then described human infections with swine influenza A viruses in the US, some 

of which have been observed this past season. A total of 35 human cases of swine influenza A 

virus infection were identified from December 2005 through November 2011. These viruses are 

known to circulate in swine and do not typically circulate to humans, but CDC does receive 

periodic reports of cases observed in humans. Previously about 1 case is reported every 1 to 2 

years, but better diagnostics and testing at state health departments and greater awareness of 

occurrence may be contributing to why more cases have been observed in the last couple of 

years. These are all triple reassortant swine-origin viruses, meaning that they contain genetic 

material that has its origin in avian, swine, and human viruses. Included within the 35 instances 

that have been observed, there has been representation of H1N1 (n=13), H3N2 (n=20), and 

H1N2 (n=2) infections. 

The 12 cases of swine-origin influenza A(H3N2) variant that were observed between July 2011 

through November 2011 were reported from 5 states (Maine, Iowa, Indiana, West Virginia, 

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Pennsylvania). These cases were of swine origin H3N2 with the matrix (M) gene from A(H1N1) 

pandemic 2009 strain. Most of the cases were in children. The median age was 3 years, with a 

range of 11 months to 58 years. The illnesses were primarily characterized by mild to moderate 

influenza-like illness. Three persons were hospitalized, but all recovered. The estimated 

incubation period was about 2 to 4 days, with a range of 1 to 7 days. Exposures are interesting 

to consider. As with most of these instances, typically there is exposure to swine either directly 

or indirectly, although there are occasionally cases in which this is not observed. In this 

particular group of cases, 4 individuals had direct exposure to pigs, 2 had indirect exposure, and 

6 had no discernible exposures and represent potential human-to-human transmission. There 

has been no sustained human-to-human transmission, however, which is important to consider. 

The hemagglutinin genes in this virus are related to H3N2 viruses that circulated during the 

1990s, so as a result adults and some older children may have some limited immunity to these 

viruses. However, the current seasonal vaccine is not anticipated to provide significant 

protection. At present, there is not a vaccine specifically for these strains. Vaccine candidate 

strains have been distributed to manufacturers, but sustained spread is not being observed. 

The last case was reported in November 2011, but monitoring for new cases continues. 

With regard to influenza vaccine safety monitoring for the 2011-2012 season, the formulation is 

unchanged from 2010-2011 seasonal influenza vaccine. This is the first season of use for 

intradermal trivalent inactivated influenza vaccine (TIV), and it is the second season of use for 

high-dose TIV. Monitoring is in place for these vaccines as well as the other influenza vaccines 

in the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink 

(VSD). To data, no unexpected or new safety concerns have been detected. 

Discussion Points 

Regarding the map that shows the estimated activity by state, Dr. Meissner pointed out that 

sometimes there is considerable variation from one state to another. He wondered whether this 

depicted an accurate reflection of the amount of influenza in a state, or if it was reflective of 

differences in surveillance by state. 

Dr. Grohskopf replied that there is some variation within jurisdictions in terms of how a region is 

different. The definitions for “no activity, sporadic, local, regional, and widespread” involve 

several different parameters and can be somewhat complicated. One aspect of this is the 

number of regions within a state that a considered to be having influenza activity. This may vary 

from state-to-state as they define “local.” 

Dr. Bresee (SME) added that in general, while there are state-to-state variations, the proportion 

of states that show widespread or regional disease correlates quite well with other surveillance 

systems. 

Regarding the H3N2 data and the suggestion that the M gene came from the pandemic H1N1, 

Dr. Duchin requested clarification regarding whether it came from the human virus or if it was 

possible that it shares the same gene as another precursor that was common to both viruses. 

Given the level of influenza activity, he also wondered whether there would be data about the 

effectiveness of the high dose vaccine in the population for which it is indicated. 

Dr. Grohskopf responded that regarding the M matrix gene, it is susceptible to 

influenza viruses that infect swine, avian, and humans. The term that is used is that they make 

good mixing vessels. The M gene is similar to the one that is in the pandemic H1N1 strain, so 

theoretically of this virus had spread to swine at some point that would allow for some kind of 

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recombination. The working group expects to receive an update on the high dose vaccination 

sometime in the near future. She requested that a sanofi pasteur representative comment on 

the timeline for that update. 

Dr. Greenberg (sanofi pasteur) responded that the post-licensure efficacy trial is on-going and 

results are anticipated within the next two years, depending upon the number of cases 

ascertained each season, the strains, and the match with the vaccine. 

Dr. Temte thought the lack of childhood deaths observed this season was stunning. He knew 

the influenza branch tended to be very conservative and holds their comments “close to the 

hip,” but he had to assume that there must be incredible effects of universal vaccine policy, 

recurrence of the same strains, and the likelihood that there will be little influenza this year. He 

has been amazed in Wisconsin in terms of influenza surveillance and general morbidity and 

mortality with hospitalized older patients. He was on a teaching service the first two weeks of 

January and had virtually no admission for chronic obstructive pulmonary disease (COPD) or 

congestive heart failure exacerbations. He wondered whether there were any guesses about 

current population immunity. 

Dr. Grohskopf replied that there was nothing as far as a broad population-based evidence-base. 

Dr. Bresee (SME) added that while the hope is that there will be little influenza this year, CDC’s 

take on it is that there could be more influenza so it is not too late to get vaccinated. 

Dr. Schuchat added that there is year-to-year variability in terms of when the influenza season 

starts. In recent years, it has been very early. It has been a long time since it has been late like 

this. It would be premature to conclude that there is not going to be an influenza season. 

Instead, it appears that the influenza season will have a really late start. 

Dr. Bennett requested information about immunization rates across the age span. 

Dr. Grohskopf responded that for the current season, this could not yet be done. 

Dr. Baker congratulated CDC and the liaison organization for the intensity of messaging to the 

public through a variety of media, which has been impressive. She was also impressed by the 

incredible job pharmacies were doing as an alternative venue for vaccines. She would like to be 

optimistic along with Dr. Temte regarding the combination of increasing immunization rates, 

some communities with herd immunity, and a low influenza season being responsible. She 

reminded everyone that the first thing that was observed with rotavirus vaccines was a delay in 

the rotavirus season. 

Dr. Duchin noted that some research had been published to suggest that H1N1 produced a very 

broad spectrum cross-reactive immunity against other influenza viruses. That has some 

interesting implications about vaccine formulations and the impact of epidemiology on 

subsequent viruses that might appear. He wondered if any thought had been given to whether 

the broad pandemic with H1N1 had generated some sort of protective effective in the population 

for the current season and perhaps subsequent seasons. 

Dr. Grohskopf responded that it has been interesting that the same vaccine has been used 

essentially for two seasons. It is known from other studies that immunity declines, but the 

degree and the rate to which it declines occur depends on the population. There is an anomaly 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

in that H1N1 2009 vaccine has been used for two seasons plus the pandemic season, so it 

does make for somewhat unique circumstances. 

Dr. Bridges indicated that final coverage data would not be available until Spring, but in 

November internet panel surveys were conducted of pregnant women and healthcare workers, 

and in the national influenza survey data people are asked about receipt of vaccine and if 

individuals definitely intend to be vaccinated. Those two numbers combined tend to correlate 

fairly well with the end of season coverage. The November data indicate that this year is on 

track with last year, with similar coverage rates. 

Dr. Pickering wondered whether Dr. Bridges or Dr. Foster had any information on the rates of 

increase, decrease, or steadiness of influenza immunizations given in pharmacies. 

Dr. Foster (APhA) responded that according to CDC numbers, last year was 18% and the 

previous year was 10%. He expected this to be higher this year. 

Dr. Jenkins observed that it is super markets as well as pharmacies. Some super markets are 

offering a 10% discount on groceries with receipt of an influenza vaccine. They are 

aggressively marketing influenza vaccine. 

Dr. Foster (APhA) clarified that super markets and stores are all pharmacies. 

Dr. Baker pointed out that a license was required to inject someone. 

Dr. Bridges added that many people do not know when they go to a grocery store whether they 

were vaccinated by a visiting nurse or pharmacists, which is why it is lumped into retail 

locations. That proportion has increased for adults to 20% to 21%. 

Dr. Poland (ACP) emphasized that in many grocery stores, Sam’s Clubs, et cetera, it is the 

Visiting Nurse Association (VNA) and other nursing associations that go there to administered 

vaccines. The VNA has done a wonderful job with this. 

Antiviral Medications 

Tim Uyeki MD, MPH, MPP 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Uyeki emphasized that antiviral agents are an important adjunct to influenza vaccination in 

terms of the prevention and control of influenza. There is a very high prevalence of resistance 

to the adamantane class of antivirals among circulating influenza A viruses worldwide, so there 

is a tendency to focus on the neuraminidase inhibitors, oseltamivir and zanamivir, for prevention 

and control. As Dr. Grohskopf indicated, more of the viruses tested so far this year are 

influenza A H3N2. Among all of the H3N2 viruses, B viruses, and the 2009 H1N1 viruses, no 

resistance has been observed to oseltamivir and zanamivir, which is very good news. In July 

and August of last year, there was local transmission of oseltamivir-resistant 2009 H1N1 virus in 

Southeastern Australia. That raised an alarm, but there is no evidence of that so far in the US. 

Oseltamivir or zanamivir is recommended for treatment of influenza A or influenza B virus 

infections. Treatment is recommended as soon as possible for any patient who has confirmed 

influenza is suspected to have influenza, especially those who have severe, complicated, or 

progressive illness; people who require hospitalization; or outpatients who are at higher risk for 

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influenza complications. The administration of antiviral drugs should not be delayed while 

waiting for results of diagnostic testing if clinically indicated. Otherwise healthy patients who 

present early (e.g., within 48 hours of illness onset) with uncomplicated confirmed or suspected 

influenza can be treated based upon clinical judgment [ACIP Guidance for Use Antiviral Agents 

http://www.cdc.gov/flu/professionals/antivirals/guidance/; Updates on antiviral resistance can be 

found at: http://www.cdc.gov/flu/weekly/]. 

The groups at higher risk for influenza complications include the following: 

 Persons <2 or ≥65 years of age 

 Persons with the following conditions: 

→ chronic pulmonary (including asthma) 

→ cardiovascular (except hypertension) 

→ renal, hepatic, hematological (including sickle cell) disease 

→ neurological, neuromuscular, or metabolic disorders (including diabetes mellitus) 

 Immunosuppression, including that caused by medications or by HIV infection 

 Women who are pregnant or post-partum (2 weeks) 

 Persons younger than 19 years of age who are receiving long-term aspirin therapy 

 American Indians and Alaskan Natives 

 Persons who are morbidly obese (body-mass index ≥40) 

 Residents of nursing homes and other chronic-care facilities 

In terms of inhaled zanamivir dosing, zanamivir is approved for those aged 7 years and older for 

the treatment influenza A and B. The dosage is 10 mg (two inhalations) twice daily. It is not 

approved for treatment in those under the age of 7 years. For chemoprophylaxis, zanamivir is 

approved for influenza A and B for those aged 5 years and older at 10 mg (two inhalations) 

once daily. It is not recommended for persons with underlying airways disease. Administration 

requires correct use of inhalation device. 

Oral oseltamivir is FDA-approved for treatment of influenza A and B for persons 13 years of age 

and older. There are differences in the dosing in terms of pediatric ages. The dosage is 75 mg 

twice daily for those 13 years of age and older. For those ages 1 through 12 years, dosage is 

determined by weight. Those who are over 40 kg receive adult dose. It is also approved for 

chemoprophylaxis for influenza A and B in persons 1 year of age and older. It is not FDAapproved for children aged less than 1 year. This drug was used for this age group during the 

pandemic through an Emergency Use Authorization (EUA), which expired in June 2010. There 

was extensive use of the drug, there are observational data, and there is a randomized clinical 

trial that would include this age group that has been presented at meetings, but has not yet 

been published. ACIP and CDC recommend that this drug be used in children of this age for a 

number of reasons, given that this age group is at very high risk of severe influenza 

complications, there have been pediatric influenza-associated deaths, and children less than 6 

months of age are not approved to receive influenza vaccination. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

With regard to duration of treatment, for therapy the standard course is 5 days. Longer courses 

may be considered for persons who remain severely ill after 5 days of treatment, especially 

hospitalized patients. For chemoprophylaxis, the recommended course is 10 days following 

household exposures and 7 days after most recent exposure in other situations. For control of 

outbreaks in long-term care facilities and hospitals, prophylaxis for a minimum of 2 weeks and 

up to 1 week following last exposure is recommended. Other groups who may be considered 

for receipt of chemoprophylaxis are those who are immunosuppressed and for those for whom 

vaccine is contraindicated [MMWR 2011, Volume 60 (#RR-1), p.7, Table 2]. 

Discussion Points 

Ms. Rosenbaum noted that one of the background documents the ACIP members were sent in 

preparation for this meeting was what she considered to be an extremely disturbing CDC review 

of an outbreak in a nursing home in Ohio. This was a long-term residential facility housing only 

130 of the most disabled children and adults. Apparently, they were immunized and yet, 

influenza struck approximately 80 of the 130 residents. Reading between the lines, one of the 

findings was that the nursing facility did not move fast enough at the first signs of illness to 

recognize the symptoms of influenza and begin antiretroviral treatment. It was unclear why the 

failure rate on the vaccine was so high. She wondered what CDC and CMS might do jointly on 

a letter to all state Medicaid agencies drawing their attention to this outbreak and the CDC and 

local health agency findings. As much as they would like to think so, the average state 

Medicaid director probably does not have access to and does not read MMWR. The speed with 

which a nursing facility or other institution introduces antiretroviral agents is a basic patient 

safety matter. There were 7 or 8 deaths, and these were the most vulnerable people in society. 

Knowing that this information is not going to get cross-walked to state Medicaid programs 

without some nudging on the part of the two federal agencies, Ms. Rosenbaum urged that ACIP 

recommend this kind of action. 

Dr. Wharton (SME) thanked Ms. Rosenbaum for the suggestion. 

While Dr. Poland had no issues with the recommendations and recognized that they were 

consistent with the current data, he felt compelled to mention something that he raised as an 

issue in a working group and published as a commentary in Clinical Infectious Disease two 

years earlier—the idea that there is no RNA virus that would be treated with a single drug. This 

principle is used for a good reason, which is that those drugs provide mutational pressure and 

as yet unclear, instances in which it seems to drive resistance. This was observed a couple of 

years ago with the pandemic with a rising rate of Tamifu® resistance, which fortunately has 

resolved. The adamantane drugs were used for years until suddenly, inside of a year, there 

was almost complete resistance. As a research need, he raised the idea that it is in the longterm interest to better understand the effects of using a single antiviral drug in the case of RNA 

viruses. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Future Activities 

Lisa Grohskopf, MD, MPH 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Grohskopf reported that upcoming working group activities prior to the June 2012 ACIP 

meeting include the following: 

 On-going review and discussion of vaccine products in development, as indicated and 

appropriate; 

 Discussion of vaccine virus strain selection for 2012-2013 season, and the potential impact 

this may have on recommendations (e.g., dose recommendations for children 6 months 

through 8 years of age); and 

 Review of the evidence using GRADE, with Dr. M. Hassan Murad of the Mayo Clinic to 

perform the analyses. 

Regarding vaccine strain selection for 2012-2013, the WHO Consultation and Information 

Meeting on the Composition of Influenza Virus Vaccines for the Northern Hemisphere 2012­

2013 ran from February 20-22, 2012 and will conclude the 22nd, meaning that something should 

be known by the next day or soon afterward. Once WHO makes its recommendations, the 

individual countries that will be producing vaccines and their regulatory bodies decide what they 

are going to recommend. In the US case, this is the FDA. FDA Vaccine and Related Biologic 

Products Advisory Committee (VRBPAC) is scheduled for February 28-29, 2012 at which time 

the WHO recommendations will be considered. 

Recommendations: Reiteration of Recommendations for 

Annual Vaccination for all Persons 6 Months of Age and Older 

Lisa Grohskopf, MD, MPH 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Grohskopf indicated that currently, no new language, changes, or recommendations were 

being proposed to put to vote. The current recommendation will be reiterated for the time being, 

which is that annual influenza vaccination is recommended for all persons aged 6 months and 

older. No changes to the groups recommended for annual influenza vaccination are proposed 

at this time. Any proposed changes will be presented for discussion and vote and the June, 

2012 ACIP meeting. 

Discussion Points 

Dr. Pickering asked how many times the Northern and Southern Hemisphere selection of 

vaccine strains had been similar. He also wondered whether there was any follow-up 

information on uptake and implementation of immunizing patients with egg allergies, and how 

successful that had been. 

Dr. Grohskopf responded that she did not know how often the Northern and Southern 

Hemisphere strains had been similar, but it does occur. Regarding egg allergies, she did not 

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yet have any information on uptake. CDC is still in communication with its allergist colleagues, 

and understand that additional study data will probably be coming out over the next year or so 

regarding vaccination with egg-produced vaccines in allergic patients. 

Dr. Baker thought that for patients with egg allergy, pediatricians and family practitioners would 

be much more likely to administer influenza vaccine. She wondered if those practitioners would 

be queried as well as the allergists. 

Dr. Grohskopf replied that pediatricians and family practitioners would be included as well. 

Dr. Bresee (SME) indicated that in the last 12 years, the recommendations from the Northern 

Hemisphere to Southern Hemisphere have changed maybe 3 or 4 times. Otherwise, at least 

one strain has changed. 

Dr. Vasquez inquired as to whether any thought had been given to recommendations for 

protection of infants 0 to 6 months of age who currently cannot receive the vaccine themselves, 

but knowing that there is mounting data to show that if their mother is immunized, that is a way 

of protecting the infant. 

Dr. Grohskopf responded that the current guidance is that the best way to protect these children 

is for their parents, caregivers, and others who have contact with them to be vaccinated. Given 

the current age indications for influenza vaccines, ACIP would not be able to make a 

recommendation for vaccination from a regulatory perspective. However, they will continue to 

follow the research. Currently, the advice in communications materials is to promote 

vaccination of caregivers for those in this age group as an important means of preventing them 

from getting infected. 

Dr. Baker added that, similar to pertussis, pregnant women are immunized with influenza 

vaccine to prevent their enhanced morbidity. As far as protecting the newborn, she did not think 

there was a clear picture of whether it extended to age 5 and 6 months. Overall, it induces 

protection. The problem with immunizing infants after immunizing the mother is the issue of 

potential interference of maternal antibody. There has been considerable discussion about this 

with regard to pertussis. 

Dr. Price (NMA) noted that many years were spent blasting the lack of penetration of adequate 

supplies of influenza vaccine into communities of need. He commended the unified efforts of 

many organizations, including ACIP, CDC, and CMS. After a somewhat late start, there were 

ultimately adequate supplies in communities of need. He expressed his hope that an effort 

would be made to have adequate supplies of the intranasal influenza vaccine in the coming 

season, given that it seemed to be taken up by clients much better because of the lack of using 

a needle. This is also true with the intradermal vaccine. 

Dr. Keitel inquired as to whether uptake of the intranasal product was across all age groups that 

are recommended. 

Dr. Price (NMA) replied that the Cobb Institute for NMA is involved along with CMS and CDC in 

an influenza education program. They do find that there is better acceptance among people 

who are covered fiscally for the vaccine. One of the problems with the adult population, even 

though they can be educated about the importance of a vaccine and the option of having 

intranasal, non-painful administration of vaccine, if they cannot pay for it, they get no vaccine at 

all. He expressed his hope that ACIP would address this moving forward. 

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Discussion 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

13-Valent Pneumococcal Conjugate Vaccine (PCV13) 

Introduction 

Nancy M. Bennett, MD, MS 

Pneumococcal Vaccines Working Group Chair 

Advisory Committee on Immunization Practices 

Dr. Bennett introduced the pneumococcal session, noting that she had recently taken over as 

chair of the Pneumococcal Vaccines Working Group. As a reminder, 13-valent pneumococcal 

conjugate vaccine (PCV13) was licensed on December 30, 2011 for use among adults 50 years 

of age and older. The FDA approved this indication under the Accelerated Approval Pathway, 

which is a pathway that is used for products that address serious and life-threatening conditions. 

The licensure was based on non-inferior immunogenicity compared to PPSV23. In this case, 

immunogenicity is not a correlate of protection, but is rather a surrogate for assessing whether a 

vaccine works well. The indications are prevention of pneumococcal disease, including 

pneumonia and invasive disease, in adults 50 years of age and older; and prevention of disease 

caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F 

and 23F. This approval was given with the caveat that there be a post-licensure randomized 

controlled trial of PCV13 against pneumococcal pneumonia among adults 65 years of age and 

older, and this trial is ongoing in the Netherlands. 

The Pneumococcal Vaccines Working Group terms of reference are to: 

 Review data on immunogenicity, efficacy, and cost-effectiveness of pneumococcal 

conjugate vaccines in adults; 

 Determine whether data available to date on PCV13 immunogenicity and cost-effectiveness 

are sufficient to determine value of immunizing adults with PCV13; and 

 Develop a revised statement on pneumococcal immunization if determined that one 

including PCV13 recommendations for adults is necessary. 

The working group has been presented with quite a bit of data on PCV13 for adults, including 

immunogenicity results from Phase III studies from Pfizer; immunogenicity data for PCV from 

published literature; and cost-effectiveness and public health impact of different adult 

pneumococcal vaccination strategies. Evidence that will not be available to help with decisionmaking, which has been very worrisome to the committee, includes efficacy against pneumonia, 

which will come from the Netherlands trial in approximately 2013; or the indirect herd effects of 

PCV13 use in children. Tremendous effects were observed from introduction of PCV7 in the 

child population on the elderly, and it is anticipated that similar effects will occur from PCV13, 

but it is too early to tell. 

The working group has been engaged in applying the GRADE process to the PCV13 data, and 

decided to provide the GRADE evidence during this session for those over the age of 65 and for 

adults with immunocompromising conditions. The working group hopes by June 2012 to have a 

recommendation and potentially a vote on the use of PCV13 in immunocompromised adults, as 

well as an update on the indirect effects of PCV13 on adults from its administration in children. 

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In October 2012, the working group hopes to have an additional update on the indirect effects of 

PCV13 use in children, and by February 2013 to see a report on the CAPITA trial results as well 

as an update on the indirect effects of PCV13 use in children. By June 2013, the working group 

believes that there should be sufficient data to be able to make a recommendation about the 

use of this vaccine in those over the age of 65 years. 

Considerations for Age-Based Recommendations for 

Pneumococcal Conjugate Vaccine for Adults: GRADE of Evidence 

Tamara Pilishvili, MPH 

Respiratory Diseases Branch, 

National Center for Immunizations and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Pilishvili’s presentation focused on considerations for age-based recommendations for 13­

valent pneumococcal conjugate vaccine among adults. Invasive pneumococcal disease rates in 

adults have declined dramatically through indirect effects of the 7-valent conjugate vaccine use 

in children following 10 years of conjugate vaccine use among children. The incidence rate 

increases with increasing age and ranges from 8 cases per 100,000 among young adults to 68 

cases per 100,000 among adults 85 years of age and older [CDC, ABCs, unpublished, 2012]. 

Currently, 23-valent pneumococcal polysaccharide vaccine is recommended by ACIP for all 

adults 65 years of age or older and adults 19 through 64 years of age with chronic and 

immunocompromising conditions [Advisory Committee on Immunization Practices, MMWR 

2010]. 

