DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION 

Advisory Committee on 

Immunization Practices (ACIP)

Summary Report

October 29-30, 2014 

Atlanta, Georgia 

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Table of Contents Page

Agenda 4-6

Acronyms 7-9

Wednesday: October 29, 2014

Welcome and Introductions 10-19

Agency Updates

 Centers for Disease Control and Prevention (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)

19-22

Influenza

 Introduction

 Influenza Surveillance Update

 Update : Effectiveness of Live-Attenuated and Inactivated Seasonal Influenza Vaccines in Children and Adolescents

 Administering Afluria®Influenza Vaccine via PharmaJet® Stratis® Needle-Free Injection

22-39

Vaccine Supply 40

Novel Influenza

 Introduction

 Influenza A (H5N1) Epidemiology and Vaccine

 GRADE and Policy Options for Influenza A (H5N1) Vaccine

40-52

Pertussis

 Introduction

 Healthcare Personnel and Tdap Vaccination

52-61

General Recommendations

 Introduction

 Timing and Spacing, Contraindications and Precautions, Vaccine Administration

61-74

Child/Adolescent Immunization

 Introduction

 Child/Adolescent Schedule 2015

74-78

Adult Immunization

 Introduction

 Adult Immunization Schedule 2015

78-85

Hepatitis

 Introduction

 Update on Hepatitis A Disease Burden and Hepatitis A Population Protection

85-92

Public Comment Day 1 92

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Thursday: October 30, 2014

Meningococcal Vaccine

 Introduction

 4CMenB Serogroup B Meningococcal Vaccine

 rLP2086 Serogroup B Meningococcal Vaccine

 Epidemiology of Serogroup B Disease in the United States

 Considerations for Use of Serogroup B Meningococcal Vaccines in the US

 Public Comment

92-115

Typhoid Vaccines

 Introduction

 Typhoid Vaccines Update

115-121

Vaccine Safety

 Proposed Changes to the Vaccine Adverse Event Reporting System (VAERS) Reporting Form

121-125

Human Papillomavirus (HPV) Vaccines

 Introduction

 Program Summary and New 9-Valent HPV Vaccine Trial Data 

 Cost-Effectiveness of 9-Valent HPV Vaccine

 GRADE for 9-Valent HPV Vaccine

 Policy Option and Discussion

125-150

Public Comments Day 2 150

Certification 151

Membership Roster 152-160

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MEETING OF THE ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES (ACIP) 

Centers for Disease Control and Prevention 

1600 Clifton Road, NE, Tom Harkin Global Communications Center (Building 19), Kent "Oz" Nelson Auditorium 

Atlanta, Georgia 30333 

October 29-30, 2014 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AGENDA ITEM PURPOSE PRESIDER/PRESENTER(s)

 

Wednesday, October 29th 

8:00 Welcome & Introductions Dr. Jonathan Temte (ACIP Chair) 

Dr. Larry Pickering (ACIP Executive 

Secretary; CDC) 

Dr. Thomas Frieden, Director, CDC Remarks 

 8:30 Agency Updates 

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

 

Dr. Ruth Karron (ACIP, WG Chair) 

Dr. Lisa Grohskopf (CDC/NCIRD) 

Dr. Brendan Flannery (CDC/NCIRD) 

8:45 Influenza 

·Introduction 

· Influenza surveillance update 

· Update on effectiveness of live-attenuated and 

inactivated seasonal influenza vaccines in children and 

adolescents 

· Administering Afluria® Influenza Vaccine via 

PharmaJet® Stratis® Needle-Free Injection 

Information &

Discussion 

Dr. Charles Altman (bioCSL) 

 10:05 Vaccine Supply 

 

Information Dr. Jeanne Santoli (CDC/NCIRD)

 

10:20 Break

 

10:50 Novel Influenza 

· Introduction 

· Influenza A (H5N1) epidemiology and vaccine 

· GRADE and policy options for influenza A (H5N1) 

vaccine 

 

11:50 Pertussis 

· Introduction 

· Health-care personnel and Tdap vaccination 

Information & 

Discussion 

Dr. Jon Temte (ACIP, WG Member)

Dr. Sonja J. Olsen (CDC/NCIRD)

Dr. Sonja J. Olsen (CDC/NCIRD)

Information & 

Discussion

Dr. Art Reingold (ACIP, WG Chair) 

Dr. Jennifer Liang (CDC/NCIRD) 

12:50 Lunch

 

2:05 General Recommendations 

· Introduction Information & Dr. Marietta Vázquez (ACIP, WG Chair)

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· Timing and spacing; contraindications and precautions; 

vaccine administration

Discussion 

Vote 

 

 

Dr. Andrew Kroger (CDC/NCIRD)

3:10 Child/Adolescent Immunization Schedule 

· Introduction 

· Child/Adolescent schedule 2015 

Information & 

Discussion 

Vote

Dr. José Romero (ACIP, WG Chair) 

Dr. Raymond Strikas (CDC/NCIRD) 

3:55 Break 

 

4:15 Adult Immunization Schedule 

· Introduction 

· Adult immunization schedule 2015 

Information & 

Discussion 

Vote

Dr. Laura Riley (ACIP, WG Member)

Dr. David Kim (CDC/NCIRD)

 4:45 Hepatitis 

· Introduction 

· Update on hepatitis A disease burden and hepatitis A 

population protection 

 

 

Dr. Arthur Reingold (ACIP, WG Chair) 

 Dr. Noele Nelson (CDC/NCHHSTP) Information & 

Discussion 

 

5:30 Public Comment

 

5:45 Adjourn

Thursday, October 30th 

8:00 Unfinished Business Dr. Jonathan Temte (Chair, ACIP)

 8:15 Meningococcal Vaccines 

· Introduction 

· 4CMenB serogroup B meningococcal vaccine 

· rLP2086 serogroup B meningococcal vaccine 

· Epidemiology of serogroup B disease in the United 

States 

· Considerations for use of serogroup B meningococcal 

vaccines in the US

Public Comment - meningococcal vaccines 

 

Information & 

Discussion 

Dr. Lorry Rubin (ACIP, WG Chair) 

Mr. Jim Wassil (Novartis) 

Dr. Laura York (Pfizer) 

Ms. Jessica MacNeil (CDC/NCIRD) 

Dr. Manisha Patel (CDC/NCIRD) 

 

10:00 Typhoid Vaccines 

· Introduction 

· Typhoid vaccines update 

 

 

 

 

 

10:30 Vaccine Safety 

· Proposed changes to the Vaccine Adverse Event 

Reporting System (VAERS) reporting form 

Information & 

Discussion 

Vote

Dr. Barbara Mahon (CDC/NCEZID)

Dr. Brendan Jackson (CDC/NCEZID)

Information & 

Discussion 

Dr. Tom Shimabukuro (CDC/NCEZID)

10:45 Break 

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11:00 Human Papillomavirus (HPV) Vaccines 

· Introduction 

· Program summary and new 9-valent HPV vaccine trial 

data 

· Cost effectiveness Cost effectiveness of 9-valent HPV 

vaccination 

· GRADE for 9-valent HPV vaccine 

· Policy options and discussion 

Information & 

Discussion 

Dr. Joseph Bocchini (ACIP, WG Chair) 

Dr. Alain Luxembourg (Merck) 

Dr. Marc Brisson (Laval University, 

Quebec, Canada) 

Dr. Emiko Petrosky (CDC/NCHHSTP) 

Dr. Lauri Markowitz (CDC/NCHHSTP) 

1:00 Public Comment

 1:15 Adjourn

Acronyms

CDC Centers for Disease Control & Prevention

CMS Centers for Medicare and Medicaid Services 

DOD Department of Defense

DVA Department of Veterans Affairs

FDA Food and Drug Administration

GRADE Grading of Recommendations Assessment, Development and Evaluation

HRSA Health Resources and Services Administration

IHS Indian Health Service

NCHHSTP National Center for HIV, Hepatitis, STD and TB Prevention [of CDC/OID] 

NCIRD CDC National Center for Immunization & Respiratory Diseases [of CDC/OID] 

NCEZID National Center for Emerging and Zoonotic Diseases [of CDC/OID]

NIH National Institutes of Health

NVPO National Vaccine Program Office

Tdap Tetanus, Diphtheria, and acellular Pertussis Vaccine

WG Work Group

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Acronyms 

AAFP American Academy of Family Physicians 

AAP American Academy of Pediatrics

ABCs Active Bacterial Core Surveillance 

ACA Affordable Care Act

ACCV Advisory Commission on Childhood Vaccines 

ACIP Advisory Committee on Immunization Practices

ACNM American College of Nurse Midwives 

ACOG American College of Obstetricians and Gynecologists 

ACP American College of Physicians 

AE Adverse Events

AFP American Family Physicians

AIS Adenocarcinoma in Situ 

AMA American Medical Association

ANA American Nurses Association 

APHIS Animal and Plant Health Inspection Service 

ARI Acute Respiratory Infection

ASH Assistant Secretary for Health (HHS)

BARDA Biomedical Advanced Research and Development Authority 

BLA Biologics License Application

CBER Center for Biologics Evaluation and Research (FDA)

CDC Centers for Disease Control and Prevention

CDRH Center for Devices and Radiological Health 

CIN Cervical Intraepithelial Neoplasia 

CISA Clinical Immunization Safety Assessment 

CMS Centers for Medicare and Medicaid Services

COI Conflict of Interest 

CSTE Council of State and Territorial Epidemiologists 

DHS Department of Homeland Security 

DoD Department of Defense

DSMB Data Safety Monitoring Board 

DTaP Diphtheria, Tetanus, and Acellular Pertussis Vaccine

DVA Department of Veterans Affairs

ED Emergency Department

EIP Emerging Infections Program 

ELISA Enzyme-Linked Immunosorbent Assay 

EMA European Medicines Agency 

EMR Electronic Medical Record

EOC Emergency Operations Center 

EPSDT Early and Periodic Screening, Diagnostic and Treatment 

FDA Food and Drug Administration

fHbp Factor H Binding Protein 

FLU VE Influenza Vaccine Effectiveness Network

GIE-STFM Group on Immunization Education – Society for Teachers of Family Medicine 

GMC Geometric Mean Concentration

GMFR Geometric Mean Fold Rise 

GMTs Geometric Mean Titers

GRADE Grading of Recommendation Assessment, Development and Evaluation 

GRWG General Recommendations Work Group 

GSK GlaxoSmithKline

HA Hemagglutinin 

HAV Hepatitis A Vaccine 

HBIG Hepatitis B Immune Globulin 

HCP Healthcare Personnel

HCUP Healthcare Utilization Project 

HCV Hepatitis C Virus 

HHS (Department of) Health and Human Services 

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Hib Haemophilus influenzae Type b 

HICPAC Healthcare Infection Control Practices Advisory Committee 

HIV Human Immunodeficiency Virus 

HPAI Highly Pathogenic Avian Influenza 

HP2020 Healthy People 2020

HPV Human Papillomavirus

HR Hazard Ratio

HRSA Health Resources and Services Administration 

hSBA Human Serum Bactericidal Assay 

IAC Immunization Action Coalition

ICD International Classification of Diseases

IDSA Infectious Disease Society of America 

IHS Indian Health Service 

IIS Immunization Information System 

IIV Inactivated Influenza Vaccine 

ILI Influenza-Like Illness

ILINet Influenza-Like Illness Surveillance Network

IM Intramuscularly 

IND Investigational New Drug 

IOM Institute of Medicine

IPD Invasive Pneumococcal Disease 

IRAT Influenza Risk Assessment Tool 

ISO Immunization Safety Office

ISTF Immunization Safety Task Force 

IVS Institute for Vaccine Safety 

JIFI Jet Injection for Influenza 

LAIV Live Attenuated Influenza Vaccine 

LTBI Latent Tuberculosis Infection 

MATS Meningococcal Antigen Typing System 

MCRF Marshfield Clinic Research Foundation 

MCV4 Meningococcal Conjugate Vaccine 

MedDRA Medical Dictionary for Regulatory Activities 

MMR Measles, Mumps, Rubella

MMWR Morbidity and Mortality Weekly Report

MSM Men Who Have Sex With Men 

NACI National Advisory Committee on Immunization, Canada

NadA Neisserial Adhesin A 

NAPNAP National Association of Pediatric Nurse Practitioners 

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

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

NCVIA National Childhood Vaccine Injury Act 

NFID National Foundation for Infectious Diseases

NHANES National Health and Nutrition Examination Survey 

NHBA Neisseria Heparin Binding Antigen 

NHIS National Health Interview Survey 

NGOs Non-Governmental Organizations 

NIH National Institutes of Health

NIS National Immunization Survey 

NIS-Teen National Immunization Survey-Teen

NMA National Medical Association

NNDSS National Notifiable Diseases Surveillance System 

NNII National Network for Immunization Information 

NNV Number Needed to Vaccinate

NREVSS National Respiratory and Enteric Virus Surveillance System 

NVAC National Vaccine Advisory Committee 

NVICP National Vaccine Injury Compensation Program

NVP National Vaccine Plan 

NVPO National Vaccine Program Office

NYC DOHMH New York City Department of Health and Mental Hygiene 

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OB/GYN Obstetrician/Gynecologist 

OHCS Office of Health Communication Science

OMV Outer Membrane Vesicles 

PCR Polymerase Chain Reaction 

PCV Pneumococcal Conjugate Vaccine

PEP Post-Exposure Prophylaxis 

PPE Personal Protective Equipment 

PI Principal Investigator 

PPSV Pneumococcal Polysaccharide Vaccine 

PRISM Post-Licensure Rapid Immunization Safety Monitoring 

QALYs Quality Adjusted Life Years 

QI Quality Improvement 

RCT Randomized Controlled Trial

RT-PCR Reverse Transcription Polymerase Chain Reaction 

SAEs Serious Adverse Events 

SAGE Strategic Advisory Group of Experts (WHO)

SAHM Society for Adolescent Health and Medicine 

SBA Serum Bactericidal Assay 

SCC Squamous Cell Carcinoma 

SME Subject Matter Expert

Td Tetanus-Diphtheria

Tdap Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis

TIV Trivalent Inactivated Vaccine 

UAMS University of Arkansas for Medical Sciences 

UCHealth University of Colorado Health 

UCLA University of Southern California, Los Angeles

UK United Kingdom

UPMC University of Pittsburgh Medical Center 

US United States

USC University of Southern California

USDA US Department of Agriculture 

VA Department of Veterans Affairs 

VAERS Vaccine Adverse Event Reporting System

VaIN Vaginal Intraepithelial Neoplasia 

VE Vaccine Effectiveness

VEC Vaccine Education Center 

VFC Vaccines for Children

VICP National Vaccine Injury Compensation Program

ViCPS Vi capsular polysaccharide 

VIN Vulvar Intraepithelial Neoplasia 

VLP Virus-Like Particles 

VRBPAC Vaccine and Related Biologic Products Advisory Committee 

VRC Vaccination Report Card 

VSD Vaccine Safety Datalink

WG Work Group

WHO World Health Organization

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Welcome 

Dr. Larry Pickering 

Executive Secretary, ACIP / CDC

Following Dr. Temte’s greeting and call to order, Dr. Pickering welcomed everyone to the 

October 2014 Advisory Committee on Immunization Practices (ACIP) meeting. He indicated 

that the proceedings of this meeting would be available to people not in attendance via the 

World Wide Web, and 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 

meeting to assist with various meeting functions: Stephanie Thomas, Natalie Greene, Reed 

Walton, and Chris Caraway. 

Emphasizing that there would be a full agenda for both days of the meeting, 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 during this 

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

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

meeting minutes will be available on the website within 90 days following this meeting. Meeting 

minutes are posted on the ACIP website generally within 90 days of the meeting. Members of 

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

Jamila Howard Jones or Jason McDonald for assistance in arranging interviews. 

Dr. Pickering welcomed the following international guests in attendance: 

 

 Dr. Aisha Mohammed Alshammary, Manager, National Immunization Program for the 

Ministry of Health, Saudi Arabia 

 Dr. Hsiu-Yun Lo, Section Chief, Division of Acute Infectious Diseases, Centers for Disease 

Control, Taiwan 

 Dr. Yu Min Chou, Deputy Director, Division of Acute Infectious Diseases Centers for 

Disease Control, Taiwan 

As a reminder for future international visitors to ACIP meetings, due to changes in Department 

of Homeland Security (DHS) Policy, additional forms will be required for each meeting at the 

time an international guest registers. It is critical that international visitors complete and submit 

these forms as soon as possible following registration. Stephanie Thomas, Committee 

Management Specialist, will be able to help with any questions and concerns about the process. 

The next ACIP meeting will convene at CDC on Wednesday and Thursday, February 25-26, 

2015. Registration for all meeting attendees is required and will be open Friday, October 31, 

2014. The registration deadline for United States (US) citizens is Monday, February 9, and for 

non-US citizens is Monday, February 2. Registration is not required for webcast viewing. 

Welcome and Introductions

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Dr. Pickering offered the following notes regarding members and liaison representatives: 

Members 

 Kathy Harriman and Doug Campos-Outcalt are unable to join the meeting. 

Liaisons

 Tami Thomas attended this meeting on behalf of Patsy Stinchfield, representing the National 

Association of Pediatric Nurse Practitioners (NAPNAP). 

 Chad Rittle will be replacing Katie Brewer as the American Nurses’ Association (ANA) 

liaison. 

 Ian Gemmill will be replacing Bryna Warshawsky as the National Advisory Committee on 

Immunization (NACI), Canada. 

 The Healthcare Infection Control Practices Advisory Committee (HICPAC) has withdrawn as 

a liaison organization to ACIP. 

To avoid disruptions during the meeting, Dr. Pickering requested that those present turn off all 

cell phones. He 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. Time for 

public comments also may be provided prior to specific votes by ACIP to enable these 

comments to be considered before any votes. Those who planned to make public comments 

were instructed to visit the registration desk in the rear of the auditorium to have Stephanie 

Thomas record their name and provide information about 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. 

This is the 50-year anniversary of ACIP, which held its first meeting in May 1964 in a building 

that no longer exists. Dr. Frieden joined the October 2014 meeting for a few moments to 

commemorate this notable anniversary. An article titled, “History and Evolution of the Advisory 

Committee on Immunization Practices — United States, 1964–2014” was published on October 

24, 2014 in the Morbidity and Mortality Weekly Report (MMWR) [63(42); 955-958]. A longer 

article titled, “History of the United States Advisory Committee on Immunization Practices” will 

be published in the journal Vaccine. 

Safety issues will continue to be presented during every ACIP meeting. A separate vaccine 

safety presentation was planned for the second day of the October 2014 meeting. 

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 

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prohibited from participating in 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. It is 

important to note that at each meeting, ACIP members state any conflicts of interest. 

Applications for ACIP membership are due no later than November 14, 2014 for the 4-year term 

beginning July 2015. Detailed instructions for submission of names of potential candidates to 

serve as ACIP members may be found on the ACIP web site: 

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

Nominations: http://www.cdc.gov/vaccines/acip/committee/req-nominate.html

A current CV, at least one recommendation letter from a non-federal government employee, and 

complete contact information are required. These may be submitted as e-mail attachments to 

Stephanie Thomas at hkp4@cdc.gov

During every ACIP meeting, an update is provided with regard to the status of ACIP 

recommendations. ACIP has a policy that every three to five years each recommendation is 

reviewed, and then renewed, reaffirmed, or retired. Links to these recommendations and 

schedules can be found on the ACIP website. A listing of recommendations that have been 

published since the June 2014 ACIP meeting follows: 

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The following algorithm designed by the Pneumococcal Vaccines Work Group (WG) illustrates 

the pneumococcal conjugate vaccine (PCV)13 and PCV23 recommendation made during the 

August 2014 ACIP meeting for adults aged >65 years of age: 

 

The following resource information pertaining to ACIP is available on the CDC website: 

Vaccine Safety: 

www.cdc.gov/vaccinesafety/index.html

Immunization Schedules (2014): 

http://www.cdc.gov/vaccines/schedules/index.html

Vaccine Toolkit: 

http://www.cdc.gov/vaccines/hcp/patient-ed/conversations/index.html

Immunization for Women (American College of Obstetricians and Gynecologists): 

www.immunizationforwomen.org

You Are the Key to HPV Cancer Prevention: 

http://www.cdc.gov/vaccines/youarethekey

Vaccines for Preteens and Teens: 

http://www.cdc.gov/vaccines/who/teens/index.html

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Dr. Pickering announced that friend, colleague, and former ACIP member, Dr. Mike Marcy, died 

on September 5, 2014 following a very short battle with cancer. At the time of his death, Dr. 

Marcy was a Clinical Professor of Pediatrics at both University of Southern California (USC) and 

University of Southern California, Los Angeles (UCLA). He served on the ACIP from July 1, 

2008 to June 30, 2012. Committee chairs during his tenure were Drs. Dale Morse and Carol 

Baker. 

 

While a member of ACIP, Dr. Marcy was chair of the Pneumococcal WG and a member of the 

Human Papillomavirus (HPV) and Meningococcal WGs. He was nationally and internationally 

recognized in the field of pediatric infectious diseases, was a member of the American Academy 

of Pediatrics (AAP) Red Book Committee, and a recipient of many national awards. Dr. Marcy 

was a unique ACIP member in that he arrived in Atlanta one to two days before each meeting to 

read all of the extensive information provided to members before each meeting. In addition, 

during meetings, the discussions in which he was involved were always very stimulating. Dr. 

Marcy is survived by his beloved wife, Joan, and their two adult children, Stephanie and Josh, 

and by all who knew him well. We are all sorry that he is gone, but happy for what he has left 

us. Thank you, Mike. 

Before officially beginning the meeting, Dr. Temte called the roll to determine whether any ACIP 

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

 Belongia: Receives research funding from MedImmune 

 Bennett, Bocchini, Harrison, Karron, Jenkins, Kempe, Pellegrini, Reingold, Riley, Romero, 

Rubin, Temte, and Vazquez: No conflicts 

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Dr. Temte extended an expression of gratitude to all of the staff at CDC who have been working 

non-stop over the last several months in terms of the response to the Ebola outbreak in West 

Africa. A number of subject matters experts (SMEs) who typically assist ACIP have been 

deployed either domestically or internationally to help in this effort. The number of hours these 

folks are putting in agency-wide is unimaginable. 

This marks the 50th anniversary of the ACIP, as Dr. Pickering noted. The MMWR publication, 

“History and Evolution of the Advisory Committee on Immunization Practices — United States, 

1964–2014” published on October 24, 2014 was authored by Drs. Jean Smith, Alan Hinman, 

and Larry Pickering. Dr. Temte took this opportunity to talk about the Who, What, When, 

Where, and Why of ACIP. He began with an introduction of the three new members: 

 Ed Belongia, MD

Dr. Belongia is the Senior Epidemiologist/Director of the Epidemiology Research Center at 

Marshfield Clinic Research Foundation (MCRF) in Marshfield, Wisconsin. Dr. Belongia is an 

internationally recognized expert in the epidemiology of infectious diseases, vaccine safety and 

effectiveness, and antimicrobial resistance. He has also been a Principal Investigator (PI) for 

the Vaccine Safety Datalink (VSD) for Marshfield Clinic, and has worked extensively with the 

Influenza Vaccine Effectiveness (Flu VE) Network. 

 Laura Riley, MD

Dr. Riley is the Director of Labor and Delivery and Obstetrics and Gynecology Infectious 

Disease at Massachusetts General Hospital in Boston, Massachusetts. Here interests are in 

human immunodeficiency virus (HIV) disease in pregnancy, infectious disease complications of 

pregnancy, medical complications of pregnancy, and high-risk pregnancy. She was previously 

the liaison to ACIP for the American College of Obstetricians and Gynecologists (ACOG), and is 

the first Obstetrician/Gynecologist (OB/GYN) to serve on ACIP, pointing to the increased 

number of issues related to vaccination during pregnancy. 

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 Jose Romero, MD

Dr. Romero is a Professor in the College of Medicine and Department of Pediatrics, the Section 

Chief of Infectious Diseases, and a Horace C. Cabe Endowed Chair in Pediatric Infectious 

Diseases at the University of Arkansas for Medical Sciences (UAMS) in Little Rock, Arkansas. 

Dr. Romero has served on the Food and Drug Administration’s (FDA’s) Vaccine and Related 

Biologic Products Advisory Committee (VRBPAC), and is interested in healthcare delivery and 

research among underrepresented minority communities. He has extensive expertise in 

molecular virology, pediatric infectious disease, and vaccine science. 

The following is the first ACIP meeting agenda. The topics included influenza, pertussis, 

smallpox, measles, and rubella: 

Taken from the Charter [www.cdc.gov/vaccines/acip/committee/charter.html], ACIP’s role is to 

provide guidance: 

“... regarding the most appropriate selection of vaccines and related agents for effective control 

of vaccine-preventable diseases in the civilian population. 

... on population groups and/or circumstances in which a vaccine or related agent is 

recommended. 

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... on contraindications and precautions for use of the vaccine and related agents and provides 

information on recognized adverse events. 

... deliberations on use of vaccines to control disease in the U.S. shall include consideration of 

disease epidemiology and burden of disease, vaccine efficacy and effectiveness, vaccine 

safety, economic analyses and implementation issues. 

... periodically review and, as appropriate, revise a list of vaccines for administration to children 

and adolescents eligible to receive vaccines through the Vaccines for Children Program.”

17

Dr. Temte shared a humorous video about herding cats to illustrate the work of ACIP, which can 

be found at the following link: 

https://search.yahoo.com/search;_ylt=AoJhOPj6FiUg7CH_e0ZLYzKbvZx4?p=herding+cats+vid

eo&toggle=1&cop=mss&ei=UTF-8&fr=yfp-t-302&fp=1

The first ACIP meetings were convened in Room 207, Building 1 of CDC. The room was so 

small that it would not have accommodated the current members. ACIP meets three times a 

year in February, June, and October. Sometimes special meetings are convened to address 

specific issues, such as the meeting in August 2014 to vote on PCV13 and PCV23. The August 

2014 meeting was conducted via teleconference and included over 1200 attendees. The 

following table indicates the number of cases of disease prevented for the cohort of children 

between 1994 and 2013, a 20-year time frame. During that timeframe, 322 estimated illnesses, 

21 million hospitalizations, and 731 premature deaths due to vaccine-preventable illnesses were 

averted in this cohort: 

 

Dr. Temte shared a clip from Laura Huber, the mother of twins, in which she describes the 

autopsy of her son Abe who died at 5 months of age from pertussis. She concludes by saying, 

“The worst part is I think he got it from me.” This clip can be found at the following link: 

http://www.youtube.com/watch?v=2_CdlAg9FH0. He also shared this quote, “It wasn’t just the 

pain of their loss that tormented them. It was that the love for their children was still in them, 

and it had nowhere to go...” from Neely Tucker [Love in the Driest Season, 2004]. Since the 

inception of ACIP, the world has witnessed the global eradication of smallpox, measles 

elimination in the US, and the verge of global polio eradication. 

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Thomas R. Frieden, MD, MPH 

Director, Centers for Disease Control and Prevention 

Administrator, Agency for Toxic Substances and Disease Registry 

Dr. Frieden thanked the ACIP for all that it does. ACIP is a wonderful example of what the 

public health community aspires to, which is ensuring that decisions are made based on data, 

openly and objectively derived, in a public process, and having that information be widely 

adopted throughout the country to save lives. He welcomed the three new ACIP members, Drs. 

Belongia, Riley, and Romero and thanked them for dedicating their time and efforts to this 

process. 

This is the 50th year of ACIP. Last week, CDC published an MMWR detailing the history of 

ACIP. Much has changed in that 50-year period. There are many new vaccines, with an 

increase from 6 to 16 childhood and adolescent vaccines and a total of 15 adult vaccines. 

During his first ACIP meeting as Director, Dr. Frieden teased one of the members that ACIP is 

turning our children into pin cushions will all of these vaccines, and the member replied, “No, 

we’re doing that to adults also.” Yet, there is still so much further to go in terms of closing the 

gaps between vaccine recommendations and vaccine delivery, and in developing new vaccines 

that are even more effective against more disease and that will protect more children and adults 

and will save more lives. ACIP will continue to be central to that process. 

A lot of progress has been made. Influenza season is upon us, and thought is being given to the 

importance of influenza and pneumococcal pneumonia vaccines and how important those are. 

Consideration is also being given to connectivity, because it is known controlling disease within 

one population protects other populations as well. Disease rates decrease generally when 

childhood vaccination rates are increased. As vaccination against influenza is increased, the 

hope is that this will be observed with influenza as well. The pneumonia vaccination 

recommendations are complicated and they are new, but they are important because 

pneumonia and pneumococcal disease are important to fight. Of course, PCV13 is still included 

in the standard childhood vaccine schedule and pneumococcal polysaccharide vaccine (PPSV) 

23 is recommended for children at higher risk as well. 

Public health is a best-buy. Vaccines are a great demonstration of that best-buy. In working to 

stop Ebola in West Africans and to protect Americans in the US, careful consideration is being 

given to two vaccine candidates. In the near future, it is hoped that these two vaccines will 

undergo randomized trials—one a standard RCT and the other a step-wedged design that CDC 

may be leading. This is important because vaccines are very powerful weapons. It is important 

to determine where vaccination can play a role in disease control anywhere it might be possible. 

This is yet another reminder of how critically important vaccines are to health, and what a strong 

tool they are for disease control. 

In conclusion, Dr. Frieden thanked the ACIP members for all of the work they do, for saving 

lives, and for keeping children and adults healthy. Ultimately, the roles of ACIP and CDC are to 

rigorously assess what the science shows; openly state what is known and what is not known; 

set the best possible policy based on the best possible science; and support all partners in state 

and local health departments, hospitals, health centers, communities, and patient advocacy 

Dr. Frieden’s Welcoming Remarks

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groups to get the best possible recommendations implemented and information provided to 

patients and doctors in order to protect as many lives as possible. He also encouraged those 

who had not received their influenza vaccine to get it. 

Centers for Disease Control and Prevention (CDC) 

Dr. Schuchat reported that the National Influenza Vaccination Week events will be December 7-

13, 2014. This offers an opportunity to promote late-season vaccination. CDC plans to 

convene its Immunization Information Systems (IIS) Metrics Blue Ribbon Panel to help define 

metrics for success for the future priorities the agency plans to implement. The Ebola response 

is currently CDC’s highest priority, and most CDC staff are involved in this effort. The agency is 

working with others across the US government and partners in West Africa, industry, and other 

countries to try to accelerate vaccine evaluation and potential availability for Ebola. The 

epidemic’s evolution is such that vaccines may be needed to control it. CDC’s primary role at 

this point is working on a step-wedged vaccine design plan to be implemented in Sierra Leone 

and possibly additional locations. The agency has a team in Sierra Leone working with their 

counterparts in the government, as well as the United Kingdom (UK), to flesh out plans for that. 

Simultaneously, the National Institutes of Health (NIH) has efforts underway to develop a 

randomized controlled trial (RCT) for implementation in Liberia. Dr. Schuchat recently attended 

a World Health Organization (WHO) meeting that assembled the stakeholders and those who 

are keen to make progress as rapidly as possible. The focus of the work that CDC is 

developing would be the target of vaccine evaluation for the healthcare personnel (HCP) and 

other frontline caregivers in Sierra Leone. Beginning October 1, 2014, Dr. Nancy Messonnier 

became the Deputy Director of the National Center for Immunization and Respiratory Diseases 

(NCIRD). Dr. Messonnier is known for her expertise in bacterial meningitis, pertussis, and 

infectious disease prevention and response. She will be working closely with everyone in the 

immunization effort. 

Centers for Medicare and Medicaid Services (CMS)

Dr. Hance reported that the Centers for Medicare and Medicaid Services (CMS) is in the 

process of updating and clarifying Medicare coverage of pneumococcal vaccines given the 

recent ACIP recommendations using an expedited process. CMS anticipates having more 

information to share during the February 2015 ACIP meeting. In addition, CMS has worked with 

the National Vaccine Program Office (NVPO) again this year to release weekly information on 

influenza cases in Medicare. The FluView map and Flu Trends data are available on the NVPO 

website. 

Department of Defense (DoD)

Dr. Geibe reported that there have been no new Department of Defense (DoD) immunization 

policies since the last ACIP meeting, other than an update on annual influenza guidance. The 

DoD goal is 90% for service members by 15 December 2014. That is expected to be reached, 

as it was last year. Although Dr. Geibe will remain involved with the ACIP, there will be a DoD 

replacement representative for the next ACIP meeting. He also announced that the Ebola 

responders would be receiving their influenza vaccinations that day in the Emergency 

Operations Center (EOC). 

Agency Updates

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Department of Veteran’s Affairs (DVA)

Dr. Kinsinger announced that the Department of Veteran’s Affairs (DVA) launched its VA Retail 

Immunization Care Coordination Program in September 2014. This retail partnership is with 

Walgreens. Information about certain vaccines given by Walgreens pharmacists to VA-eligible 

Veterans will be sent electronically to their VA medical record, and will be viewable by their VA 

providers in the regular place where all immunizations are recorded. For this year, information 

about influenza, pneumococcal, and zoster vaccines will be transmitted to recipients’ VA 

electronic medical records (EMR). The VA is funding about 75,000 influenza vaccines for 

Veterans enrolled in the VA for healthcare. All Walgreen stores throughout the country are 

participating. Other retail pharmacies will be added as the program is expanded. The VA is 

working to update its clinical guidance and electronic decision support tool, called Clinical 

Reminders, for the pneumococcal vaccination to align with the recent ACIP recommendation for 

PCV13 in older adults. That will be in place in a couple of months. Work is also underway to 

develop a Clinical Reminder for the Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular 

Pertussis (Tdap), Tetanus-Diphtheria (Td), and zoster vaccines. Week 42 influenza activity is 

low across the VA, as it is across the country based on number of hospitalizations, influenza-like 

illness (ILI) visits, testing, and positive laboratory results. Since August, approximately 900,000 

doses of vaccine have been administered to Veterans in the VA healthcare system. 

Food and Drug Administration (FDA) 

Dr. Sun reported that the FDA has prioritized review of the two meningococcal B vaccines 

manufactured by Pfizer and Novartis. Those reviews are ongoing, with a regulatory action 

anticipated soon. The FDA is also involved in the Ebola outbreak response working with CDC, 

NIH, and other regulatory agencies to implement human testing with available vaccines. There 

have been two noteworthy approvals since the last ACIP meeting. The first was the approval of 

AFLURIA®, to be given by the PharmaJet® needle-free injection system. This approval was 

based on an immunogenicity non-inferiority study in approximately 1200 subjects 18 through 65 

years of age with a 1:1 randomization. The second was the approval of Menactra® for use as a 

booster for ages 15 through 55. This was evaluated as an open-label study among 834 

subjects 11 years of age and older who received their last dose 4 to 6 years previously. 

Health Resources and Services Administration (HRSA)

Dr. Houston indicated that the Advisory Commission on Childhood Vaccines (ACCV) has made 

recommendations to amend the Vaccine Injury Table on several dates, the latest being 

September 5, 2014. These recommendations are based on the Institute of Medicine’s (IOM) 

review of the scientific literature on vaccines and adverse events. These recommendations are 

being considered by the agency. Increasing numbers of petitions are being filed by the National 

Vaccine Injury Compensation Program (NVICP) each year. The highest number of claims filed 

with the program occurred during fiscal year 2014, which was 611. Increasing numbers of 

claims are also being compensated. In fiscal year 2013, 351 claims were compensated and in 

fiscal year 2014, 365 claims were compensated. Over $200 million were paid in compensation 

to petitioners. The NVICP, which compensates individuals and families of individuals who have 

been injured by vaccines, which is a rare event, is an alternate to the traditional tort system. 