The remainder of this session focused on reviewing the evidence to consider recommendations 

for the newly licensed 13-valent pneumococcal conjugate vaccine for adults. The working group 

applied the GRADE system to consider PCV13 recommendations for adults. The following 

steps were included in the process of evaluating a body of evidence and moving from evidence 

to recommendations: 

1. Formulate specific policy questions 

2. Identify and rank relative importance of outcomes 

3. Summarize relevant evidence for each outcome, including number needed to vaccinate 

(NNV), where possible 

4. Assess quality of evidence for each outcome 

5. Summarize quality of evidence across outcomes 

6. Review health economic data 

7. Assess the balance of risks and benefits 

8. Determine the recommendation category 

First, the working group formulated a specific question to be answered by a recommendation, 

“Should PCV13 be administered routinely to all adults 65 years of age or older?” The target 

population was defined as adults 65 year of age or older, the intervention was a 13-valent 

pneumococcal conjugate vaccine (PCV13) administered as a single dose injection, and the 

control group was 23-valent pneumococcal polysaccharide vaccine (PPSV23). The rationale for 

focusing the key question on adults 65 years or older was that the disease burden remains in 

this age group with 1.4 million hospital days due to pneumococcal pneumonia1

 and 

pneumococcal pneumonia contributes to 15,000 invasive pneumococcal disease cases and 

2,600 deaths2

; current ACIP universal recommendations target this age group; and a clinical 

trial evaluating the efficacy of PCV13 against pneumococcal pneumonia currently is on-going in 

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the Netherlands that targets this age group [1Huang et al . Vaccine 2011; 2Active Bacterial Core 

Surveillance, 2010]. 

The working group next identified and ranked the relative importance of health outcomes. In the 

selection of outcomes, the following questions were considered: 

 Which outcomes are important or critical for making a recommendation? 

 How important is each outcome to prevent? 

 Are data available to evaluate each outcome? 

Pneumococcal working members were queried and their responses were summarized. The 

working group members were asked to list relevant health outcomes, including both desirable 

and undesirable effects. Each member was asked to score the importance of each outcome. 

The average score for each outcome was used to determine the relative importance of each 

outcome. The possible options for summary ranking were: 

 Critical outcome: should be included in the evidence profile 

 Important but not critical: can be included in the evidence table if evidence for critical 

outcomes is missing 

 Not important for decision making: should not be included in evidence base 

The following outcomes were ranked as critical: invasive pneumococcal disease (IPD), 

pneumococcal pneumonia, hospitalizations, deaths, serious adverse events, and systemic 

adverse events. All critical outcomes were included in the evidence profile. Immunogenicity, 

office visits, local adverse reactions, and cost-effectiveness were ranked as important but not 

critical outcomes. From important outcomes, immunogenicity outcomes were included in the 

evidence profile because it was a criterion used for licensure and because data were missing for 

3 out of 4 critical outcomes. 

The working group next summarized relevant evidence for each outcome, including the number 

needed to vaccinate where possible, and assessed the quality of evidence for each outcome. 

For each outcome included in evidence profile, Dr. Pilishvili summarized the available evidence 

and assessed the quality of evidence. For the critical outcome of IPD, there was one doubleblind, randomized, placebo-controlled. This was an efficacy trial among HIV-infected adults in 

Malawi (N=496). All enrolled subjects had recovered from documented IPD. In this trial, the 

intervention was 2 doses of PCV7 given 4 weeks apart. The vaccine efficacy against PCV7­

serotype IPD was estimated at 74%. This estimate was statistically significant [French N, et.al. 

N Engl J Med 2010;362:812-22]. 

To answer the question regarding what effect might be expected based on these data among 

persons >65 years old in the US, the number of persons 65 years and older needed to 

vaccinate in order to prevent a single case of PCV13-type IPD was estimated. The rates of 

PCV13-type IPD were acquired from Active Bacterial Core surveillance data, which was the 

Rateunvaccinated (14 cases per 100,000 population1

). Efficacy against PCV13-type IPD was 

assumed to be 74% (30%, 90%)2

 based on the trial in Malawi, and the upper and lower 95% 

confidence intervals were applied to the unvaccinated rate in order to estimate the rate among 

vaccinated, and to estimate the number needed to vaccinate. According to these estimates, 

over 9600 people 65 years of age or older would need to be vaccinated in order to prevent a 

single case of PCV13-type IPD. [1

PCV13-type IPD rate among adults >65 years old in the US. 

CDC, ABCs, 2010; 2

French N, et.al. N Engl J Med 2010;362:812-22]. The caveat in this 

estimation is that the number needed to vaccinate is estimated based on efficacy versus 

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placebo. In the trial in Malawi, the comparison was a placebo. The number needed to 

vaccinate would be higher if compared to PPSV23. The results of the sensitivity analyses that 

were conducted using the 95% confidence intervals addressed some of these caveats. 

The body of evidence for each outcome was categorized into four types / four levels of quality 

which reflect the confidence in the estimated effect of vaccination on each health outcome: 

1. Randomized controlled trials, or overwhelming evidence from observational studies. 

2. Randomized controlled trials with important limitations, or exceptionally strong evidence 

from observational studies. 

3. Observational studies or randomized controlled trials with notable limitations. 

4. Observational studies with important limitations, or randomized controlled trials with 

several major limitations, or clinical experience and observations. 

RCTs initially are classified as evidence type 1, and observational studies as evidence type 3. 

Five GRADE criteria are used for moving down the quality of evidence: risk of bias, 

inconsistency, indirectness, imprecision, and publication bias. Indirectness was a major factor 

for moving down the quality of evidence for all outcomes included in this evidence profile. For 

the critical outcome of invasive pneumococcal disease, one RCT was included, which was 

downgraded from type 1 to type 3 due to indirectness. Evidence can be considered indirect in 

the following four situations: 1) the population that participated in studies may differ from the 

population of interest, 2) the vaccine that was evaluated may differ from the vaccine of interest; 

3) the outcome that was assessed may differ from that of primary interest; or 4) the primary 

interest is head-to-head comparisons of the 2 vaccines, but instead one vaccine was compared 

with placebo. For the IPD outcome and one RCT included in the evidence profile, the limitation 

due to indirectness was considered “very serious” due to the fact that the study was conducted 

in HIV+ adults in Malawi1

; the efficacy of 2 doses of PCV7 were evaluated when given 4 weeks 

apart; and, most importantly, the study included as a comparison group a placebo and not 

PPSV as in the policy question under consideration. Given that the efficacy of PPSV among 

older immunocompetent adults ranges from 50% to 80%2

 according to studies, the efficacy 

estimate of 74% would be an overestimate if it was employed as a comparison a group 

vaccinated with PPSV [1

French N, et.al. N Engl J Med 2010;362:812-22; 2ACIP 

Recommendations for PPSV23, 2010]. 

For the critical outcomes of pneumococcal pneumonia, hospitalizations, and deaths due 

pneumococcal disease, no data were available. The missing data on a critical outcome of 

pneumococcal pneumonia did not contribute to estimation of the overall quality of evidence, but 

was considered in decision making. Though there are no data available on the clinical efficacy 

of PCV13 against pneumonia in adults, the trial currently being conducted in the Netherlands is 

a randomized, placebo controlled trial in 85,000 community-dwelling, pneumococcal vaccine 

naïve adults ≥65 years. The primary objective of the study is to determine the efficacy against 

the first episode of vaccine serotype community-acquired pneumonia (CAP). The secondary 

objectives include efficacy against non-bacteraemic VT CAP and VT IPD, all pneumococcal 

CAP, and death. The results of this study are expected in 2013. 

Next, the working group reviewed evidence for the critical outcome of serious adverse events. 

The results of safety studies were included from PCV13 Phase III trials. Overall incidence of 

reported SAEs was low, ranging between 0.2% and 1.1%, with no differences reported between 

the treatment groups among both PPSV23 naïve and pre-immunized subjects. Death occurred 

in 16 subjects in the 8 studies, with more than 6000 subjects enrolled. None of the deaths were 

considered vaccine-related. Significant differences in the incidence of systemic adverse events 

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between the 2 treatment groups were reported in 2 out of 3 Phase III studies, for the outcomes 

of fatigue, rash, new generalized muscle pain, and use of medications to treat fever. A 

significantly lower proportion of these events occurred following PCV13 receipt compared to 

post-PPSV23 [Presented by Pfizer during the February 2011 ACIP meeting]. For the critical 

outcome of serious and adverse events, the evidence quality was judged to be type 1 because 

no serious concerns were noted due to biases, inconsistency, indirectness, or other 

considerations. 

Antibody response to PCV or immunogenicity was ranked as an important outcome. While 

demonstration of non-inferior immunogenicity was a major criterion for licensure, the lack of a 

correlate of protection in adults was an important limitation of the available studies to be able to 

use this outcome as a substitute for clinical outcomes. The studies included in the evidence 

base utilized different assays (ELISA versus. OPA) and analytic methods; and differed in 

populations studied by age group, presence of comorbidities, and previous vaccination status. 

In the evidence for immunogenicity outcome, 2 Phase III immunogenicity studies of PCV13 and 

4 published PCV7 studies were included. The detailed results of these studies were presented 

to ACIP by Pfizer during the February and October 2011 meetings. The first study (004) 

included 740 pneumococcal vaccine naïve adults 60 to 64 years of age. Comparisons between 

the treatment groups after a single dose of PCV13 versus a single dose of PPSV23 showed that 

PCV13 resulted in a statistically superior response compared to PPSV23 for 9/13 serotypes, 

and a response as good as that of a PPSV23 for 4/13 serotypes. The second study (3005) 

included 924 adults 70 years old or older who received PPSV23 >5 years prior. Comparisons 

between the treatment groups after a dose of PCV13 versus a dose of PPSV23 showed that 

response post-PCV13 was superior compared to PPSV23 for 11/13 serotypes, and response 

was as good as post-PPSV23 for 2/13 serotypes. 

Regarding the 4 published immunogenicity studies of PCV7 included in the evidence profile, in 

the studies by Goldblatt (2009) and deRoux (2008), comparisons between the treatment groups 

after a single dose of PCV7 versus a single dose of PPSV23 showed that PCV7 resulted in a 

statistically superior response compared to PPSV23 for some or most serotypes, and the 

response was as good as that of a PPSV23 for some serotypes. The studies by Ridda (2009) 

and Miernyk (2009) showed that response post-PCV13 was similar to PPSV23 for 4 out of 4 

serotypes evaluated. Comparisons for the remaining 3 serotypes were not done in these 

studies. For the outcome of immunogenicity, which included Phase III PCV13 studies and 

published immunogenicity studies of PCV7, the evidence quality was judged to be type 2. Lack 

of defined correlates of protection and the lack of clearly superior immunogenicity prevented the 

working group from extrapolating individual benefits used for licensure to population benefits 

needed for recommendations. 

The working group next determined the overall quality of evidence across all outcomes. The 

overall evidence type is a combined evidence type across all outcomes considered critical for a 

recommendation. Because only critical outcomes should be considered, in this case, quality of 

evidence for a single outcome of IPD determined the overall evidence quality. Data were not 

available for the three other critical outcomes, so the overall evidence type defaulted to the 

quality of evidence type for the IPD outcome, which is based on one study with limitations when 

applied to the key question under consideration. In spite of the vast amount of immunogenicity 

data evaluated, immunogenicity outcome was not considered to be critical, so the overall quality 

of evidence had to be based on one study and one critical outcome and the low quality of 

evidence for that outcome, so the overall evidence was judged to be type 3. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

The working group then reviewed results of health economic studies. There were two 

independent models that evaluated the cost-effectiveness and public health impact of PCV13 

for adults1,2. Both of these studies previously were presented to ACIP. These models showed 

that PCV13 in adults could be highly cost-effective. Both models relied heavily on assumptions 

about the indirect effects of PCV13 on non-bacteremic pneumonia and PCV13 efficacy against 

pneumonia. The current PPSV strategy is favored if PCV13 effectiveness is low against nonbacteremic pneumonia. The results were sensitive to assumptions regarding PCV13 

effectiveness against non-invasive pneumonia, PPSV effectiveness against IPD and herd 

immunity effects on the likelihood of PCV13-type disease [1

Smith et al. JAMA 2012 in press; 

2

Weycker et al. Manuscript in preparation]. 

Next, the working group assessed the balance of risks and benefits and determined the 

recommendation category. The answers to the following 4 questions were considered to 

determine the recommendation category, and the working group members reached a general 

consensus on the answers to each of these questions: 

1. Is the quality of available evidence considered to be lower? The working group concluded 

that the evidence is of low quality due to limited data on efficacy against IPD (only one RCT 

in HIV+ in Malawi, and placebo-controlled) and missing data on PCV efficacy against other 

critical outcomes, in particular against non-invasive pneumonia. 

2. Is there uncertainty about the balance of benefits versus harms? The working group 

concluded that uncertainty existed because indirect effects of PCV13 use in children may 

reduce the potential net benefits of PCV13 use in adults, and there is uncertainty about 

PCV13 effectiveness against non-invasive pneumonia in adults. 

3. Is there high variability or uncertainty in relative importance assigned to outcomes? There 

was low variability and no uncertainty in relative importance assigned to health outcomes. 

The working group members assigned high values to all the critical outcomes, and there 

was a consensus reached on which outcomes were considered critical to prevent. 

4. Is there uncertainty about whether the net benefits are worth the costs? The working group 

felt that there was an uncertainty about whether the net benefits are worth the costs. 

After considering the answers to the above questions, the working group reached a consensus 

that no recommendation would be issued at this time for routine PCV13 use among older adults 

because critical data to help with decision making are not yet available. 

In addition to the outcomes evaluated, the working group also considered an additional and very 

important key factor that is not clearly accounted for by GRADE process; that is, the indirect 

effects of pediatric PCV13 program may reduce the proportion of adult IPD caused by PCV13 

types, and that the net benefits of PCV13 use among adults would be reduced. 

With regard to trends in incidence of IPD among adults 65 years of age and older, introduction 

of the 7–valent conjugate vaccine in children in the late 2000 has led to near elimination of IPD 

caused by PCV7 types among adults. Incidence of IPD caused by 6 serotypes has increased. 

The 13-valent vaccine replaced the 7-valent for use in children in mid-2009. This raises the 

question regarding what should be expected in terms of the potential indirect effects of PCV13 

use. The early effects of pediatric use of PCV13 on rates of IPD among young children are 

already being observed. Comparing the rates of IPD caused by PCV13 serotypes in the 

quarters after PCV13 introduction to average rates of IPD before PCV13 introduction, by the 

beginning of 2011, statistically significant reductions were already observed in the incidence of 

PCV13-type IPD. These data demonstrate that the 13-valent conjugate vaccine is working as 

expected in children [Active Bacterial Core surveillance (ABCs), unpublished]. 

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The early impact of pediatric PCV13 program on disease rates among adults was also 

examined among adults by age group. Although it may still be early to expect significant 

reductions in adult IPD, among adults 65 years of age and older for most calendar quarters in 

2010-2011, compared to the same quarters before PCV13 introduction (2006-2008), some 

reductions were observed. However, these changes were not statistically significant. Among 

adults 18 through 49 years of age, more consistent reductions are being observed for all 

quarters by late 2010 and for all quarters in 2011. This was expected, given that the earliest 

reductions post-PCV7 implementation were observed among adults in this age group. 

In summary of what should be expected in terms of the indirect effects of PCV13 on invasive 

disease, it is known that PCV7 introduction led to near elimination of PCV7-type IPD among 

adults of all age groups. There were significant declines in PCV13-type IPD in children within 

the first year post-PCV13 introduction. There is possible early evidence of declines in PCV13­

type IPD in adults. Recent data show that PCV13 prevents colonization with PCV13 

serotypes1,2. A key point is that indirect effects of PCV13 on adult IPD are likely to be observed 

[

1

R. Cohen, ICAAC 2011; 2A. Desai, ISPPD 2012]. 

The working group concluded that at this time, the available evidence is insufficient to 

recommend routine use of PCV13 among older adults, and that the critical data elements 

needed to make a recommendation are not available at this time. The impact of indirect effects 

of PCV13 use in children on serotype distribution of adult pneumococcal disease is unknown 

and there are no data on the clinical efficacy of PCV13 against non-invasive pneumonia in 

adults. Despite the vast number of immunogenicity studies showing that PCV13 is 

immunogenic in adults, the clinical relevance of these data is not clear without defined 

correlates of protection. Cost-effectiveness studies show that PCV13 may be cost-effective 

when used among adults; however, the studies rely heavily on assumptions of efficacy against 

pneumonia and potential herd effects of the pediatric PCV13 program. 

In terms of next steps, the Pneumococcal Working Group will continue to evaluate the relevant 

data as these become available, and will continue updating the committee during the upcoming 

ACIP meetings. Within the next month, the working group will publish a brief note in the MMWR 

to inform readers about the licensure of the vaccine for adults 50 years of age and older; 

summarize the available evidence which led to the licensure of the vaccine; outline the working 

group decision to wait with universal adult recommendations until more evidence is available; 

and outline plans for future ACIP deliberations. The working group will revisit the question of 

age-based recommendations as additional data become available. 

Discussion Points 

Dr. Keitel called attention to steps 7 and 8 for determining the recommended category, “Is there 

uncertainty about the benefits versus harms and burdens?” She wondered whether the working 

groups should view this in the context of PCV13 versus PCV23. One way to look at this is that if 

PCV13 is used, adults may be left unprotected against serotypes that are not contained in 

another vaccine that has shown efficacy against invasive pneumococcal disease. She also 

requested that Dr. Pilishvili comment on the CAPTA trial for the US where children are routinely 

immunized for PCV13. 

Dr. Pilishvili replied that the CAPITA trial would offer key information regarding the efficacy of 

13-valent vaccine against non-invasive pneumonia. There is more consensus that the currently 

licensed 23-valent polysaccharide vaccine is effective in preventing invasive disease, but there 

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is definitely less consensus that the vaccine is effective against non-invasive pneumonia. Noninvasive pneumonia accounts for a higher burden of disease, especially in the age groups of 

interest. This is where the effect on the net benefits came into play in the working group’s 

decision making, that if efficacy is shown against non-invasive pneumonia, the net benefits 

would clearly be larger and would outweigh the harms and burdens. 

Dr. Sawyer asked whether the level of evidence would need to be downgraded based on the 

indirectness of the evidence in the Netherlands to the population in the US. 

Dr. Pilishvili responded that one of the strongest points for downgrading evidence with respect 

to the Malawi trial was the comparison group for the outcome of invasive disease. The working 

group believed that the comparison group of a placebo would clearly over-estimate the efficacy 

if it was compared to PPSV23. That is because there is evidence to suggest that PPSV23 may 

be as effective as 50% to 80% against invasive disease. There is less consensus that PPSV23 

will be efficacious against non-invasive pneumonia. So, having that placebo comparison in a 

trial with a pneumonia endpoint would be less of a limitation and would not lead to downgrading 

of the evidence. 

Dr. Baker inquired as to whether the Netherlands has the same schedule as the US for PCV13 

for children. This could be confounding. 

Dr. Whitney from the Reparatory Diseases Branch (RDB) replied that the Netherlands has good 

vaccine coverage of children, and they have been switching from vaccine to vaccine. They 

began with PCV7 and were now on PCV10. The situation would be somewhat similar in that 

they use a 2+1 schedule, and they have good coverage with even the third dose, so it is a 

similar population. 

Dr. Poland (ACP) noted that one other factor to consider is that the studies referenced for 

efficacy were in relatively short time periods after immunization. The problem suffered in adult 

medicine with use of the polysaccharide vaccine is that with few exceptions, adults receive the 

vaccine one time. If they live to 85 years of age, this leaves 20 years of hoping that a 

polysaccharide vaccine is going to protect them. This is not modeled in the data presented by 

Pilishvili and was not likely to be addressed by the study mentioned. 

Dr. Pilishvili said she presumed Dr. Poland was referring to the immunogenicity studies that 

were included with the comparisons of one vaccine to the other. The follow-up period is 4 to 6 

weeks, which is a relatively short period of time. The data from the Phase III trials of PCV13, 

which also had comparisons between the 13-valent vaccine and PPSV23, show that the 

antibodies do come down following each vaccine, more so for one than the other. It remains 

unknown how the antibody level translates into clinical protection, and whether one is more 

likely than the other to continue to offer protection. 

Given the complicated issues, Dr. Duchin emphasized the need to continue to conduct studies 

after vaccines are licensed. For example, he could imagine that a vaccine like PCV13 may 

protect against invasive disease and, with luck, against non-invasive pneumococcal pneumonia 

in the first few years after vaccination. Subsequently, susceptibility to non-invasive 

pneumococcal pneumonia may return. Therefore, following these patients out for a number of 

years is desirable. 

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Dr. Tan (AMA) emphasized that one way the evidence is developed is when a vaccine is used. 

Therein lies a certain amount of paradox. He asked Dr. Pilishvili to comment on any other 

studies that would shed light on the age group 50 years and older with regard to PCV13. He 

also requested that she comment on the data that the working group reviewed versus what the 

FDA reviewed with regard to their approval of the indication of 50 years of age and older. There 

does not seem to be a clear timeline. There is an FDA-approved vaccine for 50 years of age 

and older that physicians are beginning to hear about, but there is no ACIP recommendation 

that is clearly visible coming down the pipeline. It would be helpful to inform physicians. 

Dr. Pilishvili replied that data the FDA used to license the vaccine is the same that the working 

group has been evaluating over the past year, and is the same data that was included in the 

evidence base. For the particular key question the working group was considering for GRADE, 

only a subset of data was extracted to address a single dose of one versus the other. That is, 

while only a subset of the data was used for GRADE, the working group did review all of the 

data that was presented to FDA for licensure. The working group is aware of the fact that the 

vaccine is licensed, but at the same time feels that ACIP’s role is to use the evidence in order to 

develop the best recommendations for use of the vaccine that will result in the maximum public 

health impact. The working group does not feel at this time that there is sufficient evidence to 

recommend the vaccine. Regarding the question about forthcoming data on the 50 and older 

age group, the studies presented to the working group from the FDA included this age group. 

The rationale was presented for why the working group focused on 65 years of age and older, 

but even if they had evaluated the same question for those 50 years of age and older, the same 

evidence base would have been used and that would not have changed the conclusion of the 

working group in terms of the age-based recommendations. Regarding on-going studies, the 

two key pieces of evidence that are missing are the CAPITA trials in the Netherlands for which 

there should be data in 2013, and the herd effects data that will continue to be evaluated 

through ABCs data. This is more or less real-time data from which the impact of the pediatric 

PCV13 program can be observed on the change in distribution on the serotypes causing adult 

disease. 

Dr. Baker requested clarification about whether by “non-invasive pneumonia” Dr. Pilishvili meant 

pneumonia that is not accompanied by bacteremia, given that pneumonia by definition is 

invasive. Dr. Pilishvili answered affirmatively. 

Dr. Paradiso (Pfizer) reported that the Netherlands uses the PCV10 vaccine from GSK. They 

began with PCV7 and transitioned to PCV10. It is an infant program, but it is not with Prevnar 

13®, so there would be less herd effect in that population. Regarding the issue of placebo 

control trials in some of these populations, the trial that was conducted in Malawi by Dr. French 

was a follow-up to a trial that was conducted in Uganda with the polysaccharide vaccine, also in 

an HIV-positive adult population, 5 or 6 years prior to that. The Uganda trial actually showed 

negative efficacy of the polysaccharide vaccine; that is, it was worse to receive the 

polysaccharide vaccine than to not. When Dr. French decided to conduct the trial with PCV7, it 

was not possible to use a polysaccharide control in that group because it was considered 

unethical by the ethics committee, so it had to be a placebo controlled trial. While there is not a 

direct comparator in that trial, it was conducted by the same investigator and was fairly 

comparable to that. In those 65 years of age and older, morbidity from pneumonia and 

hospitalizations and invasive disease is quite substantial. The majority of people in that age 

group already have been vaccinated with a polysaccharide vaccine, and there is currently no 

recommendation for them to be revaccinated. Dr. Paradiso suspects that at least 50% of 

disease in that population is in that group, because it includes many of people who were 

vaccinated at some point. The data from the 3005 trial shows the immunogenicity, both priming 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

and boosting, of the conjugate of vaccine in this population of people over 65 years for which 

there is not currently a recommendation. He was interested in knowing whether the working 

group considered this to be a high risk population. Because there is not a recommendation, 

there is not a comparator since that group is at risk. The data Pfizer presented during the last 

ACIP meeting pertained not only to the quantity of immunogenicity following a dose, but also to 

the quality of that response. The quality of the response observed with the conjugate vaccine 

has been demonstrated repeatedly in terms of protection against invasive disease and 

pneumonia, with response that are quite comparable to what is observed in children and adults 

with efficacy. 