The Health Resources and Services Administration (HRSA) has instituted an outreach 

campaign in order to inform people that this is a safety net that is available to them in the event 

that they are injured by vaccines. HRSA will reach out to partners in order to promote 

awareness of the program. 

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Indian Health Services (IHS)

Ms. Groom reported that the Indian Health Service (IHS) has begun an aggressive influenza 

campaign. IHS also has developed a new Influenza Vaccination Action Plan to align with the 

goals of the Healthy People 2020 (HP2020) that includes a number of strategies, including 

performance measures to help IHS achieve that goal. IHS has administered 184,000 doses of 

influenza vaccine to date in its patient population. IHS is also rolling out its Hepatitis B Clinical 

Reminder for people with diabetes mellitus, which was to go live in the next week, and is 

working with the VA on the PCV13 Clinical Reminder and hope to have that rolled out within a 

month. 

National Institutes of Health (NIH) 

Dr. Gorman emphasized NIH’s continued interest in antimicrobial resistance, which is 

tangentially associated with ACIP. Through its Antimicrobial Resistance Leadership Group, NIH 

is working on stewardship, behavioral changes, development of new antibiotics, and exploration 

of the role of vaccines in addressing the continued problem of antimicrobial resistance. NIH and 

CDC are working collaboratively to develop a clinical trial for Coccidioidomycosis (Valley Fever) 

in the affected areas of California and Phoenix, with implementation anticipated in summer 

2015. NIH’s hepatitis C virus (HCV) candidate trial continues to enroll well, and results for that 

trial should be available soon. The agency is soon to go into the clinic with its first broadly 

protective (alternatively called “universally protective) influenza vaccine. Regarding Ebola, he 

echoed Dr. Schuchat’s observation that “it takes a village to save the world.” This is an 

incredible effort on the part of the US government, other governments, non-governmental 

organizations (NGOs), HCPs, and the pharmaceutical industry all working together to try to 

address this situation. Currently, NIH plays a role throughout the entire spectrum of 

development of agents and is presently evaluating five potential therapeutics and three potential 

vaccines, and is assessing preclinical targets and testing previously approved medications and 

medications specifically developed for Ebola to determine whether they may be effective against 

this agent. Toxicity studies for the vaccines have been accelerated to meet some FDA 

requirements, and the number of non-human primates in studies have been expanded to 

acquire better data on potential correlates of protections. System biology is being utilized to 

assess the differences between the vaccine candidates that protect and those that do not 

protect non-human primates. Enrollment has been completed for a Phase 1 vaccine trial in the 

US for one candidate vaccine, and planning is underway for several other potential Phase 1 and 

Phase 2 trials for different candidates. In terms of the potential efficacy or effectiveness trial, 

considerations continue regarding the best possible design that is implementable and that will 

result in data to offer confidence that these vaccines work and are safe and effective. 

 

National Vaccine Advisory Committee (NVAC) 

Dr. Orenstein announced that the National Vaccine Advisory Committee (NVAC) published a 

report on enhancing uptake of vaccines recommended for pregnant women, and is now 

embarking on the second phase to determine how to incentivize development of vaccines 

intended for pregnant women for existing vaccines with that indication and new vaccines 

intended for that group. NVAC is also involved in the mid-course review of the National Vaccine 

Plan (NVP), which is a 10-year plan, and will be working with the National Vaccine Program 

Office (NVPO) and potentially making recommendations for change. NVAC has two WGs, one 

which focuses on improvement of HPV vaccine uptake for which recommendations are 

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anticipated soon, and another that focuses on overcoming vaccine confidence/hesitancy for 

which preliminary recommendations should be ready for review during the next NVAC meeting. 

National Vaccine Program Office (NVPO) 

Dr. Gellin reported that the previous week, HHS Secretary Burwell announced the appointment 

of a new Acting Assistant Secretary for Health (ASH), Dr. Karen B. DeSalvo. She is the 

National Coordinator for Health Information Technology, an area that does not go unnoticed in 

immunizations. Before coming to the Department of Health and Human Services (HHS), she 

was the Health Commissioner in New Orleans and was significantly involved in the rebuilding of 

the health system there following Hurricane Katrina. With CMS, NVPO published a piece in 

Medscape that explains the Affordable Care Act (ACA) and immunizations. The piece is 

intended for providers and includes resources. He also thanked ACIP for having Dr. Frieden 

introduce the importance of adult immunizations. NVPO is in the process of clearing an adult 

immunization strategic plan. ACIP will have an opportunity to review and offer input on the draft 

plan.

Introduction 

Ruth Karron, MD 

Chair, Influenza Work Group

Dr. Karron reported that since June 2014, the Influenza WG has focused primarily on 2013-

2014 vaccine effectiveness estimates for live attenuated influenza vaccine (LAIV) and 

inactivated influenza vaccine (IIV). They have heard data from the US Flu VE Network, the 

Armed Forces Health Surveillance Center, and MedImmune on a post-marketing study of 

quadrivalent LAIV. During this session, updates were presented on influenza surveillance, 

effectiveness of LAIV and IIV seasonal influenza vaccines in children and adults, administering 

AFLURIA® influenza vaccine with the PharmaJet® Stratus® needle-free injection device, and the 

influenza vaccine supply. 

Influenza Surveillance Update

Lisa A. Grohskopf, MD, MPH 

Influenza Division 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Grohskopf indicated that during Week 42, widespread influenza activity was reported by 

Guam. Local influenza activity was reported by Puerto Rico and five states: Alaska, 

Connecticut, Florida, North Carolina, and Texas. Sporadic influenza activity was reported by 

the US Virgin Islands and 36 states: Alabama, Arkansas, California, Colorado, Delaware, 

Georgia, Hawaii, Indiana, Iowa, Kentucky, Louisiana, Maine, Maryland, Massachusetts, 

Michigan, Minnesota, Mississippi, New Hampshire, Nebraska, New Jersey, New Mexico, New 

York, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, South Carolina, South Dakota, 

Utah, Vermont, Virginia, Washington, West Virginia, Wisconsin, and Wyoming. No influenza

Influenza

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activity was reported by the District of Columbia and nine states: Arizona, Idaho, Illinois, 

Kansas, Missouri, Montana, Nevada, Rhode Island, and Tennessee. 

Based on FluSurv-NET data for laboratory-confirmed influenza hospitalizations by age reported 

to the system during the period October 1, 2013 to April 30, 2014, the highest rates of 

hospitalization were observed among people aged 65 and older. In the previous season, 2012-

2013, the next highest rates were observed among the very youngest in the US population, 

those zero through 4 years of age. Neither of these is atypical. Last season, the next highest 

rates of hospitalization were observed in middle-aged adults, those aged 50 through 64 years of 

age. In terms of the proportion of hospitalizations contributed from each age group, the 2013-

2014 season was the first H1N1 predominant season since the pandemic of 2009-2010. It is 

interesting to note that the portion of hospitalization contributed by adults 19 through 64 years of 

age was 57%, which is the highest in that age group since the pandemic. 

There has been one pediatric death report thus far the 2014-2015 season. For the 2013-2014 

season, a total of 109 pediatric deaths were reported to CDC. Among the isolates for which 

subtyping was performed, 44 Influenza A (2009 H1N1), 6 were Influenza A (H3N2), 38 were 

Influenza A (subtype not determined), 17 were Influenza B, 2 were Influenza A and B coinfection, and the subtyped was not determined for the remaining 2. 

The following graphics depict influenza positive tests reported to CDC by the US WHO National 

Respiratory and Enteric Virus Surveillance System (NREVSS) collaborating laboratories for the 

2013-2014 compared to the 2014-2015 season: 

While 2009 H1N1 predominated the 2013-2014 season, only 1% of H1N1 has been observed 

thus far in the 2014-2015 season. Only three weeks into the current system, it is far too early to 

make a statement about what type of season this will be. 

Regarding what is being observed specifically with H3N2 viruses, the WHO recommendation for 

composition of the 2014-2015 Northern Hemisphere vaccines is the same as it was for the 

2013-2014 season, A/Texas/50/2012. The Northern Hemisphere recommendations are usually 

made in February and the Southern Hemisphere recommendations are usually made in 

September. WHO convened in September to discuss the recommended vaccine composition 

for the 2015 Southern Hemisphere vaccine. Of note, they recommended a different H3N2 virus, 

A/Switzerland/9715293/2013 (H3N2)-like virus, for the upcoming Southern Hemisphere 2015 

vaccine. Dr. Grohskopf briefly reviewed some of the data upon which this recommendation was 

based. Antigenic characteristics of H3N2 viruses collected from February through August 2014 

were assessed using panels of post-infection antisera, including hemagglutinin (HA) inhibition 

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and virus neutralization assays. Many isolates were still well-inhibited by antisera raised against 

the cell-propagated reference viruses A/Texas/50/2012 and A/Victoria/361/2011; that is, they 

were similar to the viruses included in the 2013-2014 and 2014-2015 Northern Hemisphere 

seasonal vaccines. However, an increasing proportion were poorly inhibited by these antisera, 

and antisera raised against egg-propagated A/Texas/50/2012. On that basis, the 2015 

Southern Hemisphere H3N2 is an A/Switzerland/9715293/2013 (H3N2)-like virus. Based on 

this information from surveillance, antigenic drift is anticipated among H3N2 viruses in the 

Northern Hemisphere for the 2014-2015 season. 

Discussion Points 

Acknowledging that it is early in the season, Dr. Reingold asked whether the vaccine strains are 

a reasonable match for the H3N2 strains being observed. 

Dr. Grohskopf replied that antigenic characterization data for the isolates seen thus far this 

season would probably not be available for another three to four weeks. In terms of antigenic 

characterization for the 2013-2014 season, the overall match was pretty good. 

Based on previous experience, Dr. Temte asked how predictive the first few weeks are in terms 

of the distribution of H3N1 viruses. 

Dr. Grohskopf responded that it is difficult to make generalizable statements across seasons. 

Last season, a fair amount of H1N1 was observed early and that did persist. There was a later 

uptick in B, but not near the prevalence of H1N1. 

Update on Effectiveness of LAIV and IIV Inactivated 

Seasonal Influenza Vaccines in Children and Adults 

Brendan Flannery, PhD 

Influenza Division 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Flannery reminded everyone that the US Flu VE Network provides estimates of seasonal 

influenza vaccine effectiveness against circulating influenza viruses each season. In past 

seasons, the US Flu VE Network has presented to ACIP interim estimates of vaccine 

effectiveness during the season as well as end-of-season estimates. The US Flu Vaccine 

Effectiveness Network is a cooperative agreement between CDC and the following five sites 

within the US. 

 University of Michigan and Henry Ford Health System 

 University of Pittsburgh Schools of the Health Sciences and University of Pittsburgh Medical 

Center (UPMC) 

 Baylor Scott and White Health, Texas A&M University Health Science Center College of 

Medicine 

 Group Health Research Institute 

 Marshfield Clinic Research Foundation 

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LAIV use within the network has been increasing, which has allowed the opportunity to evaluate 

effectiveness by vaccine type. The objectives of this presentation were to compare the 

effectiveness of LAIV and IIV vaccines among children and adolescents during three influenza 

seasons (2011-2012, 2012-2013, and 2013-2014); and summarize other data from 

observational studies that evaluated LAIV and IIV effectiveness among children and 

adolescents during the 2013-2014 influenza season. 

As a review of the methods used by the US Flu VE Network, participating sites enroll 

outpatients aged 6 months and older who present with acute respiratory illness and cough 

within 7 days of symptom onset. This is a prospective case-control study that uses a testnegative design. All enrolled outpatients are tested for influenza by reverse transcription 

polymerase chain reaction (RT-PCR). Cases are outpatients with confirmed influenza, while 

controls are outpatients who test negative for influenza. Vaccination status is confirmed by 

medical record or immunization registry data. Only those considered fully vaccinated per the 

ACIP recommendations 14 or more days before illness onset are included. Vaccine 

effectiveness (VE) is calculated as 1 minus the adjusted odds ratio times 100. Estimates are 

adjusted for age, sex, study site, days from illness onset to enrollment, high risk health status, 

calendar time, race and ethnicity, and parental-rated general health status. The analysis 

presented by Dr. Flannery included only enrollees ages 2 through 18 years of age who received 

only one type of vaccine in a season. He presented VE of LAIV versus unvaccinated children, 

VE of IIV versus unvaccinated children, and the relative effectiveness of LAIV to IIV which 

directly compares these two groups. 

Since the pandemic H1N1 virus emerged in 2009, it has continued to circulate as a seasonal 

virus, although at varying amounts each season. Last season had the largest number of H1N1 

viruses since the 2009 pandemic. Based on the number of influenza positive subjects of all 

ages by type/subtype enrolled in the US Flu VE Network for the past 3 influenza seasons, cases 

due to the 2009 H1N1 pandemic virus were identified in each of the 3 seasons but contributed a 

small proportion of all cases in 2011-2012 and 2012-2013 seasons. 

In terms of the total number of influenza-positive cases included in the analysis and the number 

of cases vaccinated with LAIV, in the first two seasons, the adjusted VE estimates were high 

and had largely overlapping confidence intervals. In 2013-2014, the VE estimate was not 

statistically significant. When the data were stratified by age group (2 through 8 years of age 

and 9 through 18 years of age) low VE was seen for the 2013-2014 season in the younger age 

group. The adjusted VE of IIV against any influenza was high and statistically significant for all 

seasons included in this analysis. Unlike LAIV, a VE estimate was observed in 2013-2014 that 

was similar to those from previous seasons. When stratified by age group, similar estimates 

were found. 

In a side-by-side comparison of LAIV and IIV against no vaccine for 2 through 18 years old by 

influenza type and subtype, for the H1N1pdm09 virus for the three seasons combined, very low 

effectiveness was observed for LAIV against the pandemic H1N1 virus, moderate IIV 

effectiveness was seen against the pandemic H1N1 virus, there was a slightly lower overall 

significant effectiveness for H3N2 for IIV and a very similar point estimate for LAIV, and there 

was moderate effectiveness for B strains that was similar for LAIV and IIV. A similar pattern is 

observed among 2 through 8 year olds, with low effectiveness of LAIV over those three seasons 

against the H1N1 pandemic strain and similar effectiveness for both vaccines for H3N2 and B 

strains. 

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For the analysis of the relative effectiveness of LAIV compared to IIV, an odds ratio less than 1 

indicates superior effectiveness of LAIV, an odds ratio greater than one indicates superior 

effectiveness of IIV, and that 1 indicates no difference in effectiveness between vaccine types. 

During the 2011-2012 and 2012-2013 seasons, VE of LAIV and IIV were equivalent among 2 

through 18 year olds, with confidence intervals that include one. In 2013-2014, IIV had higher 

relative effectiveness than LAIV and the difference was statistically significant. When stratified 

by age group, for children 2 through 8 years of age, point estimates indicated higher relative 

effectiveness of LAIV compared to IIV in 2011-2012 and 2012-2013, although differences were 

not significant, with confidence intervals including 1. However, in 2013-2014, the relative 

effectiveness of IIV was higher than LAIV and statistically significant. LAIV and IIV 

effectiveness was equivalent for all three seasons among the older children and adolescents. 

Analyses of US Flu VE Network data are subject to several limitations. It is not possible to 

disentangle single season versus pandemic H1N1-specific effects since there was low 

circulation of the 2009 pandemic H1N1 virus in the study populations in the seasons preceding 

the 2013-2014 season. The ability to measure age-group specific VE by vaccine type in the US 

Flu VE Network depends both on vaccine uptake and sample size. In the analyses presented 

during this session, there was limited ability to control for potential confounding variables due to 

small sample sizes. 

In summary, during the 2011-2012 and 2012-2013 influenza seasons, relative effectiveness 

favored LAIV versus IIV in young children but was not statistically significant. During the 2013-

2014 season, relative effectiveness favored IIV versus LAIV in young children. H1N1pdm09 

was the predominating virus for the first time during the 2013-2014 season. The subtypespecific analysis is consistent with poor VE for LAIV against this virus. However, a specific 

issue related to the 2013-2014 season cannot be ruled out such as an issue with the study 

enrollees or design, unmeasured confounding, or a vaccine issue. For that reason, CDC asked 

the manufacturer and the DoD to review their data for LAIV effectiveness. The data from both 

were presented to the Influenza WG, and Dr. Flannery presented a review of the available data 

from the 2013-2014 season on LAIV and IIV effectiveness in children and adolescents from 

MedImmune and the DoD. 

MedImmune study results are similar to CDC results based on data from a post-licensure 

effectiveness study MedImmune is conducting. This is the first season of that study. However, 

LAIV effectiveness was observed for influenza B. There was not enough B in the US Flu VE 

Network to make an estimate specifically for influenza B for LAIV that was significant. 

MedImmune found no significant effectiveness for A/H1N1 pandemic virus overall. They found 

significant differences in effectiveness observed by vaccine lot shipping time, but have no clear 

explanation for that at present. Comprehensive investigations into potential explanations are 

ongoing. They do believe that there are differences by lot that might be explained by H1N1 

strain potency loss. A/California LAIV is more susceptible to thermal degradation due to a 

unique HA stalk sequence, and those results have been published [Cotter et al, PLoS 

Pathogens, 2014]. The sequence is not present in seasonal influenza LAIV strains, which were 

used for the clinical trials of IIV versus LAIV. 

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The MedImmune Study of LAIV effectiveness includes community-dwelling children 2 through 

17 years of age in the following US locations: 

 Vanderbilt/Tennessee 

 Wake Forest/North Carolina 

 Scott and White/Texas 

 Marshfield Clinic/Wisconsin 

Two of these sites are from the US Flu VE Network, but the children are not recruited from the 

same clinic so there is no overlap with the data presented from the US Flu VE Network study. 

MedImmune used a similar test-negative design, with RT-PCR confirmed influenza, medically 

attended acute respiratory illness with onset <5 days, and a vaccination history confirmed by 

medical record or registry. The study excludes children vaccinated <14 days before their visit. 

The MedImmune data shared by Dr. Flannery were based on the 1033 subjects included in this 

analysis. 

While there were overlapping confidence intervals in these data, there was a suggestion of 

lower effectiveness for LAIV. Broken down by subtype, it is clear that there was a difference in 

the point estimates for the H1N1 in LAIV versus IIV. For B the estimates are similar and high for 

both vaccines. In the analysis being conducted to assess the week that a lot was shipped, 

weeks when the lots may have been exposed to high temperatures that could have affected the 

lots were assessed (e.g., Weeks 4 through 9 or early August through mid-September). These 

are the weeks during which high temperatures could have affected the lots, specifically in terms 

of the potency of the H1N1 2009 vaccine virus. MedImmune found no effectiveness for the 

children who received those lots of vaccines versus a pretty reasonable effectiveness estimate 

for early or later shipments. The same effect was not observed in the US Flu VE Network data 

analyzed with the same information regarding the date of shipping lots. 

Dr. Flannery also presented data from the DoD’s influenza vaccine effectiveness study in Air 

Force children 2 through 17 years of age for the 2013-2014 influenza season. This study was 

limited to Air Force dependents, given that it is the only service that has a database of 

immunizations for all dependents. They also used a test-negative design; however, they 

included both PCR+ and culture-confirmed influenza versus PCR-negative controls. Their testnegatives are essentially all PCR-confirmed negative, even though they used PCR or culture. 

The analysis controlled for month of diagnosis, confirmed vaccine history from Air Force 

immunization tracking, included those who received vaccine >14 days prior to lab test, and 

adjusted for up to a 5-year vaccination history. DoD found moderate VE for any vaccine type 

and significant VE for IIV for all age groups. No VE was shown for LAIV for any age group. 

They believe that the low LAIV VE may be related to the predominance of A/H1 circulation this 

season. They did not have a large enough sample size to have significant VE when analyzed 

by subtype, but the subtype analysis is very consistent with no or low VE for the pandemic 

H1N1 2009 strain. 

In conclusion of all of the observational data presented during this session for the three US 

studies conducted during the 2013-2014 season, all used a test-negative design and all 

reported low VE for LAIV4. All three studies reported higher and significant VE for IIV among 

the same groups of children and adolescents. All three studies reported low VE for LAIV4 

against H1N1pdm09 in 2013-2014. The MedImmune post-licensure study reported significant 

VE for LAIV4 similar to IIV against influenza B-Yamagata, but not for H1N1pdm09. 

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Grading of Recommendation Assessment, 

Development and Evaluation (GRADE) of LAIV

Lisa A. Grohskopf, MD, MPH 

Influenza Division 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

In the interest of putting this information in the context of recent decisions voted upon in June 

2014 related to LAIV and IIV for children, Dr. Grohskopf presented some summary 

observations. Prior to the current season, healthy children 2 through 8 years of age would have 

been recommended to receive either LAIV or IIV with no specific preference recommended for 

either vaccine. Leading up to the June 2014 ACIP meeting, there was discussion of several 

studies that suggested potential advantages of LAIV over IIV, including better vaccine efficacy 

and better heterotypic protection against drifted strains. Several countries (Canada, the UK, 

Israel, Germany) and two US states (Washington, Oregon) previously expressed some degree 

of LAIV preference for young children. The age ranges and specific details of the populations to 

which the preference applies vary, but some form of language was expressed by these 

jurisdictions. In June 2014, ACIP recommended that LAIV should be used when available for 

healthy children aged 2 through 8 years, following a Grading of Recommendation Assessment, 

Development and Evaluation (GRADE) assessment of data from two comparative RCTs. 

The GRADE assessment was presented during the June 2014 ACIP meeting, with numerous 

outcomes discussed. The most relevant outcome for this particular conversation is laboratoryconfirmed influenza, which was valued as a critical outcome for policy decision-making. The 

data evaluated for this outcome are from two RCTs, Belshe1 and Ashkenazi2, which were both 

comparative studies of LAIV and IIV. One arm was included for each of these vaccines. 

Overall, the pooled relative risk ratio was 0.46 with a confidence interval of 0.39% to 0.54% 

favoring LAIV for providing increased protection relative to IIV against laboratory-confirmed 

influenza. For this analysis, it is important to remember that the influenza cases included all 

influenza types and subtypes (all A(H1N1), A(H3N2), and B) without regard to antigenic 

similarity to viruses in vaccine during that given season [1Belshe et al, NEJM 367;7: 685-696; 

2Ashkenazi et al, PIDJ 2006;25:870-879].

To the extent that it was reported in the Belshe and Ashkenazi manuscripts, type-specific 

information was assessed. Belshe (2007) was conducted for the 2004-2005 season. This was 

a randomized, placebo-blinded comparative trial of LAIV and IIV. For example, if a child 

received LAIV they received a placebo for IIV. Because no children received only placebo, it is 

not possible to assess absolute VE from this study. Only relative LAIV as compared to IIV could 

be evaluated. All H1N1s that season were antigenically matched to the vaccine, which that 

season included A/New Caledonia/20/1999. As this study was conducted over the 2004-2005 

season, it was pre-pandemic, so the 2009 H1N1 was not yet in the mix for circulation or 

vaccine. Relative VE for LAIV versus IIV specifically for H1N1 was 89.2% and had a significant 

confidence interval of 67.7% to 97.4%. All H3N2 were antigenically mismatched compared to 

the vaccine—all were drifted. Nevertheless, the relative VE for LAIV versus IIV was 79.2% with 

a significant confidence interval of 70.6% to 85.7%. B viruses from both lineages were 

circulating and were represented in the samples from that study. Some matched vaccine and 

some did not. Relative VE for the matched strains was 27.3%, but the confidence interval was 

not significant at -4.8% to 49.9%. Relative VE for the mismatched was 6.3%, again with a 

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confidence interval that was not significant at -31.6% to 33.3% [Belshe et al, NEJM 367;7: 685-

696].

Ashkenazi (2006) was conducted for the 2002-2003 season. This was a randomized, openlabel comparative trial of LAIV versus IIV with no placebos given. The authors note in the paper 

that cases included A(H1N1), A(H3N2), and B viruses regarded as antigenically similar to 

vaccine, as well as some H3N2 cases that were regarded as antigenically distinct from vaccine. 

The vaccine A(H1N1) was the same as the Belshe study, A/New Caledonia/20/1999. Again, 

this was a pre-pandemic study. Results specific to the mismatched strains alone are not 

reported. They are mainly relevant for H3N2. For type/subtype-specific A(H3N2), without 

regard to match, the relative VE of LAIV versus IIV was -47.9% with a very wide confidence 

interval of -236.5% to 32.6%. This is difficult to interpret, and is probably due to the small 

numbers in the sample [Ashkenazi et al, PIDJ 2006;25:870-879].

To summarize, comparative studies of LAIV and IIV were conducted prior to 2009 pandemic. 

There are no H1N1pdm09-specific efficacy data available from RCTs, and there is relatively 

little effectiveness data for monovalent LAIV that was administered during the pandemic. 2013-

2014 was the first H1N1-predominant influenza season since 2009 pandemic. The data 

presented during this session provide what is believed to be the first clear indication of 

suboptimal effectiveness of LAIV for H1N1pdm09 virus. Ongoing investigation is in progress, 

given that the explanation for the 2013-2014 findings is not known. As alluded to by Dr. 

Flannery in his presentation, differences by lot shipping time in the MedImmune data are 

currently under investigation. Good VE for LAIV against influenza B has been observed, with 

similar findings for H1N1 in three different datasets. Therefore, it is not clear whether there is a 

specific handling issue since that would be expected to impact influenza B as well. Current data 

are from observational studies, so there is a potential for biases or residual confounding. 

However, somewhat similar findings seen in three different datasets at this point strengthens the 

observations. 

As noted in Dr. Flannery’s presentation, LAIV H1N1pdm09 may be less stable and more subject 

to thermal degradation than seasonal H1N1 LAIV viruses have been [Cotter et al, 2014]. The 

sequence in HA stalk confers higher susceptibility to thermal degradation. It is conceivable that 

this potentially could affect stability and/or the replicative fitness of the vaccine virus. This is a 

live virus vaccine, so in order to work, it does need to multiply in the nasal mucosa. That would 

be a potentially biologically plausible explanation, and could also be consistent with previous 

good VE observed with seasonal H1N1 strains and 2013-2014 observations of good 

effectiveness of LAIV against influenza B isolates. 

Looking forward, the 2014-2015 vaccine has already been produced. No changes are 

anticipated this season. The US Flu VE Network is receiving additional resources to increase 

enrollment of children, and this issue will continue to be evaluated. The WG will continue to 

discuss additional data from these and other sources as it becomes available. 

Discussion Points 

Dr. Karron emphasized that the “Silver Lining” in identification of a problem with the H1N1 

component of LAIV was due to the strong VE network and information from DoD. This problem 

may not have been recognized this quickly 5 to 10 years ago. Regarding early circulation of A 

strains and prediction of what will circulate during the season, she wondered if would be a fair 

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statement, based on the VE network data, to say that generally one A strain predominates and 

the A strain that is identified early in the season tends to be the predominant strain. 

Dr. Flannery replied that in the season that followed the pandemic, there was similar circulation 

of the pandemic H1N1 and H3N2 viruses. That is uncommon and that analysis was able to give 

subtype-specific estimates for VE. If there is co-circulation of both A subtypes this season, it 

would add to the data on this phenomenon and would allow for comparison of the H3 and H1 

VE for those two vaccines for the same season. In most seasons, one A strain seems to 

dominant and the subtype-specific analysis does not make sense until some seasons are 

combined. 

Dr. Reingold asked whether the stalk issue pertains only to H1N1 or is also an H3N2 issue. In 

addition, he said that while he understands the issues of observational studies and confounding, 

he is not personally persuaded that confounding and uncontrolled confounding is the issue here. 

He did not see how it could pertain to the effectiveness estimates for H1N1 and not for B. 

Dr. Grohskopf responded that it appears that the issue is specific to the sequence that confers 

that particular vulnerability with the H1N1pdm09 virus. Her understanding is that this was 

observed in the wild type 2009 pandemic viruses early in the pandemic, but that there since has 

been some evolution away from that and the current wild type viruses are more stable. This 

does not appear to be an issue with seasonal H1N1 or H3N2 viruses. 

In terms of moving forward, Dr. Harrison inquired as to whether there are ways to assess the 

current lots that have been produced and avoid the issue of problematic lots from last year. 

Dr. Grohskopf replied that more information is anticipated from the DoD prior to the February 

ACIP meeting. The US Flu VE Network will also continue to collect data. In regard to moving 

forward and the vaccine, the vaccine has been produced for this season. She requested that a 

representative from MedImmune comment on that. 

Regarding replacement of the 2009 pandemic H1N1 component with a more stable virus, Dr. 

Karron noted that a paper published earlier in the year discussed a more stable, later isolated 

variant. 

Kathleen Coelingh (MedImmune) responded that this is an odd immunoassay sequence in the 

stalk region in the pandemic strain. The exact copy was used and was introduced into 

MedImmune’s vaccine because that was the sequence they were supposed to use for the 

vaccine. Currently, the strains have lost that particular change. So, MedImmune is very 

interested in making a change in its vaccine for the 2015-2016 season if the strain does not 

change. They would get an antigenically similar strain to the 2009 H1N1 California strain, which 

does not contain the mutation that is undesirable in the stalk. That would be one of the more 

recent strains. It would be an update. 

Dr. Karron asked whether MedImmune has thoughts about ways to assess the thermostability 

or infectivity that would help decide whether the replacement strain is better than the one 

currently in the vaccine. 

Kathleen Coelingh (MedImmune) responded that they do. 

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Dr. Kempe expressed confusion about whether the lot issue is really the problem. She asked 

whether it was possible to assess the different lots in other datasets such as the Air Force data 

to determine whether there was variability between different lots. 

Dr. Flannery replied that he did not have the data for the Air Force by lot, and he did not believe 

they assessed this. The US Flu VE Network analyzed the same way for lot does not show this. 

Dr. Romero asked whether data could be obtained from countries in the Southern Hemisphere 

regarding the effectiveness of LAIV. 

Dr. Grohskopf responded that she did not know the prevalence of LAIV in the Southern 

Hemisphere, and welcomed comments about that from MedImmune. It is licensed in Canada, 

the UK, Germany, and Israel. However, in many of those countries it has been licensed only 

recently. The US has had it since 2003, but Canada and the UK use has been relatively recent. 

Kathleen Coelingh (MedImmune) added that the vaccine is not currently licensed in any of the 

Southern Hemisphere countries. 

Dr. Temte asked whether in the usual approach, illness severity was assessed in people who 

presented with acute respiratory infection (ARI) and cough. He also wondered how rapidly the 

annual VE estimates could be calculated once the season is over. 

Dr. Flannery indicated that there have been a couple of attempts in the US Flu VE Network to 

assess scores that are essentially cumulative numbers of symptoms and self-described severity 

of illness by ambulatory patients. Those scores have not differentiated very well in terms of 

evaluating differences in VE. Dr. Belongia’s group has performed some of those assessments. 

In terms of when data will be available for this season, in retrospect, it would have been 

possible to assess effectiveness for the 2013-2014 season earlier had interim data been used. 

This is typically not used for vaccine-specific VE in order to wait for documentation and 

verification. However, self-report is quite good for LAIV versus IIV types of comparisons. 

Therefore, it should be possible to provide interim estimates to help update the analysis 

presented during this session. Again, it will depend upon what circulates this season. 

Dr. Belongia added that differences have not been observed in severity; however, the universe 

of people in the study are those who have presented to see a physician. People who stay home 

are not captured. There has been some methods work on this that suggests that the study 

design being used is, under reasonable assumptions, probably a valid measure of VE for 

preventing influenza illness, not just for preventing medically attended influenza. In terms of the 

other severity issue, in general, approximately 80% to 90% of people with influenza meet the ILI 

criteria even though that is not required to be in the study. Only cough is required. 

Dr. Schuchat mentioned that for some years, CDC also supported VE evaluation against 

hospitalized, laboratory-confirmed influenza through the Emerging Infection Program (EIP) 

network. After a couple of years, the conclusion was made that there was comparable VE for 

hospitalization and medically attended illness, and that it was more cost-effective to use the 

outpatient system for estimates of VE and the EIP network for estimates of disease burden. 

This is believed to be a reasonable approach for the more and less severe ends of the 

spectrum. 

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Regarding the data presented, Dr. Michael Decker (Sanofi Pasteur) pointed out that there have 

been publications on LAIV and IIV suggesting that one’s response to vaccination depends in 

part upon prior exposure to influenza vaccine. He wondered whether the VE network has 

collected information regarding prior influenza vaccination exposure, or might do so in the 

future. 

Dr. Flannery replied that this is one of the questions raised by Dr. Reingold about potential 

confounders not being very convincing. However, it is difficult to separate out the group that 

received LAIV from the sites that have relatively high vaccination rates. He shared a table 

showing the LAIV recipients for various age groups in 2013-2014 compared with the receipt of 

vaccine in 2012-2013. Not shown is the LAIV group in 2013-2014 that was unvaccinated in 

2012-2013 because there are so few of them. Almost all LAIV recipients had received either 

LAIV or IIV in the previous season, and several had received vaccines over several seasons. 

The take-home message is that the percentage of influenza positives looks very similar for LAIV 

recipients no matter what they received in the previous season, but the numbers are very small. 

That is the issue with potential confounding. It looks lower in the IIV group for this season, and 

most of those received IIV in the previous season. In terms of the number of cases left out, 

there were only 34 LAIV recipients total. Only a few LAIV recipients either received two doses, 

with their first season in 2013-2014, or received one dose but had not received a vaccination in 

the previous season. Prior vaccine is being assessed as an explanation, but the age-specific 

findings are not understood. It may be that they are not so age-specific, but is just something 

related to sample size and the populations being studied. 

Dr. Decker (Sanofi Pasteur) said that while those were interesting data, that was not the 

question he was asking. ACIP recommended LAIV preferentially for persons from 2 through 8 

years of age—not the entire population because there is evidence that as people age and have 

more experience with influenza, the differential benefit of LAIV disappears perhaps because of 

sufficient antibody. The question regards whether improved vaccination of the pediatric 

population in the last decade since those randomized studies were conducted changed the 

environment such that LAIV is no longer as beneficial in young people as it used to be, because 

they have now had several doses of vaccine before the age at which LAIV is indicated. 

Dr. Flannery said he understood the question, and if “you have a hammer, everything still looks 

like a nail.” He would still probably use this same slide to answer the question. There is limited 

ability to assess the effects of several years of prior vaccination on take of vaccine, whether it is 

by type or by any vaccination. That is an area of great interest and a lot of work in the US Flu 

VE Network. It is difficult to do that with observational data. It would also be difficult to design a 

trial to assess that question. It does seem that prior vaccination or prior infection changes the 

response not only to LAIV, but also to IIV. He would argue that the data seen in the 2013-2014 

season in the US Flu VE Network challenges that idea because both the younger and older 

children had received several vaccinations. The older group might have had more natural 

infections during the pandemic. It suggests that the older group, and maybe some in the 

younger group, received some benefit of vaccination. It perhaps elicited their immune 

response, their memory response, to that particular antigen. Even though the younger group 

had been vaccinated, there appeared to be less response to the LAIV. That is the group who, if 

they had a low baseline, would be expected to respond better to LAIVs. The answer is that this 

is still not understood, but it is an area of active research. 

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Regarding Dr. Flannery’s Slide 14 with 95% confidence intervals over three season for H3N2, 

Dr. Kimberlin (AAP) asked whether LAIV was not statistically significantly affected. 

Dr. Flannery responded that there is slight overlap with no effectiveness. H3N2 estimates over 

three seasons are complicated by whether the same vaccine virus is in the vaccine and what is 

circulating. There was confidence in doing that for these three seasons for H1N1 because there 

was very little antigenic change in what was circulating, and very little antigenic change in the 

virus. Multiple year analyses have been performed for H3 effectiveness, but as Dr. Grohskopf 

presented, for trials all influenzas are used and match is broken down by antigenic match and 

mismatch of the vaccine. Those are mixed in this analysis, so the three-season analysis was 

not meant to make a comparison of LAIV to IIV for the H3N2 subtype. It could certainly be said 

that there are issues with both vaccines in terms of the effectiveness of the H3N2s for the 

younger group. 

Dr. Karron requested that Dr. Flannery show these data for 2 through 8 year olds, noting that 

while the distributions are somewhat different, the point still holds. 

Dr. Plotkin (Vaccine Consultant) pointed out that the stability problem was reported by 

MedImmune in January 2014, meaning that they knew it well before that time. That suggests 

that the standard stability tests that are done for licensure should have shown a problem with 

the H1N1 strain. MedImmune might have data anticipating what happened. For the future, 

everyone believes in LAIV for young children based on prior studies. Those studies were of a 

live vaccine that induced both serum antibody and mucosal antibody. He suggested that for the 

coming seasons, the study of immune responses should be repeated because there is no magic 

involved in this. If those same responses can be shown, it would indicate that the problem in 

the last year will not be repeated, so it is crucial. MedImmune should have retrieved material 

that that was sent out this season to titer it, because it is a live virus. Therefore, it can be 

determined whether the vaccine is still potent by titering the materials that were stored. 

Dr. Christopher Ambrose (MedImmune) affirmed that Dr. Plotkin was correct about this mutation 

being known. It was in the pandemic 2009 A/California strain, which is why it is in 

MedImmune’s vaccine strain. The monitoring of the stability of the 2013 vaccine, like all years, 

is done. Several lots are monitored for stability and potency over time. That is stored in 2 to 8 

degrees Celsius without any deviations from the recommended storage of the vaccine. No 

stability problems were observed with any of the monitored lots of the H1N1 vaccine strain. The 

data published in the paper show that potentially, exposures to higher than 2 to 8 degrees 

Celsius that could occur during distribution, may have an impact. MedImmune does not have 

knowledge that this did occur, but is investigating whether that could have happened during the 

warmest or hottest weeks of the year when the vaccine is being loaded or offloaded. 

MedImmune is in the process of working with its distributors to assess potency of distributed 

vaccine for this year. All of the available data have been confirmed, and there is no evidence of 

any breaks in the cold chain this year or problems with potency. 

Dr. Schaffner (NFID) commented that if this is a stem stability problem, he remained confused 

about the age effect and the postulated lot effect. He was also curious about the FDA’s role in 

this. 

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Dr. Sun (FDA) indicated that the FDA had a discussion with CDC about these data, and has 

also undergone some internal investigations to evaluate the immunogenicity of vaccines through 

the FDA’s evaluation process. Because there are so many potential variables at this point, the 

FDA is still in the investigational stage. Further discussion with MedImmune may be needed, 

but this is currently a work in process. 

Dr. Grohskopf noted that one of the ideas discussed regards whether it might be a vulnerability 

settling effect that would not necessarily manifest itself on a standard stability assay, but would 

perhaps have some effect on the replicative fitness of the virus. That might not be inconsistent 

with an observed difference in age because efficacy of any influenza vaccine by age is known to 

be variable for many reasons. Some other unknown factor might be interacting. 

Dr. Temte recapped that ACIP would be interested in assessments of lot potency; monitoring 

the strains likely to be in circulation this year, which will affect performance of the vaccine and 

ACIP’s recommendations; and early availability of interim VE estimates from the US Flu VE 

Network in terms of future planning. 

Administering AFLURIA® Influenza Vaccine 

Via PharmaJet® Stratus® Needle-Free Injection 

Charles (Chip) Altman, MD, MBA 

US Head, Medical Affairs 

bioCSL, Inc.

Dr. Altman reminded everyone that the FDA recently approved AFLURIA® for use in a new 

needle-free delivery system. While this delivery system is not for every patient, it is an 

important option. Trypanophobia is the fear of needles that applies to children and adults. 

Recently published surveys show that about one quarter of all adults fear needles. It is 

estimated that 7% of adults avoid immunizations due to fear of needles. Some very prominent 

people fear needles, including a talk show host, a former heavy weight boxing champion, and a 

famous karate stunt man. Needle fear is taken very seriously, given that it is a barrier to 

immunization. 

The fear of needles is a barrier not only for the patients, but also for the people administering 

the vaccines. Annually, there are approximately 800,000 needle-stick injuries in the US and 3.5 

million worldwide. There are also fiscal and psychological burdens, with $2 billion in burden in 

the US alone. The cost of needle-stick testing/counseling is approximately $3,000. The cost of 

needle-stick treatment ranges from $3,000 to $100,000. Needle-sticks transmit many bloodborne diseases; however, needles are reused 40% to 70% in the developing world [International 

Health Care Worker Safety Center, Needlestick and Sharps Injury Prevention Act, American 

Journal of Industrial Medicine].

It might be good to avoid the use of needles in certain settings such as the workplace. In Dr. 

Altman’s workplace, a cart is wheeled around to administer influenza vaccine to employees. 

There really is not a great way to dispose of sharps, so the idea of being able to deliver 

influenza vaccination without needles is an important option. That is why bioCLS partnered with 

a very innovative device company in Colorado, PharmaJet®. PharmaJet® developed a Stratis®

needle-free injection system. Jet injection systems for administering vaccines are not new. 

They have existed for about 100 years. During World War II, many immunizations were given 

by jet injection, some well-received and some not so well-received. The new and improved 

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system developed by PharmaJet® to deliver AFLURIA® influenza vaccine has an invisible, 

narrow, precise fluid stream that penetrates skin and enters the deltoid muscle in approximately 

0.1 second. The injector has a small single use cartridge at the end of it that injects the thin 

fluid stream to the proper depth. There is no needle involved in the entire process. The multidose vial of AFLURIA®

 that is used with needle and syringe can also be used with this 

PharmaJet®system. In many states, the cartridges can be discarded using non-sharps 

containers because there are no needles. The amount of time it takes to use the jet injector is 

comparable to using a standard needle and syringe. 

The RCT conducted to receive FDA approval was known as the Jet Injection for Influenza (JIFI) 

study. JIFI was an RCT clinical trial conducted at the University of Colorado Health (UCHealth) 

system to demonstrate non-inferiority of jet injection versus needle and syringe for 

administration of AFLURIA® trivalent inactivated vaccine (TIV) influenza vaccine. The study 

recruited 1250 healthy adults 18 through 65 years of age. This study was published in The 

Lancet in May 2014. The primary objective of the study was to evaluate the non-inferiority of 

AFLURIA® influenza vaccine administered intramuscularly (IM) by jet injection using 

PharmaJet® Stratis®. AFLURIA® was administered IM by needle and syringe in healthy adults 

based on serum hemagglutination inhibition reciprocal titers. Given that this study was 

conducted in 2012-2013, the prevalent Northern Hemisphere strains used included A/H1N1 

(A/California/7/2009), A/H3N2 (A/Victoria/361/2011), and B (B/Hubei-Wujiagang). The 

secondary objectives were to compare the safety and tolerability of the vaccine administered by 

PharmaJet® Stratis® or needle and syringe based on specifically solicited local and systemic 

reactions through 7 days post-vaccination, and adverse events spontaneously reported through 

day 28 post-vaccination. The study was randomized but not blinded, so patients knew if they 

received a jet injection or needle and syringe. However, the people evaluating safety and 

immunogenicity were blinded. 

There were six co-primary endpoints, which included the geometric mean titer (GMT) titers and 

the seroconversion rates for each of the three strains. Criteria were set up in advance of the 

study for non-inferiority. The GMT ratio had to be ≤ 1.5 at 28 days and the seroconversion rate 

differences could not exceed 10% to show non-inferiority [Based on Guidance for Industry 

Clinical Data Needed to Support Licensure of Seasonal Inactivated Influenza Vaccines 2007].

Secondary safety endpoints included immediate reactions in the 30-minute observation period, 

solicited local and systemic adverse events (AEs) through the diary cards, and unsolicited AEs 

and serious adverse events (SAEs) up to and including 28 days after vaccination. Exploratory 

immunogenicity endpoints included seroprotection and geometric mean fold rise (GMFR). 

Exploratory patient experience questions were also asked to assess whether patients liked the 

jet injection and would take it again.

The demographics of the study participants in both arms were comparable by age, sex, and 

race. The GMTs were nearly identical for jet injection versus needle and syringe, showing that 

AFLURIA® administered by jet injection results in the same immune response as administering 

AFLURIA® by needle and syringe at Day 28 post-injection. The overall rate of seroconversion 

was comparable in both groups, with nearly identical percentages for jet injection versus needle 

and syringe. The criteria were met for non-inferiority on the GMT ratio and the seroconversion 

rate. Regarding secondary endpoints, GMFR and seroprotection were also comparable in both 

groups. Overall, very little difference was observed in AFLURIA®administered by jet injection or 

by needle and syringe.

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More jet injection subjects complained of immediately occurring local symptoms or signs, but 

the rates were similar between the two groups at later time points. There was a higher 

frequency of low-grade local reactions with jet injection, but all were low grade. Systemic 

adverse events were comparable between groups. Of the subjects, 3 experienced 6 SAEs. 

There was 1 SAE in the jet injection group and there were 2 in the needle and syringe group. 

All were deemed to be unrelated to the study drug and injection procedure as judged by the 

clinical investigator. In terms of the patient vaccination experience, subjects were interviewed 

immediately post-immunization. They were asked, “Would you chose to receive this type of 

injection again?” Of those who received jet injection, 89% indicated that they would receive it

again for their next immunization. More post-marketing surveys have been conducted asking 

this question since that time, one of which was at the University of Tennessee (UT). Of those 

surveyed, 80% to 90% have said that they would get the jet injection again despite some of the 

early complaints that are mild and resolve quickly. 

36

In conclusion, needle fears and needle stick injuries are barriers to influenza immunization. 

AFLURIA® TIV influenza vaccine delivered by PharmaJet® Stratis® needle-free jet injector met 

non-inferiority criteria for immunogenicity versus needle and syringe. Local injection-site 

reactions were reported more frequently in the PharmaJet® Stratis® injector group, but all were 

mild to moderate. Systemic AEs were comparable between AFLURIA® given with needle and 

syringe and the jet injector. Post-marketing surveys support patient and health care provider 

satisfaction with needle-free influenza immunization. The overall goal is to support increased 

influenza immunization coverage. 

Discussion Points

Dr. Reingold recalled working with the Ped-O-Jet in West Africa with which vaccines could be 

administered to large numbers of people without a needle. One of the concerns with Ped-OJets and Med-E-Jet had to do with the machine not being perpendicular to the skin, in which 

case blood could be produced through some sort of sheering or cutting phenomenon. There 

were problems with blood contamination of the port. He noted that Dr. Altman presented no 

data regarding what is known about blood contamination around the needle-free syringe, or 

what is known about transmission of blood-borne viruses. 

Dr. Altman said his understanding was that the small disposable cartridge is what makes the 

difference. It is about an inch long. The entire cartridge that is used to fill up from the multidose vial is discarded, so there is a separation between the skin and the actual jet injector. That 

piece is disposed of and no needle is involved. No problems have been observed with the 

cartridge piece, and in many states it can be discarded in a non-sharps container. 

Dr. Harrison wondered whether subjects were asked which vaccine they would prefer rather 

than the way the question was asked. 

Dr. Altman responded that they did not. Those who received the PharmaJet® jet injection were 

asked, “Would you chose to receive this type of injection again?”

Dr. Harrison stressed that those are very different questions. It sounded like the subjects were 

not asked preferentially, but were asked only whether they would get this vaccine again in the 

jet injection. 

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Regarding the thickness of the adipose tissue in the arm, Dr. Romero asked whether this device 

would be sufficient to deliver the vaccine to the muscle and not deposit it in the fat tissue in an 

obese individual. He also observed that for those who do not like shots because it hurts, this 

does not accomplish much. 

Dr. Altman replied that it is a “one-size-fits-all” for adults. This injector was studied only with 

AFLURIA®and only with adults. There have been no stipulations about the size of anyone’s 

arm or obesity.

Dr. Vazquez said she was also thinking about obese patients and that depth matters. She 

asked whether there were any data to show that penetration using the jet injector remains the 

same in different individuals. Depth of penetration may not matter for this vaccine, but thinking 

ahead for other vaccines, it might make a difference. 

Dr. Altman responded that he did not have data on penetration, but in the development of this 

device, depth was intended to reach the muscle. He requested that someone from PharmaJet®

offer further information. 

Heather Callender-Potters (Co-Chairman, PharmaJet®) indicated that the syringe has an autodisable feature so that it cannot be reused. The end of the orifice touches the skin. When the 

high velocity of fluid is created that penetrates the skin, for a moment there is an opening in the 

skin. In theory, there is a split second where tissue, fluid, or blood could be seen because a 

hole is being created. However, unlike the Ped-O-Jet, there are no laceration issues with the 

PharmaJet® technology. The spring has been modulated to be appropriate to deliver to target 

tissues. To address that issue, PharmaJet®has submitted 510(K) data to FDA’s Center for 

Devices and Radiological Health (CDRH) that includes gel and tissue studies to demonstrate 

depth of penetration. PharmaJet® has also conducted its own imaging studies, and has studied 

a variety of other vaccines (IM, subcutaneous, and intradermal). Depth and amount deposited 

have been assessed in the intradermal evaluations. She believes that PharmaJet® engineering 

has adequately addressed the concept of reaching the target tissue. 

Regarding infection control, Dr. Rubin pointed out that the common use part of the device is 

reused so presumably this is reloaded. Vaccinators may choose to wear or not wear gloves 

during vaccination. Obviously, they should be performing hand hygiene. He wondered whether 

there were any recommendations for wiping down the device to decontaminate between 

patients or between reloading of the device. 

Heather Callender-Potters (Co-Chairman, PharmaJet®) said they addressed that with the user 

interface, in that the injector never touches the patient. There is an auto-eject button on the 

injector so that once an injection has been given, it is never necessary to touch the patient or 

the single use syringe, and it can be adequately disposed of. PharmaJet®has also tested all of 

the materials in relation to its injector. A number of common disinfectants can be used and 

there are heavy plastics and titanium-coated steel, so all of the standards required for hygiene 

and good practice are met. 

As the UT representative who was highly involved in the study Dr. Altman mentioned, Dr. Foster 

(APhA) said they gave over 2000 vaccines in one day to HCP and the PharmaJet® was 

accepted quite well. Approximately 500 (25%) of the vacinees immediately chose the 

PharmaJet®. He got the needle-free injection himself just to try it out. It is not pain-free, but he 

did not observe any difference for himself in the jet injection versus needle and syringe. 

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Dr. Kenneth Schmader (AGS) asked why people over the age of 65 were excluded in the 

bioCLS study. 

Dr. Altman replied that this study was designed with FDA guidance to evaluate adults. While 

they did not study the older age group in this particular study, he agreed that it would be 

beneficial to think about in the future. 

Dr. Susan Even (ACHA) expressed interest in knowing how fast using the PharmaJet® injector 

might be, because it seemed like it might be faster than single dose needle and syringe. 

Heather Callender-Potters (Co-Chairman, PharmaJet®) indicated that PharmaJet® has 

conducted a number of time studies and trials, and the needle-free injector is comparable to 

needle and syringe for one individual. PharmaJet® has participated in a number of mass 

immunization activities, the needle-free injector has been deemed several times faster. There is 

a process associated with loading the injector and downloaded, but that can be curtailed with 

some extra help. 

Dr. Sandra Fryhofer (AMA/ACP) asked how much the PharmaJet®needle-free injector costs in 

comparison to standard delivery mechanisms, noting that she was unable to locate any 

information on the Internet and had not yet received a response from an email she wrote to the 

company the week before. 

Heather Callender-Potters (Co-Chairman, PharmaJet®) replied that the PharmaJet® system 

compares favorably to needle and syringe delivery. The PharmaJet®device is slightly more 

expensive than a needle and syringe, but there is generally expense reduction in the sharps 

disposal because many choose to use no sharps disposal. Treatment cost, liability, and needlestick testing are not required because there are no risks associated with those issues. 

PharmaJet® also tends to be efficient in vaccine recovery. The device has been engineered 

such that there is basically no wastage of vaccine. This is a very compelling delivery method 

that is highly cost-effective. The injector has been tested for 30,000 cycles and the device is 

warranted for 20,000 uses. PharmaJet®actually does not know when the device will fail. 

Depending upon the volume of the user, the device tends to sell for $250.00 per injector, so it is 

fractional pennies per delivery. If people are buying large quantities, PharmaJet® simply gives it 

away. In terms of the retail price of the cartridge, historically cost tends to be about $1.00 per 

shot. Needles tend to cost between $1.08 and $1.35 depending upon the needle solution that is 

used, and whether two needles are used to download the vaccine from the vial. 

Dr. Gellen (NVPO) asked for a status on PharmaJet® work with other formulations and other 

manufacturers for increased flexibility in programs in the future. 

Heather Callender-Potters (Co-Chairman, PharmaJet®) indicated that PharmaJet® is working 

broadly with a variety of vaccines in clinical testing with its collaboration partners. PharmaJet®

is highly interested in being an effective tool for influenza vaccines. With its partner, bioCSL 

AFLURIA®, is anticipated to involve more and longer-term cooperation. These details are not 

generally shared, but PharmaJet® is extremely grateful for all of the support that has been given 

to them. They have a great relationship with CDC, WHO, and the FDA. She invited anyone 

interested in speaking with them further to visit them in the back of the room after this session. 

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Influenza Vaccine Supply Update

Lisa A. Grohskopf, MD, MPH 

Influenza Division 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Grohskopf reported that while distribution for the current season started off more slowly than 

in many previous seasons over the last 10 years (2004-2005 - 2014-2015), it exceeded last 

year’s rate of distribution in mid-September and is currently at approximately the same level as 

vaccine distribution in the 2012-2013 season. 

At the national level, the current projection for the US market across all manufacturers is 151 

million to 156 million doses. This projection exceeds the total doses distributed during the 2013-

2014 season of 134.5 million doses. As of 10/17/14, 117.8 million doses of influenza vaccine 

have been distributed. Overall, this represents approximately 75% of the vaccine anticipated for 

the season. 

Despite early season shipping delays experienced by several US manufacturers (e.g., GSK, 

MedImmune, and Sanofi Pasteur), manufacturers anticipate that the majority of their influenza 

vaccine distribution will occur by the end of October, with some providers continuing to receive 

partial shipments during November. 

National level distribution data can be insufficient to characterize distribution at the local level. 

For example, because the early season shipping delays impacted certain vaccine brands and 

specific products within brands differently, some providers may be experiencing spot shortages 

while other providers are not. 

Discussion Points

Dr. Bocchini asked whether the Vaccines for Children (VFC) distribution of influenza vaccine 

was on par with the private sector. 

Dr. Bennett said that her understanding from providers in her region was that VFC distribution 

was limited by the prior month’s order, and that there has been an issue this year with respect to 

large providers acquiring sufficient doses from the VFC. 

Dr. Santoli responded that overall, the VFC receives doses equitably with the private sector. 

State programs play an important role in VFC distribution in terms of how they want to allocate 

doses to providers. Not every state operates in the same way. Some states determine that 

some providers might be priority providers because of the patients they serve. Partial 

shipments are fairly common to get everyone started so that everyone has at least some 

vaccine, even if there is not enough vaccine to fill entire orders. At the national level, doses are 

received in a way that is comparable. However, the way each jurisdiction handled their 

distribution was probably not identical. Depending upon what providers ordered, they may have 

experienced receipt differently in one jurisdiction versus another. 

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Dr. Jeanne M. Santoli 

Immunization Services Division 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

During this session, Dr. Santoli presented updates for pertussis-containing vaccines and 

adult hepatitis A and B vaccines. 

Regarding pertussis-containing vaccines, Sanofi Pasteur has sufficient supplies of 

Pentacel®, Daptacel®, and Adacel® (both vials and syringes) vaccines and has removed 

all allocations of these vaccines. There are currently shipping delays for GSK’s Kinrix®

vaccine (DTaP-IPV vaccine). 

Twinrix®, GSK’s combination hepatitis A/B vaccine is currently out of stock in the private 

market. This vaccine is licensed for use in those 18 years of age and older, so its use in 

the VFC program is limited. However, adult formulations of Havrix® (hepatitis A 

vaccine) and Engerix B® (hepatitis B vaccine) are available in sufficient amounts to 

meet anticipated demand. 

CDC’s Vaccine Supply/Shortage Webpage can be found at:

http://www.cdc.gov/vaccines/vac-gen/shortages/default.htm

Introduction 

Jon Temte, MD, MS, PhD 

Advisory Committee on Immunization Practices 

Dr. Temte indicated that the rationale for a novel influenza recommendation is that there are two 

FDA-licensed vaccines for the highly pathogenic influenza A (H5N1) virus. There is a need for a 

recommendation for use during inter-pandemic periods, especially for those who have an 

increased risk of exposure. ACIP was seen as the most appropriate body to develop 

recommendations for these vaccines. This WG was formed because the Seasonal Influenza 

WG has a full workload. The Novel Influenza WG was formed in February 2014, and was 

charged with developing recommendations for use of influenza A (H5N1) vaccine during interpandemic periods. The policy question was, “Should licensed influenza A (H5N1) vaccine be 

recommended to adults with increased risk of exposure during the inter-pandemic time period?” 

If so, the exposure must be determined and the recommendation must be defined. 

Vaccine Supply

Novel Influenza

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In terms of progress to date, the Novel Influenza WG has been meeting at least monthly and 

sometimes more frequently. Between February and October Oct 2014, the Novel Influenza WG 

has met 11 times. This session included presentations from Dr. Sonja Olsen, the CDC Lead for 

the Novel Influenza WG, on Influenza A (H5N1) epidemiology and vaccine, and GRADE and 

policy options for influenza A (H5N1) vaccine. The WG anticipates presenting a 

recommendation for a vote during the February 2015 ACIP. 

Influenza A (H5N1) Epidemiology and Vaccine 

Sonja J. Olsen, PhD 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Olsen reported that influenza A (H5N1) is a highly pathogenic avian influenza (HPAI) virus 

that causes a highly transmissible, severe respiratory disease in birds. The influenza A (H5N1) 

virus is endemic in poultry in at least six countries (Bangladesh, China, Egypt, India, Indonesia, 

and Vietnam), but has also recently been found in Laos and Cambodia. Poultry outbreaks 

occur frequently in these and neighboring countries. Infections have occurred in humans, the 

first of which were recognized in Hong Kong in 1997. At that time there were 18 cases in 

humans, and Hong Kong culled the entire poultry population of approximately 1.5 million 

chickens. The virus reemerged in Asia in 2003, and the number of infections peaked in 2006. 

However, every year, including this year, there have been sporadic cases with high mortality. 

Between 2003 and September 2014, there have been 667 cases in 16 countries. Of these, 393 

have died for a mortality of 59%. Most cases occur from close contact with infected live or dead 

birds, or H5N1 virus-contaminated environments. Human-to-human transmission is extremely 

rare. In 2014, there were 9 cases in Cambodia, 4 in Egypt, 3 in China, and 2 each in Vietnam 

and Indonesia. The following depicts the number of cases from each country: 

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The H5N1 virus continues to evolve. Evolution is monitored using the sequence of the HA 

gene. Viruses are grouped into clades based on phylogenetic characterization and sequence 

homology. Knowledge of currently circulating clades and antigenic distance from existing 

candidate vaccine viruses is relevant to updating pre-pandemic vaccine recommendations.

The following shows all H5 clades: 

The red stars highlight the 13 clades that have not been detected since 2008. The clades 

highlighted with colors indicate the countries where that clade has been detected. The asterisks 

highlight clades and locations where H5 viruses were detected in 2014. For example, Clade 

2.1.3, shown in the reddish color, is found in Indonesia and there were viruses detected there 

this year. 

The WHO Strategic Advisory Group of Experts (SAGE) Working Group on Influenza Vaccines 

and Immunizations has developed global recommendations for use of licensed H5N1 vaccine 

during inter-pandemic periods. These recommendations were first drafted in 2009 and were 

reevaluated and reaffirmed in 2013 with no changes. Vaccine is strongly recommended for 

laboratory workers involved in certain high-risk activities, such as large-scale production with 

virus. Vaccine is recommended for first responders and health care providers managing 

patients. Vaccine is not recommended for persons who may only potentially come into contact 

with infectious animals, workers in areas where the virus is enzootic, and the general 

population. These recommendations are not specific to any vaccine. 

Because H5 viruses continue to evolve, this necessitates frequent development of 

representative candidate vaccine viruses. WHO recommends that countries consider candidate 

vaccine viruses for pandemic preparedness purposes based on an assessment of public health 

risk and needs. Globally, there are currently 26 candidate vaccine viruses in development and 

4 in preparation. 

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In the US, H5N1 vaccines are not made commercially. The US government has supported their 

development. Candidate vaccine viruses are chosen for vaccine development using a 

standardized Influenza Risk Assessment Tool (IRAT). Currently, there are four vaccines in the 

stockpile. The following table shows the four vaccines, highlighting the virus in the vaccine, 

clade represented, and licensure status: 

Virus Clade FDA Licensure

A/Vietnam/1203/2004 1 Yes (Sanofi)

A/Indonesia/5/2005 2.1.3.2 Yes (GSK)

A/bar-headed goose/Qinghai/1A/2005 2.2 No

A/Anhui/1/2005 2.3.4 No

 

Only the first two vaccines are licensed by FDA. Vaccines in the stockpile are for use during a 

pandemic or for clinical studies of the vaccines. Strain changes are permitted only during an 

emergency. These vaccines are not meant for use during inter-pandemic times. 

One FDA-licensed vaccine (Q-Pan) is being produced post-licensure. The US government 

supported additional vaccine production post-licensure. The manufacturer is producing one lot 

of approximately 100,000 doses. It is currently anticipated that this vaccine will be ready in 

early 2015. A portion of this vaccine will be stored at NIH and made available to investigators, 

with the rest to be entered into the stockpile. 

Q-Pan H5N1 vaccine is made by ID Biomedical Corporation of Quebec, which is a subsidiary of 

GSK. The vaccine is an emulsion that consists of 3.75μg HA of the influenza virus strain 

A/Indonesia/05/2005, as well as the AS03A adjuvant emulsion (full dose, 11.86mg tocopherol). 

The vaccine is administered intramuscularly in 2 doses 21 days apart. The licensure states that 

it is approved for use in persons >18 years of age at increased risk of exposure to the influenza 

A virus H5N1 subtype contained in the vaccine. 

Q-Pan is the first vaccine with AS03 to be licensed in the US. There are no adjuvanted 

seasonal influenza vaccines licensed in the US. AS03 is an oil-in-water emulsion adjuvant. 

There are several reasons to use AS03 in influenza vaccines, including increased 

immunogenicity, antigen dose-sparing, and influenza cross-strain neutralization or an ability to 

induce an immune response to other strains. AS03 was used in H1N1pdm09 monovalent 

vaccines, Pandemrix made by GSK in Germany and Arepanrix made by ID Biomedical 

Corporation in Quebec. 

There have been reports of AS03-adjuvanted pH1N1 vaccines associated with narcolepsy. 

Several studies of Pandemrix, used in many European Union countries, have found an 

increased risk of narcolepsy in all ages though this is highest in children and adolescents. 

There have been no studies to date with negative findings. The attributable risk has been as 

high as 6.25 cases per 100,000 persons vaccinated. In addition, a recently study was released 

of Arepanrix used in Canada and Brazil. The population-based study in Quebec found a relative 

risk similar to that observed in European studies of Pandemrix. The attributable risk was lower 

at 1 case per 1,000,000 doses, but the baseline incidence of narcolepsy was also lower than 

was found in Europe. Adjuvanted monovalent H1N1pdm09 vaccines were not used in the US. 

However, because of these findings, CDC sponsored an international study on adjuvanted 

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H1N1pdm09 vaccines (Arepanrix and MF59-adjuvanted vaccines) and narcolepsy. This study 

is in progress, with preliminary results expected in late 2015. 

Q-Pan is licensed for adults at increased risk of exposure. The following table defines persons 

at increased risk of occupational exposure to the H5N1 virus in the US: 

Given that persons at increased risk of exposure to H5N1 virus are a fairly narrowly defined 

group, it was important to estimate the size of the population and thus the possible vaccine 

demand. In 2014, there were 173 Principal Investigators (PIs) who had licenses to work with 

highly pathological avian influenza viruses. Each of the three PIs at CDC has about 15 

laboratorians, so it was estimated that in the US, about 2500 laboratory workers may have an 

interest in being vaccinated. There are approximately 250 public health responders. Based on 

this estimation, the total number of laboratory workers and public health responders at 

increased risk is fairly low at approximately 3000 total persons. At 2 doses per person, that 

would be approximately 6000 doses of vaccine. 

It was also important to quantify the risk of an exposure to H5N1 virus in these persons in order 

to appropriately weight the risks against the benefits. In the US, highly pathogenic avian 

influenza viruses are regulated by the US Department of Agriculture (USDA) as Select Agents 

under Code of Federal Regulation (Title 9, Part 121). The Select Agent regulations require 

entities in the US to do the following, “An individual or entity must immediately notify the Animal 

and Plant Health Inspection Service (APHIS) or CDC upon discovery of a release of a select 

agent or toxin causing occupational exposure or a release of a select agent or toxin outside of 

the primary barriers of the biocontainment area.”

Between 2007 and 2013, there were 44 reported incidents or an average of 6 per year. The 

types of incidents reported include needlesticks, animal bites, leaks, work outside a containment 

facility, or failure in equipment of personal protective equipment (PPE). It is important to note 

that an incident does not necessarily equate to an exposure. For example, a needle stick injury 

with a solution and no virus could still be reported and included here. Based on a review of the 

reports, the annual frequency of incidents per laboratory worker was estimated to be <1% per 

year. None of these reported incidents resulted in infection. In other words, no persons were 

infected. 

In summary, H5N1 remains a global concern and it has a high mortality rate. The US has two 

licensed vaccines, one of which is being made post-licensure. The total population at increased 

risk of occupational exposure is small. The available data suggest that the risk of transmission 

through occupational exposure is zero to extremely low. There are some limitations. 

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Laboratory events certainly could have gone unreported, which would have underestimated the 

number of incidents. In addition, reporting is not restricted to H5N1. It includes other HPAI 

viruses, which could have resulted in an overestimation. However, it is known that most of 

these reported incidents were related to H5N1. Finally, no systematic data are collected on 

public health responders, but it is known that there have been no infections in public health 

responders. 

Discussion Points 

Dr. Harrison was unclear about the issue of the adjuvanted vaccines and the issue of 

narcolepsy in terms of whether this is a vaccine-specific issue, antigen-specific issue, or 

adjuvant-specific issue. 

Dr. Olsen replied that the issue is unclear. 

Dr. Shimabukuro (ISO) added that the findings have been observed in Pandemrix®, the 

monovalent H1N1 vaccine that was widely used in Europe and the study Dr. Olsen mentioned in 

Quebec. There is a CDC study underway to assess Adjuvant System 03® (AS03®) and MF59®

adjuvanted vaccines for which preliminary results should be available in late 2015. 

Dr. Reingold requested further information about whether this vaccine is in bulk, what the shelflife is, and what the commitment to continuing to have stockpiles will be. 

Dr. Olsen responded that currently, the vaccine is kept in bulk at the manufacturer’s facility. The 

antigen and adjuvant are separate. In terms of the supply, there is already a precedent. Some 

of the vaccine was sent to NIH for clinical trials. NIH has prepared and distributed the vaccine, 

so there is a mechanism in place through NIH for some of the delivery. However, some delivery 

issues still need to be worked out. 

Dr. Gellin (NVPO) added that the vaccine stock is managed in bulk so that formulation can 

occur at the right quantities when needed. That is the plan going forward and there is no 

endpoint to that at this time. Currently, there are a number of clades in the stockpile that can be 

handled in the same way. When the product is in bulk, it does not have a shelf-life. 

Given the number of clades, Dr. Orenstein (NVAC) asked whether there are any data from 

animal studies regarding cross-protection or antibody events. That is, would this vaccine induce 

antibodies against the other clades as well as its own clade? 

Dr. Olsen indicated that in general there is a diminished response, and that the data on 

heterologous immunity can be found in the extra slides that she did not present during this 

session. The response depends upon the virus being tested against the vaccine. 

Dr. Belongia inquired as to the level of exposure of the estimated 2600 people who should 

receive this vaccine. 

Dr. Olsen responded that this is a rough calculation based on information known about PIs at 

CDC. There is variability in terms of how much someone works in the laboratory. 

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GRADE and Policy Options for Influenza A (H5N1) Vaccine

Sonja J. Olsen, PhD 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Olsen reminded everyone that the WG was charged to answer the policy question, “Should 

licensed influenza A (H5N1) vaccine be recommended to adults with increased risk of exposure 

during the inter-pandemic time period?” First, the WG members enumerated all possible 

outcomes of interest, independent of whether data were available. Each member independently 

scored outcomes using the following numerical scale: 

 Critical to decision making (7-9)

 Important, not critical (4-6)

 Low importance (1-3)

The rankings were then summarized. Safety and immunogenicity outcomes were identified, 

which are shown in the following tables: 

 

The next step was to define the data to review. To do this, it is helpful to understand what 

vaccines there are. GSK’s H5N1 AS03 adjuvanted vaccines are manufactured in two different 

places. This is relevant because the manufacturing process differs between the two plants. 

Pumarix/Q-Pan is manufactured in Québec, Canada and contains A/Indonesia/05/2005 

Clade 2.1. Prepandrix/D-Pan is manufactured in Dresden, Germany and contains 

A/Vietnam/1194/2004 Clade 1 and A/Indonesia/05/2005 Clade 2.1. The vaccine of interest is 

the FDA-licensed vaccine Pumarix/Q-Pan containing A/Indonesia/05/2005. 

In addition, GSK makes a number of seasonal influenza vaccines and has made pandemic 

influenza vaccines as shown in the following table: 

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Vaccine Description Manufacturer 

Location

Haemagglutinin 

(HA) per 0.5 mL 

dose

Adjuvant

Seasonal Vaccines

FluLaval® U.S.-licensed seasonal 

influenza vaccine (trivalent, 

inactivated, split virion)

Québec, Canada 15 μg HA None

FluLaval® 

Quadrivalent

U.S.-licensed seasonal 

influenza vaccine (inactivated, 

split virion)

Québec, Canada 15 μg HA None

Fluarix® U.S.-licensed seasonal 

influenza vaccine (trivalent, 

inactivated, split virion)

Dresden, Germany 15 μg HA None

2009 Pandemic Vaccines

ArepanrixTM GSK’s H1N1 AS03-

adjuvanted pandemic vaccine

Québec, Canada 3.75 μg HA AS03A

PandemrixTM GSK’s H1N1 AS03-

adjuvanted pandemic vaccine

Dresden, Germany 3.75 μg HA AS03A

The WG decided that it would be difficult to extrapolate data for some of these other vaccines 

due to differences in the manufacturing process in Québec versus Dresden; antigen content 

(3.75μg vs. 15μg); and adjuvant (none vs. AS03). In addition, avian H5 HA is less 

immunogenic than those of human influenza viruses. For those reasons, the WG chose to 

focus on data using the Q-Pan vaccine manufactured in Quebec. 