Dr. Pilishvili responded that the working group considered all adults and assessed those at 

highest risk. Among the general population of adults, those 65 and older and even 85 and older 

are at higher risk. However, in terms of the herd effects of PCV7 use, those 65 and older and 

85 and older have benefitted as well. In terms of the gaps, the next presentation by Dr. Dooling 

would show the rationale as to why, based on the burden of disease and the potential herd 

effects that are expected in various groups, adults with immunocompromising conditions are 

clearly at a much higher risk. Those 65 years of age and older do benefit from herd effects, and 

are at medium risk compared to those with immunocompromising conditions. Adults with 

immunocompromising conditions will be the next focus of the working group. 

Dr. Paradiso (Pfizer) said his point was that this was the only group that would benefit from the 

herd effect over time, even though the burden is current. 

Dr. Pilishvili replied that those 65 years of age and older are expected to benefit from herd 

effect, but that is not the only consideration for waiting. The other consideration for waiting is 

lack of data on efficacy against pneumonia. 

Regarding Dr. Paradiso’s comments about the quantity and quality of the antibody response, Dr. 

Baker requested clarity regarding whether he was assuming functionality measured by OPA. 

Dr. Paradiso (Pfizer) replied that it was all based on functionality measured by OPA. The 

response to the first dose wanes over time and then boosts either by a second dose of the 

conjugate or a dose of polysaccharide. Giving conjugate vaccine before PPS23 results in a 

much better response to the polysaccharide vaccine. 

Dr. Keitel added that the data appeared to show that the boost with the polysaccharide results in 

a significantly better response than with a second dose of conjugate. 

Dr. Paradiso (Pfizer) responded that a first dose is given of the conjugate followed by a dose of 

either the conjugate or the polysaccharide 3 or 4 years later. With a second dose of conjugate, 

the response was at least as good as the first dose and for the majority was higher. With a 

second dose of polysaccharide, the response was the same only it was even higher than the 

booster response to the conjugate vaccine for half a dozen or so subjects. This is probably 

because the first dose primed for memory cells and booster response, which was then followed 

by 25 mg of polysaccharide, which is a large bolus that really boosts the immune response to 5 

to 10 times more than would have been achieved with the polysaccharide and much more than 

two doses of polysaccharide. 

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Following up on what Dr. Tan said, Dr. Decker noted that the working group has been very 

thorough and very careful, which is commendable. However, he was struck by the fact that 

nevertheless, life goes on in medical practices in which people present at age 65 every day and 

are given polysaccharide vaccines which are known to exhaust the B-cell component, will 

provide short-term protection, and will render them incapable of boosting. Meanwhile, there is a 

conjugate vaccine in the marketplace. Although the conjugate covers only 13 of the 23 

serotypes, with respect to at least those 13 serotypes, it will amplify rather than destroy the Bcell component and will enable them to be boosted. He was very troubled by not giving clearcut guidance as early as possible about this, because the polysaccharide vaccines are 

wonderful when that is all there is, but once the conjugates became available, he did not think 

they should be using the polysaccharides. 

Dr. Baker requested that Dr. Sun comment on the presentation on pneumococcal conjugate 

vaccine and accelerated approval through the FDA for licensure or approval. 

Dr. Sun (FDA) indicated that there are really only three ways that vaccines are approved in the 

US: 1) traditional approval, 2) accelerated approval, and 3) an animal rule. No vaccines have 

been approved by animal rule yet. A number of vaccines have been approved through 

accelerated approval, all of which were influenza vaccines. During the shortage, this 

mechanism supported the increase of the number of available vaccines on the market. 

Approval of Prevnar 13® in those 50 years of age and older is the first bacterial vaccine to be 

approved under the accelerated mechanism. In order to apply for accelerated approval, a 

vaccine has to address a serious and life-threatening illness, which pneumococcal pneumonia 

and invasive disease in the elderly are. It also has to offer a meaningful therapeutic benefit over 

existing treatment. The existing treatment in this case is Pneumovax 23®, and its effectiveness 

against bacteremia pneumonia is controversial. The study conducted must be adequate and 

well-controlled study demonstrating safety and effectiveness based on a surrogate. This is a 

departure from what has been done with previous bacterial vaccines. In this case, the surrogate 

is an immunologic assay, which is a functional assay. The FDA has determined that this is 

relatively likely to predict clinical benefit. It is not an absolutely correlated. As part of the 

approval, the manufacturer is required to conduct a clinical endpoint study with due diligence. 

Usually, these studies are already on-going at the time of the approval, which is true in this 

case. The overall point is that if a vaccine is approved under this mechanism, in the GRADE 

system, it will not have the typical clinical data that shows prevention of disease. This may be 

an issue for ACIP. 

Dr. Schaffner (NFID) requested information about what would occur if a clinical trial cannot be 

completed for some reason or does not demonstrate efficacy. 

Dr. Sun (FDA) replied that the FDA has the authority to withdraw the approval. 

Dr. Pickering asked whether this approval pathway would ever be used for a vaccine that does 

not have clinical data in a population. 

Dr. Sun (FDA) replied that this would depend upon the surrogate. This is a mechanism to 

approve vaccines for which there are no clinical endpoint data. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

13-Valent Pneumococcal Conjugate Vaccine Use in Adults 

With Immunocompromising Conditions: GRADE of Evidence 

Kathleen Dooling, MD, MPH 

Respiratory Diseases Branch 

National Center for Immunization & Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Dooling’s presentation focused on considerations for use of 13-valent pneumococcal 

conjugate vaccine among adults with immunocompromising conditions. The policy question 

considered by the working group was, “Should ACIP recommend 13-valent pneumococcal 

conjugate vaccine (PCV13) for immunocompromised adults?” Given that the working group 

consensus was to wait for additional evidence before making an age-based recommendation, a 

question regarding why a risk-based recommendation might be made at this time might arise. 

There are three reasons to consider a recommendation for PCV13 for immunocompromised 

persons at this time. The first reason is the very high incidence of invasive pneumococcal 

disease in adults with immunocompromising conditions. Individuals with hematological cancer 

and HIV/AIDS have the highest risk for IPD, with over 20-fold increased rates of disease 

compared to persons without these conditions. The second reason to consider a risk-based 

recommendation is that these data demonstrate high rates of disease for immunocompromised 

persons despite the indirect effects of PCV7. Rates of PCV7-type IPD in this population are 

several-fold higher than those among immunocompetent persons. Finally, in contrast to the 

age-based policy question for which a clinical trial is pending, in HIV-infected patients there is 

already a published clinical trial and no additional data are expected in the near future. 

The GRADE process followed by the working group to evaluate evidence for this question was 

the same as that presented in the previous presentation. To reiterate, first, the working group 

formulated a specific policy question and then identified and ranked the relative importance of 

the outcomes. Next, summarized all evidence for critical and important outcomes was 

summarized, including number needed to vaccinate where possible, and assessed the quality of 

evidence for each outcome. Once that was complete, the working group summarized the 

quality of evidence across all outcomes. After a review of health economic data, the next step 

was to assess the balance of risks and benefits and determine the recommendation category. 

As previously noted, the policy question to be GRADED was, “Should PCV13 be administered 

routinely to adults with immunocompromising conditions?” The population under consideration 

was adults 18 years of age and older with immunocompromising conditions. The intervention 

the working group evaluated was PCV13 administered as a single dose. The control or 

comparison group was PPSV23 recipients. 

The next step was to decide which disease outcomes should be considered and the relative 

importance of preventing each of them. The working group agreed that IPD, pneumococcal 

pneumonia, hospitalizations, deaths, and serious and systemic adverse events were all 

outcomes of critical importance. Unfortunately, as with the previous presentation, there were no 

data available to evaluate pneumococcal pneumonia, hospitalizations, or deaths. Although 

immunogenicity was deemed by the working group to be important, but not critically important, it 

was included in the evidence profile. 

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The next steps in the GRADE process were to summarize all existing evidence for critical and 

important outcomes, including number needed to vaccinate where possible, and then to assess 

the quality of evidence for each outcome. Dr. Dooling repeated these steps for each of the four 

outcomes considered. 

As previously indicated, there was only one study that evaluated the critical outcome of IPD 

defined by isolation of pneumococcus from a normally sterile site. This was a double-blind 

randomized placebo-controlled trial among HIV-infected adults in Malawi. All 496 enrolled 

subjects had recovered from documented IPD. Study participants were given 2 doses of PCV7 

4 weeks apart as opposed to the GRADE intervention of 1 dose of PCV13. The vaccine 

efficacy against PCV7 serotype IPD was 74%, and this was statistically significant [French N, 

et.al. N Engl J Med 2010;362:812-22]. 

In order to calculate the number needed to vaccinate, the working group applied the efficacy of 

PCV7 from the Malawi RCT to the US incidence of IPD in HIV-infected adults. An estimated 

rate of 64 IPD cases with HIV/100,000 persons with AIDS was used based on 2007 data. 

Assuming 74% efficacy and 100% coverage, the working group estimated a rate of 17 cases 

per 100,000 in vaccinated HIV-infected people. Therefore, the estimated number needed to 

vaccinate to prevent one IPD case would be 2011. 

The fourth step in the GRADE process is to assess the quality of evidence for each outcome. 

RCTs or overwhelming evidence from observational studies are considered the highest level of 

evidence and are scored as a 1. RCTs with important limitations or exceptionally strong 

evidence from observational studies are scored as a 2. RCTs with notable limitations or 

observational studies are given a 3. RCTs with several major limitations, observational studies 

with important limitations, or clinical experience and observations are given the lowest grade of 

4. 

In order to grade the evidence type for the critical outcome of IPD, several factors were 

considered. There were no serious concerns with study design, bias, or imprecision. The 

working group felt that there were very serious concerns, however, with indirectness or 

generalizability of the results because the population studied was in Malawi, only IPD survivors 

were recruited for the study, and only 13% of the participants were on anti-retroviral therapy. 

Additionally, PCV13 is licensed for a single dose in adults in the US and the intervention used in 

the study was 2 doses of PCV7. Recall that the initial policy question concerned all 

immunocompromised adults; therefore, the working group had additional concerns with 

extrapolation of the Malawi trial results to HIV negative immunocompromised population. 

The next critical outcome evaluated was serious adverse events. As presented in the previous 

presentation, Phase III studies found only 0.2 to 1.1% serious adverse events, with no 

difference between treatment arms and no deaths considered to be vaccine-related. These 

results are also from Phase III trials presented previously, and there was no increased incidence 

of systemic adverse effects in PCV13 recipients. In fact, there was a significantly reduced risk 

of fatigue, rash, generalized muscle pain, and treated fever in PCV13 recipients compared to 

PPSV23 recipients [Phase III studies, presented at February 2011 ACIP]. 

In addition to the Phase III trials, immunogenicity and adverse events of the 7-valent conjugate 

vaccine have been evaluated in published RCTs. The three studies considered (e.g., 

Penaranda, Lesprit, and Feikin) showed no statistically significant difference in systemic 

adverse events following immunization. 

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To evaluate the quality of evidence for the critical outcome of serious and systemic adverse 

Events, 6 RCTs were considered in total. The only serious concerns involved indirectness 

because the Phase III clinical trials were not done in an immunocompromised population and 

the published studies were done using the 7-valent conjugate vaccine as opposed to the 13­

valent vaccine. 

The working group next went on to grade the important outcome of immunogenicity. Four 

published studies in HIV-positive subjects were considered. All studies were conducted in high 

income countries with subjects who had CD4 counts of at least 200. Response to a single dose 

of PCV7 was non-inferior or superior to PPSV23 at all time points studied [Feikin 2004, USA; 

Lesprit 2007, France; Penaranda 2010, Spain; Crum 2010, USA]. 

The randomized controlled trials of immunogenicity were used for FDA licensure and were 

presented in the previous talk (e.g., 004 and 3005). They show that in the HIV-uninfected adults 

over 60 years old, PCV13 is equal to or better than PPSV23 in generating antibodies to the 

serotypes they share [Presented by Pfizer at February 2011 ACIP]. 

Thus, the quality of evidence for the important outcome of immunogenicity varied based on the 

population under study. The 4 published immunogenicity studies used PCV7 instead of PCV13; 

therefore, the working group had serious concerns regarding the indirectness of the 

intervention. The Phase III trials were not carried out in an immunocompromised population; 

therefore, the working group had very serious concerns about the indirectness of the study to 

the population of interest. All studies suffered from the absence of an established clinical 

correlate of protection. Ultimately, the evidence type assigned by the working group for this 

outcome was 2 and 3. 

Having considered the quality of the evidence for each outcome, the working group next 

summarized the quality of evidence across all outcomes. The quality of evidence for all 

outcomes considered ranged from 2 to 3. For the critical outcome of IPD, the evidence type 

was 2 / 3. Therefore, the working group assessed the overall evidence type to be 2 / 3. 

The next step in the GRADE process was to review the health economic data. As presented 

previously, the economic models demonstrate that PCV13 could be cost-effective, but the 

models are sensitive to assumptions regarding PCV13 effectiveness against non-invasive 

pneumonia, PPSV effectiveness against IPD, and indirect effects. No models have considered 

the immunocompromised population specifically. 

The final steps the working group completed included an assessment of the balance of risks 

and benefits of vaccination and a determination of the recommendation category. In order to 

determine the recommendation category, the working group considered 4 questions: 

1. Is the evidence quality “Lower“? Yes. The working group thought that the very serious 

concerns with indirectness, as well as a lack of evidence for critical outcomes, meant 

that the overall level of evidence was low. 

2. Is there uncertainty about the balance of benefits versus harms and burdens? No. The 

working group agreed that the very high burden of disease in the immunocompromised, 

despite the indirect effects from PCV7, demonstrates the potential for a net benefit from 

PCV13 use in the immunocompromised population. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

3. Is there variability or uncertainty in what is important? No. The working group reached 

consensus regarding critical outcomes. 

4. Is there uncertainty about whether the net benefits are worth the costs? Yes. In this 

case, there is still uncertainty regarding the cost-effectiveness of PV13 relative to 

PPSV23. 

Ultimately, these considerations led the working group to propose a Category B 

recommendation meaning that the desirable consequences probably outweigh the undesirable 

consequences. 

The working group concluded that there remains an extremely high burden of pneumococcal 

disease among immuocompromised adults. The GRADE process led the working group to 

conclude that PCV13 is effective in this group and that benefits likely outweigh harms. Unlike 

age-based recommendations, no additional RCT data is expected to influence GRADE 

conclusions for the immunocompromised group. Finally, the indirect effects of PCV13 use in 

children are unlikely to eliminate PCV13 serotypes from the immunocompromised adult 

population. 

The next steps for the working group include grading of the evidence for PCV13 followed by 

PPSV23 compared to PPSV23 alone. They must also address the issues of timing and interval, 

as well as the optimal sequence, if two pneumococcal vaccines are to be recommended for this 

population. Additionally, the working group must reach consensus regarding exactly which 

conditions shall be considered immunocompromising. Before the next ACIP meeting in June 

2012, the Pneumococcal Working Group plans to draft recommendation language for a possible 

vote. 

Dr. Dooling concluded with the following questions for ACIP members: 

 Do ACIP members agree with the working group’s GRADE evaluation of the evidence 

supporting a recommendation for use of PCV13 in immunocompromised adults? 

 What additional issues should the working group consider before bringing a 

recommendation for a vote? 

Discussion Points 

Dr. Baker inquired as to whether a cost-effectiveness analysis had been done for this group, 

and if not whether there was a plan to do so by the June 2012 ACIP meeting. 

Dr. Dooling replied that a cost-effectiveness analysis had not been undertaken for the 

immunocompromised population specifically. One thing that would vary in this group would be 

the increased incidence of disease, but the model would likely still be sensitive to several 

factors, including PCV13 effectiveness against non-invasive pneumococcal pneumonia; 

PPSV23 effectiveness against IPD, which has certainly had mixed results in the literature; and 

the indirect effects that are likely to have some effect in reducing disease in the 

immunocomprised population, but certainly not in eliminating disease. There is no plan to 

conduct a cost-effectiveness analysis before the June 2012 ACIP meeting, but this could be 

taken into consideration. 

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Regarding the critical outcome of IPD and vaccine efficacy of 74%, Dr. Coyne-Beasley pointed 

out that the confidence interval for vaccine efficacy was between 30% to 90%, which is quite 

large. She wondered whether the working group varied its assumptions based on what the 

efficacy could be, and whether this would change their final recommendation. 

Dr. Dooling replied that the confidence interval does vary from 30% to 90% around the point 

estimate of 74%. There were only 493 participants in the trial; therefore, the power effects led 

to a large confidence interval. The number needed to treat on the two broad ends of the 

confidence interval were not presented, but the range was shown on Slide 11: NNV = 2,011 

(1,736 to 5,208). The recommendation did not change based on the range. 

Dr. Sawyer asked Dr. Dooling to help him understand the expected impact of indirect effect in 

the immunocompromised adult population compared to the 65 and older population, and 

whether that was based on the observations with PCV7 indirect effect or if it was a theoretical 

consideration. 

Dr. Dooling responded that there was a study by Cohen et al that shed light on that particular 

question. This study compared adults with HIV infection to adults without HIV infection following 

the introduction of PCV7 in 2000. There was a fairly precipitous decrease in all serotype 

disease, but primarily in the conjugate vaccine serotype disease in adults with and without HIV 

infection [Cohen, AIDS 2010;24(14):2253-62]. In 2007, after the indirect effects are presumed 

to have been fully realized, the incidence in HIV-infected individuals was still 64 / 100,000; 

whereas, in the adult population without HIV infection, the incidence had decreases to nearly 

non-existent for vaccine serotype disease. 

Regarding whether there were other considerations for the working group, Dr. Poland (ACP) 

indicated that the American Society of Hematology (ASH) has a group that issues bone marrow 

transplant guidelines; that group already has recommended PCV13. Most tertiary care medical 

centers that are doing high volume solid organ transplants already have this as part of their 

protocols. There is at least one professional society that will soon release some 

recommendations. At a minimum before June 2012, it would be helpful for ACIP to offer some 

interim guidance with a layout of the data and evidence, even if it is to acknowledge that a 

decision will be made in the June timeframe. 

Dr. Middleman (SAHM) wondered whether the population was ≥18 or ≥19, because there is 

already a recommendation for those through the age of 18. 

Dr. Dooling replied that the pediatric recommendations include high risk people up to 19 years 

of age. The working group will make sure that this is clear and is not overlapping. 

Dr. Keitel asked Dr. Poland whether the groups he mentioned made any comments about the 

use of 23-valent vaccine relative to the PCV13 vaccine. 

Dr. Poland (ACP) responded that while he could not speak to all of them, ASH did. ASH has a 

series, following a bone marrow transplant, of PCV13 and PPSV23. 

Dr. Baker added that her understanding was similar, but that there were differences between 

centers. 

Dr. Foster (APhA) said he was not getting a clear picture of the serotypes that cause disease in 

the over 64 year old age group. 

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Dr. Dooling replied that the serotype distribution is slightly different for the HIV-infected and nonHIV-infected groups. As with other populations, 19A has emerged as the most common strain. 

For people living with HIV, the proportion of IPD due to serotypes in PCV13 is about 39%, while 

disease due to all PPV23 serotypes accounts for approximately 57%. Disease caused by a 

serotype not in either vaccine is about 43%. Importantly, PCV13 has the potential advantage of 

preventing IPD caused by serotype 6C. The serotype 6A antigen, which is included in PCV13 

but not in PPV23, has recently been shown to cross-react with serotype 6C. Therefore, it is 

possible that PCV13 could provide protection against an additional 8% or if cross-coverage is 

good [Cooper, Vaccine 2011;29(41):7207-11)]. The following represents the rank order 

serotype distribution of the top 16 serotypes: 

Dr. Foster (APhA) said his assumption was that they were talking about using this in addition to 

rather than in place of 23-valent PPSV. 

Dr. Dooling replied that those options are up for consideration. 

Dr. Baker said that given that final recommendations had not been made, she assumed the 

working group was talking about the use of PCV13 followed by PPSV23 vaccine. 

Dr. Dooling replied that one of the next steps is to grade the evidence for PCV13 plus PPSV23 

versus PPSV23. 

If feasible, Dr. Baker said that it would be nice with the recommendation to see some influence 

on cost-effectiveness for this population. For example, for meningococcal vaccine in 2 to 10 

year olds, the number of 2 to 10 year olds at risk for a very terrible disease is quite small; 

however, the benefit is quite great. Therefore, the cost is quite reasonable because the 

population is so small. 

Dr. Bennett was curious about the cost-effectiveness analyses that have been done and 

whether sub-group analyses were included within those to address the immunocompromised 

population. 

Dr. Dooling said she was not aware of any sub-group analyses that had been done for the 

immunocompromised group. 

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Discussion 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Dr. Loehr (AAFP) asked for clarification regarding whether the number needed to vaccinate in 

Dr. Dooling’s presentation of 2011 was a sub-group of the 10,000 indicated in Dr. Pilishvili’s 

presentation. 

Dr. Dooling replied that it was not. Those were both number needed to vaccinate evaluations 

for which the efficacy was based on the Malawi trial, and the underlying rates of disease were 

both independently ascertained from the surveillance data and studies. 

Dr. Loehr (AAFP) said for himself and others who recently have joined ACIP, he would be 

interested in knowing the number needed to vaccinate for other common vaccines and whether 

this was comparable to give him some reference points. 

Dr. Baker emphasized that the cost-effectiveness analysis would also help everyone better 

understand comparability to other vaccines. The population at risk may be such that it is quite 

reasonable to bear the costs. 

Dr. Zimmerman reported that he and his colleagues had a study published that day titled “CostEffectiveness of Adult Vaccination Strategies Using Pneumococcal Conjugate Vaccine 

Compared With Pneumococcal Polysaccharide Vaccine.” This study is of a cohort of 50 year 

olds that was followed to death. Within this cohort, subjects developed immunocompromising 

conditions. While a sub-group analysis was not done only of immunocompromised persons, the 

cohort includes them as they age, develop immunocompromising conditions, and often pass 

away [Kenneth J. Smith; Angela R. Wateska; Mary Patricia Nowalk; Mahlon Raymund; J. Pekka 

Nuorti; Richard K. Zimmerman JAMA 2012;307 804-812]. 

Dr. Middleman (SAHM) did not remember all of the GRADE information for the younger 

populations, but it sounded as though people were thinking about recommending this for 

immunocompromised adults. It is worded as a clinical permissive for younger adolescents, so 

she wondered whether there were plans to assess younger adolescents to determine whether a 

unified recommendation could be made to make this easier for providers. 

Dr. Dooling thought this was a great suggestion, pointing out that there is an off-label permissive 

recommendation for the pediatric population aged 6 to 18 years of age. The working group will 

find as many commonalities as possible to make the recommendation easier for providers. 