As part of the literature review, the key terms searched were H5N1 vaccine AND Indonesia; a 

few additional references were provided by the manufacturer. Several of the WG members 

independently reviewed the abstracts from all of the 108 studies found with the key term search 

and the 5 provided by the manufacturer. Full article reviews were conducted on 20 papers. Of 

those, 16 were excluded because the primary vaccine strain differed or was made in the wrong 

plant and the following 4 studies were included and were assessed in detail: 

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The WG reviewed data from all four manuscripts. Langley (2010) was an RCT with no placebo. 

Its question focused on different adjuvant doses (full vs. half) and different manufacturing sites 

(Quebec vs. Dresden). Langley (2011) was an RCT with a placebo. Laskos (2011) was an 

RCT with no placebo that compared different dosing schedule. Nagai (2011) was a descriptive 

study with no comparison group. All studies assessed safety and immunogenicity. The one 

study that was designed to answer the WG’s question (vaccine yes/no) was the Langley (2011) 

placebo-controlled study, which is the study the WG used to GRADE the evidence. For those 

interested, Dr. Olsen noted that the data from all four studies were included as extra slides. The 

outcomes available from the Langley (2011) study are shown in the following table: 

As reflected in the table, several of the critical safety outcomes were missing and data were 

available only on the homologous etiologic outcomes. 

For the safety outcome of any vaccine-related SAE (ranked as critical), imprecision was 

downgraded because the sample size was too small to detect rare SAE. This resulted in the 

quality of evidence being rated as Moderate (2). The quality of evidence for mortality (also 

ranked as critical) was rated as High (1). The quality of evidence for the safety outcomes 

ranked as important (fatigue, headache, joint pain, muscle aches, and shivering) was rated as 

High (1). For the outcome of sweating (ranked as important), imprecision was downgraded 

because the confidence interval included 1; therefore, the quality of evidence was rated as 

Moderate (2). For the outcome of syncope (ranked as important), imprecision was downgraded 

due to the small sample size and thus the inability to detect a rare event; the quality of evidence 

was rated as Low (3). Imprecision was downgraded for the outcome of fever (ranked as 

important) due to the wide confidence interval, and the quality of evidence was rated as 

Moderate (2). 

In terms of immunogenicity outcomes ranked as critical, the quality of the evidence was 

considered to be High (1) for 21-day homologus seroprotection and 21-day homologus 

seroconversion. For the immunogenicity outcomes ranked as important, 6-month homologus 

seroprotection and 6-month homologus seroconversion, imprecision was downgraded for small 

sample sizes and wide confidence intervals and the quality of the evidence was considered to 

be Moderate (2). Overall, the WG rated the quality of evidence as Moderate (2). 

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There are other considerations in addition to the GRADE data for formulation of 

recommendations. The first is to consider the balance between the benefits and harms. The 

issues the WG weighed were that the evidence was based on a single study; the benefits may 

not be generalizable due to Clade evolution; data were absent for 4 of the 6 critical harms, 

resulting in uncertainty about balance of benefits vs. harms; there were no data on efficacy; the 

risk of exposure is low; and there is a zero to low transmission risk. Overall, the evidence type 

was Moderate (2) for safety and High (1) for immunogenicity. In terms of values and 

preferences, there were no data regarding how the target group values the outcome. The 

potential recipients were few in number (<3,000) in the US. Usually, these analyses take into 

account health economic data, which is not really relevant here because the vaccine is paid for 

by US government so it was not considered. 

For consideration and discussion during this session, the WG put forward the following draft 

recommendation for influenza A (H5N1) vaccine: 

Discussion Points 

Dr. Kempe asked for clarification about when the additional safety data will be available and 

whether it will contain all of the critical elements that are currently lacking. She did not 

understand what additional data CDC is collecting regarding safety. 

Dr. Olsen replied that additional data are not anticipated specific to this vaccine. Data are 

expected in 2015 from the CDC-sponsored narcolepsy study, which is not specific to this 

vaccine. The CDC study is assessing monovalent vaccines from the 2009 pandemic that 

contained the same adjuvant. Also, it is important to remember that it is necessary to vaccinate 

a large number of people in order to find very rare outcomes, which will not be done with H5N1 

vaccine. 

Dr. Shimabukuro (ISO) added that the CDC-sponsored study on narcolepsy is assessing 2009 

monovalent H1N1 adjuvanted vaccines that contained AS03® or MF59® used in countries 

outside of Europe. That does not pertain to the vaccine Dr. Olsen was discussing. 

Dr. Rubin asked whether the placebo recipients in the primary trial received the adjuvant as part 

of the placebo, and whether this is a purified hemagglutinin (HA) or a split vaccine with the 

amount of HA indicated. 

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Dr. Leonard Friedland (GSK) replied that the vaccine used in the placebo arm did not contain 

adjuvant. This is a split, inactivated subvirion vaccine similar to the seasonal vaccines used. In 

this case, it was for H5N1. 

Dr. Reingold asked whether he understood correctly that ACIP would be asked to vote on a 

recommendation for use of the H5N1 vaccine during the February 2015 meeting. He noted that 

the Strategic Advisory Group of Experts (SAGE) of the World Health Organization (WHO) went 

through a similar process for pandemic influenza vaccine. He was on that working group and 

found that to be a difficult discussion. One item discussed was “storage” of the vaccine in 

humans; that is, priming large numbers of individuals with a first dose so that if there is a 

pandemic, only one additional dose would have to be given to those individuals to achieve 

protection versus having to dispose of large quantities of vaccine when it reaches the end of its 

self-life. There was also discussion of other potential populations who should be protected in 

the event of a pandemic. It sounded like in terms of policy, the Novel Influenza WG had already 

focused on this group. 

Dr. Olsen replied that this was only tangentially discussed because the group was focused on a 

specific question and did not want to become sidetracked. Ultimately, the SAGE 

recommendation said that there were not enough data to recommend priming. 

Dr. Belongia noted that there is a spectrum of potential exposures among people who fall within 

these categories, such as people who have rare occasional exposures to samples or people 

who have repeated frequent exposures. Given the uncertainties and the limited amount of data 

currently available regarding safety, it would be helpful to clarify that this pertains to people who 

have repeated or frequent potential exposures rather than people who have rare or uncommon 

exposures. 

Dr. Olsen replied that the WG discussed this. There are no data addressing frequency of 

exposure and there are no transmission events. The WHO recommendations discuss work with 

large amounts of virus or work with virus for extended periods of time; however, they do not 

quantify any of that. The WG decided that this was too nebulous and it would be clearer to say 

someone who does or does not work with the virus. The WG can further consider this issue. 

Dr. Sun (FDA) indicated that as with all vaccines, subsequent to the FDA approval of Q-Pan 

H5N1, the manufacturer is required to evaluate the vaccine in children and conduct additional 

safety studies. 

Dr. Leonard Friedland (GSK) indicated that a pediatric study was conducted in infants 6 months 

through 17 years of age. GSK recently shared the findings with the FDA, and discussions are 

underway to amend the Biologics License Applications (BLA) in the future to include a license 

indication below the current age of 18. 

Dr. Weber (SHEA) requested further clarification of the meaning of “public health responders.” 

For example, he has a colleague on his campus who works with emerging viral diseases. If that 

individual is exposed, he would be required by policy to present to the hospital’s emergency 

department (ED) to be evaluated and possibly be admitted. Would “public health responders” 

include the 300 members of the ED Care Team who would take care of him, as well as the 

Occupational Health Department? 

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Dr. Olsen clarified that “public health responders” would include US healthcare personnel (HCP) 

deploying someplace to investigate illness. For example, this would include HCP going to 

Indonesia to investigate a cluster of illness due to H5N1 in humans or an H5N1-associated 

poultry die-off. Because there are no cases in the US, this does not include HCP or first 

responders in the US. The WG understands that the situation is fluid and could change in the 

future. 

Dr. Orenstein (NVAC) was intrigued by the statistically significant 5-fold reduction in mortality in 

the vaccinated group. He presumed that they thought this was a statistical artifact, but 

wondered whether there was any biologic plausibility to that. Many people are involved in 

research studies conducting surveillance for influenza in various animal populations 

domestically and abroad. He presumed that unless this work was being done specifically in a 

high-risk H5N1 situation, those people would not fit into the risk category for receiving the 

vaccine. 

Dr. Olsen replied that in terms of the 5-fold reduction in mortality, these were not vaccineassociated deaths. This was mortality that occurred during the study, primarily in older persons. 

This did not raise concerns among the WG members. The investigators conducting influenza 

surveillance would not be included in the risk category for receiving the vaccine. 

Dr. Bennett pointed out that not long ago, many people in this country were vaccinated against 

smallpox. The wording was very similar, and there may be a lot of opportunity for 

misinterpretation. It might be useful to describe more specifically what is meant by “public 

health responders.”

Thinking about the public health responders who may go to several outbreaks and laboratorians 

who have frequent and repeated exposures to these viruses, Dr. Schaffner (NFID) was 

interested in the anticipated duration of immunity. He wondered whether consideration was 

being given to one-time immunization versus re-immunization of those who have frequent and 

repeated exposures over time. 

Dr. Olsen replied that while this is a good question, it was not addressed by the WG. The 6-

month immunogenicity outcomes were assessed, and the immune response was found to be 

diminished. There are no data to assess that the need to a booster dose because they do not 

have longer outcomes. 

Dr. Loehr (AAFP) disagreed with the statement that the health economic analyses is not 

relevant because it is paid for by the US government. If the cost of a vaccine was $1 million per 

dose versus $10 per dose, that would be relevant. If there is no evidence of laboratory 

transmission, he wondered whether laboratory workers need this vaccine. Also, are animal 

study workers more at risk than laboratory workers because they are handling infected animals? 

Those issues have not been teased out. 

Dr. Olsen said she appreciated what Dr. Loehr said about cost, and that the WG could revisit 

the health economic analysis issue. There are no known cases of transmission in a public 

health responder or laboratory worker. That contributed to the recommendation of a Category B 

rather than Category A. The WG can also discuss this further. 

Dr. Temte asked if there have been any reports of routine administration of antivirals in the case 

of laboratory breaches. 

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Dr. Olsen responded that in general, this would be the recommendation, but she did not know 

how many had taken antivirals. 

Dr. Harrison did not think much guidance was actually provided, and wondered whether there 

had been any discussion in the WG about creating a clear recommendation. 

Dr. Temte responded that there is the option for a Category A recommendation, which uses 

language such as “should receive.” The WG engaged in significant deliberation about this 

issue, and felt that Category B was appropriate for individual clinical decision-making based on 

one’s own exposure and concern about that exposure, plus all of the unknowns in terms of the 

risks and long-term benefits. Despite ACIP’s disdain for Category B recommendations, the WG 

felt that a Category B recommendation was appropriate in this situation. 

Dr. Kempe pointed out that the key will be the risk/benefit information given to people. This in 

itself simply allows people to obtain the vaccine. 

Dr. Temte expressed appreciation for the depth of the discussion, which can go back to the WG 

for further consideration and modification prior to the February 2015 ACIP meeting. 

 

Introduction 

Art Reingold, MD 

Chair, ACIP Pertussis Vaccine Work Group 

Dr. Reingold reminded everyone that the terms of reference for the Pertussis Vaccine WG are 

to: 

 Review existing statements on infants and young children (1997), adolescents (2006), 

adults (2006), and pregnant and postpartum women and their infants (2008) and consolidate 

them into a single statement. 

 Review new data on Tdap including 

 Effectiveness of ACIP recommendations 

 Interval between Td booster and Tdap 

 Use of Tdap in adults ages 65 years and older 

 Pregnant and breastfeeding women 

• Use of Tdap 

• Cocooning strategies 

 Vaccinated HCP and need for post-exposure prophylaxis 

 Tdap revaccination 

• Pregnant women 

• Healthcare personnel 

• “Cocooning”

 Review updated epidemiology of tetanus and diphtheria in the US 

Pertussis

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Two Tdap products are licensed in the US, both of which are licensed for single use. GSK’s 

BOOSTRIX® vaccine has an age indication of 10 years and older, while Sanofi Pasteur’s 

ADACELTM vaccine has an age indication of 10 through 64 years of age. The current ACIP 

recommendations for Tdap and Td is for a single Tdap dose for all persons aged 11 years and 

older, preferred administration at 11 or 12 years of age. Pregnant women are recommended to 

receive Tdap with every pregnancy. This is primarily designed to provide protection to the 

newborn baby. A decennial Td booster is recommended for those who have received 1 Tdap 

vaccine, and a booster is recommended at 5 years for wound management. Diphtheria, 

tetanus, and acellular pertussis (DTaP) vaccine coverage among children is high and 

adolescent Tdap coverage has greatly improved; however, adult Tdap coverage remained low 

at 14% as of 2012. Tdap coverage is also low among pregnant women at approximately 15%. 

Administering Tdap to pregnant women raises safety concerns. There have been 62 Tdap 

reports in pregnant women to the Vaccine Adverse Event Reporting System (VAERS) since the 

last ACIP update in February 2014. Tdap was given during the third trimester in 66% of reports 

with data on gestational age at time of vaccination. Of the reports, 53 were non-serious reports. 

There were 9 serious reports, including 1 neonatal death that was due to umbilical cord 

occlusion with fetal vascular thrombus formation. Conditions among other serious reports 

included 2 non-anaphylaxis allergic reactions and 1 report each of elevated blood 

pressure/abdominal pain, severe headache, rhabdomyolysis, multiple systemic symptoms (e.g. 

fever, chills, myalgias), pneumonia, and hypoglycemia in an infant. Overall, there were no 

concerning patterns of adverse events. 

 

CDC’s Immunization Safety Office (ISO) monitors maternal Tdap safety through VAERS, in 

which no safety signals have been identified. Safety data from the VSD on obstetric events and 

birth outcomes were presented during the February 2014 ACIP meeting. Analyses of VSD data 

are in progress regarding the interval between prior tetanus-toxoid containing vaccines and 

current Tdap vaccination, and concurrent administration of Tdap and influenza vaccines. The 

Clinical Immunization Safety Assessment (CISA) Project has implemented a prospective 

observational clinical study of Tdap safety in pregnant women [Vanderbilt University and Duke 

University; registered at ClinicalTrials.gov NCT02209623]. The WG has also requested 

additional data from the military or other groups that may have extensive experience with use of 

the vaccine in pregnant women, and is trying to maintain as much awareness as possible 

regarding what is occurring in pregnancy. 

June 2013, ACIP took into consideration that there is an increasing burden of pertussis, with a 

substantial burden nationally; that there is good evidence to suggest that a second dose of Tdap 

is safe and immunogenic; that protection wanes in a few years after Tdap; and that the costeffectiveness model suggests that a reduction of the disease burden would be limited 

with a second dose of Tdap. 

In June 2014, ACIP concluded that the public health impact of routinely recommending a 

second dose of Tdap would be limited, and that no change should be made to the current Tdap 

recommendation. ACIP recognized that the focus should be on preventing pertussis in infants, 

and ensuring that pregnant women receive Tdap during each pregnancy. ACIP supported the 

WG to consider additional doses for special populations, including HCP and close contacts of 

infants. 

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This session included presentations on Tdap vaccine, pertussis in HCP, the impact of 

vaccinating HCP, and the WG’s conclusions.

HCP Pertussis and Tdap Vaccination 

Jennifer L. Liang, DVM, MPVM 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

As Dr. Reingold noted, ACIP made considerations over a year ago for a second dose of Tdap 

for the general population but did not change the current recommendation. Since then, the WG 

has considered Tdap vaccination of HCP and evaluated the need for and potential impact of 

additional doses of Tdap. For today’s discussion, Dr. Liang presented a summary of these data 

and the WG’s conclusions. 

Currently, both Tdap vaccines are licensed only for a single dose. As previously reviewed by 

ACIP, a second dose of Tdap is safe and immunogenic. There are several published clinical 

trials from other countries on a second dose of Tdap at 5 or 10 years after the first dose. 

Reported adverse events were generally comparable to those after the first Tdap. The majority 

of local and systemic adverse events were mild to moderate and self-limited. Of the few serious 

adverse events reported, none were determined to be related to receipt of the second Tdap. 

Safety profiles were comparable at the 5 and 10 year intervals. For immunogenicity after 

receipt of a second Tdap, tetanus and diphtheria are essentially 100% protected. For the 

pertussis components, responses are similar at 5 and 10 year intervals. Response is also 

comparable to historic and contemporaneous first dose. 

After a single dose of BOOSTRIX®, similar geometric mean concentration (GMC) curves are 

observed through 10 years. Response to a second BOOSTRIX® after a 10-year interval was 

similar to the response after the first at a 10-year interval. A second dose of ADACELTM at a 10-

year interval also showed similar response after a first dose. For ADACELTM, after a 5-year 

interval, response to a second Tdap was robust, but was lower compared to the response after 

the first dose. But at 5 years, the baseline for pertussis antibodies before a second Tdap were 

higher. 

In the US, both pharmaceutical companies are conducting clinical trials of a second dose of 

Tdap. Sanofi Pasteur’s US study for ADACELTM is complete and was presented to the WG and 

summarized to ACIP in February 2013. A revaccination study in Canada will finish later this 

year and Sanofi Pasteur plans to submit to FDA consideration of label updates for ADACELTM. 

GSK’s revaccination program for BOOSTRIX® is also underway. One revaccination study of 

young adults who received their first Tdap as adolescents 10 years earlier is complete. A 

revaccination study in adults is underway. GSK plans to submit data to FDA for consideration of 

label updates to BOOSTRIX® that will be dependent on pertussis epidemiology and ACIP 

recommendations. 

Tdap is effective, but protection starts to wane within three years. Previous estimates of Tdap 

vaccine effectiveness range between 66% to 78%. However, all of these studies involved 

adolescents who received some whole cell vaccines as part of their childhood series. At the 

time, the effectiveness of Tdap among adolescents who had received all acellular vaccines in 

childhood was unknown. During the 2012 epidemic in Washington, the CDC in collaboration 

with the Washington State Department of Health conducted a large-scale vaccine effectiveness 

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study in adolescents who only received acellular pertussis vaccines. Estimated Tdap VE was 

65%, which is consistent with previous studies. This study also assessed the duration of 

protection [Rank C, et al. Pediatr Infect Dis J. 2009 28(2):152-3; Wei SC, et al. CID 2010 

51(3):315-321; Skoff et al. NIC 2011, Washington, DC; Acosta A, et al. Publication pending]. 

During the 2012 pertussis epidemic, Wisconsin2 also evaluated Tdap vaccine effectiveness and 

duration of protection in their adolescent population that also only received acellular vaccines. 

Despite the methodologies being different, both studies demonstrated substantial waning of 

protection over time. In Washington1, the initial effectiveness within 12 months of Tdap 

vaccination was 73%. Following this, the effectiveness declined substantially. Between 2 and 4 

years post-vaccination, the VE was only 34%. This waning in protection is consistent with the 

observed epidemiology. Wisconsin published results that were very similar to CDC’s findings 

showing that Tdap vaccine effectiveness decreased with increasing time since receipt [1Acosta 

et al. Tdap Vaccine Effectiveness and Duration of Protection Among Adolescents During the 

2012 Washington State Pertussis Epidemic. Publication pending; 2Koepke et al. Estimating the 

Effectiveness of Tdap Vaccine for Preventing Pertussis: Evidence of Rapidly Waning Immunity 

and Differences in Effectiveness by Tdap Brand. The Journal of Infectious Diseases 2014]. 

For indirect protection, it is unclear what the effect of Tdap vaccination is on preventing 

pertussis transmission. For people vaccinated with acellular pertussis vaccines, symptoms are 

not as severe and presumably less likely to transmit. An Australian cocooning case-control 

study found a modest decrease in the risk of pertussis in infants whose mothers were 

vaccinated at a sufficient time to boost their immune response relative to the infants’ pertussis 

incubation period. This effect was also seen in infants whose mothers were vaccinated postpartum. But it is unclear whether the lower risk for infants was attributable to a short-term 

impact on transmission for recently vaccinated mothers or lack of exposure to infants [Quinn HE 

et al. Parental Tdap boosters and infant pertussis: a case-control study. Pediatrics. 2014 

Oct;134(4):713-20]. 

An animal model showed that acellular pertussis vaccinated baboons were protected against 

disease but not infection. Bacterial colony counts from nasopharyngeal washes were 

comparable to those observed in unvaccinated animals. Infected but asymptomatic baboons 

transmitted pertussis to other cohoused baboons. Although these results are striking, it is 

unclear if this animal model represents what happens with humans, vaccines, and infection. 

There is currently no human challenge model [Warfel JM et al. Acellular pertussis vaccines 

protect against disease but fail to prevent infection and transmission in a nonhuman primate 

model. 2014 Jan 14;111(2):787-92]. 

Pertussis occurs in HCP, but probably is not a significant contribution to the overall burden of 

disease. Occupational exposures to pertussis occur in health-care settings. The frequency and 

proximity of patient interaction puts HCP at increased risk for infection with the potential to 

expose many. 

Nosocomial infections in health-care settings have been documented. The index case has been 

identified as an HPC, patient, or hospital visitor. There have been numerous published reports 

of pertussis outbreaks in a variety of health-care settings. Anecdotally, states recently hard-hit 

with pertussis have not identified or reported health-care outbreaks, including California, 

Wisconsin, and Washington. The last one reported to CDC was in 2011 [Valenti WM, et. al. 

1980; Steketee RW, et. al. 1988; Fisher MC, et al. 1988; Addiss DG, et al. 1991; Christie CDC, 

et. al. 1995; Shefer A, et. al. 1995; CDC. MMWR 2005:55(03); Boulay BR, et. al. 2006; Pascual 

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FB, et. al. 2006; Vranken P, et. al. 2006; Bryant KA, et. al. 2006; Zivna I, et. al. 2007; Baggett 

HC, et. al. 2007; CDC. MMWR 2008:57(22); Leekha S, et. al. 2009; Yasmin S, et. al. 2013]. 

The measured risk and burden of disease in HCP are not well-defined. National surveillance 

does not collect HCP status for pertussis cases. There are few population-based estimates on 

the relative risk of pertussis for HCP. One study in the Province of Quebec estimated a 1.7 fold 

increased risk for HCP compared to their adult population. This was based on 384 reported 

adult pertussis cases, 32 of which were HCP. Another study found 1.3% to 3.6% annual 

incidence in emergency department residents, nursing, and patient-care staff. Incidence was 

based on serologic evidence. Some infections were asymptomatic. Published studies note that 

yearly infection rates among adolescent and adults varied from 1% to 6%, based on serologic 

studies. In general, the risk among HCP and the general population is comparable [Deserres G, 

et al. Morbidity of pertussis in adolescents and adults. J Infect Dis 2000; 182:174-179; Wright, 

SW, Decker MD, Edwards KM. Incidence of pertussis infection in healthcare workers. Infect. 

Control Hosp. Epidemiol. 1999. 20:120-123; Cherry JD. The present and future control of 

pertussis. Clin Infect Dis. 2010 Sep 15;51(6):663-7]. 

Pertussis exposure management in health-care settings is complicated, time-consuming, and 

costly. Several studies have estimated the cost of investigation and control measures which are 

substantial; however, Tdap vaccination would not change that [Zivna I, et al. Impact of 

Bordetella pertussis exposures on a Massachusetts tertiary care medical system. Infect Control 

Hosp Epidemiol. 2007 Jun;28(6):708-12; Calugar A, et al. Nosocomial pertussis: costs of an 

outbreak and benefits of vaccinating health care workers. Clin Infect Dis. 2006 Apr 1;42(7):981-

8; Baggett HC, et al. Two nosocomial pertussis outbreaks and their associated costs - King 

County, Washington, 2004. Infect Control Hosp Epidemiol. 2007 May;28(5):537-43; Yasmin S 

et al. Healthcare-Associated Pertussis Outbreak in Arizona: Challenges and Economic Impact, 

2011. J Ped Infect Dis. 2013 3(1):81-84]. 

Current guidance on post-exposure prophylaxis (PEP) for HCP is based on likely contact with 

patients at risk for severe disease and not Tdap vaccination status. One study looked into the 

need of PEP for Tdap vaccinated HCP, but the results were inconclusive. Very few exposed 

HCP were infected regardless of PEP or not. Infection was based on serologic evidence and 

none was symptomatic. These HCP were vaccinated within 4 years prior to their exposure 

[CDC. Immunization of Health-Care Personnel Recommendations of the Advisory Committee on 

Immunization Practices (ACIP). MMWR 2011 60(No. SS-7): 1-45; Goins WP et al. A 

Comparison of 2 Strategies to Prevent Infection Following Pertussis Exposure in Vaccinated 

Healthcare Personnel. Clin Infect Dis. 2012 Apr;54(7):938-45].

Since 2006, HCP have been recommended to receive a single dose of Tdap and a routine Td 

booster every 10 years. Hospital-based Tdap coverage rates vary, and a lot of effort has been 

put into increasing coverage from campaigns to mandates. As we approach 10 years since the 

introduction of Tdap, national HCP coverage for the first dose is 31% [Calderon M, et al. 

Implementation of a pertussis immunization program in a teaching hospital: an argument for 

federally mandated pertussis vaccination of health care workers. Am J Infect Control. 2008 

Aug;36(6):392-8; Weber DJ, et al. Assessment of a mandatory tetanus, diphtheria, and 

pertussis vaccination requirement on vaccine uptake over time. Infect Control Hosp Epidemiol. 

2012 Jan;33(1):81-3; CDC. Noninfluenza Vaccination Coverage Among Adults — United States, 

2012. MMWR. 63(05);95-102]. 

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The benefits and costs of vaccinating HCP with Tdap were modeled previously to look at 

preventing a nosocomial pertussis outbreak. Vaccinating HCP was shown to substantially 

reduce the risk of hospital-based outbreaks and was cost-effective/cost-saving. But model 

inputs included Tdap vaccine efficacy estimates higher than current estimates and assumed 

vaccination would decrease transmission and prevent secondary cases. At this time, there is no 

direct evidence and the role of vaccination in transmission and prevention is unclear. There are 

plans to update the CDC’s model [Greer AL, Fisman DN. Keeping vulnerable children safe from 

pertussis: preventing nosocomial pertussis transmission in the neonatal intensive care unit. 

Infect Control Hosp Epidemiol. 2009 Nov;30(11):1084-9; Greer AL, Fisman DN. Use of models 

to identify cost-effective interventions: pertussis vaccination for pediatric health care workers. 

Pediatrics. 2011 Sep;128(3):e591-9; Calugar A, et al. Nosocomial pertussis: costs of an 

outbreak and benefits of vaccinating health care workers. Clin Infect Dis. 2006 Apr 1;42(7):981-

8]. 

The WG has struggled with the lack of updated disease and vaccine data specific to HCP and 

are left with a number of uncertainties. Over the past several years, more has been learned 

about acellular pertussis vaccines. In acellular-primed adolescents, Tdap is effective but 

protection wanes substantially within a few years. For adults who were vaccinated with wholecell pertussis vaccines, Tdap provides protection but would be difficult to study or better 

characterize. As the population ages, there will soon be more adults who received only 

acellular pertussis vaccines. Is the assumption valid that Tdap vaccination protects contacts? 

The evidence is unclear. Also, with the timing of any potential indication on additional doses of 

Tdap, does the committee wait or are we compelled to make an off-label recommendation? 

After much discussion, the WG has made a number of observations regarding pertussis and 

vaccinating HCP. The WG recognizes that pertussis transmission occurs in health-care settings 

and that the frequency and proximity of patient interaction puts HCP at increased risk of 

exposure to pertussis. However, it is unclear how much pertussis exposure results in disease. 

There is a lack of updated data specific to HCP. The WG also recognizes that it is no small 

thing to implement recommendations for HCP. There is no supportive evidence that additional 

doses would be beneficial in prevention of disease and transmission in a health-care setting. 

Even if additional Tdap doses are recommended, there would be no change to risk 

management of pertussis exposures. 

At this time, the ACIP Pertussis Vaccines WG does not propose changes to the current Tdap 

recommendation for HCP. With a record of more than 48,000 pertussis cases reported in 2012, 

and 2014 numbers already higher than at this time last year, the WG acknowledges the current 

resurgence of pertussis, and the burden this places on state and local health departments and 

providers. The WG has expressed a desire for CDC to consider agency guidance on the role of 

repeat Tdap doses for HCP in response to outbreaks in health-care settings. CDC is 

considering potential guidance language for the CDC pertussis website that would include 

encouraging consultation with state public health and CDC during outbreaks in health-care 

settings since each outbreak is unique, and guidance should be catered to the situation. The 

focus should be on the current Tdap program. This includes improving adult coverage, 

including among HCP, and vaccinating pregnant women during every pregnancy to protect 

infants. 

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Dr. Liang mentioned some pertussis-related projects underway with CDC’s collaborators that 

will help address some data gaps. Results from these studies will be presented at future ACIP 

meetings. There are several vaccine effectiveness studies underway, including DTaP and Tdap 

vaccine effectiveness with the emergence of pertactin-negative strains. Through EIP’s 

enhanced pertussis surveillance, the clinical characteristics of vaccinated and unvaccinated 

pertussis cases will be evaluated. Also through EIP’s enhanced pertussis surveillance, reported 

pertussis cases who work in a health-care setting are being identified. There are plans to 

update the cost-effectiveness model of vaccinating HCP. For the Tdap pregnancy 

recommendation, there is a cocooning and pregnancy Tdap evaluation and an infant blood-spot 

study to measure the effectiveness of maternal Tdap against pertussis. 

In conclusion, Dr. Liang highlighted additional CDC activities related to the Tdap pregnancy 

recommendation, including the following: 

 Assessment Branch (ISD/NCIRD) 

 Measuring Tdap coverage among pregnant women 

• PRAMS (with DRH/NCCDPHP) 

• Internet panel survey on pregnant women during influenza season 

 Immunization Safety Office (DHQP/NCEZID) 

 Safety monitoring in pregnant women following Tdap administration 

• Vaccine Adverse Event Reporting System (VAERS) 

• Vaccine Safety Datalink (VSD) 

• Clinical Immunization Safety Assessment (CISA) Project 

 Health Communications Science Office (NCIRD) 

 Formative Research Plans to Develop a Maternal Tdap Vaccination Campaign 

Discussion Points 

In terms of epidemiology, Dr. Temte wondered how transmittable pertussis is for someone who 

is asymptomatic. 

Dr. Liang responded that people who have been exposed to pertussis who are colonized and 

asymptomatic are highly less likely to transmit because they are not coughing, so they are not 

actually spreading bacteria. 

Dr. Bennett inquired about the potential for developing mandatory Tdap vaccination of HCP. 

The uptake of 31% is striking and is about what it was 5 to 10 years ago for influenza prior to 

mandatory programs. 

Dr. Weber (SHEA) indicated that his hospital is 100% compliant, with the exception of a few 

people who have medical contraindications, because Tdap is required along with measles, 

mumps, and rubella (MMR) and varicella vaccines. Pertussis remains one of the most common 

exposures to HCP. Over the last 5 years, about 1 out of 200 of their HCP has been exposed to 

pertussis. They are offered PEP with azithromycin, and virtually all of them accept it. None of 

their HCP have developed pertussis in the last 5 years. At this time, there is insufficient 

evidence for the WG to make an evidence-based recommendation for revaccination. SHEA has 

pointed out the significant logistical problems; however, if ACIP recommends no revaccination, 

budgeting will be lost because many have budgeted into the future for this vaccine. At 10 years, 

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HCP will be getting their 10-year Td vaccines. If a few years later the evidence supports a 

booster, they will not be happy about needing an extra vaccine. He also noted the contradictory 

nature of requiring the vaccine for incoming first-year HCP who are at low risk when protection 

is known to wane, only to tell them later that they do not need a booster. That is difficult to sell, 

particularly as a requirement for initial work. The SHEA board members felt that if additional 

data are going to be available in the next few years, that initially it would be better to 

recommend a booster and then stop if necessary rather than trying to reinstitute one in the 

future. 

Dr. Fryhofer (AMA) indicated that the AMA would be meeting in the upcoming week with the 

House of Delegates. A resolution was introduced by the Oregon State Delegation that 

expresses confusion about Medicare coverage of Tdap vaccinations. For the record, she 

requested clarification and specific input about how to administer Tdap vaccine within the office 

and get it covered. 

Dr. Liang responded that currently, Tdap vaccination is covered in Part D of Medicare for those 

65 years of age and older. It is not included as part of the routine Part B series. 

Ms. Hance (CMS) added that she would follow up to see if she could acquire further information 

from her Medicare colleagues. 

Dr. Temte said the follow-up question pertains to all of the ACIP-recommended immunizations 

for patients on Medicare in terms of what type of rule changes would be possible to ensure that 

all ACIP-recommended vaccines are covered under Part B. 

Given 15% uptake of Tdap vaccine among pregnant women, Dr. Pickering requested that Dr. 

Ault from American College of Obstetricians and Gynecologists (ACOG) and Dr. Loehr from 

American Academy of Family Physicians (AAFP) comment on what those two organizations are 

doing to increase coverage among pregnant women. 

Dr. Ault (ACOG) indicated that he and Dr. Riley are on ACOG’s Immunization WG. One of 

ACOG’s more successful strategies has been to provide toolkits to OB/GYN physicians that 

include scripts and other information to help them. ACOG is also conducting a series of 

Webinars to inform OB/GYN physicians and their office personnel about Tdap 

recommendations. In addition, ACOG had an app that can be downloaded to Androids and 

iPhones to access the toolkits and Webinars. 

Dr. Loehr (AAFP) reported that the AAFP is also trying to disseminate this information to as 

many family physicians as possible, so he was disappointed to hear that the coverage rate is 

only 15%. 

Dr. Baker (IDSA) congratulated ACOG for doing a wonderful job in collaboration with CDC on 

education of HPC and pregnant women. However, reimbursement continues to be a barrier. 

For example, although California delivers a lot of babies, Tdap is not paid for by California 

Medicaid. Aside from the problems of purchasing the vaccine, storing it in the office, and other 

practical barriers, administering this vaccine prevents death. The UK has demonstrated that 

there is over 90% vaccine effectiveness when the vaccine is given to pregnant women in the 

third trimester. That is a tremendous benefit. Tdap reimbursement in the US for pregnant 

women is an important issue for well-meaning HCP who know it is recommended for this 

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population and have the ability to administer the vaccine, but are not reimbursed for it. Dr. 

Baker also applauded the increased safety monitoring for pregnant women. 

Regarding California Medicaid coverage of Tdap, Ms. Hance (CMS) explained that due to the 

way the program exists currently, there is some disconnect in coverage of vaccines in general 

for adults. CMS is aware of this. Under the Medicaid expansion, all of the ACIP-recommended 

adult vaccines are covered. This includes women under 21 years of age who are pregnant who 

would be covered through the Early and Periodic Screening, Diagnostic and Treatment 

(EPSDT) in the traditional Medicaid program. The gap lies with people who are in the traditional 

Medicaid program who do not have coverage through the Medicaid expansion. This gap was 

created with the ACA and CMS is aware of it. Legislative change will be necessary to address 

this gap, and this is on CMS’s agenda and has been included in a couple of bills. The Medicaid 

program is a state option, so states can choose to cover or not cover vaccines. However, this is 

not all or nothing. Some states have chosen to cover some vaccines even if they do not cover 

Tdap. The hope is to achieve across-the-board coverage at some point. 

Dr. Harrison asked for a report from the manufacturers on development of next generation 

vaccines. 

Dr. Decker (Sanofi Pasteur) responded that manufacturers are assessing what can be done 

about improved pertussis vaccines, but the structural barriers are formidable. For example, he 

does not believe anyone has figured out a way to license a new pertussis vaccine—certainly not 

a new infant pertussis vaccine. The regulatory authorities would require an endpoint clinical 

trial. There is no accepted generic correlate of immunity for pertussis. It is vaccine-specific. 

Every pertussis vaccine licensed throughout the world was licensed on the basis of a specific 

efficacy trial. Those cannot be conducted in a practical way any longer because there is no 

place in the world that does not recommend pertussis vaccine. The efficacy of acellular 

pertussis vaccine in the primary series is 90%, so the sample size required to meet noninferiority criteria is larger than the population of a single country. These problems must be 

figured out. In addition, although some work is being done on perfecting animal models, no 

animal model has proven to be a valid correlate to the human response. He suggested doing 

the best they could with the available vaccines, because he could not predict when there would 

be new ones. 

Dr. Phil Hosbach (Sanofi Pasteur) said he was heartened to see the focus on improving adult 

coverage, including HCP. Raising the immunization rates in pregnant women from 15% is 

going to take a lot of work. Focusing on maternal immunization is targeted and appears to be 

very effective, but it is going to take time to reach 80% to 90% coverage. In the meantime, he 

suggested using the tools available to ensure that there is a focus on immunizing those who 

take care of infants as well, including fathers, grandparents, HCP, and daycare providers. 

Dr. Leonard Friedland (GSK) reported that GSK’s research and development group is assessing 

how new and potentially improved pertussis vaccines can be developed. Meanwhile, their focus 

is on doing what they can to help the healthcare community understand how to improve adult 

and elderly coverage of Tdap vaccines. They are also committed to generating data regarding 

maternity immunization with Tdap vaccine so that groups such as ACIP can make informed 

decisions about how to use these vaccines safely and effectively in pregnant women. 

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Dr. Kempe, who is an Implementation Scientist, emphasized that there are major 

implementation issues for OB/GYNs in addition to payment concerns. These practitioners are 

beginning to deliver a lot of vaccines, health system development and other issues must be 

addressed. ACOG has recently agreed to conduct a survey, that will be funded by CDC, to 

assess the processes that are lacking, define what OB/GYNs need to deliver vaccine more 

effectively, and determine what types of systems can be adopted from other specialties. 

Ms. Pellegrini pointed out that a recent NVAC report on maternal immunization beautifully 

encapsulated the challenges for OB/GYNs who have not had a long history of considering 

themselves to be vaccinators. A substantial initial investment is required in the equipment and 

vaccine itself. There is also a tremendous learning curve, and there are shortage issues. This 

is a daunting prospect for many practices, so she emphasized the importance of helping them 

address the obstacles. 

Ms. Amy Middleman (SAHM) asked whether the WG had considered making the 10-year 

booster dose recommendation to be Tdap rather than Td. This would be beneficial in terms of 

stocking, doses, physician implementation, and ease of recommendations. 

Dr. Liang replied that the WG has been discussing a change from decennial Td to decennial 

Tdap, but by adding a second dose. Because Tdap is only licensed for a single dose, the 

guidance from ACIP in January 2013 was to consider adding a second dose and not expanding 

it to a decennial Tdap. The conclusion for the second dose for the general population was not 

to make any changes. No changes are being made for HCP recommendation either. 

In thinking about vaccinating mothers during each pregnancy, Dr. Baker (IDSA) asked CDC’s 

position on revaccinating the mother’s cocoon members during her successive pregnancies.

Dr. Liang responded that the WG has been discussing this and plans to present on this topic 

during the February 2015 ACIP meeting. When CDC receives calls about this, the agency’s 

current guidance is that because this vaccine is licensed for a single dose, all family members 

should be up-to-date with their Tdap vaccination. 

Introduction 

Dr. Marietta Vázquez 

Chair, ACIP General Recommendations Work Group

Dr. Vazquez reminded everyone that the General Recommendations document is published in 

the Morbidity and Mortality Weekly Report (MMWR) every 3 to 5 years, and addresses a broad 

range of clinical practice issues that are relevant to all vaccines as opposed to the vaccinespecific publications. The General Recommendations are intended to address topics that 

cannot be attributed to a single vaccine, but that are germane to the practice of immunization in 

general. A number of topics have been or are being revised, including the following: 

General Recommendations

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 Timing and Spacing of Immunobiologics 

 Contraindications and Precautions 

 Preventing and Managing Adverse Reactions 

 Reporting Adverse Events After Vaccination 

 Vaccine Administration 

 Storage and Handling of Immunobiologics 

 Altered Immunocompetence 

 Special Situations 

 Vaccination Records 

 Vaccination Programs 

 Vaccine Information Sources 

As a reminder, content already viewed and discussed by ACIP including timing and spacing of 

immunobiologics and contraindications during the February 2013 meeting, contraindications and 

precautions during the February 2013 meeting, preventing and managing adverse reactions 

during the June 2013 meeting, vaccine administration during the October 2013 meeting, and 

vaccine storage and handling during the February 2014. Because a vote is necessary for CDC 

clearance and posting, the plan for this session was to vote on the first half of the document. 

The purpose of this session was to review changes that have occurred since ACIP last 

discussed the document so that a vote could be taken. Major revisions were made in the 

following four areas, which were discussed during this session: 

 Timing and spacing (febrile seizures and simultaneous vaccination) 

 Contraindications and precautions (vaccination and anesthesia/surgery/hospitalization) 

 Vaccine Administration (vaccine preparation and timely disposal) 

 Vaccine Administration (clinical implications of non-standard vaccination practices) 

The Vaccine Information Sources section was also discussed during this session, but was not 

included in the vote for the October 2014 ACIP meeting. It will be included for the vote on the 

second half of the document during the February 2015 ACIP meeting. 

Timing and Spacing, Contraindications and Precautions, Vaccine Administration 

Andrew Kroger, MD, MPH 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Kroger reiterated that the content to be discussed during this session was presented to 

ACIP in previous meetings throughout the past year. He presented brief background 

information for each of the four major topics to be addressed during this session, discussed 

what has occurred since the information was last presented, and showed relevant content. For 

each of these topics, he referred to the page and line numbers in the draft statement provided to 

ACIP members. 

Information regarding the subtopic of Febrile Seizures and Simultaneous Vaccination, which 

falls under the section of the General Recommendations titled Timing and Spacing of 

Immunobiologics was presented to ACIP in February 2013, and new data were presented by 

ISO in June 2014. In 2010, there were reports of an increase in febrile seizures following the 

use of AFLURIA® vaccine in the Southern Hemisphere at 9 per 1000 doses in children 6 months 

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through 4 years of age, as well as high rates of fever in children 5 through 8 years of age. 

Follow-up safety surveillance by ISO detected increased rates of febrile seizures in children 12 

months through 23 months of age receiving simultaneous vaccination with IIV and PCV13. 

These data were presented to ACIP in February 2011, which was about one month following the 

last iteration of the entire General Recommendations document was published. Information has 

been published in subsequent ACIP influenza-specific vaccine statements. 

Language was added to the ACIP document to accommodate recognition of attributable risk of 

febrile seizures with simultaneous vaccination of IIV and PCV13. The language proposed 

during the February 2013 meeting reads as follows: 

“During the 2010-2011 influenza season, surveillance systems detected safety signals 

for febrile seizures in young children following TIV and PCV13 vaccines. CDC studied 

the healthcare visit records of more than 200,000 vaccinated children 6 months through 

59 months of age through the Vaccine Safety Datalink Project during the 2010-2011 

influenza season. The analyses found that febrile seizures following TIV and PCV13 

vaccines given to this age group were rare but did occur at higher than expected rates. 

The risk for febrile seizures peaked in children age 16 months and were more common 

when the two vaccines were given during the same healthcare visit. In this group, about 

one additional febrile seizure occurred among every 2,200 children vaccinated. After 

assessing benefits and risks, ACIP continues to recommend that TIV and PCV13 be 

given concomitantly if both are recommended (Leroy Z, Vaccine 2012).” [PAGE 5, LINE 

18]

Since February 2013 when that language was presented, additional information has been 

presented to ACIP with a number of conclusions to the data. For the 2012-2013 and 2013-2014 

seasons, no febrile seizure signal for IIV was observed with the formulation change. The VSD 

found persistence from 2010-2011 to 2011-2012 when the formulation of IIV remained the 

same. A CISA study found a higher rate of fever. While they did not assess febrile seizure, 

fever with simultaneous vaccination of IIV and PCV13, adjusted for DTaP vaccination, was 

evaluated. Most recently, additional VSD and Pregnancy Risk Assessment Monitoring System 

Post Licensure Rapid Immunization Safety Monitoring (PRISM) analyses found that increased 

risk of febrile seizures is not an independent effect of IIV. These data were presented to ACIP 

during the February 2014 meeting. Additional VSD and PRISM studies were split on whether 

there is an effect of PCV13 or DTaP on the risk of febrile seizures with simultaneous vaccination 

with IIV. In the VSD study, the highest risk was seen with all three vaccines administered 

simultaneously (PCV13, IIV, and DTaP). The attributable risk was 38 febrile seizures per 

100,000 persons vaccinated. The PRISM study found no increased risk with TIV plus PCV13. 

ISO reviewed these data and recommended no change to the language presented in February 

2013. At issue is the fact that these vaccines are recommended to prevent disease. Risk of 

disease is high, while febrile seizures are benign. Hence, the decision not to recommend 

withholding these vaccines and to administer them simultaneously if they are recommended. 

The next topic, Vaccination During Anesthesia/Surgery/Hospitalization, is the Contraindications 

and Precautions section of the document. This is placed in this section because these 

represent circumstances in which a provider must decide whether to completely withhold a dose 

of vaccine or wait to give it based on the clinical conditions of the recipient. Information on this 

topic was presented to ACIP in 2013. A contraindication means that a vaccine should be 

withheld for individuals with certain conditions, while a precaution is a condition in a vaccine 

recipient that permits the provider to conduct a risk/benefit analysis to decide to whether to wait 

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to give a vaccine or withhold it. An example of a precaution would be a situation in which 

vaccination can be deferred if someone is acutely, moderately, or severely ill. The issue of 

vaccination during hospitalization is also relevant. CMS uses as a performance measure the 

offering of IIV to patients who are hospitalized with pneumonia. The reason this issue first arose 

for general recommendations is that CDC was contacted by an Australian pediatrician in 

December 2010 to inquire about the issue of deferring elective surgery when a vaccine has 

already been given, and whether there should be an interval. 

Prior to February 2013, the WG assessed the evidence from 20 sources that discussed 

hospitalization, surgery, and anesthesia. Of these studies, 15 addressed immune response, but 

only 5 of those addressed immune response following a dose of vaccine. These 5 studies were 

comprised of 1 systematic review, 1 editorial, and 3 letters. The remaining 15 studies that 

evaluated the immune response during hospitalization, surgery, or anesthesia were 

inconsistent. Of these, 11 studies assessed specific cell types (antibodies versus lymphocytes). 

Of those 11 studies, the variation was significant. Some showed levels increasing for one type 

and decreasing for others. There was also a lot of inconsistency in 6 papers that specifically 

assessed infants and children. Some of these studies showed increases in the immune 

response during anesthesia, hospitalization and surgery in infants and toddlers. Some showed 

decreases in the immune response in infants and toddlers. Others showed differences between 

toddlers and infants in the same paper. The evidence summary was presented to ACIP during 

the February 2013 meeting. That summary concluded that most studies that have explored the 

effect of surgery or anesthesia on the immune system were observational, included only infants 

and children, and were small and indirect, in that they did not look at the immune effect on the 

response to vaccination specifically. They do not provide convincing evidence that recent 

anesthesia or surgery significantly affect the response to vaccines. Along with this summary, 

which appears in the document, is the following statement: 

“The optimal time for vaccination may be hospital discharge to avoid superimposing any 

vaccine-induced adverse effects on underlying conditions or avoid confusion in 

determining the etiology for conditions that occur or are exacerbated during the 

hospitalization. For patients who are deemed moderately or severely ill at the time of 

discharge, vaccination should occur at the earliest opportunity (i.e., during immediate 

post-hospitalization follow-up care, including home or office visits) when patients’ clinical 

symptoms have improved.”

This statement was presented to ACIP in February 2013. Based on the discussion pertaining to 

this language, specifically in the context of influenza vaccine, the General Recommendations 

Work Group (GRWG) revised the language of the statement to emphasize “during the 

hospitalization or at discharge.” The revisions are as follows: 

“The optimal time for vaccination may be hospital discharge to avoid superimposing any 

vaccine-induced adverse effects on underlying conditions or avoid confusion in 

determining the etiology for conditions that occur or are exacerbated during the 

hospitalization. Efforts should be made to ensure vaccine administration during the 

hospitalization or at discharge. For patients who are deemed moderately or severely ill 

throughout the hospitalization, vaccination should occur at the earliest opportunity (i.e., 

during immediate post-hospitalization follow-up care, including home or office visits) 

when patients’ clinical symptoms have improved.” [PAGE 20, LINE 26]

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The change in this language better ties the concept into a precaution, in that the language is 

maintained for patients deemed moderately or severely ill throughout the hospitalization. In 

those circumstances, it makes sense to vaccinate near the end of the hospitalization as 

opposed to the beginning. The WG wanted to include information that would allow providers to 

administer vaccines at other times. Regarding the context of elective surgery following a dose 

of vaccine, Dr. Kroger reminded ACIP of language in the document that was added since 2011 

that was presented in February 2013 that states a new criteria for labeling a situation a 

precaution, shown as follows: 

“A precaution is a condition in a recipient that might increase the risk for a serious 

adverse reaction, might cause diagnostic confusion or that might compromise the ability 

of the vaccine to produce immunity.” [PAGE 19, LINE 19]

The only change is the underlined content, and is in the same section of the document that 

precedes administration during hospitalization, anesthesia, and surgery. This provides an 

option for providers who are concerned about elective surgery, or concern in hospitalized 

patients about the confusion of a post-surgical fever and the fact that giving a vaccine dose 

might cause diagnostic confusion. 

Content for Vaccine Administration: Safe Injection Practices, was presented to ACIP in October 

2013. At the time, the discussion regarded preparation and timely disposal and multi-dose vials. 

CDC’s Vaccine Safe Injection Practices program had specific language on its website, some of 

which is still there, which includes specific information regarding reinsertion of used needles in 

multi-dose vials. The GRWG was troubled by situations in which multi-dose vials can be 

opened in proximity to the patient. The CDC Vaccine Safe Injection Practices program is part of 

a WG tasked to address such administration issues. They do impact the ACIP General 

Recommendations, and they have pushed content that has cleared CDC with regard to this 

topic. The presentation of this content during the October 2013 meeting generated a lot of 

discussion. The following is the language taken verbatim from the CDC’s Vaccine Safe 

Injection Practices program at the following link: 

http://www.cdc.gov/injectionsafety/providers/provider_faqs_multivials.html 

“Vaccines should be drawn up in a designated clean medication area that is not adjacent 

to areas where potentially contaminated items are placed. Multi-dose vials to be used 

for more than one patient should not be kept or accessed in the immediate patient 

treatment area. This is to prevent inadvertent contamination of the vial through direct or 

indirect contact with potentially contaminated surfaces or equipment that could then lead 

to infections in subsequent patients. If a multi-dose vial enters the immediate patient 

treatment area, it should be discarded after use.” 

There was discussion in October 2013 about the context of community vaccination clinics, mass 

vaccination clinics, and satellite clinics in terms of how this could be done if the space to 

vaccinate is small. Those at CDC who are involved with the Vaccine Administration WG 

discussed this and determined that a lot of this language, though not all of it, is posted on CDC’s 

website already. Therefore, the GRWG proposed to revise the language as follows: 

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“Multi-dose vials to be used for more than one patient should not be kept or 

accessed in the immediate patient treatment area. This is to prevent inadvertent 

contamination of the vial through direct or indirect contact with potentially 

contaminated surfaces or equipment that could then lead to infections in 

subsequent patients. If a multi-dose vial enters the immediate patient treatment 

area, it should be discarded after use.” [PAGE 34, LINE 26] 

Content for Vaccine Administration: Clinical Implications of Non-Standard Vaccination Practices

was also discussed with ACIP in October 2013. This pertains to the route of administration, 

and much of this stems from a different section of the General Recommendations that 

discusses providers treating patients with hemophilia. There is language in the 

recommendations, that there is no intent to revise, which indicates that for vaccines approved 

for intramuscular administration, providers can use the intramuscular route for patients with 

hemophilia if the bleeding risk is acceptable. Some providers might take this to be a license to 

administer vaccines subcutaneously. The question is: Should such doses count? The 

challenge is that the evidence varies by vaccine. The General Recommendations do state that 

vaccines approve for subcutaneous use only may be given IM and will be counted. 

Hepatitis B vaccine is approved for IM use. Data have been published by Shaw, Redfield, and 

Coleman showing that immunogenicity is lower if administered in the gluteus, presumably into 

subcutaneous deep fat, or intradermally. Newer studies show comparable immunogenicity 

when comparing IM versus subcutaneous vaccine specifically performed in hemophiliacs 

receiving hepatitis B immune globulin (HBIG) vaccine and who are specifically at risk for 

infection by hepatitis B virus (HBV) [Shaw F, Jr., et al, Vaccine 1989;7:425—30; Redfield RR, et 

al, JAMA 1985;254:3203—6; Coleman PJ, et al, Vaccine 1991;9:723—7; Gazengel C, et al. 

Scand J Haematol, 1984; Janco RL. J Pediatr, 1985; Zanetti AR, et al. Am J Hematol, 1986; 

Hedner U, et al. Scand J Haematol, 1984]. 

These available data limit the evidence for immunogenicity. Patients may already have been 

exposed to the virus by virtue of their risk. They may have received HBIG. However, the 

studies do not tease out all of the possibilities. Therefore, the WG basically concluded in 

October of 2013 that the recommendation should be maintained to repeat doses of hepatitis B 

vaccine given subcutaneously. There are some ongoing studies, but the current plan is to 

continue to recommend repeating doses of this vaccine given subcutaneously. 

Rabies vaccine is also approved for IM. While an intradermal vaccination is used 

internationally, it is not used in the US. The current recommendation is to repeat doses 

administered in the gluteus, presumably into subcutaneous deep fat. The WG does not suggest 

any revisions to that recommendation. 

HPV vaccine is approved for IM injection. There are no data to indicate reduced 

immunogenicity or effectiveness if administered by another route. The general practices is to 

recommend repeat dosing if administered subcutaneous, which is recommended on the basis of 

expert opinion and licensure alone. 

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Meningococcal conjugate vaccine is approved for IM administration. Polysaccharide vaccine 

(MPSV4) is approved for subcutaneous administration. CDC assessed the data for 

subcutaneous administration of MenACWY and found the doses to be immunogenic. Of the 38 

subjects who received subcutaneous administration, 36 had protective titers. Therefore, CDC 

does not recommend repeating these doses [CDC. Inadvertent misadministration of 

meningococcal conjugate vaccine—United States, June-August 2005. MMWR 2006;55:101-7]. 

Hepatitis A vaccine (HAV) is recommended for IM administration. There is a paper that 

discusses comparable immunogenicity found in children with hemophilia when administered 

HepA vaccine either IM or subcutaneously. Seroconversion was comparable. The paper did 

not define a cutoff, but did show significant differences in the GMTs, but the authors concluded 

that there is not an appreciable difference in immunogenicity when HepA vaccine is 

administered subcutaneously [Ragni MV, et. Al, Hemophilia, 2000]. During the October 2013 

ACIP meeting, HAV was added to MCV4 for vaccine for which ACIP does not recommend 

repeating the dose. 

Haemophilus influenzae Type b (Hib) vaccine was not discussed during the October 2013 ACIP 

meeting. It is approved for IM administration. There are data to suggest a dose of Hib vaccine 

administered subcutaneously can be counted. A study by Christenson was published in the 

Journal of Infectious Diseases in 1992 of 20 splenectomized children, with one hemophiliac 

child who received the dose subcutaneously. Immunogenicity was comparable. On this basis, 

Hib was added to the list of vaccine for which ACIP does not recommend repeating the dose. 

[PAGE 44, LINE 5] 

It is important to determine whether it is possible to generalize vaccines when the weight of the 

evidence available differs for various vaccines. Doses are validated in the current draft with no 

need to repeat if given subcutaneously, even though the evidence is weak, for HepA, Hib, and 

meningococcal conjugate vaccine. Doses are invalidate, supported by the evidence, which also 

is weak for HepB and rabies vaccines. Doses are also invalidate that are supported by the FDA 

package insert only for HPV vaccine. There is no guidance for other vaccines recommended to 

be administered IM, for example DTaP and meningococcal conjugate vaccine. Dr. Kroger 

developed the following proposed language, which he shared with the GRWG: 

“DTaP and PCV13, like all other vaccines approved for intramuscular use, should be 

administered by the intramuscular route. However, for DTaP and PCV13, there is no 

evidence to support repeating doses of these vaccines if given subcutaneously. 

Providers should address circumstances in which dose(s) of these vaccines have been 

administered subcutaneously on a case-by-case basis.”

The second half of the document, which will be voted on in February 2015, contains a short 

section on vaccine information sources that has not yet been presented to ACIP. This section 

contains a listing of organizations with websites and contact information, and is the last section 

of the revised document to be reviewed by ACIP. This section will be voted on with the other 

remaining topics during the February 2015 meeting. The following organizations are listed in 

this section: 

 CDC-INFO Contact Center 

 CDC’s National Center for Immunization and Respiratory Diseases

 Morbidity and Mortality Weekly Report (MMWR) 

 American Academy of Pediatrics (AAP) 

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 American College of Physicians (ACP) 

 American Academy of Family Physicians (AAFP) 

 Immunization Action Coalition (IAC) 

 National Network for Immunization Information (NNII) 

 Vaccine Education Center (VEC) 

 Institute for Vaccine Safety (IVS) 

 Group on Immunization Education – Society for Teachers of Family Medicine (GIE-STFM) 

 State and Local Health Departments 

In conclusion, Dr. Kroger indicated that ACIP members have seen the draft document and have 

had an opportunity to weigh in on certain topics other than the ones presented during this 

session. Six of the members replied, three of whom indicated that they identified no issues and 

three of whom made specific comments pertaining to the following: 

 Timing and Spacing, and Tables: Update TIV to IIV, depending on intent. Dr. Kroger noted 

that IIV is a general abbreviation that will be taken by providers as inclusive of IIV3, IIV4, 

CCIIV, and all IV3. The General Recommendations discuss inactivated vaccines versus live 

vaccines. 

 Timing and Spacing: Cross-reference live vaccines having a potential suppressive effect on 

the response to tuberculin skin tests and Interferon Gamma Release Assay tests for latent 

tuberculosis infection (LTBI). This is already in the text, but needs referencing in other parts 

of the document, namely the tables. 

 Timing and Spacing: Change the language to de-emphasize blunting effect of PPSV23 on 

PCV13. Instead, emphasize the positive priming effect of PCV13 on PPSV23. The 

document will go through CDC clearance, so Dr. Kroger envisioned using language from the 

pneumococcal vaccine-specific statement that was recently published. 

While these changes were not reflected in the draft presented during this session, Dr. Kroger 

will ensure that these changes are made. 

Discussion Points

Dr. Kempe thought it was fair to say that there are no data regarding Hib, given that there was 

only 1 child in the study assessed. She also asked how many subjects were in the HepA study. 

Dr. Kroger replied that the HepA study involved 45 subjects who received the vaccination 

subcutaneously, all of whom were hepatitis A negative at baseline. 

In terms of vaccine given subcutaneously rather than IM, if a vaccine is one for which there is a 

serologic definition of protection, such as hepatitis A or hepatitis B surface antibody, Dr. Rubin 

wondered whether language should be included for that as evidence of immunity. 

Dr. Fryhofer (AMA/ACP) expressed her appreciation for the brief explanation on page 1 of the 

difference between conjugate and polysaccharide vaccines, which should be beneficial to 

practitioners. On page 6 and 12, there is a warning not to give the MCV4-D (Menactra®

) 

vaccine together with PCV13. She did not believe a lot of practitioners realized that. The 

patients to which that would apply are those with anatomic or functional asplenia, and it would 

be helpful to include this on the adult schedule. The abbreviation used, MCV4-D, is now 

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MenACWY on the adult schedule. All of the acronyms are very confusing for practitioners, so 

she suggested including more acronyms that mean the same thing. 

Dr. Byington (AAP) reported that AAP is receiving a lot of questions from anesthesiologists 

about delaying elective surgery post-immunization. She asked whether there is specific 

language stating that this does not need to be done. 

Dr. Kroger responded that language will be included that vaccine can be administered at any 

time during the hospitalization. There is discussion regarding the strength of the evidence, but it 

will probably not be as prescriptive as Dr. Byington suggested based on the evidence. 

Dr. Byington (AAP) clarified that the questions AAP is getting regard immunizations that have 

already occurred in the outpatient setting, and now the child is presenting for an elective 

procedure. Anesthesiologists are turning them away for 10 days to two weeks following 

immunization in the outpatient setting. That seems to be a misinterpretation of the 

recommendations. 

Dr. Kroger said the issue regards how strongly that statement can be made. The WG is not 

going as far as to say that there is no need to wait an interval. There are no plans to include 

that language directly in the document, but he is open to further discussion for potentially 

including it. 

Dr. Temte added that many children who have scheduled surgery are presenting to 

pediatricians or other practitioners for a pre-operative examination. Technically, that has to be 

30 days before the procedure. Many practitioners use that opportunity to catch up on 

vaccination, so that is a very salient point. Also, a number of surgeons are reluctant to 

vaccinate prior to discharge because of the likelihood of a fever. People do not stay in the 

hospital as long as they used to. They are being sent home with explicit instructions to call back 

if there is a fever. They are unlikely to reach the person who discharged them, and often that 

results in an emergency department (ED) visit with labs, radiographs, et cetera. This is not a 

minor issue. 

Ms. Pellegrini pointed out that while the recommendation regarding subcutaneous 

administration of DTaP and PCV13 stated that “there is no evidence to support repeating doses 

of these vaccines if given subcutaneously,” there is also no evidence to say doses should not be 

repeated. She suggested stating this more neutrally. She wondered if there was any new 

evidence anticipated in the future that would offer providers more constructive guidance. 

Dr. Kroger replied that what is currently happening is that in the context of one patient, it is 

recommended to repeat the dose. In contexts where there may be hundreds or thousands of 

patients, that becomes more problematic and raises the question of whether it is even possible 

to generalize on the issue at all. If not, the argument could be made to take this out and not 

even have any discussion about it in the General Recommendations on immunization, which is 

a viable option. If it is possible to generalize, then something has to be said for this 

circumstance. The language could be stated more neutrally. 

Dr. Baker (IDSA) pointed out that most children have surgical procedures as outpatients. She 

understands the problem of no evidence. ACIP did not have much evidence when they 

recommended immunizing pregnant women. She wondered whether they could say something 

like, “there is no contraindication.” She asked what the AAP recommends in the Red Book.

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Dr. Kroger responded that with the proposed language, that is defined as a precaution. In the 

implementation of these recommendations, stating that it is not a contraindication would be a 

valid statement to make. It would be possible to include that language in the document. 

Dr. Kimberlin (AAP) added that the only place the word “anesthesia” or “anesthetic” appears in 

Section 1 of the Red Book pertains to topical anesthesia to numb a site before an injection. 

Dr. Baker suggested considering the addition of the information pertaining to surgery to the Red 

Book before publication. 

Dr. Rubin’s institution has made a general suggestion that inactivated vaccines should not be 

given within 2 days prior to surgery and live vaccines within 14 days prior to surgery, but if those 

vaccines are inadvertently given, there is no reason to cancel surgery. 

Dr. Temte emphasized that there would never be sufficient evidence one way or the other; 

therefore, expert opinion is reasonable in this situation. If they wait, this document will be 

incomplete for years. 

It seemed to Dr. Rubin that if a vaccine approved for IM use is given by the wrong route, unless 

there is evidence that giving the vaccine subcutaneously generates adequate antibody, that 

vaccine should not receive a pass. The vaccine should be repeated as a policy. 

Dr. Temte asked whether the members would be more comfortable keeping Hib as a repeat 

given the importance of this vaccine in terms of child health, given that the evidence is very thin. 

Dr. Kroger said that they could do that. 

With no other comments or questions raised, Dr. Temte asked whether the ACIP members felt 

that they could move forward with a vote at this time. 

Dr. Vazquez put forth a motion to approve the recommendations as presented, with the 

changes discussed. Dr. Bocchini seconded the motion. 

Dr. Bennett said she was anxious about voting without seeing the revised version, given the 

number of changes suggested during the discussion.

Dr. Temte requested that the revisions be made and presented to the group during the 

Unfinished Business session the next morning. Others agreed that this would be beneficial and 

acceptable, given that it was not entirely clear what they were voting on. 

Dr. Vazquez withdrew the motion, with stipulation that during the Unfinished Business section 

the next day, the revised language would be submitted for a vote. 

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Revised Language for the Vote 

Andrew Kroger, MD, MPH 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

At the request of the ACIP members, Dr. Kroger incorporated the discussion points raised 

during the General Recommendations session during the first day of the meeting and presented 

the revised language during the Unfinished Business session the next morning. This 

information is included with the information from the General Recommendations session for 

continuity and ease of reading. 

Dr. Kroger reminded everyone that the following issues related to wording that needed revision: 

 Wording presented to ACIP on 10/29/14 that needed some revision 

1. Contraindications and Precautions 

• Vaccination during anesthesia/surgery/hospitalization 

2. Vaccine Administration 

• Clinical Implications of Non-Standard Vaccination Practices 

2a) Statement regarding subcutaneous administration of vaccines approved by the 

intramuscular route for which there are no data 

2b) Inclusion of Hib vaccine in above statement 

 Revision shared from ACIP regarding simultaneous vaccination of PCV13 and PPSV23 

1. Revision to draft language to separate these vaccines (not presented to ACIP on 

10/29/14, but shared with ACIP on 10/10/14) 

In terms of Contraindications and Precautions, Dr. Kroger previously showed the evidence 

summary based on the lack of data regarding whether an interval is needed before or after 

vaccines and surgery/anesthesia. The available evidence includes observational and indirect 

studies and do not assess the immune effect on the response to vaccination specifically, or at 

least the vast majority of studies do not do that and do not provide convincing evidence that 

recent anesthesia or surgery significantly affect the response to vaccine. He did not propose a 

change to that or to the action statement. 

ACIP concerns from the previous day focused on the issue of patients recently vaccinated who 

may be scheduled for elective surgery. It was noted that some providers already use intervals. 

However, there must be some flexibility as to the timing of when to vaccinate. Concerns were 

also expressed by liaison members from the AAP and IDSA regarding the current language in 

the document defining hospitalization/surgery/anesthesia as a precaution, given that this might 

lead to withholding vaccines that can be protective by preventing disease in someone with 

upcoming surgery. Concerns may be different for different vaccines. Guidance is needed, but it 

cannot be too prohibitive. The proposal was to connect the evidence summary and the action 

statement with a bridging statement about the fact that current, recent, or upcoming 

anesthesia/surgery/hospitalization is not a contraindication to vaccination. The full statement 

would read as follows: 

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“Efforts should be made to ensure vaccine administration during the hospitalization or at 

discharge. For patients who are deemed moderately or severely ill throughout the 

hospitalization, vaccination should occur at the earliest opportunity (i.e., during 

immediate post-hospitalization follow-up care, including home or office visits) when 

patients’ clinical symptoms have improved. Current, recent, or upcoming 

anesthesia/surgery/hospitalization is not a contraindication to vaccination. 

In terms of Vaccine Administration: Clinical Implications of Non-Standard Vaccination Practices, 

ACIP members expressed several concerns related to the statements regarding counting or not 

counting a dose of vaccine given subcutaneously. The current language places the burden on 

the evidence to demonstrate that doses of DTaP and PCV13 administered subcutaneously 

need to be repeated. The burden cannot be placed on the evidence to demonstrate that doses 

need to be counted generally, because there is no such evidence for HPV vaccine. Hib vaccine 

cannot be grouped with Hepatitis A vaccine and MCV4/MenACWY since the level of evidence is 

not met to avoid grouping Hib with DTaP and PCV13. All of this was in the context of providing 

more neutral language that does not put forward a specific action step. The revised language 

would read as follows: 

“DTaP, Hib, and PCV13, like all other vaccines approved for intramuscular use, should 

be administered by the intramuscular route. However, for DTaP, Hib, and PCV13, there 

is no evidence related to immunogenicity of these three vaccines given subcutaneously. 

Providers should address circumstances in which dose(s) of these vaccines have been 

administered subcutaneously on a case-by-case basis.”

Regarding Timing and Spacing of Immunobiologics: Simultaneous Administration of PCV13 

and PPSV23, the draft document was sent to ACIP on October 10, 2014. A comment was 

received on October 20, 2014 to emphasize the positive priming effect of PCV13, as opposed to 

any effect of PPSV23 to blunt the immune response to subsequent doses. The ACIP 

membership wanted to see this change before voting. The GRWG proposal is to adopt 

language from the Pneumococcal Vaccine Specific Statement from 2014 [MMWR. 2014;63 

(37);822-825]. The language will need to flow with the rest of the General Recommendations 

document. The following language was proposed, taken almost completely from the 

pneumococcal-specific statement: 

“In patients recommended for both PCV13 and PPSV23, the two vaccines should not be 

administered simultaneously. Immunogenicity studies evaluating responses to PCV7 

and PPSV23 administered in series showed a better immune response when PCV7 was 

administered first. An evaluation of immune response after a second pneumococcal 

vaccination administered 1 year after the initial study doses showed that subjects who 

received PPSV23 as the initial study dose had lower antibody responses after 

subsequent administration of PCV13 than those who had received PCV13 as the initial 

dose followed by a dose of PPSV23, regardless of the level of the initial response to 

PPSV23. PCV13 should be administered first. If PPSV23 has been administered first, 

PCV13 should be administered no earlier than one year later.” 

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Discussion Points

Dr. Temte thanked Dr. Kroger for his hard work in putting this presentation together overnight. 

For the PCV13/PPSV23 statement, Dr. Belongia suggested placing the action item at the 

beginning. The statement would then read: 

“In patients recommended for both PCV13 and PPSV23, the two vaccines should not be 

administered simultaneously. PCV13 should be administered first. If PPSV23 has been 

administered first, PCV13 should be administered no earlier than one year later. 

Immunogenicity studies evaluating responses to PCV7 and PPSV23 administered in 

series showed a better immune response when PCV7 was administered first. An 

evaluation of immune response after a second pneumococcal vaccination administered 

1 year after the initial study doses showed that subjects who received PPSV23 as the 

initial study dose had lower antibody responses after subsequent administration of 

PCV13 than those who had received PCV13 as the initial dose followed by a dose of 

PPSV23, regardless of the level of the initial response to PPSV23.” 

Dr. Kroger indicated that he would make this revision. 

Dr. Reingold said that while he has not been a clinician for a long time, he did not know what he 

would do with the last sentence in the statement pertaining to DTaP, Hib, and PCV13 reading, 

“Providers should address circumstances in which dose(s) of these vaccines have been 

administered subcutaneously on a case-by-case basis.”

Dr. Temte said that in all of his years of practice, he was not aware of any of his patients ever 

being administered an IM in a subcutaneous route. If it did occur, it would depend on the 

situation. If it is a repeat immunization for which a patient has already been primed, he would 

not be concerned. However, he feels strongly that an initial Hib vaccine needs to be 

administered appropriately. This is a situation in which there is no evidence one way or the 

other, and it is unlikely that new evidence will be forthcoming. In this situation, a “fuzzy” 

statement may be acceptable. 

Dr. Loehr (AAFP) agreed that a “fuzzy” statement was appropriate due to lack of evidence either 

way; however, he suggested including language to articulate specifically that there is no 

evidence one way or the other. 