Hepatitis B Vaccine 

Introduction 

Mark Sawyer, MD, Chairman 

Hepatitis Vaccine Working Group 

Dr. Sawyer indicated that having completed the work that was voted upon during the last ACIP 

meeting regarding Hepatitis B (HepB) vaccination of adults with diabetes mellitus, the Hepatitis 

Vaccine Working Group has begun to address a new term of reference, which is to ensure 

hepatitis B protection for healthcare personnel (HCP), including trainees, who may have 

received hepatitis B vaccination in the remote past, without having had post-vaccination 

serologic testing. This term of reference will not cover the overall long-term protection by 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Hepatitis B vaccine, except as related to waning hepatitis B surface antibody levels among 

healthcare personnel. It also will not cover management of healthcare personnel who are 

known to be hepatitis B surface antigen positive (e.g., those with chronic infection), as 

management of known hepatitis B surface antigen-positive healthcare personnel does not 

involve an immunization question. 

A couple of case scenarios may be useful to define the term of reference. Scenario Number 1 

is an 18 year old female entering nursing school. She has documentation of receiving the 

complete Hepatitis B vaccine series in infancy as part of universal recommendations. However, 

she has never received post-vaccination serologic testing, as post-vaccination serologic testing 

is not recommended following routine infant or child Hepatitis B vaccination. Scenario Number 

2 is a 48 year old hospital laboratory technician who has documentation of the complete 

Hepatitis B vaccine series, which was provided by his employer 18 years ago. He is unaware of 

whether any post-vaccination serologic testing was performed, and is now working in a different 

healthcare system. 

The history of this issue dates back at least a couple of years. In February 2011, ACIP 

approved a consolidated statement of existing recommendations for immunization of healthcare 

personnel. 

Three options were presented for ensuring hepatitis B protection of vaccinated healthcare 

personnel without post-vaccination serologic testing. These options, although not formal 

recommendations, had not been previously considered by ACIP. ACIP requested that the 

Hepatitis Working Group deliberate prior to voting on the options. The three options consist of: 

1) No action unless exposed; 2) Pre-exposure hepatitis B surface antibody measurement, and 

3) Administration of a challenge dose of hepatitis B vaccine, which would be followed by 

antibody measurement 1 to 2 months later. 

During this meeting, the working group planned to define the term of reference and ask ACIP 

members for specific questions they may have about this term of reference. In June, the 

working group will present the cost-effectiveness analysis and proposed wording for ACIP 

policy. In October, the proposed policy options will be reviewed and the working group will ask 

whether ACIP is ready to vote. 

Ensuring Hepatitis B Protection for Remotely Vaccinated Healthcare Personnel 

Sarah Schillie, MD, MPH, MBA 

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

Centers for Disease Control and Prevention 

Dr. Schillie reported that an increasing proportion of healthcare personnel have received a 

documented hepatitis B virus (HBV) vaccination series in infancy, or as catch-up in 

adolescence. There is no recommendation for post-vaccination serologic testing after routine 

infant or adolescent vaccination. Experienced healthcare personnel may change employers 

and lack post-vaccination serologic testing results that were obtained earlier in their careers. 

Healthcare schools and institutions are seeking guidance to ensure that these healthcare 

personnel and trainees are protected against Hepatitis B infection. As noted by Dr. Sawyer, the 

term of reference for the Hepatitis Working Group is to ensure hepatitis B protection for HCP, 

including trainees, who received Hepatitis B vaccination in the remote past without postvaccination serologic testing. 

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Dr. Schillie reviewed the 2011 ACIP hepatitis B vaccination recommendations for HCP. These 

recommendations were made when most hepatitis B vaccination occurred upon matriculation or 

employment, both allowing for post-vaccination serologic testing soon after vaccination. The 

following key points of the recommendations are either copied or paraphrased as follows 

[MMWR 2011;60 (RR-7)]: 

 All unvaccinated persons whose work- and training-related activities involve reasonably 

anticipated risk for exposure to blood or other infectious body fluids should be vaccinated 

with the complete ≥3-dose HepB vaccine series. 

 Because higher exposure risk has been reported during the professional training period, the 

vaccination series should be completed before trainees have contact with blood. 

 To determine the need for revaccination and to guide post-exposure prophylaxis, postvaccination serologic testing should be performed for all HCP at continuing high risk for 

occupational percutaneous or mucosal exposure to blood or body fluids. 

 Post-vaccination serologic testing should be performed 1-2 months after administration of 

the last dose. 

 Persons determined to have anti-HBs concentrations <10mIU/mL soon after receipt of the 

primary series should be revaccinated. 

 Administration of a second complete 3-dose series on an appropriate schedule followed by 

post-vaccination serologic testing 1 to 2 months after the 3rd dose is usually more practical 

than antibody testing after each additional dose of vaccine. 

 Persons determined to have hepatitis B surface antibody levels <10mIU/mL after 

revaccination should be tested to determine infection status. 

The Occupational Exposure to Bloodborne Pathogens Standard was published by OSHA in 

1991. It requires that employers provide Hepatitis B vaccination to employees, ensure use of 

personal protective equipment (PPE), and describe how engineering and work practice controls 

would be used. The Needlestick Safety and Prevention Act became effective in 2001 and 

established in greater detail requirements that employers identify and use effective and safer 

medical devices [http://www.osha.gov/needlesticks/needlefact.htm]. 

Long-term protection after a HepB vaccine series correlates with anti-HBs ≥10mIU/mL 

measured 1 to 2 months after series completion. Vaccine-induced protection lasts 22 years or 

longer. Anti-HBs after primary HepB vaccine series wanes over time. Breakthrough HBV 

infections resulting in disease are uncommon among immunocompetent vaccine responders, 

even when surface antibody levels wane [Leuridan E. Clin Infect Dis 2011;53:68-75]. Because 

surface antibody levels wane over time, an antibody level <10mIU/mL years after the primary 

HepB vaccine series does not differentiate those healthcare personnel who are protected from 

those who are delayed responders or those who are non-responders [Tohme R. Infect Control 

Hosp Epidemiol 2011; 32:818-21; McMahon B. J Infect Dis 2009;200:1390-6]. Hepatitis B virus 

remains viable for 7 or more days on environmental surfaces1

 and occupationally-infected HCP 

may not be aware of, or report an exposure2

. A literature review indicated that approximately 

54% (38%-67%) of percutaneous injuries are reported3-7 and approximately 17% (7%-44%) of 

mucosal exposures are reported3-7 [1

Bond W. Lancet 1981;1:550-1; 2MMWR 2001;50 (RR-11); 

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3

Boal W. Am J Ind Med 2008;51:213-22; 4Gershon R. Ind Health 2007;45:695-704; 5Gershon 

R. Am J Infect Control 2009;37:525-33; 6

Kessler C. Am J Infect Control 2011;39:129-34; 

7

Trinkoff A. Infect Control Hosp Epidemiol 2007;28:156-64]. 

During its deliberations, the Hepatitis Working Group will consider the changing epidemiology of 

occupational HBV infection. Fewer HCP may be at risk because of sharps with engineered 

sharps injury protections, as well as increases in vaccination coverage. Hepatitis B infection 

may have decreased among source patients due to the declining incidence of acute hepatitis B 

and possible changes in the prevalence of chronic HBV [http://www.osha.gov/SLTC/ 

bloodbornepathogens/standards.html; Viral Hepatitis Surveillance, 2009, 

http://www.cdc.gov/hepatitis/statistics/2009surveillance/; Wasley A. J Infect Dis 2010;202:192­

201]. 

As presented by Dr. Sawyer, the options under consideration by the Hepatitis Working Group 

include 1) No action unless exposed, 2) Pre-exposure anti-HBs, and 3) Challenge dose of HepB 

vaccine. Note that all three options are used by healthcare systems in the US. Dr. Schillie 

briefly explained these. 

In Draft Option 1, matriculating or newly hired healthcare personnel who provide documentation 

of the complete Hepatitis B vaccine series would not be evaluated for Hepatitis B protection 

unless exposed to blood or body fluids. Healthcare personnel who report percutaneous or 

mucosal exposure to blood or body fluids to occupational health would be assessed for anti-HBs 

and the vaccination history would be reviewed. The source patient would be tested for HBsAg. 

Based on these results, the healthcare personnel may receive Hepatitis B vaccine and/or 

Hepatitis B immune globulin (HBIG). Draft Option 1 relies upon recognition of the exposure and 

timely reporting. 

In Draft Option 2, healthcare personnel would receive a pre-exposure surface antibody 

measurement upon matriculation or hire. If anti-HBs are ≥10mIU/mL, no further action would be 

required. If anti-HBs are <10mIU/mL, 1 additional dose of HepB vaccine would be 

administered, followed by surface antibody testing 1 to 2 months later. If anti-HBs remains 

<10mIU/mL, current recommendations would be followed to revaccinate and measure anti-HBs. 

In Draft Option 3, the healthcare personnel would receive a challenge dose of Hepatitis B 

vaccine upon matriculation or hire. Anti-HBs would be measured 1 to 2 months later. If antiHBs are ≥10 mIU/mL, no further action would be taken. If anti-HBs were <10mIU/mL, current 

recommendations would be followed to revaccinate and re-measure anti-HBs. 

The working group looks forward to presentations of additional data and a cost-effectiveness 

analysis of these options at the June ACIP meeting. Dr. Schillie invited input from ACIP 

members in terms of any other relevant options or considerations, as well as questions to 

consider. 

Discussion Points 

Dr. Coyne-Beasley wondered where she fit in. There seemed to be a focus on matriculation or 

hire. She had hepatitis B vaccine over 22 years ago, does not know her titers, and does not 

plan to matriculate or transfer anywhere. However, it was unclear whether she was at risk of 

exposure and should be revaccinated. 

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Dr. Schillie responded that there is no current recommendation for someone in Dr. CoyneBeasley’s situation to have pre-exposure surface antibody testing or a challenge dose of 

Hepatitis B vaccine. 

Dr. Foster (APhA) pointed at that many hospitals and facilities are instituting their own 

recommendations. 

Dr. Schillie replied that they have confirmation that all three of the options presented are in use 

in healthcare systems in the US. 

Dr. Brewer (ANA) said that while there is the 2001 Needlestick Act and there are data to show 

that nurses are still concerned about needlesticks because employers and other health facilities 

are not supplying safety devices, ANA believes there is gross under-estimation of needlesticks 

as Dr. Schillie pointed out. While the act is important, it still has not fixed the problem. 

Regarding the three options being practiced, Dr. Jenkins wondered whether there was any 

knowledge about outcomes, satisfaction, or measures of how successful these approaches are. 

Dr. Schillie replied that they do not have any outcomes comparing the three approaches. There 

are some data from different healthcare systems regarding the risk of exposure and risk of 

source patients being Hepatitis B surface antigen positive. 

Given the data presented regarding the frequency of reporting exposure, it was unclear to Dr. 

Bennett why Option 1 was even being considered. 

Dr. Schillie explained that it is included for baseline purposes. 

Ms. Stinchfield (NAPNAP) reported that Children’s Hospital in Minnesota where she works uses 

Option 1, which is based on reliance on education and making sure that healthcare providers 

know the risks. While there is a concern about any hospital that does not offer safety devices, 

the reverse is true when they are offered and people choose not to use them because they 

learned on the non-safety devices. Healthcare workers have secret stashes and sometimes do 

not use what they are provided. People are concerned when they receive a needlestick. They 

want to take action, they do it quickly, and it is really about making sure they know what to do 

when that happens. From a practical standpoint, Options 2 and 3 would be quite expensive and 

onerous on the employer. 

It seemed to Dr. Zahn (NACCHO) that the utility of getting an anti-Hepatitis B surface antigen 

study would depend upon how long it had been since they received their vaccine. He assumed 

that how long a vaccine would be useful and what the cutoff should be would be part of the 

conversation. 

Dr. Schillie replied that the working group is considering this issue and plans to present 

additional data during the June 2012 ACIP meeting. 

Dr. Schaffner (NFID) expressed interest in the magnitude of the problem, and noted that no data 

had been presented on occupationally-acquired Hepatitis B. That is, there was no discussion 

regarding how many people fall into the category of having been immunized but not 

serologically tested who turn out after an exposure to have acquired Hepatitis B. 

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Discussion 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Dr. Schillie responded that every day in US hospitals, there are approximately 1000 

percutaneous injuries. Their data of about 7000 injuries indicate that source patient positivity for 

Hepatitis B surface antigen is approximately 1%. With regard to case reports in the literature of 

actual infection among healthcare personnel who have been vaccinated, there was a case 

report of a nurse in the Netherlands who was a delayed responder to vaccine, but ultimately 

was a vaccine responder who did acquire symptomatic acute Hepatitis B infection. He was also 

MSM, so it is difficult to determine whether his infection was acquired as a result of an 

occupational exposure or as a result of his MSM behavior. Also, the 2009 CDC surveillance 

data indicate that among approximately 1500 case reports of acute Hepatitis B infection with 

information on occupation, 13 indicated that the person who acquired infection was employed in 

a medical or dental system. However, it cannot be said whether that infection was acquired as 

a result of occupational exposure. 

Dr. Moore (AIM) raised an issue about which she often receives questions, and suggested that 

it be addressed in the recommendation. That is, there is a tendency to want to use a challenge 

dose to check anti-HBs as a way to confirm a history of vaccination when documentation of 3 

doses of vaccination cannot be found. She and Dr. Andrew Kroger have had this issue arise in 

other work groups in terms of whether this is a meaningful way to check. 

Vaccine Supply 

Dr. Jeanne Santoli 

Vaccine Supply and Assurance Branch 

Immunization Services Division 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Santoli offered an update on the vaccine supply for adult hepatitis A vaccine, MMR-V 

vaccine, and zoster vaccine. 

With regard to hepatitis A vaccine, Merck anticipates availability of its adult hepatitis A vaccine 

by late 2012. Production and supply of GSK’s adult hepatitis A vaccine and hepatitis A/hepatitis 

B combination vaccine currently are sufficient to meet demand for routine adult usage of adult 

Hepatitis A vaccine. 

MMR-V combination vaccine remains unavailable. Merck is committed to returning ProQuad® 

to the market. Details on timing and availability will be provided at a later date. Merck has an 

adequate supply of both M-M-R II® and VARIVAX® to meet current demand. 

With respect to zoster vaccine, in December 2011, Merck cleared all backorders for 

ZOSTAVAX® and resumed routine 2-day shipping. 

CDC’s Vaccine Supply/Shortage Webpage is available at: 

http://www.cdc.gov/vaccines/vac-gen/shortages/default.htm 

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Discussion 

Discussion 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Day 1: Public Comment 

Michael Royals, DVM 

Chief Scientific Officer 

Global Head of Applications Development 

PharmaJet, USA 

I am the Chief Science Officer for PharmaJet, and clearly I am conflicted because of my 

employment in this company. Last October, the FDA issued a statement that recommended 

against the use of jet injectors to deliver influenza vaccine. The statement indicated that this is 

based on the observation that no data on safety or efficacy had been submitted by vaccine 

manufacturers on the delivery of their vaccines with jet injection. On January 9, 2012, 

advocates for the use of the technology held a meeting with the FDA to identify approximately 

30 members from all branches of the FDA, representatives of jet injection companies, and users 

of the technologies from various public health sectors, including those from state level public 

health immunization programs, US corrections institutions, and US retail pharmacies. The 

content of the meeting covered historical and current use of jet injectors to deliver a wide range 

of vaccines, including influenza. Speakers pointed to the fact that the MMWR and “Pink Book” 

both have references to the use of jet injectors as an alternative to needles for delivery of 

vaccines. Since 1958, 22 controlled studies have been published on the use of jet injectors to 

deliver influenza, none of which indicated inferiority between delivery methods. The Navy and 

Coast Guard have, for the past several decades and up to the present, used jet injectors to 

vaccinate both soldiers and their dependents. The various stakeholders urged the FDA to 

reassess the October statement and to find a way forward that would permit users to reestablish influenza vaccine delivery using needle-free jet injection. We recently heard from the 

FDA Office of the Commissioner the stated quote, “We are taking this seriously and will be 

getting back to you. We did not want you to think the issue had gone into a ‘black hole.’” 

Additionally, we are in discussions with three of the companies that have US licensed influenza 

vaccine. While we do not have definitive direction from FDA on the matter, there appears to be 

some progress. Thank you. 

February 23, 2012 

Agency Updates 

Centers for Disease Control and Prevention (CDC) 

Dr. Schuchat indicated that CDC traditionally has had an annual immunization conference. In 

concert with budget cutting efforts, the agency is alternating an in-person physical meeting with 

a virtual on-line meeting. A fantastic program has been developed for the first national 

conference on-line, which is March 26-28, 2012. The www.cdc.gov/vaccines contains a lot of 

information about this meeting. There will be three afternoons of sessions that will also be 

archived. Those who watch the broadcast live will be able to participate in discussions. Poster 

sessions will also be available. Next year’s conference will be in-person in Atlanta in early June 

2013. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

April 21-28, 2012 is National Infant Immunization Week. A number of local, state, national, and 

international activities have been planned. There is a new family of communications materials, 

including public service announcements (PSAs) for radio and television that will be launched 

that week and will be available for others to pay for for placement. These are very creative and 

build on an enormous amount of research focusing on vaccination of young children and the 

issues that parents find important. These materials are very clever, as well as evidence-based. 

Related to this, there is a series of materials that are also available on-line. These are vaccine 

resources for clinicians that were developed in conjunction with the American Academy of 

Family Physicians (AAFP), the American Academy of Pediatrics (APA), and CDC. These 

materials address the many issues that parents have, include “war stories” from families who 

have experienced these diseases, address the rights and responsibilities people have if they 

refuse vaccines, include a vaccine safety series, and have very cute associated materials. In 

keeping with budget cutting, millions of copies have not been printed, but they are available for 

free download or printing locally. CDC encouraged others to sponsor printing in their 

communities. 

On a bittersweet note, Immunization Services Division (ISD) Director Lance Rodewald will be 

moving to an international position in China where he will be working on WHO immunization. 

This is a fantastic opportunity for Dr. Rodewald and his family, and the people of China, but a 

major loss for CDC. CDC will be recruiting for this position, and she requested input to help 

them find a fantastic new applicant. 

Centers for Medicare and Medicaid Services (CMS) 

Dr. Hance indicated that CMS is close to publishing an update to administration fees for the 

Vaccines for Children Program (VFC). 

Department of Defense (DoD) 

Dr. Geibe commented on jet injectors, indicating that the Navy and Marine Corps have been 

using these safely and effectively. This is known based on DoD’s surveillance on the 

effectiveness of the vaccine when delivered with the jet injections. However, they also are 

adhering to the FDA recommendation until further guidance is provided. 

Department of Veterans Affairs (DVA) 

Dr. Kinsinger reported that DVA continues to work on a policy for deploying influenza 

vaccination, and have set a goal this season for 85% coverage. At the agency level, DVA is 

beginning to work closely with the DoD to create a joint electronic medical record (EMR). This 

is an enormous undertaking that is expected to take many years. One of the first components 

that will be developed for that joint EMR is an immunization package. She also announced that 

Dr. Andrew Kroger would be a guest speaker on two national VA calls in March 2012 to review 

the 2012 Adult Immunization Schedule. 

Food and Drug Administration (FDA) 

Dr. Sun reported that Dr. Norman Baylor retired after 20 years at Center for Biologics Evaluation 

and Research (CBER). Currently, Dr. Marion Gruber is serving as Acting Director. Since the 

October 2011 ACIP meeting, PREVNAR 13® was approved for adults 50 years and older. On 

February 16, 2012 the Adacel® label was updated to include the Td515 study discussed the 

previous day. A Vaccine Advisory Committee meeting will be convened on February 28-29, 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

2012, the topics of which will be the season’s influenza strain selection and a discussion of 

licensure pathways for pandemic influenza. On January 10-11, 2012 CBER convened a public 

workshop on the development and evaluation of human cytomegalovirus (HCMV) vaccines that 

focused on the status of the knowledge of HCMV biology, epidemiology, and vaccine 

development strategies. This information should be posted on the web soon. 

Health Resources and Services Administration (HRSA) 

Dr. Evans reported that in December 2011, the Advisory Commission on Childhood Vaccines 

(ACCV) voted to approve the Secretary’s proposal to add intussusception to the Vaccine Injury 

Table for the two currently licensed rotavirus vaccines and approved language in the Now in 

addition, the proposed paragraph for Qualifications and Aids to Interpretation (QAI), which 

defines the conditions in the table. When RotaShield® was licensed in 1998, there was a 

general category of rotavirus vaccine. Once it became determined that intussusception was 

associated with that, a second category was included with intussusception with live attenuated 

Rhesus-based rotavirus vaccines. The program adjudicated a number of claims under that 

category. After many years passed, the category was removed. With the licensure in 2006 and 

2008 of RotaTeq® and ROTARIX®, these were covered under the general category of rotavirus 

vaccines with no specific conditions. Over the past two years, published studies from South 

America and Australia show a small but attributable risk of intussusception after the first and 

second dose of both vaccines, with more data supported for ROTARIX®. Therefore, the 

program went ahead with the proposal to add intussusception to the general table category of 

rotavirus vaccines to allow a presumption of causation with an onset interval of 0 to 21 days. 

The ACCV also approved wording to the QAI section of the table to define intussusception and 

to specify alternative causes of intussusception that if present in a case would render the injury 

not to be considered vaccine-related. The ACCV approved these proposals, and under the act 

there must be a Federal Register Notice of Proposed Rulemaking with 180 days of public 

comment before a Final Rule is published. About 15 rotavirus claims have been received since 

2006. Dr. Evans will report during the June 2012 ACIP meeting on other proposals to change 

the table based on the August 2011 IOM report. 

Indian Health Services (IHS) 

Ms. Groom reported that IHS continues to put a lot of effort into influenza vaccination. IHS 

healthcare personnel coverage is approximately 74%, which is about the same as the last 4 

years. Strategies are being assessed to improve and increase that percentage to reach the 

Healthy People 2020 goal of 90%. IHS has also been monitoring coverage among its patients, 

and continues to encourage its providers to vaccinate. However, with little influenza virus in 

communities this has been somewhat challenging because of the lack of pressure. A significant 

amount of focus is being placed on adult immunization. One of the first efforts was to have all of 

the adult vaccines automatically added to the IHS core formulary as they are approved and 

recommended by ACIP. A survey is being conducted among IHS sites to determine how many 

facilities are actually providing adults vaccinations. The preliminary data show that funding for 

HPV and zoster is a major challenge for providing those vaccines to IHS patients, so the agency 

is assessing ways to address this. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

National Vaccine Program Office (NVPO) 

Dr. Gellen reported on two Institute of Medicine (IOM) committees that NVPO supports, one of 

which is assessing vaccine development priorities as part of NVPO’s priorities within the 

National Vaccine Plan (NVP). An initial phase of this, which is a model, will be released in April 

2012. The second IOM committee that is being supported by NVPO and CDC is one that was 

established at the recommendation of the National Vaccine Advisory Committee (NVAC) as part 

of their vaccine safety review. This committee has met once and plans two more meetings in 

the near future, the next of which will be in Seattle on March 8, 2012. This committee is 

assessing the health outcomes related to the schedule. This arose from concerns pertaining to 

the health outcomes of children who are vaccinated according to schedule versus those who 

are vaccinated following other schedules. Within HHS, for the past two years the Assistant 

Secretary for Health has led an Interagency Task Force on Seasonal Influenza Vaccine. 

Following the pandemic, there was an opportunity to determine what could be done to improve 

seasonal vaccine use that would help with pandemic preparedness and also emphasize some 

of the department’s priorities, particularly with regard to reducing or eliminating health 

disparities. That is about to morph into a focus more broadly than just influenza into adult 

vaccines, which fits in with the Adult Immunization Summit that is also coupled with the 

Influenza Summit. 