Ms. Groom (IHS) noted that previously, it was clear that these three vaccines probably did not 

need to be repeated. However, the proposed wording seemed unclear about whether to repeat 

doses. Just stating that there is no evidence will not give the clinician an idea about whether to 

repeat doses. 

Dr. Kroger said that from an implementation standpoint, when these vaccines are given, 

clinicians have been instructed to repeat a dose if it is for a single patient. The issue is when 

many doses are given. Hence, the case-by-case basis issue for implementation. 

Dr. Kempe’s recollection was that this is in the context of ACIP already saying there is some 

evidence for a few vaccines. The “however” in the statement seemed out of place. This would 

be saying that secondarily, for these three vaccines, there is no evidence. 

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Dr. Kroger replied that there is adequate evidence for meningococcal and HepA vaccines. 

Dr. Kempe observed that in that context, the statement made more sense and says what it 

needs to say—there is no evidence. 

Vote: General Recommendations 

Dr. Vazquez made a motion to accept the language as proposed. Dr. Bocchini seconded the 

motion. The motion carried with 13 affirmative votes, 0 negative votes, and 0 abstentions. Two 

members were absent. The disposition of the vote was as follows: 

13 Favored: Bennett, Belongia, Bocchini, Harrison, Karron, Kempe, Pellegrini, Romero, 

Reingold, Riley, Rubin, Temte, and Vazquez 

 0 Opposed: N/A

 0 Abstained: N/A 

 2 Absent: Campos-Outcalt, Harriman 

Introduction 

Dr. José R Romero 

ACIP Chair 

Child/Adolescent Immunization Work Group

Dr. Romero introduced this session on behalf of Child/Adolescent Immunization WG. He 

reminded everyone that the schedule is presented for vote every fall, given that the ACIP’s 

approval is necessary prior to publication of the schedule in January or February of the following 

year. ACIP’s approval is also necessary before its partners AAP, AAFP, and ACOG review and 

approve the schedule. No new policy is established by the schedule; rather, it reflects a 

summary of published ACIP recommendations. These edits are intended to improve readability 

and utility of the schedule, and hence translate the respective ACIP recommendations into 

language that is easy to interpret for the busy provider. 

This year, only a few vaccines’ schedules require attention. Posted on the website available to 

ACIP members are the full set of footnotes; the catch-up schedule; and revised job aids for 

DTaP, Hib, and pneumococcal vaccines discussed during the last ACIP meeting. These latter 

documents will be published by CDC, and while they do not require ACIP’s approval, the ACIP 

members were asked to review them in the next few weeks to assure they are consistent with 

the current Childhood/Adolescent Immunization Schedule. For the remainder of this 

presentation, Dr. Strikas discussed the proposed edits to some specific vaccine footnotes, as 

well as the Catch-up Table. 

Child/Adolescent Immunization Schedule

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Child/Adolescent Immunization Schedule 2015

Dr. Raymond Strikas 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Strikas reviewed the Child/Adolescent Immunization Schedule for 2015, beginning with a 

discussion of Figure 1, the age-based draft schedule for 2015: 

The changes proposed to Figure 1 are to highlight the different recommendations for influenza 

vaccination for children for 1) live attenuated influenza vaccine beginning at 2 years of age, and 

2) with a break at 8 years of age, up to when children may need two doses of influenza vaccine, 

and after which they only require one dose of vaccine. Therefore, new age groupings have 

been created for 7 through 8 years, and 9 through 10 years, to accommodate these changes. 

This is Figure 2, the catch-up schedule: 

For Hib vaccine, in the dose 1 to 2 column, the only change is the language to refer to a dose 

administered before the 1st birthday, which seems clearer than “younger than age 12 months.” 

In the Hib 2nd to 3rd dose column, the WG defined more precisely which Hib vaccines are to be 

considered for a dose to be given 4 weeks after the second dose. Those are PRP-T vaccines, 

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ActHIB®, PENTACEL®, or an unknown vaccine, which might be either of those. For an interval 

of 8 weeks between these doses, and to be the final dose in the series, the WG deleted what 

appeared unnecessary, stating “regardless of Hib vaccine used.” Also defined for children 12 

through 59 months of age is that they must have received a second dose before age 15 months 

to allow completion of the series in 8 weeks’ time with one more dose. Some language was 

deleted in the last category to read “both doses were PRP-OMP vaccines” and again used 

“before the 1st birthday.”

In the Hib dose 3 to 4 column, because any child who received 3 doses of any Hib vaccine 

before 12 months of age should receive one more dose, the vaccines named in the strikeout 

section highlighted may be deleted, and the timing of receipt need only say it was before the 1st

birthday. For pneumococcal conjugate vaccine, in the dose 1 to 2 column, minor wording 

changes are proposed, including “before the 1st birthday” rather than “younger than age 12 

months” and insertion of the word “was” before “administered” in the second segment.

In the dose 2 to 3 column, language was modified at length to better adhere to the 2010 routine 

childhood recommendations: “Dose 3 should be given 4 weeks after dose 2 if the child is 

younger than 12 months, AND the previous dose was given before 7 months of age. Dose 3 as 

the final dose should be given 8 weeks after dose 2 if the previous dose (dose 2) was given 

between 7 and 11 months of age; this 3rd and final dose should be given at 12 months of age or 

older, OR the child is 12 months of age or older and received at least one of the two previous 

doses before age 12 months,” they can complete the series at that time.

In the Tdap section, wording was simplified again using “before the 1st birthday” rather than 

“younger than age 12 months” and unnecessary language was deleted where it is already 

defined that the Td or Tdap dose will be the final dose in the series. The last Td/Tdap edit was 

to say again in the dose 3 to dose 4 column “before the 1st birthday” rather than “younger than 

age 12 months.” Minimum age for dose 1 for hepatitis A, hepatitis B, polio, meningococcal, 

MMR, and varicella vaccines is not relevant in the catch-up schedule for children already 7 

years of age, so these are indicated as “not applicable.” In the varicella section for children 7 

years and older, “person is” was deleted for simplicity. 

Here are the footnotes: 

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In footnote 3 for DTaP, language presently in the General Recommendations on Immunization 

was added, indicating children who had already received the 4th dose of DTaP at age 12 months 

can have the dose count if the dose followed the 3rd dose by at least 4 months. In footnote 6 for 

pneumococcal conjugate vaccine, language was added to follow more closely the 2010 

recommendations for high risk children 2 to 5 years of age, that they should receive 1 dose of 

this vaccine if the child had received any incomplete series of pneumococcal conjugate vaccine, 

whether 7- or 13-valent, AND such children should receive 2 doses of PCV 13 if they had 

received fewer than 3 doses of any conjugate vaccine in the past. That is verbatim from the 

2010 recommendations. 

In the influenza footnote, the only changes were to update the dates for the 2014-2015 season, 

update the references, and to point to the relevant recommendations. The meningococcal 

footnote had more substantial editing to more clearly identify the appropriate dosing schedules 

for high risk infants and children for the three different vaccines. These were stratified by 

condition and by vaccine type. This footnote had not previously addressed use of Menveo® in 

children 7 months of age and older. For children with persistent complement component 

deficiencies, a similar re-structuring was written of the footnote that is stratified by vaccine type. 

Regarding next steps, the WG will make revisions as necessary based on feedback from ACIP 

and CDC internal clearance, and will then send it to colleagues AAP, AAFP, and ACOG. The 

final edited copy will be sent to partner organizations for preparation of publication in their 

journals or their on-line publications by January 1, 2015. The hope is to publish the schedule on 

the website, with a notice in the MMWR in January or at the latest February 2015, as well as in 

publications in Pediatrics and American Family Physician no later than February 2015. 

Discussion Points

Referring to tetanus/diphtheria dose 3 to 4, Dr. Loehr (AAFP) noted that the box is correct on 

the page that has the correction. However, on all of the other pages it says “if first dose of 

DTaP/DT was administered” and “if first dose of DTaP was administered.” This needs to be 

corrected on the final copy. 

Ms. Groom (IHS) expressed gratitude for the changes to the Hib language, which she believes 

will be incredibly helpful. 

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Dr. Strikas acknowledged Elizabeth Briere and the WG’s colleagues whom work on Hib 

regularly. 

Dr. Pickering reminded the WG to use the word “through” rather than dashes for age ranges for 

clarity. 

Dr. Strikas indicated that the WG would go through the document to ensure that all of dashes 

are changed. 

Vote: Child/Adolescent Immunization Schedule 

Dr. Rubin made a motion to approve the Child/Adolescent Immunization Schedule as proposed. 

Dr. Kempe seconded the motion. The motion carried with 13 affirmative votes, 0 negative 

votes, and 0 abstentions. Two members were absent. The disposition of the vote was as 

follows: 

13 Favored: Bennett, Belongia, Bocchini, Harrison, Karron, Kempe, Pellegrini, Romero, 

Reingold, Riley, Rubin, Temte, and Vazquez 

 0 Opposed: N/A

 0 Abstained: N/A

 2 Absent: Campos-Outcalt, Harriman 

Introduction 

Dr. Laura Riley 

ACIP Chair, Adult Immunization Work Group 

Dr. Riley reminded everyone that ACIP updates the adult immunization schedule each year. 

The schedule represents and summarizes existing ACIP policy. The WG meets monthly and 

engages in ongoing consultation with vaccine subject matter experts (SMEs) to recognize 

changes over time. 

Updates on the pneumococcal vaccination recommendation were recently approved regarding 

policy changes from the additional ACIP meeting on August 13, 2015 and published in the 

MMWR on September 19, 2014. These were discussed in great detail by the WG. The 2014 

Adult Immunization Schedule was also approved by the following: 

 American College of Physicians (ACP) 

 American Academy of Family Physicians (AAFP) 

 American College of Obstetricians and Gynecologists (ACOG) 

 American College of Nurse Midwives (ACNM) 

Adult Immunization Schedule

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Adult Immunization Communication Materials 

Dr. Kristine Sheedy 

Associate Director 

Office of Health Communication Science 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Sheedy called the ACIP members’ attention to a folder of materials given to them, which 

included samples of some of the direct consumer and clinician adult immunization materials that 

have been developed. CDC is currently working with the IAC and Medscape to develop a 

series of features on adult immunization standards to cover assessment, recommendations, 

administration, referral, and documentation. 

The assessment features are available on line, and the recommendation features should be 

available soon. This feature will include case examples with common questions from patients 

about various adult vaccines, and video vignettes modeling how to answer those questions 

clearly and succinctly. Some of the pieces are currently available in Spanish, and more pieces 

will be translated as well. 

Adult Immunization Schedule 2015

Dr. David Kim 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

In this presentation, Dr. Kim described the proposed changes to the 2015 Adult Immunization 

Schedule. Here are Figures 1 and 2: 

 

The proposed changes for Figure 1 are to replace the purple bar (recommended if at risk) with a 

yellow bar (recommended) for PCV13 for adults age ≥65 years. For the Footnotes, the WG 

proposed to reformat the language from vaccine-focused to patient-focused based on a request 

to make the footnotes as user-friendly as possible. In the Contraindications Table, the WG 

proposed adding changes associated with LAIV. 

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The changes to Contraindications were based on the recent article titled, “Prevention and 

Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on 

Immunization Practices (ACIP) — United States, 2014–15 Influenza Season” [MMWR 2014;63 

(32):691-97]. Wording changes in Contraindications include the following: 

 “Severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine, or to a 

previous dose of any influenza vaccine.”

 “In addition, ACIP recommends that LAIV not be used in the following populations

 Pregnant women; 

 Immunosuppressed persons; 

 Persons with egg allergy; 

 Children aged 2 through 4 years who have asthma or who have had a wheezing 

episode within the last 12 months; 

 Persons who have taken influenza antiviral medications within the previous 48 hours. 

Avoid use of these antiviral drugs for 14 days after vaccination.”

Other changes in Contraindications and Precautions include change from the term 

“Contraindication” to “Precaution” for antiviral use within last 48 hours, and from “Precaution” to 

“Contraindication” for chronic health conditions.

Regarding the 2014 Adult Immunization Schedule for pneumococcal vaccination, there are 

footnotes for PCV13, PPSV23, and revaccination with PPSV23. Population groups were 

divided into two age categories: Age ≥19 years and Age ≥65 years of age. 

The common feedback the WG receives from those within and outside of CDC is that the 

pneumococcal vaccine recommendations are complex. That complexity comes from the fact 

that immunocompromised adults need PCV13 and two doses of PPSV23. They need to receive 

both vaccines, but there are different combinations of delivery and the intervals between those 

vaccines differ. In addition, if an adult has functional or anatomic asplenia, they need PCV13 

and 2 doses of PPSV23, but certain other conditions like CSF leaks and cochlear implants 

require PCV13 and 1 dose PPSV23. Persons with chronic health conditions (e.g., heart 

disease, hypertension, kidney disease, and others) receive only 1 dose of PPSV23. People 

who smoke and residents of long-term care facilities receive 1 dose of PPSV23. 

The addition of the recommendations for adults ≥65 years of age to receive PPSV23 contributed 

significantly to the complexity of incorporating the pneumococcal vaccination recommendations 

in the Adult Immunization Schedule. Also adding to the complexity is the need to account for 

adults 19 through 64 years of age who received pneumococcal vaccine(s) who then age into the 

≥65 years of age category and may need PCV13 and PPSV23. Crafting easy-to-understand 

messages for busy healthcare providers is difficult. Figures must be interpreted with footnotes, 

so footnotes are of paramount importance and must contain the information needed by 

providers to implement ACIP recommendations. 

Very few changes were made to the Pneumococcal Vaccination Recommendations in 2015. As 

noted earlier, the proposed changes for Figure 1 are to replace the purple bar with a yellow bar 

(recommended) for PCV13 for adults age ≥65 years. The lines are continuous rather than 

having broken yellow and purple lines. Vaccines for particular populations based on their 

medical and other conditions did not change. For the 2015 Adult Immunization Schedule, the 

footnotes basically revolve around adults 65 years of age and older by adding PCV13 on top of 

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PPSV23. The general recommendations include the following helpful information, with the last 

three bullets having already been included in previous versions of Adult Immunization Schedule 

Footnotes: 

 When indicated, only one dose PCV13 is indicated for adults 

 No additional dose of PPSV23 is needed if one was received at age ≥65 years

 Administer PCV13 before PPSV23 (but not at the same visit) 

 Administer vaccines if vaccination history is unknown 

As mentioned earlier, the pneumococcal vaccine intervals for adults became more complex with 

the addition of PCV13 needing to be administered for adults age ≥65 years. The interval 

between PCV13 and the subsequent PPSV23 should be 6 to 12 months in contrast to at least 8 

weeks for the same schedule for person 19 through 64 years of age who are 

immunocompromised or who have asplenia, CSF leaks, or cochlear implants. The interval 

between the two PPSV23 doses is ≥5 years, which has not changed. Here are the footnotes 

reflecting the three age and risk groups in the 2015 footnotes: 

This is basically an algorithmic approach. The footnote is designed for the busy provider to 

identify the patient by age and by health condition, and follow a menu to decide what the patient 

needs in terms of pneumococcal vaccine. The algorithm for adults age ≥65 years, 

immunocompromised persons 19 through 64 years of age, and adults age 19 through 64 years 

with chronic health conditions and other indications walks through what they may or may not 

have received during their pneumococcal immunization odyssey. 

The next steps for the WG are to revise the 2015 Adult Immunization Schedule based on 

ACIP’s discussion and recommendations, which will undergo another round of scrutiny by the 

influenza and pneumococcal influenza SMEs. Approval will be obtained from ACP, AAFP, 

ACOG, and ACNM. The revised schedule (figures, footnotes, and contraindications table) will 

then be submitted for CDC clearance. The goal is to submit the approved 2015 Adult 

Immunization Schedule to the MMWR and Annals of Internal Medicine in December for 

February 2015 publication. This will be done in coordination with the MMWR article on 2013 

non-influenza vaccination coverage rates in the same week as adult immunization schedule 

release. 

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Discussion Points

Dr. Kinsinger (DVA) said she really liked the simplified algorithm, but would appreciate 

simplification of the interval between PCV13 and PPSV23 so that there is one interval 

regardless of age. She suggested considering whether the interval should be at least 8 weeks 

or 6 to 12 months. That would make programming electronic decision support tools much 

simpler. She also pointed out a gap in the schedule. For example, which schedule should be 

followed for a 65 year old patient who is pneumococcal vaccine naïve, who then becomes 

immunocompromised? 

Dr. Kim responded that certain general information cases are included. When indicated, only 

one dose of PCV13 is needed and no additional PPSV23 is needed if one was received at age 

65 years or older.

Dr. Kinsinger (DVA) suggested making it clearer that the guidance for immunocompromised 

persons who are 19 through 64 years of age does not apply to patients who are 65 years of age 

and older. 

Dr. Temte reminded everyone that they could not change recommendations for pneumococcal 

pneumonia by virtue of changing the vaccination schedule. However, Dr. Bennett will take this 

back to the WG for consideration. 

Dr. Bennett added that there was considerable discussion about this and no one was happy. 

There was a weighing between making the recommendations identical versus what will be the 

most possible recommendation to implement. The sense was that people who are 

immunocompromised see their physicians far more frequently than healthy people over 65 

years of age. To state a greater than or equal to 8-week interval would imply that people have 

to receive it after 8 weeks. The concern was that more leeway is needed. The minimum 

recommendation is 8 weeks, but it can be extended. The WG is fully aware that this is not ideal 

and will discuss it again. 

Dr. Belongia said he suspected that there was an inverse relationship between complexity and 

successful and implementation of guidelines such as this. Looking at each one makes sense, 

but looking at the whole picture makes it difficult to see how anyone could keep track of this. He 

wondered if it would be helpful to create two flow charts, one for immunocompromised persons 

and one for healthy persons or one for under and one for over 65 years of age. That way, the 

busy practitioner could go down the list to answer yes/no and get to the answer quickly versus 

reading all of the footnotes. 

Dr. Kim replied that a write-up will be submitted for publication to the MMWR and the Annals of 

Internal Medicine in February 2015. In the Annals of Internal Medicine, there will be an 

opportunity to publish an algorithm that is more graphic in nature. A flow diagram will certainly 

be appropriate. This simply was not possible for the adult schedule, given the precious real 

estate on the footnotes. 

Ms. Pellegrini pointed out that the fourth bullet on the list of contraindications for LAIV refers to 

children aged 2 to 4 years, which is not relevant for the adult schedule. 

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Referring to Slide 11, Dr. Temte reminded the WG to use the word “through” between age 

ranges. He also suggested rearranging the schedule to switch the category of Adults 19 

through 64 years with Adults 19 through 64 years immunocompromised, asplenia. 

Dr. Kempe reminded everyone that some nice piloting was done with providers for the childhood 

schedule, which found that providers thought the flowcharts were difficult to understand 

compared to patient-focused efforts. She suggested piloting the flowcharts with providers for 

the adult schedule as well. 

Lynn Bozof (Minnesota Department of Health) noted that the footnotes refer to adults 65 years 

of age and older and PCV13 and PPSV23. While that is correct and everyone in the room 

understood what that meant, she thought they should be very specific about PCV13 first 

followed by PPSV23 6 to 12 months later. Even the schedule makes it looks like both are to be 

given together, and many providers are likely to do that. 

Ms. Groom (IHS) asked for clarification regarding whether the minimum interval to receive 

PPSV23 is 6 months for a 65 year old patient who received PCV13 before, meaning that if they 

received it at 8 weeks they would need a repeat dose. The absolute minimum interval should 

be spelled out in the pink table that shows the minimum age. 

Dr. Bennett emphasized how difficult this has been and how impressed she was with how well 

Dr. Kim had condensed all of this complicated information into the chart. 

On behalf of all of his colleagues in the Adult Immunization WG, Dr. Schaffner (NFID) extended 

his gratitude to Dr. Kim as well. He led the WG through this pneumococcal wilderness and 

always had good composure and a great sense of humor. 

Regarding the contraindications and precautions table, Dr. Lett (CSTE) acknowledged that the 

language had been harmonized in terms of antivirals to correspond with the language in the 

influenza statement. However, there was now some discordance in the patient taking antivirals 

for the other live viral vaccines. Those were still in the precautions column and not the 

contraindications column. She wondered whether that could be further clarified following the 

vote, or if ACIP was voting on the language shown. 

Dr. Carolyn Bridges (SME) said that the updated LAIV ACIP statement now says that in antiviral 

use, it is a contraindication. Antiviral use is a contraindication for LAIV, but is a precaution for 

varicella and zoster vaccines. The way it is in the table now is in concordance with published 

ACIP statement. 

Dr. Lett (CSTE) said her sense was that this will cause confusion. There may be scientific 

reasons why they are not the same anymore, but people tend to keep that in mind more easily 

in terms of what is a precaution. If there is an opportunity, she suggested more discussion 

among the SMEs about harmonization for that. 

Dr. Bridges (SME) said she was not clear whether this could be resolved without the other WGs 

being able to weigh in, particularly the Varicella and Zoster WGs. 

Dr. Temte’s reminded everyone that the adult schedule is intended to present existing policy 

rather than create new policy. 

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Dr. John Grabenstein (Merck) pointed out that there was some inconsistency in the footnote 

information shown in Slide 11 in that some of the wording states “have not received X but have 

received Y” and some are written “have received X but not Y.” Clinicians tend to think of what 

someone has received and that tells them what is missing, so he suggested standardizing 

those. 

Dr. Schuchat thought that the footnote made sense for Adults ≥65 years in terms of the use of 

“have not received” and “have received” and suggested not changing it.

Ms. Pellegrini agreed with Dr. Schuchat because PCV is a single dose versus PPSV sometimes 

being two doses. It is easier to think about PCV in a binary way as a first screen to determine 

whether someone has received one or two doses of PPSV. 

It was noted that the language should read “6 to 12 months” and not “6 through 12 months” 

because people might think after a year they should no longer give this vaccine. 

Vote: 2015 Adult Immunization Schedule 

Dr. Bennett made a motion to approve the Adult Immunization Schedule as proposed. Dr. Riley 

seconded the motion. The motion carried with 13 affirmative votes, 0 negative votes, and 0 

abstentions. Two members were absent. The disposition of the vote was as follows: 

13 Favored: Bennett, Belongia, Bocchini, Harrison, Karron, Kempe, Pellegrini, Romero, 

Reingold, Riley, Rubin, Temte, and Vazquez 

 0 Opposed: N/A

 0 Abstained: N/A 

 2 Absent: Campos-Outcalt, Harriman 

Public Comment 

Dr. Sandra Fryhofer 

ACP Liaison

Dr. Fryhofer thanked ACIP for voting on this new adult schedule on behalf of the ACP, the 

nation’s largest medical specialty society, representing over 141,000 doctors of internal 

medicine, medical students, residents, and fellows, as well as on behalf of patients. She also 

offered special thanks to the WG for putting together the new pneumococcal mega-footnote. 

She said that she preferred the new title “ACIP’s Pneumococcal Odyssey,” with the goal being 

to help practitioners more easily implement this new schedule. Pneumococcal infection is a 

major cause of morbidity and mortality and has killed as many as 4000 people in the US each 

year, primarily adults. Older adults are at increased risk for invasive disease, and doctors of 

internal medicine provide regular care to the majority of patients affected by these new 

recommendations. 

ACIP has done its work and now it is in ACP’s hands. ACP will work to get the word out about 

the new schedule, and has an adult immunization committee that meets regularly and is open to 

new ideas and new partnering. Current plans include a dedicated immunization portal where all 

immunization materials and programs will be updated. This includes ACP’s adult immunization 

app and adult immunization guide. ACP also has several ongoing quality improvement (QI) 

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immunization initiatives, including a CDC-funded QI program and a new “I Raise the Rates” 

program. ACP also plans to have a coaching call on pneumococcal vaccination for these 

programs. As noted, the new schedule will be published in February 2015 in the Annals of 

Internal Medicine. The most recent impact factor for this publication is 16.104, which is the 

highest of any specialty journal in the Thomson Reuters’ General and Internal Medicine 

category. This new recommendation is both comprehensive and complicated, but patients will 

benefit from collective immunization implementation efforts. 

 

Introduction 

Art Reingold, MD 

ACIP Hepatitis Work Group Chair

Dr. Reingold reminded everyone that the Hepatitis Vaccine WG was tasked with updating the 

recommendations for hepatitis A and B vaccines, and the decision was made to begin with 

hepatitis A. There are existing hepatitis A and B vaccine recommendations. The current 

recommendations and updates for hepatitis A vaccine include the following: 

 ACIP Routine Recommendation for Hepatitis A Vaccine (2006). MMWR 2006 May 

19;55(RR-7):1-23.

 Update: Prevention of hepatitis A after exposure to hepatitis A virus and in international 

travelers. Updated recommendations of the ACIP. MMWR 2007 Oct 19;56(41):1080-4.

 Updated recommendations from the ACIP for use of hepatitis A vaccine in close contacts of 

newly arriving international adoptees. MMWR 2009 Sep 18;58(36):1006-7. 

 FDA Approval of an Alternate Dosing Schedule for Twinrix®. MMWR 2007 Oct 

12;56(40):1057. 

Since the June 2014 ACIP meeting, the WG has had five teleconferences focused on hepatitis 

A vaccine coverage, the epidemiology of hepatitis A in the US, the hepatitis A multi-state 

outbreak and foodborne disease, and hepatitis A hospitalization trends. The presentation 

during this session focused largely on hepatitis A burden of disease and the population that still 

may require protection. 

In the short-term, the WG will continue to discuss updating the hepatitis A vaccination statement 

from 2006 and catch-up vaccination for children/teens age 2 through 18 years of age. The WG 

will continue to evaluate evidence, including GRADE and cost-effectiveness as data are 

available. Long-term plans are for the WG to discuss hepatitis A vaccine for PEP in adults 40 

years of age and older. While the burden of disease for hepatitis A is certainly much lower than 

it used to be, there are still gaps in immunity, particularly with the increase in importation of 

foods that pose a risk of hepatitis A infection. 

Hepatitis Vaccines

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Update on Hepatitis A Burden and Hepatitis A Population Protection

Noele Nelson, MD, PhD, MPH 

Vaccine Research and Policy Unit 

Division of Viral Hepatitis 

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

During this session, Dr. Nelson discussed hepatitis A vaccine history in the US, epidemiology of 

the disease, vaccine coverage, antibody to hepatitis A virus (anti-HAV), seroprevalence, and the 

hepatitis A outbreak and food-associated exposure risk. Hepatitis A vaccination was introduced 

incrementally in the US from 1996 to 1999. In 1996, vaccine was recommended for children at 

age 2 years in communities with high rates of disease and children through teen years in 

outbreaks. In 1999, vaccine was recommended for children at age 2 years of age in 11 states 

(Washington, Oregon, Idaho, California, Nevada, Utah, Arizona, NM, OK, SD, Alaska) with 

average annual hepatitis A rates of two times the national average at >20 cases per 100,000 

population. Vaccine was considered in 6 states (Missouri, Montana, Wyoming, Colorado, 

Texas, Arkansas) with rates above the national average at >10 cases per 100,000 population 

[MMWR 1996;45(RR-15); MMWR 1999;48(RR-12); MMWR 2006;55(RR-7)]. 

Universal childhood vaccination was introduced in 2006. Vaccine was recommended for use at 

age 12 through 23 months in all states. It was recommended that existing vaccination programs 

for ages 2 through 18 years should be considered, and catch-up vaccination should be 

continued in outbreaks and areas with increasing disease rates. Vaccine was also 

recommended for any person wishing to obtain immunity. There is no routine vaccine 

recommendation for children over 23 months of age. In addition, vaccine is recommended for 

groups at increased risk of HAV infection or severe disease, such as the following: 

 Travelers 

 Men who have sex with men (MSM) 

 Users of injection and non-injection drugs 

 Persons with clotting-factor disorders 

 Persons who work with nonhuman primates 

 Persons who anticipate close personal contact with an international adoptee 

 Persons with chronic liver disease 

 PEP for healthy persons 12 months through 40 years of age 

Regarding hepatitis A epidemiology, data collection for hepatitis A started in 1966. The highest 

number of hepatitis A cases reported was in 1971 at approximately 60,000 cases at a rate of 

about 30 cases per 100,000 population. Vaccine was recommended in 1996. The number of 

reported cases declined from 31,032 in 1996 to 1,398 cases in 2011. The rate also declined 

from 11.7 cases per 100,000 population in 1996 to 0.4 cases per 100,000 population in 2011. 

From 1996 to 2011, there was a 95.5% decrease in reported cases [National Notifiable 

Diseases Surveillance System (NNDSS); Armstrong GL. Pediatrics 2007;119:e22-9]. 

In 2011, the number of reported cases in the US reached an all-time low of 1,398 cases. In 

2012, the number of reported cases in the US increased to 1,562 cases, representing the first 

increase in cases since 1995. In 2013, the number of reported cases in the US increased again 

to 1,781 cases. Though these increases are not large at this point, and most of the increase in 

2013 is attributable to a multi-state hepatitis A outbreak, the increases from 2011 to 2013 

represent a reversal of a trend over almost two decades. CDC is exploring the etiologies of the 

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case increases, including reporting biases, and the geographic distribution of the cases 

[National Notifiable Diseases Surveillance System (NNDSS); DVH Surveillance report (2008-

2012); Noninfluenza vaccination coverage among adults - United States, 2012. MMWR. 2014 

Feb 7;63(5):95-102]. 

Increases in the rate of cases from 2011 to 2012 were reported in 4 regions. Increases in the 

rate of cases from 2012 to 2013 were reported in 6 regions, although there was a decrease in 

one region. The multi-state outbreak in 2013 was reported primarily in the Mountain and Pacific 

Regions among 8 states. However, increases from 2012 to 2013 were observed in other 

regions as well. When looking at these data at the state level, it was observed that some of the 

increases in rates occurred in states not involved in the outbreak, suggesting multiple causes for 

the increase in number and rate of cases [National Notifiable Diseases Surveillance System 

(NNDSS); DVH Surveillance report (2008-2012); Noninfluenza vaccination coverage among 

adults - United States, 2012. MMWR. 2014 Feb 7;63(5):95-102]. 

Rates of acute hepatitis A declined for all age groups from 2000 to 2012. Rates were similar 

and low among persons in all age groups in 2012 with less than 1.0 case per 100,000 

population. In 2012, rates were highest for persons aged 20 through 29 years at 0.69 cases per 

100,000 population. The lowest rates were among children less than 9 years of age at 0.15 

cases per 100,000 population. Starting in 2007, children less than 9 years of age had the 

lowest rate of infection in any age group. The Healthy People 2020 target is 0.3 cases per 

100,000 population. Only the 0 through 9 years age group has declined to a rate lower than 0.3 

per 100,000. Of note, the rates increased from 2011 to 2012 for ages 20 through 29 years and 

ages 40 and above [National Notifiable Diseases Surveillance System (NNDSS); 

http://www.healthypeople.gov/2020/topicsobjectives2020/pdfs/Immunization.pdf].

Looking at the data separately by decade of life for children (0-9 years, 10-19 years) and all 

adults (age 20 years and older) from 2008 to 2012, it is clear that the largest percentage of 

hepatitis A cases are occurring in adults [National Notifiable Diseases Surveillance System 

(NNDSS); DVH Surveillance report (2008-2012); Noninfluenza vaccination coverage among 

adults - United States, 2012. MMWR. 2014 Feb 7;63(5):95-102]. 

Taking a further look at burden of disease, a recent paper by Collier et. al. analyzed Hepatitis A 

hospitalization trends from 2002 to 2011, using primary discharge diagnosis data (ICD9 codes) 

from the National Inpatient Sample Healthcare Utilization Project (HCUP). Though a decrease 

in hepatitis A hospitalization rates was observed overall from 0.72 per 100,000 in 2002 to 2003 

to 0.29 per 100,000 in 2010 to 2011, the mean age of persons hospitalized for hepatitis A has 

increased significantly over the study time period from a mean age of 37.6 years in 2002 to 

2003 compared to 45.5 years in 2010 to 2011 [Collier MG, Tong X, Xu F. Hepatitis A 

hospitalizations in the United States, 2002 - 2011. Hepatology. 2014 Sep 29]. 

Based on information from case surveillance in National Notifiable Diseases Surveillance 

System (NNDSS) data regarding hospitalizations in reported hepatitis A cases, many cases are 

reported without hospitalization information. From 2009 to 2012, 35% to 45% of cases do not 

have data on hospitalization. Therefore, the number of cases hospitalized is likely 

underestimated. Of HAV cases, 39.3% were hospitalized in 2009 and 45.8% in 2012. Since 

2009, hospitalizations have been increasing. Though hepatitis A hospitalization rates have 

decreased overall, as shown by National Inpatient Sample primary diagnosis code data, 

surveillance data shows that hospitalization rates for all reported hepatitis A cases increased 

from 39% of cases in 2009 to 46% of cases in 2012. Looking further back, this trend of 

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increasing hospitalization rates for reported cases has been observed since 2005 with lower 

rates of 33% in 2005 [National Notifiable Diseases Surveillance System (NNDSS); 

Division of Viral Hepatitis Surveillance Report (2009-2012)]. 

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Deaths have declined since vaccine introduction for all age groups. The number of deaths 

approaches 0 for age groups less than 50 years. The total number of deaths in 2012 was 23. 

Of those, 21 deaths were in the 50+ age group and 2 deaths were in the 20 through 49 age 

group. These numbers increase slightly when multiple causes of death are considered [NCHS 

mortality files for vaccine preventable diseases (1990-2012)]. 

Regarding who is getting infected with hepatitis A virus, patients were asked about engagement 

in selected risk behaviors and exposures during the incubation period, 2 to 6 weeks prior to 

onset of symptoms. Data were collected as part of CDC’s NNDSS via passive surveillance 

through voluntary reporting from state health departments. Of the 1,562 case reports of acute 

hepatitis A received by CDC during 2012, a total of 568 (36%) cases did not include a response 

(i.e., a “yes” or “no” response to any of the questions about risk behaviors and exposures) 

making assessment of risk behaviors or exposures challenging. Of the 994 case reports that 

had a response, 80% (n=793) indicated no risk behaviors/exposures for acute hepatitis A, while 

20% (n=201) indicated at least one risk behavior/exposure for acute hepatitis A during the 2 to 6 

weeks prior to onset of illness. Travel was the most identified risk factor. Of the 713 case 

reports that had information about travel, about 13% (n= 92) involved persons who had traveled 

outside the US or Canada. Foodborne or waterborne exposures were reported less frequently; 

however, foodborne exposure is a growing area of concern and may represent a percentage of 

the cases with no risk factor identified [National Notifiable Diseases Surveillance System 

(NNDSS)]. 

Because risk factor information is often missing (i.e., no response to risk factor questions), and 

to collect supplemental information, select health departments are funded to conduct enhanced, 

population-based surveillance. An analysis of these data from 2005 through 2007 occurred at 6 

Emerging Infection Program (EIP) sites, covering an estimated 30 million population. For risk 

factors reported by cases in the EIP sites during 2005 to 2007, there are less missing data in 

funded sites compared to the NNDSS data. However, the distribution of risk factors was 

comparable. Travel was the most frequently reported risk factor (47% of cases with a positive 

response), including persons with direct international travel, and those who had contact with 

someone who traveled. This is much higher than the approximately 13% reported by passive 

surveillance, and much higher than observed in the 1980s and 1990s (4%). The molecular 

characteristics of a sample of cases confirmed they were travel related. The strains were 

related to Mexican and some Brazilian hepatitis A viral strains. Though these data are from 

2005 to 2007, it is believed that the data are similar today. Of note, over 35% of cases reported 

an unknown risk factor. Foodborne exposure may represent a percentage of these unknown 

exposures. However, based on risk data collected by both the NNDSS and the EIP Hepatitis 

Surveillance Sites, no significant association between risk factor and the increase in hepatitis A 

cases from 2011 to 2013 can be made at this time [Klevens et al. The Evolving Epidemiology of 

Hepatitis A in the United States. Arch Intern Med. 2010 Nov 8;170(20):1811-8]. 

The wider use of vaccine is largely responsible for the marked decrease in hepatitis A morbidity; 

however, vaccination rates remain low. Hepatitis A vaccine is recommended in a 2-dose series. 

In 2012, Hepatitis A vaccine coverage for children 19 through 35 months of age was 81.5% and 

53% for ≥1 and ≥2 doses, respectively. This is substantially less than the Healthy People 2020 

target of 85% for two dose coverage level in this age group [Elam-Evans LD, et. al. National, 

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state, and selected local area vaccination coverage among children aged 19-35 months - United 

States, 2013. MMWR. 2014 Aug 29;63(34):741-8]. 

In 2012, coverage among adolescents 13 through 17 years old was estimated to be about 60% 

and about 48% for ≥1 and ≥2 doses, respectively based on preliminary data. Only ≥3 dose HPV 

vaccine coverage has lower teen vaccine coverage than 2-dose hepatitis A vaccine. Of the 

adolescent vaccines routinely recommended, there is no hepatitis A recommendation for 

children over 23 months of age, while HPV (2007), Tdap (2006), and Meningococcal (2006) are 

routinely recommended for adolescents [Elam-Evans LD, et. al. National, state, and selected 

local area vaccination coverage among children aged 19-35 months - United States, 2013. 

MMWR. 2014 Aug 29;63(34):741-8]. 

Two-dose coverage for adults ages 19 through 49 years is 12.5% overall. The vaccine 

coverage for persons with chronic liver disease, a high risk group, is 17%. Vaccine coverage is 

20% for travelers. Therefore, the age groups with the highest death rate have the lowest 

vaccination coverage. The data source is the National Health Interview Survey (NHIS), which 

collects information about the health and health care of the non-institutionalized civilian 

population in the United States using nationally representative samples [Noninfluenza 

vaccination coverage among adults - United States, 2011. MMWR. 2013 Feb 1;62(4):66]. 

According to National Health and Nutrition Examination Survey (NHANES) data, significant 

increases occurred in the proportion of children with protection for ages 6 through 11 years and 

12 through 19 years, most likely due to vaccination. Minimal change in prevalence occurred 

among adults 20 through 29 and 30 through 39 years of age. However, significant decreases 

occurred in the proportion of adults with protection for ages 40 through 60 years and older. 

Overall, the prevalence of antibody among US residents remained about the same between the 

two surveys, 39% and 35%, respectively, indicating that only 1/3 of the US population had 

protection against hepatitis A infection in 2009 to 2010. The lowest prevalence of antibody was 

among adults [NHANES, National Health and Nutrition Examination Survey (ALL US ADULTS)]. 

A multistate hepatitis A outbreak occurred in the US in May 2013. The outbreak was associated 

with contaminated pomegranate arils imported from Turkey and illustrates ongoing hepatitis A 

exposures and adult susceptibility. There were 165 cases in 10 states. Most (93%) cases in 

the outbreak were aged ≥18 years. Overall, 44% of all cases were hospitalized and 45% of 

adult cases were hospitalized. Two cases developed fulminant hepatitis, and one required a 

liver transplant. In addition, multiple recent berry-associated outbreaks in Europe have been 

reported. Of note, the percent reported hospitalized in the outbreak (44%) is very consistent 

with the percent of hepatitis A cases hospitalized in 2011 based on case surveillance data 

(43%) [Collier MG, et. al. Outbreak of hepatitis A in the USA associated with frozen 

pomegranate arils imported from Turkey: an epidemiological case study. Lancet Infect Dis. 2014 

Oct;14(10):976-81]. 

Based on surveillance data, travel is the most reported risk factor for hepatitis A. However, 

there is a growing concern about the risk of exposure from contaminated food. The volume of 

imported fruit and vegetables in the US has increased from 1999 to 2013. Last year, the US 

imported over 12 million tons of fruit, and almost 9 million tons of vegetables. Imported fruit and 

vegetables originate from countries where hepatitis A is endemic, which are shown in the 

following table: 

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Fruit Vegetables

Mexico Mexico

Chile Peru

Costa Rica Guatemala

Guatemala India

Ecuador

Argentina

Brazil

Note that Turkey is not one of the countries listed [http://www.ers.usda.gov/data-products/usfood-imports.aspx]. 

The following map shows the estimated prevalence of hepatitis A virus in 2005, with the 

moderate and dark green representing areas of intermediate and high hepatitis A viral 

prevalence: 

In summary, an increasing proportion of adults in the US are susceptible to hepatitis A. This is 

due to reduced exposure to HAV early in life, significant decreases in anti-HAV seroprevalence 

in adults 40 years of age and older, and low 2-dose vaccination coverage in adults. This is 

important because it is known that morbidity and mortality increases with age. Suboptimal 1-

and 2-dose vaccination coverage also exists among children. An increase in HAV cases was 

observed from 2011 to 2012 and from 2012 to 2013. These represent the first increases since 

1995 to 1996. HAV infection rates also increased from 2011 to 2012 for ages 20 through 29 

years and ages 40 years and above. The mean age of persons hospitalized for hepatitis A 

increased significantly from 2002 to 2003 to 2010 to 2011. Hospitalization rates for reported 

hepatitis A cases increased from 2005 to 2011. HAV remains endemic in many areas of the 

world. Risk exists for travelers to intermediate and high endemic countries, as well as for 

consumption of imported HAV contaminated food from global sources. Herd protection does 

not prevent foodborne exposure. No routine or catch-up hepatitis A vaccine recommendation 

exists for adolescents or adults. 

The ACIP Hepatitis WG is currently focusing on updating the 2006 hepatitis A vaccination 

statement and discussing strategies to address the increasing number/rate of acute hepatitis A 

cases and continue progress toward the healthy people 2020 goal of 0.3 cases per 100,000 

population. The WG is discussing catch-up vaccination for children and teens 2 through 18 

years of age. Justification for expanding the age range of childhood vaccination to age 18 

includes: 1) continuing exposure to hepatitis A virus; 2) future protection of the adult population, 

since an increasing proportion of US adults are susceptible to HAV infection, and 3) maximizing 

herd protection from childhood vaccination. The WG is also discussing other strategies such as 

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vaccination for other ages. Additional information and evaluation of the evidence is needed 

before WG consensus can be reached. 

Additional information that would be helpful in support of expanding the age range for universal 

hepatitis A vaccination includes: 1) modelling hepatitis A disease and cost-effectiveness with 

higher hepatitis A vaccination coverage among children and adolescents and/or subsets of 

adults, for which planning is underway; and 2) GRADE for hepatitis A one- and two-dose 

vaccine efficacy, safety, and long-term protection, for which a systematic review is in progress. 

In addition, as became evident during the multi-state outbreak, more data are needed on 

vaccine efficacy for PEP in adults 40 years of age and older, for which planning is underway. 

Discussion Points

Dr. Karron said she suspects that given the intervals between the first and second dose, many 

travelers go to travel clinics for the first dose shortly before traveling, but never return for the 

second. Given this dismal data, she asked whether Dr. Nelson had coverage information for 

one dose in travelers. Her understanding was that two doses are given to sustain immunity, but 

very often protective levels of antibody are achieved following a single dose. 

Dr. Nelson responded that she did not have data based on one dose. A study of delayed 

booster doses in those over two months of age showed that boosters delayed up to 31 months 

have comparable results. Argentina has a one-dose universal hepatitis A vaccine strategy for 

children with about five years of follow-up data available. For two-doses, studies modeling longterm protection suggest vaccine protection for at least 25 years or more. 

Dr. Reingold agreed, noting that when he was on SAGE, countries were given permission to 

use a one-dose schedule based on the Argentina data. The data are quite convincing that one 

dose is highly efficacious, but the duration of protection is somewhat uncertain. 

Dr. Kempe noted that on the schedule, hepatitis A vaccine is recommended for catch-up after 

two years of age through adolescence. She agrees that education and focused encouragement 

are important, but that seems to be part of the current schedule. 

Dr. Nelson replied that the schedule is for 12 through 23 months, and the recommendation 

indicates that catch-up can be considered. 

Dr. Pickering stressed that catch-up is not recommended routinely for those two years of age 

and older. That way of handling things does not seem to be working, because children are not 

being immunized. A very low percentage of adults who develop hepatitis B or C are immunized 

against hepatitis A. He expressed his hope that the WG is discussing a stronger consideration 

than “should be encouraged,” which is the wording on the schedule. 

Dr. Bennett asked whether it would be possible to look at the data from the EIP for potential 

sources of infections or risk factors by age to identify the potentially greatest strategies for 

decreasing risk. 

Dr. Schaffner (NFID) added that he was particularly interested in the age and sex distribution of 

the “unknowns.”

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Dr. Nelson replied that while she did not have those data to present at this time, they are 

important to understand. CDC is trying to further define the “unknown” group, which is quite 

large. 

Dr. Gorman (NIH) asked whether there is a difference between the rate of spontaneous and 

augmented hepatitis reported among the centers. His concern was that as the disease 

becomes rarer, people are more likely to report it because it is unusual. From an unscientific 

survey of his three adult children between the ages of 20 and 29, all three have traveled to high 

risk countries. That may be a much more common event in the generation between 1995 and 

2012 than in prior generations. The increase may be that they are exposing themselves to 

more risk factors rather than some other vaccination-related episode. 

Dr. Nelson replied that she was not aware of a difference between the rate of spontaneous and 

augmented hepatitis reported. 

Dr. Temte asked what is known about patients with more severe disease and hospitalization 

and how many of them have chronic liver disease as a risk factor, given that we do an atrocious 

job of immunizing patients with chronic hepatitis C and alcoholics with chronic liver disease. 

Dr. Nelson responded that she did not know how many severe cases have chronic liver disease; 

however, CDC has analyzed data on liver failure and liver transplant hepatitis A virus cases and 

did not observe a trend over time. 

Ms. Pellegrini emphasized that another barrier for travelers who may be at risk is that travel 

vaccines tend not to be covered by health insurance. 

 

No public comments were offered during this session. 

 

Announcement 

Dr. Wellington Sun 

ACIP Liaison 

Food and Drug Administration

During the Unfinished Business session, Dr. Sun announced the approval of Pfizer’s meningitis 

B vaccine on October 29, 2014. It was included with the information for the Meningococcal 

Vaccines session for continuity and ease of reading. 

Dr. Sun reported that the meningitis B vaccine developed by Pfizer is based on surface proteins, 

so in this regard it differs from all previous Neisseria meningitidis vaccines that are based on the 

capsular polysaccharide. The indication for this vaccine is for prevention of invasive disease 

caused by serogroup B Neisseria meningitidis in persons 10 through 25 years of age. This 

Day 1: Public Comment

Meningococcal Vaccines

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serogroup has caused several outbreaks on college campuses and represents a public health 

need. The FDA granted a breakthrough therapy designation on this vaccine with that in mind. 

This allowed the agency to focus its resources, along with the manufacturer, to make the 

development pathway more efficient and allow the FDA to perform what is known as a “rolling 

review” of the licensing application, which greatly sped up the process. The approval was 

ultimately based on a determination of safety and effectiveness. Effectiveness was 

demonstrated by serum bactericidal antibody levels against four representative strains of 

Neisseria meningitidis in studies of about 2800 subjects. The safety database included over 

4000 subjects in the US, Europe, and Australia. Because the approval is based on the serum 

bactericidal antibody levels, Pfizer is required to conduct further studies after licensure to show 

breadth of coverage against other strains. FDA looks forward to ACIP’s discussion guiding the 

use of this vaccine.

Introduction

Lorry Rubin, MD 

Chair, Meningococcal Work Group 

Advisory Committee on Immunization Practices 

Dr. Rubin introduced the meningococcal vaccine session. As reported by Dr. Sun, rLP2086 

(Trumenba®) by Pfizer was licensed in the US for persons 10 through 25 years of age on 

October 29, 2014. 4CMenB (Bexsero®) by Novartis is currently under FDA review for persons 

10 through 25 years of age. These meningococcal B vaccines are distinct from the conjugate 

MenACWY vaccines because they are based on immunity to proteins rather than capsular 

polysaccharides. 

Meningococcal B vaccine has been used for outbreak responses. In 2013, two universities 

experienced outbreaks of serogroup B meningococcal disease with a combined 13 cases and 

one death reported. Vaccination campaigns were conducted at both universities in response to 

the outbreaks using one of the investigational MenB vaccines made by Novartis, which was 

obtained through an expanded access Investigational New Drug (IND) application sponsored by 

CDC. Guidance for use of serogroup B vaccines in institutional outbreaks has been developed 

and is available at: http://www.cdc.gov/meningococcal/downloads/interim-guidance.pdf

Presentations were given during this session on 4CMenB (Bexsero®) by Novartis, rLP2086 

(Trumenba®) by Pfizer, the epidemiology of serogroup B meningococcal disease in the US, and 

an overview of serogroup B meningococcal vaccines and considerations for use. 

In terms of the timeline, proposed recommendations will be presented during the February 2015 

ACIP meeting for use of serogroup B vaccines in persons ≥10 years of age with high-risk 

medical conditions, laboratory workers, and outbreaks. The ACIP Meningococcal Vaccines WG 

will review data on MenB vaccines as it becomes available and will continue discussions on use 

and potential impact of these vaccines. Updated outbreak control guidelines will be developed 

which address outbreaks due to all serogroups. 

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4CMenB Serogroup B Meningococcal Vaccine

James Wassil MSc MBA 

Clinical Development 

Novartis Vaccines

Mr. Wassil discussed the BLA accepted by the FDA’s Center for Biologics Evaluation and 

Research (CBER); 4CMenB candidate vaccine characteristics (e.g., proposed indication, 

vaccine composition, and estimated strain coverage); and clinical data in adolescents and 

young adults (e.g., pivotal trial data, supplemental data in persons from the US, and the 

demonstrated safety profile). 

Based on the proposed indications currently under review with the FDA, 4CMenB will be 

indicated for prevention of invasive meningococcal disease caused by Neisseria meningitidis

serogroup B in individuals 10 through 25 years of age. 4CMenB is a sterile suspension for 

intramuscular injection that is to be administered as 2 doses, each 0.5 mL, with an interval of at 

least 1 month between doses. It is fully liquid so it does not require reconstitution, but it does 

require refrigeration at 36°F to 46°F (2°C to 8°C), cannot be frozen, and needs to be protected 

from light. 

The serogroup B capsule is very poorly immunogenic. As a consequence, vaccine 

development strategies have focused on subcapsular protein antigens, but these are highly 

diverse. To address the diversity, Novartis took two approaches. The first was targeted to 

conserved antigens through a process called reverse vaccinology. The second was that it 

developed a multi-component approach; that is, by adding multiple subcapsular proteins into the 

vaccine. The goal was to achieve broad coverage against the circulating serogroup B strains. 

The vaccine is formulated with 50 μg each of three recombinant proteins: factor H binding 

protein (fHbp), Neisserial adhesin A (NadA), and a Neisseria heparin binding antigen (NHBA). 

The fourth component is 25 μg of outer membrane vesicles (OMV). This is the same OMV that 

was used in New Zealand to address a clonal outbreak, so safety and effectiveness has been 

demonstrated with over 3 million doses administered in that campaign. All four of these 

components are then adsorbed onto Aluminum (Al3+).

Regarding predicted strain coverage for 4CMenB, coverage is assessed based on an enzymelinked immunosorbent assay (ELISA) called the Meningococcal Antigen Typing System (MATS). 

The MATS ELISA is correlated with killing of strains by vaccine-induced antibodies in the serum 

antibacterial assay. A serum bactericidal activity (SBA) with a titer ≥1:4 is considered the 

correlate of protection against this disease. In MATS, if a strain exceeds a minimum threshold 

value for any one of the recombinant protein ELISAs or its genotype is PorA 1.4, it is highly 

likely that this strain would be killed in SBA and is, therefore, considered to be covered. 

In the US, coverage is assessed based upon a representative panel of 442 strains isolated from 

individuals between 2000 and 2008. Based on MATS, only 9% of strains were not covered from 

the strain panel. Of the 91 that were covered, 44% were covered by one vaccine component. 

However, over half of covered strains were covered by two or more components in the vaccine. 

That is, independently, each component was deemed sufficient to kill the strain on its own. For 

the subset of strains where the disease occurred in individuals 10 through 25 years of age, the 

predicted coverage did not change substantially at 92%. It is worth noting that the number of 

strains that are covered by multiple antigens did increase up to 61%. 

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In the 4CMenB trials conducted in adolescents and adults, 18,400 subjects received at least 

one dose of 4CMenB. In addition, over 6,000 individuals between 2 months and 10 years of 

age also received the vaccine. That contributes to the overall clinical database for this product. 

Focusing on the clinical studies that are supportive of the indication being sought in the US, 

3,139 subjects 10 through 50 years of age received at least one dose of the vaccine in six 

randomized control clinical studies. In addition, over 15,000 subjects received at least one dose 

at Princeton University or the University of California Santa Barbara under a 

CDC-sponsored expanded-use IND. Those results were presented to ACIP during previous 

meetings. For this session, Mr. Wassil focused on two studies: 1) V72P10/E1, a Phase IIb/III 

study conducted in Chile in healthy adolescents 11 through 17 years of age to assess different 

dosing schedules and persistence of antibodies; and 2) V102_03, a Phase II study conducted in 

the US and Poland among healthy adolescents and young adults 10 through 25 years of age to 

assess the safety and immunogenicity of an investigational ABCWY vaccine. It is important to 

note that this study included one arm in which individuals 10 through 25 years of age in the US 

received 4CMenB as a comparator. 

95

In summary, the 4CMenB clinical data in adolescents and adults showed that the vaccine is 

immunogenic after two doses in a variety of schedules. This has also been confirmed in a small 

US study. Persistence of protective titers has been demonstrated for up to 23 months after the 

2-dose schedule. The demonstrated safety profile includes three recently conducted largescale vaccine campaigns (Princeton and Santa Barbara). A third was conducted in SaguenayLac-Saint-John region of Quebec in over 43,000 individuals 2 months through 20 years of age 

who received at least one dose of the vaccine. The Ministry of Health of Quebec conducted 

active safety surveillance, with over 12,000 subjects keeping diary cards for seven days after 

vaccination. Overall, the safety profile observed in these campaigns were consistent with that 

observed in clinical studies. 

The V72P10 study evaluated the safety and immunogenicity of 1-, 2-, and 3-dose schedules in 

1,625 subjects. Blood was drawn after each visit, and safety was followed up for 12 months. 

The primary endpoint of this clinical study was the percent of subjects with human serum 

bactericidal assay (hSBA) titers ≥1:4. Immunogenicity was measured for each vaccine 

component by use of indicator strains, which were uniquely susceptible to killing in SBA to only 

one component of the vaccine. In the interest of time, Mr. Wassil did not show the results from 

the 3-dose arm because there was no statistically significant difference between hSBA GMTs 

titers for those who received 2 doses and those who received 3 doses. The vaccine 

demonstrated robust immune responses in this age group with several 2-dose schedules. One 

month after the second dose, 99% to 100% of subjects achieved hSBA titers ≥1:4. There was 

no difference in the seroresponse rate across dosing schedules. 

It is important to note that an indicator strain was not identified for NHBA at the start of the 

study, so the analysis was done post hoc. Because of this, not all of the analyses were 

conducted. Also for NHBA in this study, there were high pre-titers to the strain, presumably due 

to previous nasopharyngeal carriage. Robust responses were indicative for each of the four 

vaccine components and for all three 2-dose schedules. Tolerability was assessed in this study 

by comparing against an aluminum-based placebo and stratifying by severity. In general, the 

most common local reactions included pain at injection site and erythema. The most common 

systemic reactions were malaise, myalgia, and headache. Both were the most common in both 

the vaccine group and placebo group, respectively. Reactogenicity was higher in recipients of 

the vaccine compared to the placebo, but the majority of these were reported as mild to 

moderate and transient. Fever was uncommon and relatively similar in both groups, and fever 

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above 39 degrees Celcius was rare. There was no evidence of increasing severity with 

subsequent doses, and tolerability was acceptable to study participants as evidenced by the fact 

that there were low rates of study withdrawals. 

Persistence of antibodies was measured between 18 and 23 months after completion of the 2-

dose series (18 months after 0-6 schedule, 22 months after 0-2 schedule, 23 months after 0-1 

schedule). Overall, the majority of subjects retained seroprotective levels, with 75% to 

95% maintaining titers above 1:4. The dosing schedule did not appear to have an impact on the 

persistence of the seroprotective rates. In terms of antibody persistence based on hSBA GMTs 

18 to 23 months after the completion of the 2-dose series, GMTs overall did wane as would be 

expected. However, they still remained higher than their corresponding pre-vaccination titers. 

As noted earlier, Study V102_03 assessed different formulations of ABCWY vaccine in US and 

Polish subjects 10 through 25 years of age. This study included one arm in which 4CMenB was 

used as a comparator, given on a 0- and 2-month schedule. In terms of the percent of subjects 

with titers ≥1:5 for each of the corresponding fHbp, NadA, PorA, and NhbA antigens at baseline 

and one month after a 2-dose series, baseline titers compared to Chile were much lower. 

However, robust responses were achieved with 73% to 90% of adolescents achieving titers 

above 1:5. 

In summary, the BLA for 4CMenB has been accepted by the FDA and priority review status has 

been granted. Based upon the studies, 4CMenB is believed to generate a protective immune 

response in adolescents after two doses. This was confirmed in a small US study. Persistence 

of antibodies was demonstrated up to two years after the last dose. There was no statistically 

significant difference in hSBA GMTs between subjects receiving two doses or three doses of 

vaccines when assessing the indicator strains. Novartis has begun to collect real-life 

experience with this vaccine, which has been approved in 35 countries. Over a million doses 

have been distributed. Based on the safety data generated from over 30,000 doses at 

Princeton and the University of California Santa Barbara and over 55,000 doses in SaguenayLac-Saint-John, no particular concern for any specific event was identified in either campaign. 

rLP2086 Serogroup B Meningococcal Vaccine 

Dr. Laura York 

Global Meningococcal Lead

Medical Development, Scientific and Clinical Affairs 

Pfizer

On behalf of the many people who worked long and hard along with the FDA to license 

Trumenba® meningococcal group B vaccine, Dr. York expressed Pfizer’s excitement about the 

FDA approval received the previous day. This vaccine was introduced to ACIP as rLP2086, and 

Pfizer often refers to it as bivalent rLP2086. Bivalent rLP2086, Pfizer's meningococcal group B 

vaccine, is based on the lipoprotein 2086. This is a surface-exposed fHbp expressed in over 

97% of invasive meningococcal B strains. It is a conserved protein, and the gene is rarely 

absent from meningococcal B. The fHbp sequences segregate into two genetically and 

immunologically distinct subfamilies, A and B as shown in the phylogenetic tree: 

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Subfamily B: 71%

 Subfamily A: 29%

The length of the line identifies the similarity between those variants. The variants within a 

subfamily are highly related and have over 84% sequence identity. The bivalent vaccine 

contains two lipidated fHbp variants (A05 and B01), one from each subfamily to give complete 

protection across the two subfamilies. 

The vaccine design of a bivalent lipidated protein was supported by preclinical data. 

Consideration was given to monovalent vaccines and bivalent vaccines composed of the 

subfamilies A and B. Rabbits were immunized with the monovalent or bivalent vaccine. The 

ability of the immune sera to kill diverse MenB strains in an hSBA was assessed. The strains 

would express either as subfamily A or subfamily B, and the ability to kill in terms of an SBA that 

included rabbit complement. If a rabbit was inoculated with the monovalent vaccine of A05, 

there were good responses across the variation in the A subfamily, but not so much across the 

strains that express the B variants. Similarly, this predominantly subfamily-specific type of 

response was observed in animals inoculated with a B01 monovalent (e.g., good responses 

across the strains that express subfamily B variants, but not across the A). Only a vaccine that 

contains a protein from both of these subfamilies provides protection across the strains that 

express either A or B subfamilies. 

These data supported Pfizer in moving into clinical trials. Pfizer submitted an IND to the FDA in 

April 2008, and FDA-Pfizer collaborative discussions were initiated to define the licensure 

pathway for MenB vaccines in the US. A significant step was the decision that the SBA 

incorporating human complement could be used as the correlate to predict protection. In June 

2012, FDA and Pfizer reached agreement on immunogenicity endpoints based on measurement 

of hSBA responses. All ongoing studies were modified to provide prospective, blinded data 

based on the agreed upon endpoints. The length of time it took to come to those agreements 

reflects the complexity of defining the endpoints that would evaluate and demonstrate that a 

vaccine would be able to protect broadly across the variation seen in this protein. 

FDA licensure will be based on sufficient numbers of US subjects to show safety and hSBA 

responses (correlate to predict protection). In a clinical trial, there are limitations in the amount 

of serum. To be able to test, there must be validated assays with strains. The number of 

strains that can be tested are limited. However, in Phase I and II clinical studies, Pfizer had 

hSBA data that clearly supported and confirmed the information that was developed in the 

preclinical studies that the immune sera following three doses demonstrated activity against 

strains bearing different variants. The FDA and Pfizer came to an agreement that the hSBA 

responses against four MenB test strains one month post-dose 3 was the endpoint for four 

strains. Four strains were selected in an unbiased fashion. These strains would then represent 

the epidemiologically relevant strains in the US and the diversity of fHbp being expressed. The 

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fHbp variants expressed are not homologous to the vaccine components. The fHbp variants 

expressed (A22, A56, B24, B44) are not homologous to the vaccine components. 

The primary endpoints include the proportion of subjects achieving ≥ 4-fold increase in hSBA 

titer from baseline to post-dose 3 for each of the 4 test strains (minimum response = hSBA titer 

of ≥ 1:16); the proportion of subjects achieving post-dose 3 hSBA titer ≥ 1:8 (1:16 for the A22 

expressing strain) for all 4 test strains (composite); and pre-specified thresholds for the lower 

bound of the 95% CI for each primary endpoint. Very stringent endpoints will define this vaccine 

that, in all likelihood, will provide broad protection. 

The clinical development plan for rLP2086 was designed for the evaluation and implementation 

of this vaccine in the adolescent and young adult age groups. A number of studies have been 

conducted in the US, Europe, and Australia. In addition to large safety and immunogenicity 

studies and clinical lot consistency, studies were conducted to evaluate the vaccine when given 

concomitantly with recommended adolescent vaccines. Some studies are completed, while 

others are ongoing. 

At the time of the university outbreaks and toward the end of 2013, a significant body of data 

was available. Although designed for different purposes, the following three studies were 

conducted using validated strains expressing those antigens, which resulted in the generation of 

important hSBA data: 

Study 

Description

Age 

in Years

Design

(Control)

Bivalent

rLP2086

(120 μg)

Control 

Only

Status

Safety & Immunogenicity With 

Concomitant Gardasil(US)

11 to 18 Observer-blinded

(Gardasil)

1982 501 Completed

Safety & Immunogenicity 

2-Dose & 3-Dose Schedules (EU)

11 to 19 Single-blinded 

(saline at some 

visits)

1696 16 Completed

Safety & Immunogenicity With 

Concomitant Repevax(EU)

11 to 19 Single-blinded

(Repevax)

374 378 Completed

In fact, those protocols were amended to include the licensure endpoints and it was possible to 

move forward with the BLA submission to the FDA for the accelerated approval and priority 

review of bivalent rLP2086 on June 16, 2014. As announced earlier, Trumenba® was approved 

on October 29, 2014. Licensure was based on clinical data from pivotal trials involving over 

4500 subjects, demonstrating an acceptable safety profile, and hSBA responses that meet prespecified endpoints. Because this was an accelerated approval, there are conditions. Pfizer is 

required to submit confirmatory data from additional subjects in ongoing studies post-approval. 

Trumenba® is indicated for active immunization to prevent invasive meningococcal disease 

caused by Neisseria meningitidis serogroup B. Trumenba® is approved for use in individuals 10 

through 25 years of age. Approval of Trumenba® is based on demonstration of immune 

response, as measured by serum bactericidal activity against four serogroup B strains 

representative of prevalent strains in the US. The effectiveness of Trumenba® against diverse 

serogroup B strains has not been confirmed. Trumenba® is administered on a 0-, 2-, 6-month 

schedule. 

Dr York reviewed the hSBA results from three pivotal trials, which demonstrated that bivalent 

rLP2086, administered as a three doses series, consistently elicited bactericidal responses that 

were above the accepted correlate of protection (hSBA > 4)) and that met the specified 

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licensure immunogenicity endpoints. A high proportion of subjects achieved a four-fold rise in 

hSBA titer against each of the four test strains (range: 75-95%) when bivalent was administered 

alone or concomitantly with HPV4 or Tdap-IPV, a vaccine approved and used outside the USA 

in adolescents. Greater than 80% of subjects demonstrated an hSBA titer > 8 for all four test 

strains (composite endpoint). 

In summary, the hSBA responses to Trumenba®, the bivalent rLP2086, elicited hSBA responses 

in completed trials that met all of the pre-specified primary licensure endpoints agreed upon with 

the FDA and other regulatory agencies. The licensure criteria are designed to demonstrate 

vaccine-elicited responses that have the potential to provide broad protection against diverse 

MenB strains is well-illustrated in the exploratory analysis of recent university outbreaks. There 

was a significant 4-fold rise, which was highest against the isolates from University B. The 

percent response is very similar to what was observed in the pivotal studies. The response 

against those in University A was similarly very high. 

The safety data in over 4500 subjects were submitted to FDA. This is across seven clinical 

trials, demonstrating an acceptable safety profile. The majority of local and systemic events 

were mild to moderate in severity after each vaccination and were transient. The most common 

AEs were pain at the injection site, fatigue, headache, muscle pain, and chills. There was no 

pattern of potentiation with progressive dosing. The vaccine has demonstrated an acceptable 

profile when administered with HPV4 or with Tdap-IPV, which is not a US-licensed product. The 

rates of SAEs were comparable between the vaccine recipients and controls, 1.7% versus 

1.6%, in four controlled trials. 

In summary, Trumenba® was designed to provide broad protection against meningococcal 

serogroup B strains. The vaccine is composed of two fHbps, one from each fHbp subfamily. 

fHbp is a conserved meningococcal virulence factor. Trumenba® has been evaluated in 

adolescents and young adults who are at increased risk of meningococcal disease. hSBA data 

from pivotal studies met pre-specified endpoints established with the FDA, predicting protection 

against prevalent meningococcal serogroup B strains causing disease in the US. A favorable 

safety profile was demonstrated when bivalent rLP2086 was given alone or with concomitant 

vaccines (HPV4 or Tdap-IPV). The full public health potential of Trumenba®, an FDA-licensed 

serogroup B vaccine, will only be realized with vaccination strategies that go beyond outbreak 

control and target prevention in US populations at increased risk of meningococcal disease. 

Discussion Points

With respect to the Pfizer vaccine, Dr. Karron wondered if there were any data on achieving 

protective levels after a single dose, for example, in an outbreak situation. She also asked 

about duration of protection and whether any data are available on concomitant administration 

with ACWY vaccines. 

Regarding protective levels after a single dose, Dr. York responded that the data show a 35% to 

50% response rate after a single dose. The study conducted in the EU to assess two versus 

three doses showed that a high percentage of subjects achieved a titer of greater than 1:8 

against the four strains. Looking at several 2 dose schedules, the responses were quite 

significant. However, these would not have met the FDA criteria for licensure. Regarding 

duration of protection, Pfizer is currently generating persistence data. Pfizer can present those 

data to ACIP as soon as they are available. A study will be completing soon that assesses a 

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number of concomitant vaccines. Those data will be available in the next couple of months and 

will be provided to the WG. 

Mr. Wassil responded that Novartis has demonstrated persistence for up to 23 months, which is 

the longest data they have in those 11 to 17 years of age. In addition, data were collected in 

Study V72_29 in the UK university students that went through 11 months, which were similarly 

robust. Novartis also plans to study concomitant use with ACWY, but does not currently have 

those results. 

Dr. Reingold asked whether anything is known about the effects of either vaccine on carriage. 

Mr. Wassil responded that it is very difficult in the pre-licensure setting to demonstrate an impact 

on carriage. In many cases, it is necessary to immunize a broad population to interrupt 

transmission. That said, Novartis tried to exhibit some demonstration of carriage reduction in 

the UK in university students by giving a thousand doses of 4CMenB to one group and another 

thousand with a control. While the primary endpoint was not met (e.g., demonstrating carriage 

reduction one month after completion of the 2-dose series), follow-up between 3 and 12 months 

showed a statistical reduction overall in carriage of about 26% percent in ACWY and B isolates. 

Dr. York replied that Pfizer has not assessed the impact of its vaccine on carriage, though 

consideration is being given to the possibility. The impact on carriage pertains to new 

acquisitions. It is very difficult to set up a clinical trial to ascertain reductions in acquisition of 

new carriage. 

Ms. Pellegrini pointed out that this is another adolescent vaccine with three doses in less than a 

year, which may or not be aligned with the recommendations for the other adolescent vaccines. 

As the parent of two teenagers, she emphasized the difficulty of getting a teenager to the doctor 

for a well-visit once a year. With that in mind, she made a plea for the alignment of the 

schedules to the maximum extent possible. It is known that the completion rates for current 

meningitis and HPV series are dismal. This issue must be examined thoughtfully, or the same 

situation will occur with the MenB vaccine. 

Dr. Byington (AAP) asked whether Novartis has any data on cross-protection with other 

serotypes other than type B. 

Mr. Wassil replied that Novartis has limited data on protection demonstrated in an SBA assay 

for non-B serogroups. There is a publication on serogroup X, where they were able to cover the 

clonal outbreaks in Africa. They have also done work in the UK, Germany, France, Brazil, and 

Argentina to assess some non-B strains. Coverage of those is between 30% to 100%. 

Dr. York clarified that fHbp is a meningococcal protein and it is not specific just to MenB. While 

Pfizer has pre-clinical exploratory analyses that show that immune sera can be active against 

the other serogroups, this vaccine was developed for prevention of MenB. 

Dr. Baker (IDSA) requested further details about which other capsular serogroups. She noted 

that she asked because there are 13 capsular types, but many fewer are prevalent in terms of 

the cause of human disease everywhere in the world, especially in the US. 

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Dr. York said the gene is found in all of them (ACWY). Pfizer has some data that show 

protection against C and Y, and continues to assess other serogroups as well. As Mr. Wassail 

said, a number of studies have been conducted to assess activity toward different serogroups. 

Mr. Wassil added that when the capsular antigen is removed, it results in something very similar 

to MenB. It is a strain-specific demonstration of a response. Novartis has conducted testing in 

Argentina, for instance, and coverage was exceptionally good for W. It is not clear whether that 

means that the vaccine will impact W circulating in the US. They would have to perform the 

same SBA analysis. The reason Novartis is hesitant to give actual information about what is 

pertinent in the US environment is that non-B serogroup strains originating in the US have not 

been tested. For instance, an outbreak of W is occurring in the UK presently. Novartis tested it 

and found that the vaccine covers that exceptionally well. That has to be answered on a 

specific basis. 

Dr. Whitely-Williams (NMA) asked whether any data are available on immunocompromised 

persons, particularly HIV patients with functional asplenia or any plans to conduct those studies. 