National Vaccine Advisory Committee (NVAC) 

Dr. Orenstein highlighted two items from the February 7-8, 2012 NVAC meeting. Dr. Melinda 

Wharton presented on the expanse of the immunization system as it goes beyond vaccines for 

vaccine purchase. In light of this presentation and the potential impact that the Affordable Care 

Act will have on immunization systems and vaccine availability, the NVAC charged a working 

group with the task of identifying and describing critical functions of immunization programs at 

the national, state, and local levels to ensure their preservation and improvement. Dr. L.J. Tan 

is co-chairing that working group. The second day of that NVAC meeting was devoted almost 

exclusively to global immunization and the impact on diseases that make their way to the US, as 

well as diseases within global populations. There were presentations from Dr. Nils Daulaire 

who is the Director of the Office of Global Affairs (OGA) within HHS; and several presentations 

from CDC, FDA, NIH, USAID, and others. Afterwards, NVAC charged the working group with 

the task of reviewing the role of HHS in global vaccination, the impact of such vaccination on the 

US and global populations, and to recommend how HHS can best contribute to reducing global 

disease and the threat of that global disease coming to the US as with many of the outbreaks 

currently being observed. That working group is being chaired by Phil LaRussa. 

National Institutes of Health (NIH) 

Dr. Gorman reported that NIH has established a new center called the National Center for 

Advancing Translational Science (NCATS). The mission of this new center is to catalyze the 

generation of innovative methods and technologies that will enhance the development, testing, 

and implementation of diagnostics and therapeutics across a wide range of human diseases 

and conditions. On November 28, 2011, NIH and CDC renewed two vaccine safety program 

announcements. The purpose of these funding opportunities is to support research that will 

contribute to the overall understanding of vaccine safety. This research opportunity invites 

studies to address scientific areas potentially relevant to vaccine safety. The National Institute 

of Allergy and Infectious Diseases (NIAID) has published announcements for 6 leadership group 

applications. They are being sent out concurrently and are for clinical research networks in the 

following areas: HIV/AIDS and HIV-Associated Infections in Pediatric and Maternal 

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Discussion 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Populations; Integrated Strategies for the Prevention of HIV Infection; Microbicides to Prevent 

HIV Infection; Therapeutics for HIV/AIDS and HIV-Associated Infections in Adults; Vaccines to 

Prevent HIV Infection; and Antibacterial Resistance. The 2012 Jordon Report, a publication that 

reports on the state of science and provides valuable information about vaccine research and 

development for researchers, policy makers, and legislators, is presently public. It was 

supposed to post to the web within the next couple of days. NIAID is the lead institute at NIH 

that supports research on infectious disease. Within NIAID, the Division of Microbiology and the 

Division of Acquired Immunodeficiency Syndromes support extramural research to control and 

prevent diseases causes by virtually all human infectious agents. Both divisions provide funding 

opportunities and a comprehensive set of resources for researchers that support basic 

research, pre-clinical development, and clinical evaluation. Current vaccine trials currently 

supported by one or both of these divisions include: Anthrax, Cytomegalovirus, Dengue, 

Enterotoxigenic E-coli, Hepatitis B, Hepatitis C, Herpes Simplex, Herpes Zoster, HIV, Hospital 

Acquired Infections (HAIs), Human Papillomavirus (HPV), Human Parainfluenza Virus, 

Influenza, Leishmaniasis, Malaria, Meningococcous, Pertussis, Plague, Poliovirus, Rift Valley 

Fever, Rotavirus, Severe Acute Respiratory Syndrome (SARS), Salmonella, Septicemia, 

Shigellosis, Small Pox, Group A Strep, Group B Strep, Tetanus, Tuberculosis, Tularemia, and 

Typhoid. 

Meningococcal Vaccines 

Introduction 

H. Cody Meissner, M.D. 

Chair, Meningococcal Working Group 

Advisory Committee on Immunization Practices 

Dr. Meissner acknowledged the considerable time and effort the Meningococcal Working Group 

members have spent on a number of difficult issues. In particular, he recognized the careful 

attention of Dr. Cohn in guiding the working group through a number of difficult issues. 

He then reviewed the four meningococcal vaccines to be addressed during this session. The 

quadrivalent polysaccharide vaccine (MPSV4: Menomune®, sanofi pasteur) consists of 

capsular polysaccharide from four serogroups: A, C, Y, and W135. It was licensed in 1991 for 

persons 2 years of age or older. Currently, this vaccine is recommended for persons older than 

55 years of age or for use when meningococcal conjugate vaccine is either not available or 

cannot be used. Two meningococcal conjugate vaccines are available: 1) MenACWY-D 

(Menactra®, sanofi pasteur), which is approved for 9 months through 55 years; and 2) 

MenACWY-CRM (Menveo®, Novartis), which is approved for 2 through 55 years. Both consist 

of capsular polysaccharide from four serogroups: A, C, Y, and W135 conjugated to a carrier 

protein. In the case of Menactra®, the carrier protein is a chemically altered diphtheria toxin. 

The carrier protein for Menveo® is a naturally occurring non-toxic form of diphtheria toxin. Two 

investigational vaccines are under review by the FDA for use infants as a 4-dose series at 2, 4, 

6, and 12 months of age: 1) HibMenCY-TT (MenHibrix®, GlaxoSmithKline) consists of polyribosyl phosphate from a capsule of Hemophilus Influenzae type B conjugated to tetanus toxoid 

plus meningococcal polysaccharide from serogroups C and Y conjugated tetanus toxoid; and 2) 

MenACWY-CRM. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

In April 2011, the FDA licensed Menactra® as a two dose primary series for children 9 through 

23 months of age. The pure polysaccharide meningococcal vaccine is not recommended for 

children less than two years of age because of low immunogenicity in this age group. 

Menactra® is the first meningococcal vaccine licensed for children <24 months of age. In June 

2011, after review of data from clinical studies on safety and immunogenicity, ACIP 

recommended that children 2 through 10 years of age with certain risk factors for 

meningococcal disease receive a 2-dose series 3 months apart. Routine vaccination of children 

2 through 10 years of age who are not at increased risk of meningococcal disease is not 

recommended. This is because currently the rates of meningococcal disease due to vaccine 

containing serogroups is low in this age group. In addition, antibody concentrations wane 

quickly after the primary dose and most children may not be protected by 3 to 5 years after 

vaccination. 

As mentioned, two investigational vaccines are under investigation by the FDA for use in 

infants. For more than two years, the working group has discussed the question regarding 

whether the 4.1 million infants born each year in the US should be vaccinated routinely against 

meningococcal disease. Discussion has focused on a number of factors, including the burden 

of meningococcal disease and the relatively small amount of vaccine-preventable disease in this 

age group; the limited public health impact of routine immunization in this age group; the 

programmatic difficulties associated with implementation of an infant or toddler vaccine 

schedule; the immunogenicity data which demonstrate declining antibody concentrations 3 

years after either a 2-dose or 4-dose schedule, indicating a booster dose would be necessary 

before the routine 11- or 12-year meningococcal vaccination; and the cost-effectiveness of 

infant-toddler vaccination. 

Because neither infant meningococcal vaccine has been licensed by the FDA, the decision has 

been made simply to extend the language used for children 2 through 10 years of age down to 

children 6 through 23 months of age. This language was first published in the May 2, 2008 

MMWR in an ACIP report entitled, “The Decision Not To Recommend Routine Vaccination of All 

Children Aged 2 through 10 Years with Quadrivalent Meningococcal Conjugate Vaccine.” 

Guidance regarding the infant vaccines will be deferred until these vaccines are licensed. The 

last recommendation and report on meningococcal vaccines was published as an MMWR 

supplement in May 2005. During the past 7 years, numerous new vaccine recommendations 

have been made. In addition to the availability of a second conjugate vaccine, a draft of the 

updated supplement is being reviewed by working group members. The current draft has been 

provided to ACIP members for comment. Language regarding use of the conjugate vaccine as 

a 2-dose primary series in children 9 through 23 months of age who are at increased risk of 

meningococcal disease is contained in the revised statement. 

GRADE Assessment for MenACWY-D in Children 9-23 Months of Age 

Elizabeth Briere, MD, MPH 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Briere presented the GRADE evaluation for MenACWY-D toddler vaccines. She reviewed 

the working group’s study question for GRADE, the evaluation of meningococcal disease 

burden data quality, and the GRADE assessment of evidence for the benefits and harms 

outcomes. She indicated that while she would conclude with the working group’s determination 

of overall evidence type for the toddler MenACWY-D vaccine, a vaccine recommendation would 

not be formulated. 

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The first step in the GRADE process is to formulate the study question. The working group’s 

initial question was “Should meningococcal vaccines be administered routinely to infants and 

toddlers for prevention of meningococcal disease?” The meningococcal vaccines included the 

two infant vaccines, Menveo® and MenHibrix®, and the toddler vaccine, MenACWY-D. 

Because the infant vaccines are not yet licensed, the working group focused the study question 

and GRADE evaluation on the toddler vaccine. GRADE will be used to assess the infant 

vaccines once they are licensed. Therefore, for this presentation, the study question was 

“Should MenACWY-D be administered to all 9 and 12 month olds for prevention of 

meningococcal disease?” 

Because current low disease incidence has been such an important consideration during 

working group discussions, the working group wanted to first evaluate the quality of the 

meningococcal disease burden data. However, because these data are from surveillance and 

no intervention was tested, they could not be evaluated using the GRADE format. Instead, the 

working group assessed the disease burden data for representativeness, accuracy, and 

applicability. 

Presentations on the burden of meningococcal disease in children <5 years of age were given 

during the October 2011 ACIP meeting. A comparison of the incidence of serogroup C, Y, and 

W135 meningococcal disease during three time frames shows the large declines in incidence of 

meningococcal disease overall and in children <5 years of age [1993-2009 ABCs data 

estimated to U.S. population with 18% correction for under reporting; *1993-2005 for 

adolescents 11-22 years]. 

US meningococcal incidence data come from two sources: ABCs and NNDSS. The quality of 

the incidence data depends on these two sources. ABCs is an active laboratory and populationbased surveillance system that collects data only on culture-confirmed cases of meningococcal 

disease in 10 sites. Cases in the ABCs sites can be projected to the US population to estimate 

incidence. NNDSS is a passive surveillance system. All states and territories report data for 

nationally notifiable diseases to NNDSS. NNDSS captures information on all cases, including 

cases confirmed by PCR only and those with clinically compatible illness. However, serogroup 

information is limited. Because cases identified in ABCs are also reportable to NNDSS, ABCs 

and NNDSS are not independent surveillance systems. 

The representativeness of incidence data was assessed by comparing projected numbers of 

cases in the US from ABCs to NNDSS reported cases. Since NNDSS is national surveillance, 

meningococcal incidence rates should be representative of the US. Because ABCs covers a 

catchment area comprising only about 13% of the US population, rates using ABCs data are 

standardized by race and age, and projected to the US population. When comparing NNDSS 

and ABCs meningococcal cases less than 1 year of age, a similar distribution of cases is found. 

One limitation of these comparisons is the amount of missing data in NNDSS. Serogroup was 

missing for 50% to 70% of NNDSS cases, so a comparison with ABCs could not be done. 

Next, the accuracy of the incidence data was assessed by comparing the annual cases of 

meningococcal disease for all ages estimated from ABCs to the number of cases for all ages 

reported in NNDSS. ABCs typically estimates fewer cases compared to NNDSS, mainly 

because it does not capture cases reported as probable. In recent years, there has been a 15% 

to 20% difference between cases from ABCs and NNDSS, which means that when using ABCs 

to estimate the US meningococcal disease burden, cases are potentially being underestimated 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

by 15% to 20%. To account for this underestimate of cases by ABCs, a correction factor of 18% 

is applied to all incidence data used. 

Another limitation in the accuracy of ABCs data is that outbreaks of disease outside ABCs 

catchment areas may be missed. However, based on the data, the total number of outbreak 

cases rarely increases the overall disease incidence since cases generally make up only 2% to 

3% of total cases. 

Finally, the applicability of meningococcal incidence data to the study question was assessed. 

ABCs and NNDSS capture meningococcal disease incidence in toddlers, so the data are 

applicable to the evaluation of MenACWY-D for use in toddlers. However, incomplete data in 

NNDSS prevents assessment of the epidemiology of serogroups specific to the toddler vaccine. 

To complete the assessment of burden of disease data quality, morbidity and mortality data 

were assessed. Measuring meningococcal disease morbidity and mortality is challenging. Data 

are usually combined that are available from ABCs along with data collected from published 

manuscripts to estimate the severity of meningococcal disease in infants and young children. 

Published data on morbidity and mortality are often not representative or generalizable because 

studies often have small numbers and are usually hospital-based. There is also a wide range of 

estimates of mortality and long-term sequelae among survivors, and many of these studies do 

not give serogroup-specific estimates. Data, especially neurologic outcomes, are often not 

directly applicable to the evaluation of toddler vaccines or disease because they may be for allcause bacterial meningitis, in broad age-groups, or for all serogroups. 

Based on the evaluation of the meningococcal disease incidence, mortality, and morbidity data, 

minor limitations were found. It is not believed that these significantly affect the quality of the 

burden of disease estimates. 

Turning to the GRADE evaluation, Dr. Briere reminded everyone that this GRADE evaluation 

applied only to evidence for the toddler MenACWY-D schedule. After selecting a study 

question, the next step in GRADE is to select outcomes that the working group feels are 

important to answer this question. The quality of the evidence for these outcomes is then 

evaluated. First, the working group created a list of 5 outcomes to GRADE. Next, non-CDC 

members of the working group ranked the relative importance of the outcomes on a scale of 1-9 

with 1-3 as not important; 4-6 as important, but not critical for answering the question; and 7-9 

as critical for answering the question. Only evidence for the critical and important outcomes are 

graded. Only mild adverse events were ranked as not important. The final outcomes that were 

graded included the following: 

 Benefits: Short-term and long-term efficacy to assess the benefits of vaccination. 

 Harms: Occurrence of serious adverse events after vaccination; and interference with other 

co-administered vaccines. 

In compiling evidence to GRADE for each of these outcomes by vaccine, several inclusion 

criteria were used. US and non-US populations were included as long as the proposed US 

schedule (9, 12 months) was used for MenACWY-D. Data were compiled for MenACWY-D by 

outcome and study design type (e.g., Randomized Control Trial or Observational Study). There 

were a total of 5 studies, 4 observational and 1 Randomized Control Trial. The majority of 

studies assessed efficacy and safety outcomes. None were published at the time. Drs. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Campos-Outcalt and Briere rated the evidence separately and compared results. Differences in 

results were discussed with the working group until consensus was reached. 

In terms of benefits and harms, due to the low incidence of meningococcal disease, prelicensure clinical effectiveness studies are not feasible. Serum bactericidal antibody (SBA) titers 

are used as the immunologic correlate of protection. Multiple studies have shown that human 

SBA titers of 1:4 correlate with protection against meningococcal disease. While these studies 

were based on SBA activity against serogroup C disease, human SBA titers >1:8 are accepted 

as correlates of protection for vaccine licensure for other serogroups. Indirect data adds to the 

confidence in SBA titers used as a correlate for protection. Effectiveness was demonstrated to 

correlate with SBA titers in the adolescent MenACWY-D in the US and MenC conjugate 

vaccines in the UK [Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the 

meningococcus. I. The role of humoral antibodies. J Exp Med. 1969 Jun 1;129(6):1307-26. 

Andrews N, Borrow R, Miller E. Validation of serological correlate of protection for 

meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance 

in England. Clin Diagn Lab Immunol. 2003 Sep;10(5):780-6]. 

Based on the body of evidence for MenACWY-D, short-term efficacy is achieved for all 

serogroups after a 2 dose series. However, long-term protection is unlikely given the low 

percentage of infants with protective titers 3 years after the 2 dose series [Johnson, D.R. 

Menactra Infant Indication, ACIP June 22, 2011]. A booster dose would likely be necessary to 

protect children until the 11-12 year vaccination. 

In all studies that assessed serious adverse events, events were recorded from the time of 

vaccination through 6 months post-vaccination^ and were physician-verified. Among the 

studies for MenACWY-D, at least 1 serious adverse event was reported by 3% to 5% of study 

participants who received MenACWY-D alone or with concomitant vaccines. At least 1 serious 

adverse event was reported by 2% to 4% of controls*†. The difference between the intervention 

and control groups was not statistically significant in any of the studies. Four of the serious 

adverse events were considered related to MenACWY-D vaccine by non-blinded 

investigators**. No deaths were reported in any of the studies [^Defined as any medical 

occurrence that results in death, is life-threatening, requires hospitalization, results in 

disability/incapacity, is an important medical event. *Menactra package insert 30 Nov 2011 

v0.11. †Difference between intervention and control groups not statistically significant. **IDDM, 

respiratory distress, 2 febrile seizures]. 

Based on the body of evidence for interference with co-administered vaccines, antibody 

responses for MMRV and Hib after co-administration with MenACWY-D met the criteria for noninferiority*. Pneumococcal IgG antibody responses after PCV7 co-administration with 

MenACWY-D did not meet criteria for non-inferiority for serotype 4, 6B, and 18C. Detectable 

functional antibody was present, but did not meet non-inferiority for IgG GMC ratio criteria. The 

clinical relevance of these findings is unclear [*Menactra package insert 30 Nov 2011 v0.11]. 

Regarding the benefits and harms for a toddler MenACWY-D series, the vaccine is 

immunogenic in the short-term and is safe. However, low disease burden lowers the overall 

benefits of vaccination. 

In GRADE, all the available data for each outcome are evaluated on these 5 criteria and a final 

evidence type is assigned. “Other” includes publication bias, strength of association, and dose 

gradient. The following is the algorithm used to determine the final evidence type for each 

outcome: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Randomized Controlled Trials start out as an evidence type of 1 and observational studies start 

out as a type 3. The 5 criteria are assessed to determine whether the overall evidence type is 

moved down or up. Since the majority of studies for MenACWY-D were observational studies 

without randomized control groups, an initial evidence type of 3 was used for most outcomes. 

The first criterion assessed is risk of bias. Methodological limitations were looked for that may 

bias the estimates of the effect of vaccination. The majority of studies for MenACWY-D were 

single-blinded or not blinded at all. It was believed that blinding was likely to introduce more 

bias for a more subjective outcome, such as severe adverse events, and was less likely to 

introduce bias for an objective outcome, such as efficacy or interference. Therefore, the 

evidence for the severe adverse events outcomes was downgraded if there was single or no 

blinding. However, efficacy outcomes were not downgraded. 

As a reminder, for MenACWY-D all outcomes with observational study designs started as an 

evidence type of 3 and outcomes with randomized controlled trials started as a 1. For risk of 

bias, serious limitations were found for the serious adverse events outcomes due to single or no 

blinding, and no serious limitations were found for the remaining outcomes (e.g., short-term 

efficacy, long-term efficacy, co-administration of vaccines). No serious problems were found 

with inconsistency for any of the outcomes. As mentioned earlier, it is not feasible to directly 

measure efficacy, and SBA titers are used as a correlate of protection. Although SBA titers are 

indirect evidence for efficacy, since they are the accepted measure for vaccine licensure 

studies, the evidence type was not downgraded. No serious concerns were found with 

imprecision among the evidence for efficacy outcomes, the observational studies for SAE, or the 

evidence for interference with co-administered vaccines. The Randomized Controlled Trial for 

SAE was downgraded for imprecision because the study had a sample size <300 and had a 

wide confidence interval. No serious concerns were found for “Other.” 

In summary, the evidence was downgraded for the serious adverse events outcome, but was 

not downgraded for any of the other outcomes. Therefore, the overall evidence type was 3. 

The evidence tables and overall evidence type for MenACWY-D will be published together with 

the evidence for the infant vaccines once they are licensed. 

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Updates to the Meningococcal Vaccines Statement 

Amanda Cohn, MD 

CDR, US Public Health Service 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Cohn reminded everyone that the working group’s plan was to evaluate the evidence for the 

general question, “Should infants and toddlers routinely be vaccinated with meningococcal 

conjugate vaccines?” However, as there is no licensed infant product, only the evidence grade 

for the toddler vaccine was presented during this session. At the same time, the ACIP 

meningococcal statement, published in 2005, needs to be updated so that the most current 

recommendations are communicated clearly in one document. The updated statement will 

include language on recommendations for high risk 9 through 23 month olds and language 

indicating that 2 through 10 year olds are not recommended routinely for meningococcal 

vaccination. Data on the immunogenicity and safety of the MenACWY-D in 9 through 23 month 

olds was presented at the June 2011 ACIP meeting, and will also be included in the updated 

statement. 

In June 2011, sanofi pasteur presented data showing that the immunogenicity and antibody 

persistence of a 2-dose primary series of MenACWY-D in 9 through 23 month olds is similar to 

a single dose in young children 2 through 5 years old. A high proportion of subjects achieved 

hSBA titers of greater to or equal to 1:8 after the second dose, and most subjects did not 

maintain these antibodies 3 years after the primary series. Additionally, current incidence of 

serogroup C and Y meningococcal disease among 1 year olds is similar to disease incidence 

among 2 through 4 year-olds. Therefore, including 9 through 23 month olds is simply an 

extension of the existing recommendations for 2 through 10 year olds. 

The language in the statement is on page 33 of the draft given to ACIP members. Background 

information will include the following information: 

 MenACWY-D is licensed for use as a two dose primary series in toddlers 9 through 23 

months and a single dose in children 2 through 10 years. 

 MenACWY-CRM is licensed for use starting at age 2 years as a single dose. 

 These vaccines are safe, immunogenic, and will provide protection against meningococcal 

disease caused by serogroups A, C, Y and W-135. 

 Antibodies wane quickly in this age group and most vaccinated children will not be protected 

three years after vaccination. 

The updated language will read as follows: 

 Routine vaccination against meningococcal disease is not recommended for children ages 9 

months through 10 years. 

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 If a child receives MenACWY prior to their 10th birthday, they should also receive the 

routinely recommended doses at ages 11 through 12 years and age 16 years. 

The next steps are to publish the updated ACIP meningococcal vaccines statement as an 

MMWR recommendation and report. It is fully expected that this recommendation will be 

outdated as soon as it is updated; however, the working group believes that it is important to go 

ahead and publish the statement this year. The working group will continue to work on grading 

the evidence for infant vaccines under consideration for licensure. Each vaccine will be graded 

separately, but recommendations will be formulated for infant vaccination in general. During the 

October 2011 meeting, a rationale was presented for the working group consensus to not 

routinely recommend meningococcal vaccines for this age group. However, as language is 

developed for infant vaccination, the working group will consider harmonizing the 9 month 

through 10 year old language with the infant recommendation language. 

Discussion Points 

Dr. Keitel as the Influenza Working Group is considering its broad evidence-based grading of 

influenza vaccine recommendations, it was interesting to hear that the Meningococcal Working 

Group did not downgrade the evidence based on a correlate of protection. If that were going to 

set a precedent for ACIP, that would mean that simple immunogenicity studies could be used 

for influenza to grade the evidence for likely protection against influenza. She would have 

imagined that although there is a correlate of protection, it is not an actual demonstration that 

the vaccine did protect. 

Dr. Cohn replied that the Meningococcal Working Group discussed this at length. The primary 

reason for not giving it a serious downgrade was that, for meningococcal vaccine in particular 

because the disease incidence is so low, pre-licensure effectiveness trials are not going to be 

conducted. This was very specific to meningococcal vaccine. 

Dr. Baker added that the historical precedent for meningococcal vaccines dated back to the 

military in 1969 when the efficacy of the Group C outbreaks in the military was shown with the 

Group C polysaccharide vaccine. Since that time, hSBS titers to Group C has been accepted 

throughout the world as a correlate of protection, and has been applied to the other serogroups 

in the vaccines. 

Dr. Schuchat said she thought for the time being it would be important to assess this issue in a 

vaccine-specific manner in terms of the body of evidence underpinning a correlate of protection. 

As shown the previous day with the pneumococcal work, a correlate in adults is not really 

agreed upon and the FDA is requiring a post-licensure effectiveness study. This illustrates the 

challenge many working groups are having with GRADE as originally conceived now being 

adapted to vaccines. As an agency, CDC is considering learning from this first family of vaccine 

grading experiences and potentially generating a “Grade 2.0” that might be more user-friendly 

for the working groups. She noticed the same thing, and imagined the enormous amount of 

literature for Influenza Vaccine Working Group to be challenging. However, that group would 

need to consider what is known and knowable and not necessarily bridge from meningococcal. 

Dr. Baker asked Dr. Cohn to comment on the data for post-licensure efficacy for adolescents in 

terms of the reduction observed after recommendation of the quadrivalent conjugate vaccine. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Dr. Cohn replied that the case-control study data had taken 7 years to collect and update 

because of the low incidence of disease is correlating nicely with antibody titers waning. The 

first year after vaccination protection appears to be very high as suggested by the SBA titers. 

Over time, 3 to 5 years after vaccination, vaccine effectiveness is considerably lower. That also 

correlates with waning group-specific antibodies that have been observed. Meningococcal 

disease is also very specific in terms of not being able to mount a memory response prior to 

developing disease. For that reason, it actually correlates even better than perhaps other 

conjugate vaccines do. 

Regarding antibody titers and not downgrading because of indirectness, Dr. Campos-Outcalt 

pointed out that there are good clinical outcome data showing that those antibody levels are 

protective. 

Peter Paradiso (Pfizer) said that having spent the last 4 to 6 weeks immersed in this evidencebased approach and trying to learn it, he thought Dr. Schuchat’s comment about a vaccinespecific grading system was very important because manufacturers’ lives depend upon 

correlates of immunity for licensure of vaccines. There are two important issues to distinguish. 

For any of the meningococci, the percent of responders seems to be a correlate of immunity. 

Above a certain level there is efficacy associated with it. However, for many vaccines, it is 

showing non-inferiority to a vaccine that has proven efficacy and there is really nothing else that 

can be done besides that for these studies. That is considered a level of evidence that is as 

high as can be achieved. It is different with vaccines for which the level of evidence is about a 

response rather than a direct effect. In the consideration of how to adapt GRADE to vaccines, 

thought should be given not only to correlates, but also surrogates. Often it is the surrogate that 

can be compared to a vaccine that is proven to be efficacious. 

Public Comment 

Dr. Deborah Wexler 

Executive Director 

Immunization Action Coalition 

I am Dr. Deborah Wexler, the Executive Director of the Immunization Action Coalition (IAC). 

IAC is funded by several vaccine companies, in addition to the Centers for Disease Control and 

Prevention and that public. In the presentation this morning, I noted and was troubled by the 

language, “Routine vaccination is not recommended.” If I had a two-year old child, I would want 

my child to be vaccinated against meningococcal disease, even though the risk of disease 

would be low. These vaccines are FDA-licensed for use, they are safe, they are immunogenic, 

and individual parents may reasonably choose to have their child vaccinated. There is no 

reason to refuse a parent’s request for their child, but the statement, “Routine vaccination is not 

recommended” is a significant barrier to the child receiving the vaccine, because to a healthcare 

provider, this language may be interpreted as a prohibition to administering it. An additional 

permissive statement, “The provider may administer the vaccine to a child if the parent wishes 

it,” should be included in the recommendations to clarify that these FDA-licensed vaccines may 

be administered in these situations. Thank you. 

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Discussion 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Frankie Milley 

National Director 

Meningitis Angels 

We do receive money from some pharmaceutical companies and also the public. I also have 

parents who call me on a daily basis almost, especially from Oklahoma, “I took my child to the 

doctor. We’ve had a family member die with this or be left debilitated with this disease. We had 

an outbreak. I took my 5-year old and the doctor refused to give me the vaccine because he 

said it’s not recommended.” Now, my idea for that is to take a piece of paper and make him 

sign it guaranteeing you your child won’t get sick and that he’s refusing you the vaccine. Of 

course, I’m sure all of the doctors in the room are going, “Ahhhh.” But, I do agree with Dr. 

Wexler that there needs to be some wording so that physicians out there in the field understand 

that if a parent really wants this and they are willing to pay for it, they should have it. There is 

no reason why that child shouldn’t have it. My question, the real reason why I wanted to come 

up here, too, is I want to make sure that as you proceed with your grading, that you take into 

consideration the disease outcomes. Because meningococcal, unlike most other diseases, is 

so severe, so rapid, so deadly, so debilitating, I absolutely believe that when you grade these 

vaccines you have to take that into consideration. So, if the committee has not done that, I 

would urge you to please do that for the sake of all of our children. Thank you. 

Discussion Points 

Dr. Grogg (AOA) reported that a 4-month old died the previous week in Tulsa with 

meningococcal group Y disease. 

Dr. Marcy indicated that the working group has discussed adding language regarding persons 

wishing to protect themselves or their child against meningococcal disease, so this request has 

been heard and the working group intends to implement it. 

Measles, Mumps, Rubella (MMR) Vaccine 

Introduction 

Jonathan Temte, MD, PhD, 

University of Wisconsin 

Chair, MMR ACIP Working Group 

Dr. Temte indicated that the Measles, Mumps, Rubella (MMR) Vaccine Working Group’s terms 

of reference are to review all available data and discuss potential changes to the current 

recommendations, which are quite dated. To achieve this, the working group’s activities are to 

review epidemiology of measles, mumps, rubella, and congenital rubella syndrome (CRS); 

review the existing statements pertaining to MMR vaccine; review new data on MMR vaccine 

(e.g., safety and immunogenicity among persons with HIV; third dose for mumps outbreak 

control); and revise/update existing recommendations into a single comprehensive document. 

The MMR Vaccine Working Group’s recent activities to date have included: 1) reviewing 

measles vaccination policy, including reviewing immune response to measles vaccination at 

various ages for first dose and discussing the timing of vaccine dose in relation to measles; 2) 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

reviewing mumps vaccination policy, including reviewing the US mumps epidemiology and 

vaccination program; reviewing and discussing data from two studies that assessed the impact 

of a third dose of MMR vaccine on the course of the outbreak; and 3) reviewing rubella 

vaccination policy, including a review of the US rubella and CRS epidemiology and vaccination 

program. 

During this session, presentations were delivered on the following topics: 

 Update on the documentation of sustained elimination of endemic measles, rubella and 

CRS, US, December 2011 

 Background and epidemiology of mumps in the US 

 Impact of a third dose of MMR vaccine on the course of a mumps outbreak in Orange 

County, New York in 2009-2010 

 Third dose MMR intervention during a mumps outbreak in a highly-vaccinated population in 

Guam 2010 

 Summary of issues and discussion of options 

Dr. Temte referred participants to the February 3, 2012 edition of MMWR, which includes an 

excellent review on the progress of global measles control from 2000 to 2010. One of the 

highlights is going from an estimated number of deaths worldwide in 2000 of over 800,000 down 

to about 160,000 by 2008. 

Documentation of Sustained Elimination of Endemic 

Measles, Rubella and CRS, United States, 2011 

Dr. Mark Papania 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Papania reviewed US efforts to document the sustained elimination of endemic measles, 

rubella, and CRS, which is part of the Pan American Health Organization (PAHO) effort to 

document elimination of these diseases from the entire Western Hemisphere, which if 

confirmed, is quite an historic achievement. 

The goal is the elimination of endemic disease, which is defined as a chain of transmission of 

measles or rubella lasting 12 months or more. Elimination of endemic diseases does not mean 

there will be no cases. Imported cases with limited spread and even small outbreaks will 

continue to occur as long as the diseases are endemic elsewhere in the world. The US verified 

the elimination of endemic measles in 2000 and of endemic rubella in 2004. External panel 

reviews were conducted on the evidence of elimination and the extensive data and conclusions 

were published in a Journal of Infectious Diseases (JID) supplement for measles and a Clinical 

Infectious Diseases (CID) supplement for rubella. Tremendous progress has been made 

throughout the Americas, with the last endemic case of measles in the Western Hemisphere 

being reported in 2002 and the last endemic cases of rubella and CRS in 2009. Based on this 

success, PAHO is organizing formal verification and documentation of elimination of endemic 

measles, rubella, and CRS from the WHO region of the Americas. Each country in the region is 

working to assess their elimination status and producing a national report to be reviewed by an 

International Expert Commission. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

As part of this effort, CDC has conducted an assessment to confirm that elimination of endemic 

measles, rubella, and CRS from the US has been sustained from the time of the initial 

documentation to the present. The relevant data were compiled into a draft report and the 

information was reviewed with a panel of external experts in December 2011, including: Drs. 

Jonathan Temte, Christine Hahn, Alan Hinman, Bonnie Maldonado, and Peter Shulte. On the 

regional level, the process of documenting and verifying elimination of endemic measles, 

rubella, and CRS is well-advanced. Fourteen countries have submitted their final reports, and 

three more including the US, will submit their reports in February 2012. Five other countries are 

a little further behind. 

In terms of the overview of the evidence indicating that the elimination of endemic measles, 

rubella, and CRS from the US has been sustained, all incidences are extremely low. Reported 

measles cases have remained consistently below 1 case/million, and reported rubella cases 

have remained below 1 case/10 million. The majority of reported cases of both measles rubella 

are associated with importation. This includes internationally imported cases, and cases linked 

to importation by epidemiologic or virologic information. The remaining cases for which there is 

not an epidemiologic or virologic link to importation are considered to be unknown source cases. 

The number of reported unknown source cases of measles and rubella are insufficient to 

represent endemic chains of transmission. Although outbreaks are observed, they are small 

and of short duration. The coverage levels for measles, mumps, and rubella vaccine have been 

sustained at high levels for years. National serosurveys, such as the NHANES studies, have 

demonstrated high levels of population seropositivity to measles and rubella. Detailed 

molecular epidemiology has shown no endemic strain of measles or rubella virus in the US, and 

the surveillance system for measles and rubella is adequate to detect endemic disease if it were 

occurring. Dr. Papania briefly reviewed most of the lines of evidence of the elimination. 

Base on the data reviewed for 2001 through 2011, for measles, 40% of the reported cases were 

imported and 88% were importation-associated. Internationally imported measles cases occur in 

persons who were outside of the US during their exposure period. Import-linked cases have a 

documented epidemiologic link to an imported case. Imported virus cases do not have an 

epidemiological link to an imported case, but do have genotype information indicating an 

association to importation. Taken together, imported, import-linked, and imported virus cases 

are considered importation-associated cases and constituted 88% of reported measles cases 

from 2001 through 2011. The remaining 12% of cases are unknown source cases. In these 

cases, measles transmission occurred in the US. However, an epidemiologic link to importation 

was not detected, and there is no genotype information on these cases. It is possible and even 

likely that these cases spread from imported measles cases through an undetected link or chain 

of transmission. However, these unknown source cases must be carefully assessed to 

determine whether they might represent an endemic chain of transmission. It is important to 

note that the amount of spread from imported cases was limited, with 84% of imported cases 

resulting in no reported spread cases and only 7.5% resulting in outbreaks. The same 

definitions of importation status are used for rubella. From 2004 to 2011 there were extremely 

low numbers of reported rubella cases, with less than 20 cases reported per year. For rubella, 

38% of cases were imported and 53% were importation-associated from 2004-2011. Rubella 

unknown source cases averaged only 6 cases per year. The very low number of reported 

rubella cases makes secondary analysis somewhat less critical than for measles; therefore, Dr. 

Papania focused primarily on measles for the remainder of his presentation. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

For the period from 2001 through 2011, a total of 106 unknown source cases of measles were 

reported. Only 66 counties reported an unknown source case and only 17 counties reported 

more than 1 unknown source case in this period. In each of these situations, the reports of 

unknown source cases occurred in a restricted timeframe, with the remainder of the year having 

no additional reported unknown source cases. Los Angeles County had the most reported 

unknown source cases, with 9 cases reported total in 5 different years. For measles for this 

time period, only 16 outbreaks had more than 10 cases and the maximum number of cases was 

34 cases. Of these outbreaks, 13 had documented imported sources and 3 had genotype 

information indicating an imported virus. The longest outbreak lasted 11 weeks. For rubella, 

there were only 2 outbreaks which included 3 cases, and there were no outbreaks with more 

than 3 cases. 

The National Immunization Survey (NIS) has documented MMR 1-dose coverage of over 90% 

among children 19 through 35 months of age for the period 2001 to 2011. Adolescent coverage 

with 2 doses of MMR has been added to the survey since 2008 and runs around 90% [2010 

National Immunization Survey for children and teens, available at http://www.cdc.gov/vaccines/ 

stats-surv/imz-coverage.htm]. Serosurveys conducted from 1999 through 2004 as part of 

NHANES demonstrated an overall measles seropositivity of 95.9% among the noninstitutionalized US population aged 6 years and older, with the specific estimates of 

seropositivity for different birth cohorts shown in the following table: 

Birth Year 

Cohorts 

1949-1966

Participants 

(N) 

 3360 

Seropositive Proportion, % 

(95% CI) 

96.6 (95.5-97.5) 

1967-1976 2321 92.4 (90.8-93.9) 

1977-1986 5288 96.4 (95.5-97.2) 

1987-1998 5080 97.7 (96.4- 98.6) 

All Cohorts 16,049 95.9 (95.1-96.5) 

The overall seroprevalence of rubella antibody in persons 6 through 49 years of age in the 

NHANES surveys conducted from 1999 through 2004 was 91.3%. 

Much of the evidence for elimination of measles and rubella is based on data from the 

surveillance system, so it is critical to assess the adequacy of surveillance. It is known that the 

US surveillance system does not detect all measles or rubella cases, and unfortunately, there 

are not precise measures of the completeness of reporting. However, the question for this 

elimination assessment is whether the surveillance system in the US would detect endemic 

transmission if it were occurring. There is evidence to suggest that the system is adequate. 

The US system consistently detects imported cases, which can be the most difficult cases to 

detect because many of the cases occur in foreign visitors who are unfamiliar with the US health 

care system and may be unlikely to seek care before returning home. The US surveillance 

system detects isolated cases and small chains of transmission; therefore, it would be unlikely 

that the system would fail to detect the large chain of transmission which endemic disease 

would require. Although the surveillance system is passive, waiting for reports from providers, a 

report of a suspected case activates rapid public health response with active investigation and 

response through contact tracing. Anecdotally, this active investigation only detects a few 

unreported cases found retrospectively. The US does not monitor the numbers of suspected 

cases investigated and discarded or the numbers of IgM tests performed, which would be 

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measures of surveillance effort. However, there is a substantial IgM testing volume as 

evidenced by CDC confirmatory testing volume. Very few cases of measles or rubella are 

confirmed, even in the presence of substantial testing. 

Upon review of the draft report, each external expert concluded that elimination of endemic 

measles, rubella, and CRS from the US has been sustained. The US National Report on 

Elimination of Endemic Measles, Rubella, and CRS has been refined based on suggestions 

from the expert panel, is currently in CDC clearance, and will be submitted to the PAHO 

International Commission for review this month. 

Discussion Points 

Dr. Temte emphasized the fragility of the public health system in the US and the overwhelming 

importance of surveillance capacity. He keeps hearing at various meetings how budgetary 

issues are affecting public health, and issued a plea for people to be wise in application of public 

funds to support efforts that have really had tremendous impacts on health in this country. 

Dr. Baker concurred with the need to continue to strengthen, not weaken, the US public health 

system at the federal, state, and local levels. 

Dr. Orenstein noted that this point is exactly why a working group of the National Vaccine 

Advisory Committee was constituted to determine what is really needed for the non-vaccine side 

of public health, which would include surveillance. 

Mumps in the United States: Background and Epidemiology 

Albert Barskey, MPH 

Division of Viral Diseases 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Mr. Barskey presented on the background and epidemiology of mumps in the US, discussing 

the pre-vaccine era (1917-1967), vaccine implementation (1968-1982), mumps resurgence 

(1983-1992), the first national outbreak (1993-2008), the second national outbreak (2009-2011), 

and recent mumps vaccine performance. 

Mumps is an acute viral illness that can present with classic symptoms, including parotitis (60%­

70%), orchitis (30% in post-pubertal males), and fever. Other symptoms include non-specific 

respiratory symptoms (40%-50%) and other salivary gland swelling (10%). Complications can 

include deafness (4%), aseptic meningitis (1%-15%), and encephalitis (0.03%). Up to 30% of 

cases can be asymptomatic. 

The mumps vaccine used in the US was licensed in 1967. It is composed of a live, attenuated 

mumps virus. The Jeryl Lynn strain is used in the US, and that virus is of the Genotype A. The 

vaccine effectiveness estimates ranges are wide. One dose is approximately 77% effective, 

and two doses are approximately 88% effective [Schaffzin JK et al. Pediatrics. 2007;120:e862­

8, Marin M et al. Vaccine. 2008;26:3601-7, Cohen C et al. Emerg Infect Dis. 2007;13:12-7, 

Deeks SL et al. CMAJ. 2011;183:1014-20, Dominguez A et al. Vaccine. 2010;28:3567-70, 

Sartorius B et al. Euro Surveill. 2005;10:191-3, Harling R et al. Vaccine. 2005;23:4070-4]. 

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In the pre-vaccine era, peak incidence occurred in 5 to 9 year-olds,, and 90% of children were 

infected by age 141

. Most cases occurred in late winter and spring2. There were no remarkable 

geographic patterns3

. Most adult disease was associated with outbreaks in the military2,3. 

Mumps was a significant cause of aseptic meningitis4

 [1Collins SD. Pub Health Rep. 1929; 

44:763-826; 2

Gordon JE. Am J Med Sci. 1940; 200:412-28; 3Gordon JE. Am J Med Sci. 1949; 

218:338-59; 4

USDHEW. Mumps Surveillance: Report No. 1. 1968]. 

With regard to reported annual incidence of mumps in the pre-vaccine era, epidemic peaks 

occurred about every three years. In terms of the reported monthly cases of mumps in the US 

during the vaccine era, during the vaccine implementation period, there was a 97% reduction in 

reported cases. Notably, there was a remarkable decline in cases even before ACIP made a 

routine recommendation for 1 dose of mumps vaccine in 1977. A resurgence occurred in the 

late 1980s and early 1990s. This was marked by an increase in cases in 10 to 19 year olds. In 

the early 2000s, mumps appeared to be nearly eliminated from the US until a large multi-state 

outbreak occurred in 2006. The outbreak occurred in a population with high 2-dose vaccine 

coverage. A few years later, a second multi-state outbreak occurred also in communities with 

very high 2-dose vaccine coverage. 

Taking a closer look at the period of the resurgence from 1983-1992, some late winter and 

spring seasonality was apparent. The increase in mumps cases occurred in two waves. There 

was an abrupt rise and fall in incidence in 1986-1987, and a slow return to baseline incidence 

from 1988-1992. The 1986-1987 resurgence was attributed in an increase in susceptibility 

among older children who had not been vaccinated, but who had been spared previous disease 

exposure by declining mumps incidence1

. During 1988-1992, outbreaks associated with 1-dose 

vaccine failure were first reported.2-4 [1

Cochi SL, et al. Am J Dis Child. 1988; 142:499-507; 

2

Hersh BS, et al. J Pediatr. 1991; 119:187-93; 3Cheeck JE, et al. Arch Pediatr Adolesc Med. 

1995; 149:774-8; 4

Briss PA, et al. J Infect Dis. 1994; 169:77-82]. 

In December 1989, ACIP recommended a second dose of measles vaccine for improved 

measles control. ACIP suggested that it be administered as MMR, stating that “Mumps 

revaccination is particularly important.” Effectively, this was a recommendation for a second 

dose of mumps vaccine [1

ACIP. MMWR Morb Mortal Wkly Rep. 1989; 38(S-9):1-18]. 

Through the early 2000s, there were signs of elimination. Disease incidence fell to less than 1 

per million. Vaccination coverage was higher than the estimated herd immunity threshold. No 

seasonality was apparent, and there were no locations of sustained transmission. However, in 

2006 there was a sharp rise and fall of cases, particularly in the Midwest. This was the first 

multi-state outbreak attributable to 2-dose vaccine failure. Young adults 18 to 24 years of age 

were most affected. Most were college students, almost all had had 2 doses of vaccine, most 

had received vaccines more than 10 years previously, and dormitory living and freshman class 

status were seen as risk factors. The outbreak was geographically focused, and there was a 

sudden onset and sudden decline of cases. ACIP issued a formal recommendation in 2006 for 

2 doses of a mumps-containing vaccine for school-aged children grades K-12 and adults in high 

risk groups (e.g., healthcare facility workers, international travelers, and students at post-high 

school educational institutions [ACIP. MMWR Morb Mortal Wkly Rep. 2006; 55(22):629-30]. 

A second national outbreak occurred between 2009-2010. There was an abrupt epidemic rise 

and fall of cases during the outbreak period. This was the second multi-state outbreak in 

communities with high 2-dose vaccine coverage. Of the cases, 97% occurred within an 

Orthodox Jewish community. Adolescent males 13 to 17 years of age were the most affected 

demographic group. Approximately 90% had received 2 doses of the vaccine. Unique school 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

settings and large households were conducive to mumps transmission. Boys attend Yeshiva, or 

religious schools, where Orthodox Jewish boys study religious texts beginning at approximately 

age 12 years. School days were long, lasting up to 15 hours per day. Learning was interactive, 

often involving a Chavrusa, meaning friend or study partner. Partners sit across narrow tables 

to study texts. The format is close, face-to-face, and often animated. Several pairs sometimes 

sit at a single table. During the course of a single day, partners may rotate for several different 

sessions. These unique school settings and large households appeared to be conducive to 

mumps transmission. It appeared that prolonged, intense exposures likely overcame the 

protection afforded by the vaccine. Also in 2010, a large mumps outbreak occurred on the 

island of Guam. Many school children 9 to 14 years of age represented the most affected age 

group. Kindergarteners through middle school children attending public school had at least 95% 

coverage with 2 doses of MMR vaccine. 

Regarding recent mumps vaccine performance, the effectiveness of 1- and 2-dose mumps 

vaccine measured in recent outbreaks was compared. For 1 dose, the median effectiveness 

estimate was 77% and for 2 doses was approximately 88%. 

A study was conducted by Cohen et al in the United Kingdom (UK) during 2004-2005. This 

study took place during a time when over 50,000 mumps cases were reported in the UK in 

2005. The overall vaccine estimate was 88% for 1 dose and 95% for 2 doses. However, for the 

first dose, vaccine effectiveness declined from 96% in 2-year olds to 66% in 11 to 12 year olds. 

For the second dose, vaccine effectiveness declined from 99% in 5 to 6 year olds to 86% in 11 

to 12 year olds [Cohen C et al. Emerg Infect Dis. 2007;13:12-17]. If one assumes that age is a 

reasonable proxy for time since vaccination, then these results suggest waning immunity of full 

mumps vaccine. 

Several biological studies have been conducted to assess the duration of immunity for the 

mumps vaccine; however, correlates of protection are not well-defined. It has been shown that 

seropositivity declines over time1

, neutralizing antibody titers decline over time2, and cellular 

immunity declines less than seropositivity over time3 [

1

Davidkin I et al. J Infect Dis. 

2008;197:950-6; 2

LeBaron CW et al. J Infect Dis. 2009;199:552-60; 3Jokinen S et al. J Infect 

Dis. 2007;196:861-7]. 

In terms of these outbreaks, more than waning immunity seems to be at play. Waning immunity 

does not explain certain facets of these outbreaks, including the geographic focal nature of the 

outbreaks and the fact that in several of these outbreaks, the oldest vaccinated cohorts were not 

always the most affected. Factoring in intense exposure settings accounts for the focal nature 

and why some of the oldest cohorts were not the most affected. 

In summary, prior to use of the mumps vaccine, mumps was a universal disease of childhood. 

Use of the mumps vaccine reduced disease levels by more than 95%. The current 2-dose 

schedule is sufficient for mumps control in the general population, but outbreaks can occur in 

well-vaccinated communities. Intense exposure settings and waning immunity appear to be risk 

factors for secondary vaccine failure. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

The Impact of a Third Dose of MMR Vaccine on the Course of a 

Mumps Outbreak: Orange County, New York: 2009–2010 

Preeta K. Kutty, MD, MPH 

Measles, Mumps, Rubella and Polio Team 

Epidemiology Branch, Division of Viral Diseases 

Centers for Disease Control and Prevention 

Dr. Kutty noted that there is no current ACIP recommendation for a routine third dose of mumps 

vaccine in any setting. Prior to this intervention, the effect of a third MMR vaccine dose in 

outbreak settings has not been evaluated. In this presentation, Dr. Kutty reviewed the 

epidemiology of the Orange County outbreak, the third dose MMR vaccine intervention, selfreported adverse events following the receipt of the third dose, and the economic burden of this 

outbreak on public health. 

Of the four locations affected by the 2009-2010 Northeast mumps outbreak, Orange County had 

approximately 20% of the reported mumps cases. The outbreak was limited to a village in 

Orange County. As per the 2010 US Census, the affected village in Orange County had a 

population of 20,363 and a median age of 10.6 years. It is comprised predominantly of an 

Othrodox Jewish population. The average household size is more than twice the national 

average of 2.6, which can lead to crowded living conditions. There are 4 main physician 

practices in the village, of which two see greater than 90% of the residents. 

Reporting of mumps is mandatory in New York State [New York State Sanitary Code 

(10NYCRR 2.10,2.14)]. Active surveillance was instituted by Orange County Health 

Department after the report of the first case of mumps. They contacted the 4 physician 

practices as well as the households of the mumps cases. To define a mumps case, the 

standard CSTE case definition was used. During the outbreak period from September 1, 2009 

through June 30, 2010, 790 mumps cases were reported by Orange County to CDC. The 

median age was 14 years, with 64% being male. Approximately 70% of the reported mumps 

cases had received two doses of MMR vaccine, and approximately 57% were 11 to 17 years of 

age. A large percent of the mumps cases reported being exposed in schools and homes. 

Among the post-pubertal males 6.4% had orchitis, and among those tested for mumps IgM, 

18% were positive (n=231). The Genotype was G, similar to the genotype in the UK. 

A study was conducted to determine whether administration of a third dose of MMR vaccine in a 

highly vaccinated population is an effective strategy for controlling mumps outbreaks. IRB 

approval by CDC and New York was required for this intervention since there was not an ACIP 

recommendation. Given that the attack rate was highest among 11 to 17 years old, the 

intervention was conducted among 6th through 12th graders. Inclusion criteria for schools were 

on-going mumps transmission in preceding 2 weeks and high 2-dose MMR vaccine coverage. 

The weighted vaccine coverage was 94.3%. Criteria for student eligibility were no previous 

history of mumps and no previous history of a third MMR vaccine dose. A third dose of MMR 

vaccine was offered to assenting students who also needed to obtain informed consent from 

their parent or guardian. 

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Considering the incubation period of mumps, the analysis used three time periods of 21 days 

(e.g., pre-vaccination, post-vaccination phase 1, and post-vaccination phase 2). Analyses were 

conducted at the student level as well as the village level. For the student level analysis, the 

three time periods were based around each student’s vaccination date. At the village level, the 

time periods were defined around the vaccine intervention period of January 19th through 

February 2nd. Age specific attack rates/1000 were calculated using the following formula: 

No. of mumps cases in an age-group during a given time period 

Population at risk [US Census 2010] in that age-group during the same time period 

The intervention was conducted in 3 schools that fit the criteria; schools were provided with the 

vaccine. Of the children in the village, 98% attended one of these 3 schools. Prior to providing 

the vaccine to these students, a baseline survey, vaccine information, and informed consents 

were distributed. The baseline response rate was 94%. Of these, 89% (n=2178) had validated 

2 doses of MMR vaccine, and 81% (n=1755) received a third dose. To determine the attack 

rate among 6th through 12th grade students before and after the third dose MMR vaccine 

intervention, the pre-vaccination period was compared to the post-vaccination phase 2. The 

overall attack rate of 4.93% during the pre-vaccination period showed a significant decline 

during the post-vaccination phase 2 of 0.13%. There were very few cases in post-vaccination 

phase 2. 

Next, students with 2 previous MMR vaccine doses were assessed. The attack rates in the 

post-vaccination phase 1 and phase 2 periods were compared. The attack rate of students who 

received a third dose significantly declined from 1.6% to 0.06%. While among those who did 

not receive a third dose there was a decline from 1.7% to 0.5%, this decline was not significant. 

However, during the post-vaccination phase 2, the attack rate was 8-fold lower among 

vaccinated students, although the difference was not statistically significant (0.06% versus 

0.48% respectively, RR: 0.12 (95% CI: 0.01, 1.32; P=0.097). This finding may be because of 

the very low numbers of mumps cases in the two groups. The incremental effectiveness of the 

third dose of vaccine was 88.0%, with a large confidence interval that included 0 (95% CI: ­

31.9% to 98.9%). 

At the village or population level, the pre-intervention and post-intervention phase 1 period were 

compared. There was a 76% percent decline in the attack rates when the pre-intervention 

period was compared to the post-intervention phase 2 period. The attack rate in the targeted 

age group 11 to 17 years showed 96% decline, the highest among all age groups. The other 

age group where a decline was observed was among 5 to 10 year olds (73% relative decline). 

The relative decline in attack rates in the 11 to 17 year age group was significantly greater 

(P<0.005) than that in any of the other 4 age groups. There was a significant decline in the 

attack rate during and after the intervention. The other age group that showed a significant 

decline was the age group 5 to 10 years of age, though the decline was more gradual. 

To see how the situation looked overall, the following graphic shows the epidemiological curve 

of the 790 mump cases by week of parotitis onset, reported in Orange County from September 

1, 2009 through June 30, 2010. The red box indicates the 2-week period when the 3rd dose of 

MMR vaccine was offered to eligible 6th through 12th grade students at participating schools. 

There is a decline of mumps cases during and after the intervention: 

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The investigators returned to Orange County in April 2010 to conduct a follow-up survey, which 

also captured information on adverse events. Of the 1755 who received the third dose of MMR 

vaccine, 91% returned the follow-up survey. Of these, 7.2% (n=115) self-reported at least one 

adverse event, and 17 reported seeking medical attention. However, on further follow-up, none 

were related to the vaccine. In addition, a comprehensive search for serious adverse events 

following MMR vaccination was conducted using physician records, physician billing services, 

and VAERS. Among the serious adverse events self-reported, 3.6% reported pain, 1.8% 

arthralgia, 1.7% dizziness, and 1.3% fever. A literature review was then conducted. The 

proportions of adverse events found in the present study were lower than or within the range of 

those reported in prior studies of first- and second-dose MMR vaccine studies using Jeryl-Lynn 

strain, indicating that it is at least as safe as the first and second of MMR vaccine. 

To evaluate the economic burden, the outbreak and response activities performed, personnel 

time/materials allocated, third dose MMR vaccination intervention, laboratory testing, and direct 

costs incurred in 2010 US dollars by the New York State Health Department and Orange 

County Health Department were examined. The study period for this assessment was from 

September 24, 2009 (when the OCHD was first contacted about the mumps outbreak) through 

June 15, 2010 (when the outbreak ended). Chronological descriptions were obtained from each 

involved institution. Personnel time was based on the hours allocated to containment obtained 

from written chronological reports with the personnel in the involved institutions. Personnel time 

was converted to costs by using the reported gross wage of each individual, plus fringe benefits 

when available. Overhead costs were based on the number of person-hours and each 

institution’s accounting method. A total of 7736 hours of personnel time were expended, of 

which 3656 hours (47.3%) were by New York State Health Department and 4080 hours (52.7%) 

were by Orange County Health Department. The total estimated cost was $463,202, of which 

89% was attributable to personnel costs and overhead. The third dose MMR vaccine 

intervention cost $34,392. 

There were several limitations to the study. The mumps outbreak was probably on the decline 

when the intervention was conducted. There was not a large comparison group due to the high 

uptake of the vaccine. There was a small number of mumps cases post-intervention. This 

study is not generalizable, given that it was conducted in a specific population. In addition, the 

economic survey was done retrospectively. 

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In summary, further declines in incidence of mumps cases were observed after administration of 

a third dose of MMR vaccine. Although the decline was seen in many age groups, the most 

pronounced was in the age group targeted (e.g., 11 to 17 years of age), which showed 96% 

percent decline. The adverse events reported post-vaccine were found to be lower than or 

within the range of those reported in prior studies of first- and second-dose MMR vaccine. Use 

of a third dose of MMR vaccine to control the outbreak as routine control measure may be 

effective, especially when other routine measures are not effective. 

Third Dose MMR Intervention During a Mumps Outbreak 

In a Highly-Vaccinated Population in Guam: 2009-2010 

CDR Amy Parker Fiebelkorn, MSN, MPH 

Epidemiology Branch, Division of Viral Diseases 

Centers for Disease Control and Prevention 

CDR Fiebelkorn described the epidemiologic characteristics of the Guam mumps outbreak; the 

impact and adverse events of a third MMR dose for mumps outbreak control; and the economic 

impact of the outbreak response on the local public health sector and affected families. 

Guam is an organized, unincorporated territory of the US located in the Pacific Ocean. The 

2010 population was more than 180,000 persons. The median household size is 3.9 persons 

compared to the US mainland, which is 2.6 persons. The median household income on Guam 

is approximately $40,000 compared to nearly $50,000 on the US mainland. Guam follows ACIP 

recommendations for MMR vaccination [Guam 2008 Statistical Handbook]. 

Mumps is a reportable disease in Guam. The Guam Department of Public Health and Social 

Services and CDC implemented active surveillance of schools, daycares, select provider clinics, 

and laboratories. Cases were reported to the health department on a daily basis. Daily 

reporting forms were completed, including zero reporting. If these were not received, phone 

calls were placed to follow up on the information. Educational sessions were held for all those 

involved in active surveillance. 

Once a case was identified using the standard CSTE mumps case definition, a case report form 

collected basic demographics, diagnostic methods, illness course and complications, and 

vaccination history. Age-specific attack rates were calculated using projected 2010 Guam 

population data. For schools, school enrollment data were used. Vaccination coverage was 

assessed in schools via electronic records of all students enrolled in public schools. For all 

case-patients, vaccination verification was obtained from health-care providers. Laboratory 

tests that were used to confirm cases included mumps IgM, RT- PCR, and viral cultures. 

Mumps viral sequencing and genotyping analyses were performed at CDC. 

The outbreak period was defined as December 7, 2009 when the index case imported mumps 

from Pohnpei through December 31, 2010. During that time period, 505 cases were reported. 

The epidemic curve shows the peak of the outbreak occurring in April and May of 2010. Of the 

505 cases reported, 50% were males; the median age was 12 years, with a range of 2 months 

to 79 years of age; and 34% self-reported Chamorro ethnicity, the predominant ethnicity on 

Guam. There were 5 (3.3%) reports of orchitis among post-pubertal males, 2 (0.4%) 

hospitalizations, and no deaths. Of 312 specimens tested, 60 (19%) were IgM+ and 28 (82%) 

of 34 specimens sent to CDC were positive by RT-PCR. Genotype G was identified, but was a 

different lineage than the strain identified in the Northeast outbreak. 

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When compared with the Guam population, mumps case patients were statistically more likely 

to be 9 to 14 years of age, with a risk ratio of 16.2 and an attack rate of 8.4. Mumps case 

patients were also more likely to have reported their ethnicity as Chuukese or Pohnpeian, both 

of whom are the ethnic minority populations on Guam. Of the total 505 cases, 169 were among 

the 9 to 14 year old age group. 

CDC obtained IRB approval to administer a third dose of MMR vaccine, because a third dose in 

an outbreak setting is not currently an ACIP recommendation. Schools were eligible for the 

third dose MMR intervention if they had greater than 90% 2-dose MMR vaccine coverage 

confirmed by review of school vaccine records, evidence of on-going mumps transmission in the 

previous two weeks, and a mumps attack rate greater than 5 per 1000. An individual student 

was eligible for the intervention if he or she had no history of mumps or receipt of a third dose of 

MMR vaccine. Additionally, consent was required from the parent and assent was required 

from the child. 

A baseline survey was conducted at the time of the intervention in May, and a follow-up survey 

was administered in October among all students eligible for the third dose. On both surveys, 

information was collected on demographics, whether the child participated in the third dose 

intervention, and self-reported mumps and complications. On the follow-up survey, information 

was also collected about self-reported adverse events following immunization. 

The pre-intervention attack rate was highest among children aged 9 to 14 years in 7 schools. 

There were 4 elementary and 3 middle schools. These 7 schools were selected for participation 

in the MMR third dose intervention. These 7 schools also had evidence of on-going recent 

transmission, with attack rates ranging from 8.4 to 31.5 per 1000, as noted in the second to last 

column in the following table, and evidence of high 2-dose vaccination coverage, as noted in the 

last column: 

There were 3241 eligible students ages 9 through 14 in grades 4through 8 at the 7 selected 

schools in May 2010. Of these, 1067 (33%) received a third dose of MMR vaccine, and 2447 

(75%) eligible students returned a baseline and / or a follow-up survey. There were statistically 

significant differences between survey respondents who received the third dose and those who 

did not. Those receiving the third dose were more likely to be female, uninsured, and in the 

lower grades compared with those who did not receive the third dose. 

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With respect to mumps by age group and by time, the week of the third dose intervention 

occurred after the peak of the outbreak on May 14-27. There was an attack rate of 2.4 per 1000 

among 2-dose vaccinated students, and 0.9 per 1000 among 3-dose vaccinated students more 

than one incubation period post-intervention. When any case that occurred more than one 

incubation period following the intervention was included, 6 students in the intervention schools 

reported mumps. Of these students, 1 had received a third dose and 5 had not. Students who 

had 3 doses of MMR vaccine had a 2.6 times lower mumps attack rate compared with students 

who had 2 doses of MMR vaccine, but the difference was not statistically significant. On the 

population level, the 9 through 14 year age group had the largest relative percent decline in 

age-specific mumps attack rates during the second post-intervention period compared with preintervention at 84.4%. However, other age groups also showed significant declines. Overall, 

there was a 70.7% decline among all age groups during the second post-intervention period 

compared with the pre-intervention period. 

Regarding self-reported adverse events among those who received a third dose of MMR 

vaccine who responded to the survey, the most frequently reported adverse events were 

dizziness at 2.6% and pain and redness at the injection site and joint ache, both at 2.4%. Of the 

students responding, 32 (6.0%) indicated any adverse events. There were no life-threatening 

adverse events reported, and no medical attention was sought related to the vaccination. 

The next objective was to describe the economic impact of the outbreak response on the local 

public health sector and affected families. An economic survey was conducted from a public 

health perspective. It included all departments and individuals directly involved in the outbreak 

response, including Guam Department of Public Health and Social Services (DPHSS) and 

school nurses. The covered activities, from the time of first case reports in February 2010 

through October 22, 2010 (the time of the follow-up survey), included in the survey were hours 

spent, overhead costs, travel, telephone calls, salaries, and vaccine use. For the economic 

survey from the public health perspective, there were 73 people directly involved in the public 

health outbreak response. An estimated 8264 hours were spent controlling the outbreak, with 

DPHSS staff accruing 7484 hours (90% of the total hours). An estimated $281,856 was spent 

on the outbreak response (DPHSS: $261,798; School Nurses: $20,058). 

For the economic survey from the household perspective, telephone questionnaires were 

administered to persons affected with mumps or their parents/guardian if the affected person 

was a minor. Participants were taken from the Guam DPHSS outbreak case investigation 

database. The sample size was 102 persons. The first 20 cases and the last 82 cases of the 

outbreak were samples to assess change in the cost of the illness over the course of the 

outbreak. The survey included information on medical consultation fees, transport to a clinic, 

the number of days the case-patient or parent missed work due to mumps, cost of medications, 

and any hospitalization related to mumps. Of the responders, 95 (93%) sought treatment from a 

healthcare provider at a median cost of $20 per case for all visits, 87 (85%) incurred travel 

expenses for medical consultations at a median cost of $5 per case, 52 (51%) bought 

medications for their symptoms at a median cost of $10 per case, and 48 (47%) reported 

missing work an average of 4.6 days. The median cost per family for days lost from work was 

$601. The total median cost for the household for a typical mumps patient was $636. 

This investigation is subject to several limitations. The intervention occurred after the peak of 

the outbreak. The small numbers of mumps cases in the intervention population make it difficult 

to draw conclusions on vaccine effectiveness. Although active surveillance increased reporting, 

there was likely a fair amount of under-reporting of cases, especially when school was not in 

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session. There were differences between vacinees and non-vaccinees, making the findings 

non-generalizable. The economic surveys were retrospective. 

In summary, this was the largest reported mumps outbreak on Guam in 52 years and the third 

largest mumps outbreak in the US since 2005. The Guam outbreak occurred primarily in 

school-aged children despite high two-dose MMR coverage, and disproportionately affected 9 to 

14 year olds in seven schools. After the third dose intervention, the relative percent decline of 

mumps attack rate was 70.7% among all age groups and 84.4% among all 9 through 14 year 

olds. The post-intervention attack rate was lower for students who received the third dose 

compared with those who did not, but the intervention occurred after the outbreak peaked and 

findings were not statistically significant. The mumps outbreak response imposed a large time 

burden and cost on local staff and affected families. These findings do not provide conclusive 

evidence on impact of a third dose for outbreak control, but are consistent with potential impact. 

Summary of Issues and Discussion 

Dr. Huong McLean 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. McLean presented a summary of the issues and the working group considerations for use of 

a third dose of MMR vaccines for mumps control. The US experienced large mumps outbreaks 

in 2006 with over 6500 cases reported and in 2009-2010 with approximately 3500 cases among 

highly 2-dose vaccinated populations. Mumps outbreaks among highly 2-dose vaccinated 

populations are likely to occur in the future, given the effectiveness of 2 doses of mumps 

vaccine and the presence of endemic mumps throughout the world. Standard outbreak control 

measures, such as isolation of cases and vaccination of eligible contacts, have not been 

completely effective in controlling outbreaks in some situations. Currently, there is no 

recommendation for use of a third dose of MMR vaccine during mumps outbreaks. 

The two studies presented provide common findings with regard to the use of a third dose of 

MMR vaccine in outbreak settings. First, the target age group had the highest decline in attack 

rates following intervention compared to other age groups. In Orange County, there was a 96% 

relative decline among students aged 11 to 17 years. In Guam, there was an 84% decline 

among students 9 to 14 years of age. However, there were a number of limitations, including 

the timing of the intervention, which made it difficult to discern the effect of a third dose. A third 

dose of MMR vaccine appears to be safe. There were very few mild and no serious adverse 

events reported upon administration of a third dose of MMR vaccine in these studies. These 

vaccine interventions can be resource intensive. The cost to investigate the outbreak and 

implement the intervention was estimated to be $463,202 ($586/case) in Orange County and 

$281,856 ($558/case) in Guam. 

Given the limitations of the studies, the working group agreed that there was not enough data to 

support a firm recommendation for a third dose of MMR vaccine for routine outbreak control of 

mumps, and that more data are needed. However, the working group discussed the possibility 

of a statement to allow permissive use of a targeted third dose of MMR vaccine for mumps 

outbreak control in certain situations with appropriate guidelines. The working group discussed 

parameters to define the appropriate setting, high 2-dose coverage, and timing, specifically 

assessing minimum attack rate or number of reported cases and minimum number of 

generations as guidance for when an intervention would be appropriate. These parameters are 

meant to provide guidance, and are not strict requirements for intervention. 

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The first parameter discussed by the working group was the setting in which an intervention 

would be appropriate. Experience with previous outbreaks suggests the congregate 

environments with prolonged or repeated, intense exposures are important settings that may 

facilitate mumps transmission despite high 2-dose coverage and lead to large outbreaks. These 

settings include schools, colleges, correctional facilities, and residential or institutional settings. 

Future outbreaks in these closed settings would be appropriate for a third dose vaccine 

intervention. The working group also thought that targeting personnel in health facilities would 

be appropriate, given their potential to expose immunocompromised patients, although there 

have not been large mumps outbreaks in health facilities. 

The working group then discussed how high 2-dose coverage should be, and felt that over 90% 

coverage in the target group would be reasonable. The working group did not want to suggest a 

third dose if a population needed to catch-up on 2-dose vaccination coverage, because setting 

the coverage too high may not be practical. The working group considered national 2-dose 

coverage of MMR vaccine among adolescents aged 13 to 17 years, which is estimated to be 

90.5%1

 according to the National Immunization Survey. They also considered the estimated 

herd immunity threshold, which is about 85% to 92%2,3, and data showing MMR vaccine uptake 

in 3 large colleges to be 88% to 89% [1

MMWR. 2011; 60(33);1117-1123; 2Anderson RM, et al. 

Epidemiol Infect. Aug 1987;99(1):65-84; 3

Anderson RM, May RM. Nature. Nov 28-Dec 4 1985; 

318(6044): 323-329]. 

The last and most difficult issue the working group considered pertained to time in terms of 

when the intervention should be conducted. The working group preferred using an attack rate 

which is specific to the target population for vaccination with a minimum number of cases, which 

may vary depending upon the setting and the number at risk. An attack rate of 5 cases per 

1000 population at risk seems to be high enough above the background rate and is a 

reasonable starting point. Another aspect of timing was the number of generations, or ensuring 

that there was on-going transmission before initiating the intervention. The working group 

thought that mobilization of the intervention should start ideally after two generations of spread 

in the target group, especially since there may be unreported or asymptomatic cases. 

The Orange County mumps attack rate in 14-day intervals, which was just short of the median 

incubation period for mumps, was calculated for the 11 to 17 year old age group. In this case, a 

third dose of vaccine was administered after 7 generations of spread and over three months 

after the attack rate reached 5 per 1000. The guidelines presented suggest initiating the third 

dose after the second generation of spread when the attack rate in this population reached 5 

per 1000, which was in October instead of January. During this outbreak, there was sustained 

transmission for quite some time. In contrast, in the outbreak in Guam the total cases started to 

decline after several weeks. Because of delays in reporting, identification of the target 

population, and time to plan the intervention, by the time the third dose was implemented, the 

outbreak was declining. In a mumps outbreak at a college, the attack rate was over 5 per 1000 

with the first generation of cases, and over 5 per 1000 with the second generation as well. 

According to the guidelines presented, it would have been ideal to initiate a third dose 

intervention after the second generated had occurred at about mid-March. The last example is 

of a smaller mumps outbreak at another college. The attack rate almost reaches 5 per 1000 

during the first generation of cases, but the attack rates declined thereafter. In this case, a third 

dose intervention would not be warranted. 

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In conclusion, Dr. McLean requested that the ACIP members discuss whether permissive use of 

a targeted third dose for mumps outbreak control in certain situations would be reasonable, 

based on the guidelines presented (e.g., congregate environments with prolonged or repeated, 

intense exposure; >90% coverage with 2 doses of MMR in the target population; attack rate of 

> 5 per1000; and at least 2 generations of spread). 

Discussion Points 

Dr. Duchin commented that it was remarkable how rapidly the attack rate was decreasing 

before the intervention, but that some benefit was still found among those who were vaccinated 

compared to those who were not. He wondered whether those who were not vaccinated were 

assessed to determine whether they were at higher risk of disease (e.g., larger families). 

Dr. Kutty replied that the next step for the New York outbreak would be to assess risk factors for 

transmission. There are also plans to model the outbreak and apply the intervention at different 

time periods to determine what the outcomes would be. 

Dr. Sawyer observed that the interventions were late in the large outbreaks, and that both 

presentations emphasized that IRB approval was obtained for that. He requested clarification 

regarding whether that is really necessary in an outbreak, or whether it was sought simply 

because there was a research element to these efforts. It seems that this likely delayed the 

intervention, and people in general should not think IRB approval is required should they decide 

to administer a third dose since these are licensed products and a physician could choose to 

use it at their discretion even though it is not approved for this specific use. 

Dr. Wallace (SME) responded that IRB approval occurred relatively quickly in both of these 

cases, and it was done because of the evaluation aspect of understanding what the impact may 

be. In Guam, there were also delays in reporting. In Orange County, it was unclear whether 

vaccination was necessary because a number of these outbreaks have burned out on their own, 

but this one sustained. Once the decision is made to implement the intervention, community 

buy-in and mobilization and all of the logistics (e.g., acquiring the vaccine) must be put into 

place. This all takes longer than the IRB process itself. 

In the absence of ACIP making a formal recommendation, Dr. Sawyer wondered if it was correct 

that another jurisdiction could choose to give a third dose without involving an IRB. 

Dr. Wallace (SME) replied that there are examples of this. There have been situations that are 

not always couched as a third dose, because they did not document the first two doses. But 

groups have been vaccinated that likely have high 2-dose coverage. 

Dr. Baker requested a definition for “expedited,” because in her institution it means one month 

instead of two. 

Dr. Wallace (SME) said he thought it was shorter than that. This was CDC’s IRB along with 

New York or Guam. There were some issues with Guam, but it was very quick in these 

situations. 

Dr. Seward noted that in the Northeast outbreak, it is not so clear that the intervention was well 

after the peak. The bars were going all the way to the intervention. In some age groups, yes, 

the 18 to 24 year olds had certainly peaked. In Guam it is very clear in retrospect, but while it 

was on-going cases were being delayed, et cetera. From the CDC perspective on IRB, if 

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something is generalizable and an evaluation is being done, it is usually considered to be 

investigational research. Guidance was sought on that from CDC’s IRB. 

Dr. Sawyer noted that several studies were presented on vaccine effectiveness estimates, 

including the Cohen study from the UK in which both 1- and 2-dose vaccine effectiveness 

appeared to be over 90% at least early on. He wondered whether a conclusion should be 

drawn from this that the vaccine is less efficacious than some others, and whether there is 

research of alternative strains in the US. 

Dr. Barskey said he thought that Jeryl Lynn is one of the strains used in the UK, which is also 

used in the US. There have been similar vaccine effectiveness estimates for Jeryl Lynn as well. 

The study clearly shows that waning immunity is likely associated with the use of the mumps 

vaccine. 

Dr. McLean added that as far as vaccine effectiveness, Jeryl Lynn is the most studied. 

Dr. Seward indicated that the UK uses a derivation of the Jeryl Lynn strain, so it is essentially 

the same. 

Dr. Keitel agreed that this seemed to identify a research agenda for a more effective, long-lived 

vaccine. She was interested to see that some of the immune responses seemed to hold steady, 

which made her wonder whether anyone was assessing whether the history of vaccination 

modified the severity of disease. 

Dr. Barskey replied that there are preliminary results from the 2009-2010 outbreak in the 

Northeast, and a low rate of complications has been observed overall compared to estimates 

from the pre-vaccine era, and there are statistically significant results showing that orchitis was 

lower in vaccine recipients than in non-vaccine recipients. 

In the assessment of cost for the local and state health departments, Dr. Bennett wondered 

whether the investigators were able to distinguish between outbreak response costs and 

vaccination program development costs. 

Dr. Fiebelkorn (CDR ) replied that primarily during the period evaluated, all of the resources 

were diverted from routine vaccination activities to outbreak response activities. Therefore, 

efforts that were usually scheduled were delayed until the outbreak response period ended. 

The costs allocated were categorized (e.g., costs of administering the vaccine, other response 

activities, et cetera). 

Dr. Bennett suggested in the modeling assessing the costs that would have been saved by 

implementing the intervention sooner, preventing more cases, and having less outbreak 

management and more vaccination. It seems that this would be important in making a decision. 

Considering that and institution may have 80% coverage or 60% coverage, Dr. Marcy 

suggested dropping the word “third.” 

Dr. Wallace (SME) replied that this is the way it would be handled. If there was incomplete 

coverage, the first step would be to catch up 2-dose coverage first. In some interventions, 

people have been told that if they have any doubt or want to be vaccinated, they could go to the 

clinics being held. The point is if a group is going to be specifically targeted with a third dose, 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

there should be high coverage. Trying to raise overall immunity due to incomplete coverage is 

done routinely. 

Dr. Marcy said he was concerned about schools in various parts of the country where vaccine 

denial is fairly profound, and there may be 25% with no coverage. 

Dr. Seward responded that standard guidance already exists to address this type of situation. 

This is additional guidance to cover the unique outbreaks being observed in situations of high 

coverage of 2-dose vaccinated populations. In Guam, the major effort initially was to ensure 

that everyone was being caught up and that this was not an outbreak due to failure to vaccinate. 

Regarding the criteria for greater than 90% coverage, Dr. Duchin agreed that clearly an underimmunized population would be vaccinated. However, he would not want this interpreted that a 

third dose would not be given to people who had 2 doses and were part of a group that was 

largely under-immunized. He also thought it was remarkable that the rate of complications was 

very low in this vaccinated cohort. 

While Ms. Ehresmann understood that catch-up would be done for those with a lower rate of 

coverage; however, it was not clear why the 75% who already had 2 doses would not be given a 

third dose. 

Dr. Keitel inquired as to whether the isolates were being assessed for evidence of antigenic 

variation or other reasons they may be escaping vaccine protection. 

Dr. Wallace (SME) replied that this is routinely done. While there is some debate about this, 

there is no convincing evidence that drift or strain differences are the cause of the efficacy 

situations. Regarding the comment about high vaccine efficacy in some studies and lower in 

others, this really is more situation-dependent than vaccine- or strain-dependent. There seems 

to be something about certain situations that are able to overwhelm in some settings and not 

others. For instance, in the Northeast outbreak, despite the opportunity to get into the 

community, it never did. 

Dr. Jenkins asked whether lot numbers were assessed to determine whether there was an 

ineffective lot. 

Dr. Wallace (SME) replied that this issue arises, but nothing has ever been identified in terms of 

lot or storage issues. Orange County, lot numbers, storage records, and handling were 

assessed. There were no trends to show that there were any issues with this. 

Dr. Baker inquired as to whether in the New York outbreak girls and boys were offered the 

intervention. 

Dr. Kutty responded that the intervention was offered to both girls and boys in New York. 

Dr. Temte indicated that the working group had engaged in significant discussion regarding 

what appear to be very high levels of safety for the third dose. In terms of a potential vote in 

October, the working group will not be able to present clear evidence for efficacy based on the 

information available. However, they believe they can at least provide reassurance that this 

type of intervention has a high likelihood of benefit and is very safe. 

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Ms. Stinchfield (NAPNAP) said she was very happy to see the low degree of adverse events. 

She was curious after the third dose when the joint pain was reported. 

Dr. Kutty responded that in New York, they went through two incubation periods. But, the 

request to the parents was to report any adverse events within the 14 days post-vaccines. This 

is one of the limitations. Still, the parents were very aware of what was occurring so the 

response rates were very good. 

Dr. Hahn (CSTE) noted that health departments are always asked to do something when there 

is an outbreak, and this is obviously the kind of situation for which it is nice to know what the 

options might be. However, she requested that language be carefully worded to reflect that the 

evidence is quite weak so that health departments can consider this type of intervention to be a 

tool versus a mandate. 

Dr. Wallace (SME) agreed that there are real costs, even just in vaccine costs. This is why 

there was a great deal of discussion around these parameters. There are small clusters often, 

very few of which turn into outbreaks. However, this is very difficult to anticipate ahead of time. 

He agreed that they would not want to do this every time there were two or three cases, which 

was the rationale behind listing some parameters. 

Dr. Plotkin argued for a stronger recommendation. First, mumps is not measles and rubella. 

There are several differences, the most important of which is the fact that immunity does not last 

very long. Second, measles and rubella are being eliminated outside of the US. That is not the 

case for mumps. Relatively few countries are vaccinating against mumps and their coverage is 

not great. Therefore, the US is going to have introduction of mumps repeatedly into a situation 

in which the US vaccination is not going to be completely protective. The overall protective 

efficacy cited by Dr. Barskey is correct, but that is an overall estimate that does not take into 

account the interval between vaccination and exposure. As he showed from the British data, 

and from many other data because these epidemics are occurring elsewhere in the world 

besides the US and UK, the efficacy wanes with the waning of antibody. There has been 

discussion regarding the correlate of protection. There are older studies, notably by Frank Enis 

in a military population, that do show quite a good correlation with neutralizing antibody. The 

Cortese study also showed a correlation with neutralizing antibody, although there were 

breakthroughs such that the threshold was not absolute. A related point regards the strain in 

the vaccine and the circulating strain. It is true that there is a lot of controversy about this, but 

the facts are that the neutralization of the Iowa strain in vacinees is less than neutralization of 

the Jeryl Lynn, so when immunity wanes, heterotypic immunity wanes faster than against the 

vaccine strain. That creates another immunologic susceptibility. That does not mean that the 

genotypes correlate to serotypes, but nevertheless, there are significant differences in 

antigenicity between the vaccine strain and the circulating strain. Incidentally, the other mumps 

vaccine strains also show relatively low efficacy, but there has not been a lot of work following 

them. He thought it could be said that about 10 years after a first or second dose, there is a 

distinct drop in efficacy. The additional point is memory. A recently published study, which Dr. 

Plotkin thought was conducted by CDC, assessed B memory cells for the three different viruses 

in the MMR in previous vaccinees. Per million B cells, for rubella there were 5000 memory B 

cells, for measles 3000, and for mumps 300—barely above the threshold, so memory is not 

good. That does not mean that a booster response is not achieved with a third dose. His 

recommendation is, considering that there will be many introductions of mumps, third doses 

should be given at much lower levels than 5 per thousand and consideration should be given to 

a routine third dose recommendation for adolescents entering collectivity (e.g., college). It 

seems to Dr. Plotkin that the best way to prevent outbreaks is by administering third doses in 

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Discussion 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

situations in which immunity is known to have waned, youth are collecting, and importation is 

likely. 

Dr. Zucker, Assistant Commissioner for the Bureau of Immunization at the New York City Health 

Department, had similar epidemiology to what was observed in Orange County. She pointed 

out that if they overlaid their epi-curve with what was seen in Orange County, it would look 

essentially identical and they did not implement an intervention. She pointed this out as a 

caution in how these results are interpreted. They can assess their attack rate before and after 

the Orange County intervention to determine whether they saw similar declines in the 

magnitude. New York City would not be the ideal control group, but it may provide some 

additional evidence for what was occurring with the outbreak and what might be attributable to 

vaccine or not. Regarding the response of the health department, looking at the Orange County 

curve and when the 5 per 1000 occurred and when an intervention should be started according 

to the parameters, she did not think this would have been practical from a health department 

perspective because where the outbreak is going would be unknown. At that point, for New 

York City, there would have been a relatively low disease burden. This was all also occurring 

during H1N1, so it was difficult to mount another vaccine response. New York City had 

numerous discussions about whether to administer a third dose, and the pressure to do 

something. By the time they were even able to focus on that, they would have been past the 

peak of the outbreak. The practical nature of saying when to implement an intervention is 

always obvious in hindsight, but is not necessarily clear during the situation. 

Dr. Seward pointed out that these guidelines are just for consideration. They were not saying 

that if ACIP issued a permissive recommendation that at 5 per 1000 everyone had to implement 

the intervention. They absolutely recognize all of the points Dr. Zucker made. 

Day 2: Public Comment 

No public comments were offered on the second day of the February 2012 meeting. 

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Discussion 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Attendance Roster 

US Citizens 

Last First Citizenship 

Adams Kimberly United States 

Albright Karen United States 

Alexa Pam United States 

Allen Sandy United States 

ALVARADO ISABEL United States 

Ambrose Christopher United States 

Anderson Marsha United States 

Andrist Edward United States 

Arthur Phyllis United States 

Ashley Don United States 

Aviles-Mendoza Guillermo United States 

Ba Amy United States 

Baker Carol J. United States 

Baldwin Jennifer United States 

Bandell Allyn United States 

Barden Helen United States 

Bardi Janna United States 

Bargatze Robert United States 

Barlows Ted United States 

Bednarczyk Robert United States 

Bennett Nancy (Nana) United States 

Berns Abby United States 

Bhuyan Prakash United States 

Bobinsky Marcella United States 

Bocchini Joeseph United States 

Boone Christopher United States 

Boone Heather United States 

Boone Ethan United States 

Boone Maggie United States 

Boswell Alanna United States 

Bousselot Roger United States 

Bousselot Roger United States 

Bozof Lynn United States 

Bradley Kimberly United States 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Brady Michael United States 

Braga Damian United States 

Bravo Sandra United States 

Bresnitz Eddy United States 

Brewer Katherine United States 

Brown Veronica United States 

Browne Bonnie United States 

Bryant Chenoia United States 

Burkard Rosa United States 

Burkybile Frank United States 

Burnett Jeff United States 

BURSTIN STUART United States 

Cales Carmen United States 

Callender-Potters Heather United States 

Campos-Outcalt Douglas United States 

Cannon Patricia United States 

Capilouto Emily United States 

Cappio Kelly United States 

Cary Donna United States 

Casias Maria United States 

Chandra-Puri Anita United States 

Chaney Mike United States 

Chen-Rogers Chia United States 

Chu Virginia United States 

Chung Haejin United States 

Clark Rebekah United States 

Clover Richard United States 

Coelingh Kathleen United States 

Cole Dana United States 

Colwell Chris United States 

Conis Elena United States 

Cordell Laura United States 

Cottone Melissa United States 

Cox Kendra United States 

Cox Chad United States 

Coyne-Beasley Tamera United States 

Crumlich Brittani United States 

Csepi Bela United States 

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Cullison Mark United States 

Cundiff Kayla United States 

Dachowski Stephen United States 

Dalrymple Donald "Dack" United States 

Dana Adrian United States 

D''Antona Aida United States 

D''Antona John United States 

Davis Victoria United States 

Decker Michael United States 

Dennis Sandra United States 

DeNoon Daniel United States 

Dillard Reiannon United States 

Dinovitz Richard United States 

Donnelly Jessica United States 

Douglas Andrew United States 

DUCHIN JEFFREY United States 

Dzierba Steven United States 

Egge Steven United States 

Ehresmann Kristen United States 

Etkind Paul United States 

Evans Geoffrey United States 

Farley Monica United States 

Feltman Matthew United States 

Fernandez Carrie United States 

Fish Rebecca United States 

Foster Stephan United States 

Foster Sylvia United States 

Friedland Leonard United States 

Fryhofer Sandra United States 

Fye Jessica United States 

Gaffoglio Diane United States 

Gargano Lisa United States 

Geibe Jesse United States 

Gellin Bruce United States 

Germano Geno United States 

Gordon Lili United States 

Gorman Richard United States 

Gould Philip United States 

Goveia Michelle United States 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Grabenstein John United States 

Greenberg David United States 

Grogg Stanley United States 

Groom Amy United States 

Gruber Bill United States 

Gullick Allison United States 

Hahn Christine United States 

Hale Scott United States 

Halsey Neal United States 

Halstrom Erik United States 

Hamm Natalie United States 

Hance Mary Beth United States 

Hannan Claire United States 

Hayes Carol United States 

Henry Sarah United States 

Henry-Wallace Stephanie United States 

Hernandez Alfonso United States 

Herrera-Taracena Guillermo United States 

Homeier Barbara United States 

Hosbach Philip United States 

Houston Marsha United States 

Howe Barbara United States 

Hughes Jim United States 

Hull Harry United States 

Humiston Sharon United States 

HumphreyFranklin Donelle United States 

Hunt Matthew United States 

Interis Evelyn United States 

Jacob-Nara Juby United States 

Janssen Robert United States 

Janusz Cara Bess United States 

Jauragui Barbara United States 

Jenkins Renee United States 

Jimenez Jeanne United States 

Jodhpurkar Uday United States 

Johnson Erica United States 

Johnson David United States 

Jones Rosemary United States 

Kagan Stephen United States 

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Kalokhe Ameeta United States 

Keitel Wendy United States 

Keyes Danielle United States 

Keyserling Harry United States 

Kim Chris United States 

Kimberlin David United States 

Kinsinger Linda United States 

Kohlenberg Katie United States 

Krishnarajah Girishanthy United States 

Kurtis Hannah United States 

Kuter Barbara United States 

Laird Susan United States 

LaMarca Lou United States 

Lanphear John United States 

LaRussa Philip United States 

Lawson Wyeth United States 

Le Luu ly United States 

Lease Christian United States 

Lee Julia United States 

Leger Marie-Michele United States 

Lester Arlene United States 

Lett Susan United States 

Lewin Clement United States 

Liedtka Patrick United States 

Link-Gelles Ruth United States 

Linn Elena United States 

Loehr Jamie United States 

Long Deryl United States 

Loynes Heidi United States 

Lukus Lori United States 

Lymon Rufus United States 

Malone Robert United States 

Manzano Yecenia United States 

Marcy S Michael United States 

Martin Kim United States 

Martin Maria del Pilar United States 

Matusik Mark United States 

Mazur Marie United States 

McGowan Katherine F. United States 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

McGruder Janet United States 

McGuffin Colleen United States 

McKinney Paul United States 

McLaughlin John United States 

Meigs Wendy United States 

Meissner Cody United States 

Merritt Judy United States 

Middleman Amy United States 

Milburn Tarah United States 

Miller Kimberly United States 

Miller Jacqueline United States 

Milley Frankie United States 

Moburg Christeen United States 

Montero Jose T United States 

Moore Kelly United States 

Mukundan Maya United States 

Mulligan Mark United States 

Murad 

Mohammad 

Hassan United States 

Narula Trishna United States 

Narula Harminder United States 

Narula Neeta United States 

Nash kristen United States 

Neese Kristen United States 

Netoskie Mark United States 

Neuman William United States 

Neuzil Kathleen United States 

NGUNDUE JEROME United States 

Nicholson Jennifer United States 

Ochs Tara United States 

Offit Paul United States 

Olad Mohamed United States 

Orenstein Walter United States 

Ortlieb David United States 

Owen Bill United States 

Painter Julia United States 

Pannemann Kathryn United States 

Paradiso Peter United States 

Parker Rachel United States 

Perry Robert United States 

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Peter Georges United States 

Peters Martin United States 

Petersen Brett United States 

Peterson Diane United States 

petrofsky monique United States 

Plotkin Stanley United States 

Poffenberger Kimber United States 

Poland Gregory United States 

Pontani Dennis United States 

Porter Travis United States 

Pratt David United States 

Price Winston United States 

Pringle Meridith United States 

ProorHibKitty ProorHibKitty United States 

Proveaux Tina United States 

Purdy Jay United States 

Quinn Jane United States 

Ramjee Shilpa United States 

Reeves-Hoche Mary Kathryn United States 

REISZNER DONNA United States 

Rha Brian United States 

Richards Jennifer United States 

Richmond Heather United States 

Riley Laura United States 

Roberts Clifford Lake United States 

Rogero Heather United States 

Romano Kyle United States 

Romano Kris United States 

Rosenbaum Sara United States 

Riyals Michael United States 

Sanchez Robin United States 

Sanyour Mark United States 

Sattler Carlos United States 

Sawyer Mark United States 

Schaffner William United States 

Schmader Kenneth United States 

Senyk Michele United States 

shahram shahrooz United States 

Shannon Ellen United States 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Sharlow Diana United States 

Shaw Brian United States 

Sheffield Tamara United States 

Shelton Jerry United States 

Sherner James United States 

SIEVERT ALAN United States 

Silverstein Leonard United States 

Singletary Ivy United States 

Singletary Brandon United States 

Skjeveland Eric United States 

Slaughter Jan United States 

Smith Jason D. United States 

Smith Susan United States 

Snow Vincenza United States 

Spears Christian United States 

Stephens David United States 

Stinchfield Patricia United States 

Strutton David United States 

Stuerke Stacy United States 

Sullivan Gina United States 

Sun Wellington United States 

Temte Jonathan United States 

Tennenberg Alan United States 

Thomas Michael United States 

Thompson Brad United States 

Thorne Christopher United States 

Toback Seth United States 

Tolene Anne United States 

Tortorich Debra United States 

Tubergen Emily United States 

Tucker Miriam E. United States 

turner james United States 

Tyo Karen United States 

Ulasi Chijioke United States 

VanOss Robin United States 

Varan Aiden United States 

Vaupel Christine United States 

Vazquez Marietta United States 

Verma Bikash United States 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Veselsky Steven United States 

VierAbefe VierAbefe United States 

Vigliariolo Peter United States 

Wallace Fred United States 

Walsh margaret United States 

Ward Michelle United States 

WarreDavid WarreDavid United States 

Washington Teneasha United States 

Webster Angie United States 

Welch Verna United States 

Wentworth Marian United States 

Weston Wayde United States 

Wexler Deborah United States 

Williams Michelle United States 

Williams Mimi United States 

Wolf Tammy United States 

Wolf Jesseca United States 

Wood Laurel United States 

Wornson Bryon United States 

Worthy Margaret United States 

Yarn Sandra United States 

Zahn Matt United States 

Zavolinsky Jennifer United States 

Zimmerman Richard United States 

Zucker Jane United States 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Non US Citizens 

Last First Citizenship Organization 

Abdinur A.Olad Mohamed Somalia WHO&H 

Acemah Christian Uganda U.S. Institute of Medicine 

Arya Jaya India 

AVENDANO Luis Fidel Chile UNIVERSIDAD DE CHILE 

Baehner Frank Germany Novartis Vaccines 

BETSILL HELEN MERCK 

biehn brant Canada dynavax 

Burga Sánchez Miriam Madeleine Peru Ministerio de Salud 

Enyan Philip Ghana Student, University of Ghana 

Florez Jorge Colombia Immunoprotection 

Gowler Jeremy Canada 

Novartis Vaccines & Diagnostics 

Inc. 

Ismail Shainoor Canada Public Health Agency of Canada 

Jain Siddharth India UAB School of Public Health 

Kabore Lassane Burkina Faso UAB 

Kanda Mikiko Japan World Health Organization 

Khodneva Yulia Russia UAB School of Public Health 

Kobayashi Miwako Japan Emory University 

Lester-Swindell Mark 

United 

Kingdom Pfizer Inc 

Liao Albert Canada Novartis Vaccines and Diagnostics 

Masseria Cristina Italy GlaxoSmithKline Vaccines 

Mendoza Araujo Maria Ana Peru Department of Health 

Minaya Percy Peru National Health Institute 

Mojica Jose Alejandro Colombia Sanofi Pasteur 

Moussa Diouldé MBOW Mauritania Institut ICAD SANTE 

Murguia de Sierra Maria Mexico 

Ponce Carmen Peru Ministry of Health of Peru 

Sasraku 

Josephine Naa 

Deisa Ghana Pantang Nursing Training College 

Soler Hidalgo Maria Argentina 

Fighting Infectious Diseases in 

Emerging Countries 

STAMBOULIAN DANIEL Argentina 

Suarez Eduardo El Salvador Ministerio de Salud 

Suárez Victor Peru Instituto Nacional de Salud, Perú 

Tan Litjen (L.J) Singapore American Medical Association 

Tende Frida Cameroon UAB School of public Health 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2012 

Toledo Washington Peru 

Organización Panamericana de la 

Salud 

Upadhyay Divvy India UAB School of Public Health 

VIZZOTTI CARLA Argentina MINISTRY OF HEALTH 

Warshawsky Bryna Canada Middlesex-London Health Unit 

YORK Laura Jean France PFIZER Inc 

Zyambo Cosmas UAB 

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