Dr. York replied that Pfizer has no data at this time, though they have considered the possibility 

of following up with those studies as well. 

Mr. Wassil responded that Novartis has not studied HIV patients. As a post-licensure 

commitment to Europe, they have completed a study in people with asplenia and complementdeficient individuals. The results of that study are expected soon. 

Dr. Pickering said he could not find syncope, the most common AE in adolescents, and 

wondered whether there were any data on this. In addition, he recalled the unpleasant surprise 

with the quadrivalent vaccine when it was believed that only one dose would be adequate but it 

was later determined that two would be needed. He asked whether any modeling could be 

done to predict the duration of protection for 2 versus 3 doses. 

Dr. York responded that regarding syncope, the most common AE they observed was pain at 

the injection site. Pfizer has not done any modeling in that context. They have done modeling 

regarding the potential impact and estimated times of depletion of antibody over time, but have 

not done that to predict the actual information since they do not have the persistence data at 

this point. 

Mr. Wassil replied that Novartis has distributed over 1 million doses and they know that over 

100,000 doses have been administered. A few cases of syncope and vasovagal reactions have 

been reported in a post-licensure setting. In terms of modeling, they have 23 months of 

persistence data in Chile and 11 months in the UK. Novartis has been able to do some 

modeling, which depends upon the protection of these indicator strains and not all of the strains 

circulating. Based upon that, Novartis estimates between 6 to 8 years of persistence with this 

vaccine. However, the caveat is that this is heavily based on modeling. 

An inquiry was posed regarding whether there are any data about safety and immunogenicity, 

and how long the protection will last in children when it is given concomitantly with a routine 

childhood immunization? The quadrivalent meningococcal conjugate vaccine was introduced 

for children and adults four years ago. Since that time, all cases of meningitis have been in 

children less than six months and it has been type B. 

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Dr. York replied that the Pfizer vaccine was studied in persons 10 through 25 years of age. 

They have assessed concomitant administration with the routine immunizations that are given in 

adolescents. They anticipate having data on Adacel® and MCV4 very soon. 

Dr. Loehr (AAFP) asked whether he understood correctly that Pfizer’s vaccine has been FDAapproved for general use and Novartis’s vaccine has been approved for special situations. He 

also wondered whether both were used at Princeton and University of California Santa Barbara, 

or if that was only the Novartis vaccine. 

Mr. Wassil clarified that the Novartis vaccine has not been approved for use by the FDA. 

4CMenB was used in the Princeton and University of California Santa Barbara outbreaks under 

a CDC-sponsored expanded-access IND. Technically, it was part of a clinical program. 

Dr. York clarified that Pfizer’s vaccine, Trumenba®, was just licensed the previous day for use in 

the US. 

Epidemiology of Serogroup B Disease in the US 

Jessica MacNeil, MPH 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

Ms. MacNeil described the current epidemiology and burden of serogroup B meningococcal 

disease in the US, with a focus on adolescents and young adults and college students, followed 

by a brief review of the groups at high risk for serogroup B meningococcal disease. 

There are two sources of surveillance data for meningococcal disease in the US. The first is the 

Active Bacterial Core surveillance system (ABCs). ABCs is an active laboratory and populationbased surveillance system that collects data on culture-confirmed cases of meningococcal 

disease in 10 states. Cases in the ABCs sites can be projected to the US population to 

estimate incidence. The second is the National Notifiable Diseases Surveillance System 

(NNDSS), which is a passive surveillance system to which all states and territories report data 

for all nationally notifiable diseases. NNDSS captures information on cases, including cases 

confirmed by PCR. However, serogroup and outcome information has historically been limited. 

Since 2005, serogroup and outcome information in NNDSS has been supplemented by data 

from state health departments and ABCs to improve data quality. 

In the US, the incidence of meningococcal disease is currently at a historic low. In 2013, 564 

cases were reported to NNDSS among persons of all ages. Declines in incidence have been 

observed for all of the serogroups, including serogroup B, which is not included in the 

quadrivalent vaccines. In addition, despite the increase in coverage with quadrivalent vaccine 

among adolescents, much of the decline in incidence occurred prior to high levels of coverage 

in adolescents. 

The incidence of meningococcal disease is highest among children less than one year of age. 

In that age group, 67% of disease is caused by serogroup B. There is a smaller peak in disease 

incidence among adolescents and young adults. In that age group, approximately 40% of 

disease is caused by serogroup B. Based on incidence of meningococcal disease by serogroup 

for adolescents during two time periods, 2005 to 2007 and 2010 to 2013, incidence has declined 

for serogroup B and serogroups C and Y combined in more recent years (2010 to 2013 vs. 2005 

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to 2007). However, serogroup B disease now causes about the same amount of disease as 

serogroups C and Y in this age group. The change in the proportion of serogroups C and Y 

disease among adolescents is likely the result of quadrivalent vaccine use in this age group, as 

this has not been observed in age groups not recommended routinely for vaccination. It is 

estimated that serogroup B cases in 11 through 24 year olds have declined from 161 per year in 

the last high-incidence years (1997-1999) to approximately 48 to 56 cases annually in the 

recent low-incidence years (2010-2012). The case-fatality ratio from serogroup B is 12.5%, 

which is slightly lower than for serogroups C and Y combined for which the case fatality ratio is 

16.6%. Among adolescents and young adults, the case-fatality ratio from serogroup B is 

roughly half of that observed for serogroups C and Y combined. 

Information on college attendance for meningococcal cases is collected through ABCs but is not 

collected in NNDSS. During 1999 through 2012, 29% of serogroup B cases in all 18 through 23 

year olds reported through ABCs attended college. That proportion can be applied to serogroup 

B cases reported through NNDSS in this age group to estimate the number of cases of 

meningococcal disease occurring in college students nationwide. In the US in 2012, 

approximately 61% of young adults completed high school and enrolled in college. Therefore, it 

is estimated that there are approximately 16.6 million college students aged 18 through 23 

years in the US. From 2008 to 2012, there were approximately 11 cases of serogroup B 

meningococcal disease in college students annually, with one death in this group. This is out of 

37 cases and 2 deaths among all 18 through 23 year olds. The incidence of serogroup B 

disease in college students during the most recent years of 2008 to 2012 was 0.07 per 100,000 

compared to an incidence of 0.14 per 100,000 among all 18 through 23 year olds. While the 

incidence and number of cases of serogroup B meningococcal disease among college students 

has continued to decline, there have been five serogroup B clusters or outbreaks on college 

campuses in the last five years. These outbreaks have been described to ACIP previously. 

They had between 2 and 13 cases per outbreak and have lasted from a few days to nearly two 

years. Fortunately, meningococcal outbreaks remain rare in the US. However, these outbreaks 

cause significant anxiety and are devastating to the communities in which they occur. 

To summarize the epidemiology of serogroup B meningococcal disease, with widespread use of 

conjugate vaccine in adolescents and young adults, serogroup B now causes 40% of 

meningococcal disease cases in this age group. Approximately 50 cases occur among 11 

through 24 year olds, with one-third of cases among 18 through 23 year olds occurring in 

college students. While most serogroup B cases are sporadic, even in college students, recent 

outbreaks on college campuses have been due to serogroup B. 

Three main groups are considered to be at high risk for meningococcal disease: 1) those with 

medical conditions that place them at increased risk, including those with persistent complement 

component deficiencies and functional or anatomic asplenia; 2) microbiologists; and 3) outbreak 

at-risk populations. While these groups are all currently recommended for vaccination with 

quadrivalent vaccines, they remain at risk for serogroup B meningococcal disease. 

Persistent or genetic deficiencies in the common complement pathway are well known to 

increase risk for meningococcal disease. These deficiencies are rare and only affect about 0.03 

percent of the US population1. Individuals with persistent complement component deficiencies 

are at up to 10,000-fold increased risk for developing disease and often develop recurring 

infections 2. Eculizumab (Soliris®) treatment has not been previously included in the high-risk 

vaccination recommendations for meningococcal disease, but it functionally creates a 

complement deficiency by binding the C5 and inhibiting the terminal portion of the complement 

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cascade. Several individuals in the clinical trials for Soliris® have reportedly developed 

meningococcal infections despite prior vaccination with quadrivalent vaccine3 [1P Densen. 

Complement deficiencies and meningococcal disease. Clin Exp Immunol. Oct 1991; 86(Suppl 

1): 57-62; 2Cohn et al. Prevention and Control of Meningococcal Disease. MMWR. March 22, 

2013; 62 (RR-2); 3http://soliris.net/sites/default/files/assets/soliris_pi.pdf].

Persons with functional or anatomic asplenia also appear to be at increased risk for 

meningococcal disease. However, those data are less compelling than their risk for 

pneumococcal disease1. This group includes persons with sickle cell disease, which affects 

about 90,000 to 100,000 persons of all ages in the US2. In asplenic persons, the case-fatality 

ratio for meningococcal disease is elevated3. [1Cohn et al. Prevention and Control of 

Meningococcal Disease. MMWR. March 22, 2013; 62 (RR-2); 2http://www.cdc.gov/ncbddd/ 

sicklecell/data.html; 3Updated recommendations for the use of meningococcal conjugate 

vaccines. MMWR. January 28,2011; 60(3): 72-76]. 

Microbiologists who work with Neisseria meningitidis are also at increased risk for disease1. A 

high case-fatality ratio has been observed among microbiologists who have developed 

meningococcal infections, likely because of increased exposure to high concentrations of 

organisms and highly virulent strains. The majority of cases among microbiologists have 

occurred in people who were not using respiratory protection at the time of exposure, and these 

were not limited only to research microbiologists who routinely work with meningococcal 

isolates. There are an estimated 100,000 clinical microbiologists and about 400 research 

microbiologists who routinely work with Neisseria meningitidis in the US [1Cohn et al. Prevention 

and Control of Meningococcal Disease. MMWR. March 22, 2013; 62 (RR-2)]. 

The final high-risk group includes people in the at-risk group during a meningococcal outbreak. 

Fortunately, meningococcal outbreaks are rare and cause only about 2% to 3% of US cases1. 

However, as an example of the increased risk for meningococcal disease in the recent 

serogroup B outbreaks at college campuses, at Princeton University, there was a 1400-fold 

increased risk for meningococcal disease. Roughly 7500 individuals were recommended for 

vaccination with serogroup B vaccines in that outbreak. In the recently published guidance for 

serogroup B outbreaks in institutional settings, the threshold for vaccination has been defined as 

2 cases in institutions less than 5,000 persons and 3 cases in institutions with more than 5,000 

people2 [1 National Notifiable Diseases Surveillance System; 2http://www.cdc.gov/ 

meningococcal/downloads/interim-guidance.pdf]. The following table summarizes the risk 

groups just discussed and includes available data on cases that have occurred in each of these 

groups: 

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Excluding the at-risk population in outbreaks, it is estimated that there are less than 300,000 

individuals who fall into these high-risk groups. Although only a handful of cases have been 

documented in ABCs or the published literature, these groups are known to be at high risk for 

meningococcal infection and are currently recommended to be vaccinated with meningococcal 

conjugate vaccines. However, they remain at risk for serogroup B disease. 

In conclusion, the incidence of meningococcal infections is declining, including for serogroup 

B. In recent low-incidence years, approximately 50 cases of serogroup B meningococcal 

disease occurred in adolescents and young adults each year. In addition, persons in high-risk 

groups who are recommended for vaccination with quadrivalent meningococcal vaccines remain 

at risk for serogroup B meningococcal disease. 

Considerations for Use of Serogroup B Meningococcal Vaccines in the US

Manisha Patel, MD, MS 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Patel noted that the Meningococcal WG has been discussing serogroup B meningococcal 

(MenB) vaccine issues on work group calls, and provided a summary of some key points 

regarding these vaccines and the work group’s considerations for use of MenB vaccines in the 

US. 

Development of MenB vaccines has been challenging. The polysaccharide capsule is the 

vaccine target for MenACWY vaccines, but it is poorly immunogenic for MenB because of 

antigenic similarity to human neuronal cells. MenB vaccines that target other antigens such as 

outer membrane vesicles have been used to control several MenB outbreaks in the past, 

including a large epidemic in New Zealand in the early 2000s. However, these vaccines are 

strain-specific and provide limited cross-protection with heterologous strains, have a limited 

duration of protection, and have limited efficacy in younger children. Ideally, vaccine targets 

would require antigens to be an essential gene, be immunogenic, have relatively low diversity, 

and be surface-exposed. 

Recently, several outer membrane proteins that are found across all meningococcal strains 

regardless of serogroup have been identified that generally meet these criteria. fHbp allows the 

bacteria to evade complement-mediated lysis. fHbp is classified as either Subfamily A (Variant 

2, 3) or Subfamily B (Variant 1). NHBA promotes bacterial survival in the blood, and NadA 

allows the bacteria to adhere to and invade epithelial cells. Although these proteins can be 

found on the majority of MenB strains, they are antigenically diverse and can, therefore, impact 

vaccine effectiveness. 

There are two MenB vaccines for persons 10 through 25 years of age being considered in the 

US. As mentioned in the earlier presentations, rLP2086 is manufactured by Pfizer and is a 3-

dose series administered at 0, 2, and 6 months. It contains both subfamilies of fHbp and was 

licensed by FDA on October 29, 2014 as Trumenba®. 4CMenB, or Bexsero®, which is 

manufactured by Novartis, is a two-dose series administered at 0 and 1 to 6 months. It contains 

fHbp Subfamily B (Variant 1), NhbA, NadA, and PorA 1.4, which is the same PorA type as the 

OMV vaccine used to control the New Zealand epidemic. It was licensed in Europe, Australia, 

and Canada in 2013 for persons ≥ 2 months of age, and it was administered to almost 17,000 

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participants under an expanded-access IND protocol to control two recent university outbreaks 

in the US. In light of these outbreaks, it was granted a priority review designation, with an 

announcement regarding licensure expected by early 2015. 

Because of the low incidence of meningococcal disease in the US, pre-licensure trials using 

clinical outcomes would require very large sample sizes and, thus, are not feasible. hSBA has 

been shown to correlate with protection against meningococcal disease and is based on studies 

conducted in the 1960s that demonstrated that bactericidal antibodies were protective against 

invasive serogroup C disease in military recruits. Bactericidal antibodies in persons immunized 

with OMV vaccines during various MenB outbreaks also correlated with protection. Based on 

these data, hSBA was established as the serologic marker to infer protection with MenB protein 

vaccines during the 2011 VRBPAC meeting. 

However, there are several challenges in assessing immunogenicity with MenB vaccines. First, 

evaluating clinical efficacy in higher incidence countries would not be appropriate for licensure in 

the US because the molecular epidemiology differs between countries. Second, the 

measurement of hSBA is assay-specific and requires validation each time a parameter such as 

strain or antigen has changed. Because of the antigenic diversity among MenB strains, 

bactericidal activity against multiple strains is needed to evaluate antigen-specific responses 

and address cross-protection with heterologous strains. However, the number of strains that 

can be tested is limited by hSBA methodology, which would require large volumes of sera and 

identification of a complement source for each strain tested. 

Because the vaccine targets and the number of vaccine targets differ between the two vaccines, 

selection of the four primary strains to assess immunogenicity was performed differently for 

each vaccine. For 4CMenB, strains were selected to evaluate immunogenicity to each of the 

four antigens individually using individual human sera. For rLP2086, strains were systematically 

selected to assess immunogenicity using individual human sera from a representative collection 

of circulating strains in the US. The differences in the strains selected and the method in which 

they were selected for each respective vaccine is important to consider when interpreting 

immunogenicity data. A second key difference in how immunogenicity was assessed for the 

two vaccines is the primary endpoints. These primary endpoints were presented earlier by the 

manufacturers. For 4CMenB (Bexsero® by Novartis), the primary endpoint was the proportion of 

subjects with hSBA titers ≥1:4 or ≥1:5. Of the subjects, 73% to 100% demonstrated protective 

titers. Titers decreased by 5% to 25% at two years post-vaccination depending on the antigen 

that was tested and the population evaluated. For rLP2086 (Trumenba® by Pfizer), the primary 

endpoint was the proportion of subjects with hSBA titers at a four-fold increase from baseline 

(minimum titer ≥1:16), and a composite endpoint of hSBA ≥ 1:8 or 1:16. Of the subjects, 75% to 

100% demonstrated protective titers following 3 doses. No long-term immunogenicity data are 

available for rLP2086. Recognizing that the primary endpoints differ for each vaccine is also 

important to consider when interpreting immunogenicity data in comparing vaccines. 

The polysaccharide capsule is highly conserved among strains within each serogroup. 

Therefore, vaccines that target the capsule (quadrivalent meningococcal vaccines) typically do 

not require assessment of breadth of coverage. Because the vaccine targets for MenB 

vaccines are antigenically diverse within circulating MenB strains in the US, a multi-factorial 

approach can be helpful in estimating coverage. This includes determining the presence or 

absence of the gene, genetic sequences, level of expression of the antigen, and bactericidal 

activity by hSBA. 

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In a study by Wang, the first two factors were assessed (e.g., presence or absence of the gene 

and the genetic sequences). Through ABCs, 650 MenB isolates were collected from 2000 to 

2008 and were sequenced for the three different vaccine targets: fHbp, NadA, and NhbA. The 

following graphic illustrates the degree of genetic diversity in the subvariants circulating in the 

US, particularly for fHbp and NhbA: 

 

Genetic sequencing showed that all MenB isolates contained fHBP and that 59% were 

Subfamily B (Variant 1), which is contained in both vaccines, and 41% percent were Subfamily 

A (Variant 2, 3), which is contained only in rLP2086. NadA, which is included in 4CMenB, was 

present in only 39% of all MenB isolates. Because NadA was found in less than 10% of isolates 

that were fHbp Subfamily A (Variant 2, 3), which is not included in the vaccine, based on this 

analysis, NadA would only increase coverage for 4CMenB from 59% to 63%. NhbA is highly 

diverse and is found on all MenB isolates, but, as presented earlier, elicits lower titers in 

bactericidal antibodies. PorA 1.4, which is also included in 4CMenB, was found in less than 5% 

of MenB isolates [Wang et al., Vaccine 29 (2011) 4739-4744]. In this study, only genetic 

sequencing was assessed. The study did not measure the degree of protein expression or 

bactericidal activity for each of the isolates. 

Assessing breadth of coverage can be complicated and was performed differently for each 

vaccine. Differences in how breadth of coverage was estimated by the manufacturers is 

important in understanding how well each vaccine will protect against endemic disease. For 

rLP2086, fHbp sequence analysis and measurement of surface expression by flow cytometry 

was performed for an epidemiologically representative collection of over 1200 MenB strains, of 

which 432 were collected from ABCs surveillance sites. This analysis demonstrated variability 

between subfamilies as well as surface expression of fHbp. In a subset of isolates for which 

bactericidal activity was assessed, isolates with moderate or high-level expression of fHbp were 

predictive of bactericidal activity; whereas, there was lower correlation among isolates with low 

expression of fHbp [Jiang et al., Vaccine 28 (2010) 6086-6093]. 

Novartis used a different approach to assess breadth of coverage of 4CMenB. Because there 

are multiple antigens contained in the vaccine, there are limitations on how many strains can be 

tested by hSBA for the reasons mentioned previously. The meningococcal antigen typing 

system is a sandwich ELISA that was developed to measure both cross-reactivity with vaccine 

antigens as well as the level of expression of each antigen to predict bactericidal activity against 

a broad number of strains. MATS was previously bridged to hSBA in a subset of antigenically 

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diverse strains and was found to be greater than 80% predictive of bactericidal activity when 

one antigen was expressed above a certain threshold, and greater than 90% when at least two 

antigens were expressed above a certain threshold. Based on an analysis of over 400 isolates 

collected through ABCs, 4CMenB is estimated to cover 91% of circulating strains in the US 

[Donnelly et al., PNAS (2010) vol. 107, no. 45]. 

In summary, two MenB vaccines are available in the US: rLP2086, which was recently licensed 

as Trumenba®, and 4CMenB, which is currently undergoing priority review by FDA. A serologic 

marker was used to infer protection against MenB disease. Demonstration of breadth of 

coverage against diverse strains will be critical for evaluating vaccine effectiveness. There 

could be potential differences in immunogenicity and breadth of coverage between the two 

vaccines due to their different vaccine targets. 

Regarding WG considerations for use of MenB vaccines in the US, as Ms. MacNeil presented 

earlier, rates of meningococcal disease have reached historic lows and are decreasing for all 

serogroups. Vaccination with MenACWY conjugate vaccine is recommended for adolescents 

11 through 12 years of age, with a booster at 16 years of age. Increasing coverage with these 

vaccines has contributed to decreasing rates of disease among adolescents. However, MenB 

disease continues to contribute to about 40% of meningococcal cases, with 50 cases reported 

annually among adolescents in recent years. 

There are a number of challenges to keep in mind when considering use of MenB vaccines in 

the US. First, breadth of coverage has only been estimated. Actual breadth of coverage is 

unknown. Although there are some data for 4CMenB, duration of protection and impact on 

carriage is unknown. The potential impact of vaccine pressure on circulating strains will be 

unknown until these vaccines are used more broadly. The multi-dose schedules required for 

both vaccines make implementation challenging. Again, it is important to note that the burden 

of MenB disease is low and not all cases will be prevented by vaccination. 

The WG has been discussing a number of different options for use of MenB vaccines to address 

the immediate need to protect high-risk groups. The WG is considering vaccination of persons 

with medical conditions who are at high risk for meningococcal disease such as persistent 

complement component deficiencies or anatomic or functional asplenia, microbiologists, and for 

use in outbreak response. The WG also has been reviewing available data and discussing 

options for routine recommendations for expanded groups. 

Although the vaccines have been reviewed or are currently undergoing review through an 

accelerated pathway, additional data are still needed for both vaccines to inform policy 

decisions. This includes duration of protection; immunogenicity against additional strains to 

evaluate breadth of coverage, safety, and immunogenicity of concomitant vaccination; high-risk 

groups as well as other age groups; and additional safety data. A number of these studies are 

ongoing and will be reviewed by the work group once these data are available. 

The WG has prioritized considerations for vaccination of high-risk groups in persons ≥10 years 

of age. As presented earlier, persons with high-risk medical conditions and microbiologists 

account for less than 300,000 people in the US. Based on the interim guidelines for use of 

MenB vaccines in institutional settings, vaccination would have been recommended for all five 

MenB outbreaks reported on college campuses over the past five years for approximately 

60,000 people. The overall goal will be to align the high-risk and outbreak recommendations for 

both MenB and MenACWY vaccines. 

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Thus, the current plan for the February 2015 ACIP meeting is to present GRADE for high-risk 

groups and propose language for use of MenB vaccines in persons ≥10 years of age with highrisk medical conditions, microbiologists, and outbreaks for a potential vote. Additionally, for the 

June 2015 and October 2015 meetings, the WG will review the evidence for expanded target 

groups, which includes GRADE and economic and impact analyses, and will present the 

updated outbreak guidelines for all serogroups. 

In conclusion, considerations regarding use of MenB vaccines in the U.S. will be complex. 

Additional data following licensure will help to inform policy decisions. The WG will continue to 

review data on MenB vaccines as it becomes available, and will engage in discussions on use 

of these vaccines for expanded groups. Dr. Patel requested feedback from the full membership 

on the following topics: 

 Feedback on a two-tiered approach 

 High risk recommendation in February 2015 

 Continued discussions regarding use of MenB vaccines in broader target groups 

 Additional data ACIP would like to have presented at future meetings 

Discussion Points

Dr. Temte thanked Ms. MacNeil and Dr. Patel for their very nice, well-organized, succinct 

presentations. 

Since Bexsero is licensed elsewhere starting at two months of age, Dr. Harrison wondered 

about the plans for licensure in the US down to that age range. 

Mr. Wassil replied that Novartis has decided that sufficient progress has been made on an 

ABCWY vaccine, and he previously showed the of Phase II studies for different formulations. 

Novartis is trying to go forward with an ABCWY vaccine in infants in the US, but that is several 

years away. 

Dr. Baker (IDSA) emphasized that the current serogroup B-specific incidence is 0.1per 100,000. 

Yet in infants less than one year of age, it is 1.5 per 100,000. She asked whether there are any 

data for children less than one year of age for the first six months of life and whether any 

thought had been given to maternal immunization. She would assume a pregnant 

microbiologist would be vaccinated. She also wondered about travelers to serogroup B 

hyperendemic or epidemic areas. 

Ms. MacNeil replied that there are data in children less than six months of age, which were 

presented several ACIP meetings ago. A lot of the disease is in the younger infants. She 

thought Dr. Baker’s question about maternal immunization was a great one. Consideration has 

not been given to travelers to serogroup B hyperendemic or epidemic areas at this point. 

Dr. Belongia asked about the considerations for potential use in microbiologists who are over 25 

years of age, given that the current licensed recommendation is for those 10 through 25 years 

of age. 

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Dr. Patel replied that this pertains to the granularity of the microbiologist recommendation that 

the WG will be discussing. At this point, the WG is suggesting that the recommendation would 

be individuals >10 years of age. The difference is that the doses change for younger individuals 

and the immunogenicity is different. It is expected that the immunogenicity would be similar for 

the older age groups. 

Dr. Byington (AAP) asked whether the WG is considering a routine recommendation for college 

students, or a recommendation only for outbreak settings. 

Dr. Patel replied that the high-risk recommendations the WG is considering for February 2015 

would pertain to an outbreak response. Routine recommendations for college students and 

adolescents are still being discussed. The WG is still waiting for additional data. They are 

reaching out to non-ABCs sites, such as the MeningNet sites, to get a better understanding of 

college cases within other states that are not in ABCs. 

Dr. Temte asked whether pricing had been established for Trumenba®and Bexsero® for the US 

market. 

Angela Hwang (Pfizer US) responded that Pfizer’s current priority has been about securing 

supply, which they expect shortly. Because of the rapid nature by which this approval has taken 

place, pricing is still being finalized. While she did not have pricing at that time, she indicated 

that they would have it as soon as possible and that it would be commensurate with the supply 

that they are advancing. 

Clement Lewin (Novartis) indicated that Novartis does not discuss pricing prior to licensure, and 

their vaccine is not yet licensed. 

Dr. Even (ACHA) indicated that because the college age group is included in the licensure, the 

first question she will receive in the college health world will regard when the vaccine will be 

available. 

Angela Hwang (Pfizer) replied that Pfizer is working as quickly as possible to advance the 

supply, which they expected to be available within the next two to three weeks. 

Dr. York emphasized that Trumenba® was licensed to prevent MenB disease. The discussion of 

the breadth of coverage, the phylogenetic tree, and the diversity of the fHbp addressed 

coverage and the fact that this is a protein which is conserved and present in all MenB. Its 

function is to protect it against the immune system and to invade it. Pfizer moved very fast to 

license this vaccine, and the WG working very hard to address this. Because the vaccine was 

developed to prevent outbreaks, not to say that it is not beneficial to use in control, she asked 

whether the ACIP members would like to see data on the use of this vaccine to prevent 

outbreaks in universities brought forward sooner because of this acceleration and if so, what 

information they would need. She understood persistence data would be needed in terms of a 

routine, age-based recommendation, but wondered whether they would need those data to 

move this forward in that risk group. 

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Rino Rappuoli (Novartis) said if he understood the epidemiology data shown through 2013, in 

the age group in question there were 50 cases of meningococcus B with 12.5% mortality. 

However, during the last year, there were three deaths in that age group: one at Drexel, one at 

Georgetown, and one in San Diego. Basically, that means with a mortality of 12.5%, 300 cases 

will be needed to justify that mortality. He said he was not challenging the data before 2013, but 

in 2014, the incidence will be different because there are more deaths than projected by the 

epidemiology. While ACIP is proposing to look at the high-risk and outbreak control at the 

beginning, none of these three deaths were going to be prevented by just recommending 

outbreak control. He wondered whether that should be reconsidered. 

Public Comment: Meningococcal Vaccines

Lynn Bozof, President 

National Meningitis Association (NMA)

Many of you are familiar with my son’s story. He died in 1998 from meningococcal disease. 

There was a polysaccharide vaccine available, but unfortunately, there were no 

recommendations, so my husband and I did not know to have our son vaccinated. In October of 

2000, ACIP voted to recommend that college students be educated that they were at increased 

risk for meningococcal disease and that there was an available vaccine. It was the right thing to 

do to protect our children. In 2005, the conjugate vaccine was recommended to prevent this 

disease in adolescents and teens. Again, it was the right thing to do. Later on, the booster 

dose was recommended to ensure that these kids maintain their protection. It was the right 

thing to do. 

I have heard over and over from parents whose children have suffered from serogroup B 

disease, especially this past year. They all said the same thing, “I thought my children were 

protected.” They all wanted the broadest protection possible. I was really thrilled yesterday to 

hear that the FDA had approved licensure of one of the vaccines, and I look forward to the other 

vaccine being licensed soon. We now have the tools to protect our children against all five 

serogroups. We need to do the right thing and routinely recommend vaccination. It’s the right 

thing to do. It’s what parents do. It’s what society should do. We need to protect our children.

I also wanted to alert you to a new activity that the National Meningitis Association (NMA) is 

conducting. We’re going to convene a roundtable that includes a cross-section of 

meningococcal disease advocates, including survivors, family members, college educators, 

infectious disease specialists, and any others who have a unique perspective and knowledge 

about meningococcal disease. Our goal is to prevent the real-life impact of this disease and to 

give voice to the concerns and viewpoints of those who have been infected. We hope to have a 

report to share with the ACIP before the February meeting. Thank you. 

Stephen and Beverly Ross 

National Meningitis Association (NMA)

My name is Stephen Ross and this is my wife, Beverly. We’re here today with the National 

Meningitis Association, and we have no conflicts. We’re the parents of Stephanie Ross, and I 

hope her name still rings a bell with you. She was a Drexel University student who died after 

contracting serogroup B meningococcal in March. She went to bed early one Sunday night 

because she was feeling tired, and only a few hours later, she was fighting for life. It was a 

battle she was destined to lose. She was just 19 years old. She was an intelligent young 

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woman who was attending Drexel University on a Ben Franklin Scholarship. She was well-liked 

at Drexel, as shown by the busload of students who traveled across the vast state of 

Pennsylvania the weekend before finals to say goodbye to her. She also went out of her way to 

assist anyone who asked for help and even some who didn’t. She was quickly growing into a 

leadership role with her Phi Mu sorority sisters. In talking about her, we always like to share a 

quote that was posted on the Websites that she created before passing in connection with a 

fundraiser for the Children's Hospital of Philadelphia. It said, “Thank you for always living your 

life the way it was supposed to be lived: full of love, laughter, and kindness. It’s not just friends, 

but strangers as well.”

Since Stephanie’s passing, at least two more college students have died from the serogroup B 

disease. When will it stop? We need to say, “Enough is enough.” As a percentage of all 

students that populate our country’s college campuses, we realize that these deaths represent a 

small number. But when the student is one of yours, any number above zero is unacceptable, 

especially if it could’ve been prevented. Parents have lots of things to think about when they 

send their children off to college. We shouldn’t have to worry about this disease. Let’s do the 

right thing to help protect our children from this devastating bacteria. We seem to have the 

means to stop the spread of this disease, as evidenced by the fact that no additional cases have 

been reported from the Princeton campus since the use of the serogroup B vaccination there. 

We don't want any more parents to receive a call like we did when you hear that your child has 

died from contracting serogroup B meningitis. 

Now that the FDA has licensed the first of the serogroup B meningococcal vaccines, we hope 

that you will recommend them for adolescents and young adults. At the very least, they should 

be recommended for college students because they seem to be the largest group at risk. Like 

us, many parents and students have mistakenly believed that the previously licensed vaccines 

protected them against all the serogroups that can affect our children. In the coming weeks, 

several groups associated with Drexel University will be sending letters supporting 

recommendation for college-aged adults. Some of them will be from Stephanie’s classmates 

who would like nothing more than to be protected from the bacteria that took the life of their dear 

friend. They want to be able to win the battle over the disease that Stephanie could not 

conquer. We are here on their behalf. Now, on behalf of her sister, Jacqueline, who now is an 

only child and a freshman at one of the largest universities in the US, it will be a tragedy, like 

Stephanie’s death, to see the vaccines approved by the FDA but not widely recommended. 

Thank you for the opportunity to address you. 

Frankie Milley 

National Executive Director 

Meningitis Angels

You’ve shared stats today, and I want to share just a quick stat with you. My mother’s twin 

brother died from diphtheria. Her father died from tetanus. Her cousin died from influenza in 

the big outbreak in the early 1900s. As I grew, one of my best friends had polio and was in an 

iron lung. And later, he did survive. He was in a wheelchair and very crippled for the rest of his 

life, which was very short, I might add. My sister had chickenpox and was in the hospital for 

three weeks. We almost lost her. She had serious secondary infections and pneumonia from 

that disease. My mother died from Hib pneumonia just a few years ago. As you know, Ryan 

died from meningococcal meningitis. He went from perfect health to blood coming from every 

orifice of his body in less than 14 hours. My only child. I watched him die needlessly. 

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I don’t share this with a lot of people, but I’ve been married to my current husband for almost 41 

years. But before that, I was married for a year to someone just to show my mother I could. 

Unfortunately, out of that, I blew a scholarship to college. I said I came away with half the 

alphabet. I had TMJ from being slapped around, and I had HPV, which, ultimately, led to a 

hysterectomy, which took the part of my body that carried Ryan. It was like losing him all over. 

We now have Ebola. We don’t have a vaccination. I want to commend these people in this 

room and everybody at the CDC who has worked so hard against this disease to protect us all. 

You’re doing a great job in keeping up, and I know you don’t hear that, but I’m here to tell you, 

you do. If you look at meningococcal disease and you compare it to Ebola, it’s really similar, 

only sometimes meningococcal disease works much faster. When they survive, they’re left 

devastated. 

As you move forward, there are some things I want you to consider. In our organization, we 

have hundreds of families across the country. We just took in a new family. Their 17 year old 

son died in March of this year from meningococcal B. I talked to Scott yesterday, and he was 

on the way to Canada today to take his other son to get vaccinated against this disease. He 

can’t go through this again. Many parents don’t have that opportunity to go to another country 

and get their kids immunized, so we need to be protective of that. I also want you to consider 

we had an outbreak in 2000 in our school district of 6500. We had 15 cases of meningococcal 

disease. When I called the health department at the state and told them, asked them if they 

knew about it, they didn’t and they hadn’t had any reports. They came down, and we 

immunized 45,000 people in three days in that outbreak. The problem was, when I went to the 

hospital to find out why they weren’t reporting, they said “It costs money to send those 

specimens, and we’re just not going to do it even though it’s required.”

So, I want you to consider that the case rate may be higher than we think it is because a lot of 

times when the kids are brought to the ER, they have symptoms. They’re bombarded with 

antibiotics. We know the bacteria dies. Ryan’s cause of death on his autopsy was WaterhouseFriderichsen syndrome, which is a bilateral bleed of the adrenal glands. We know that later the 

sepsis from the meningococcal caused that. But I’m afraid that we’re missing the actual rate of 

this disease in this country because we are good at our jobs or because we’re not good at our 

jobs. That can go either way. 

Finally, I just think that in a country as great as ours and the work that you’ve all done and the 

work that industry does to bring these vaccines to us—it takes years of research, development, 

and money. Some people research and never live long enough to see their research come to 

pass. We can prevent this disease. We can’t prevent Ebola right now, but we can prevent this 

disease. Nobody in this country should die from a vaccine-preventable disease. So, moving 

forward, I know you’ve got a lot of work to do with this. I know there’s still a lot of unanswered 

questions. I have faith in this committee right here that, at the end of the day, you’re going to do 

the right thing and recommend this for aged 15 to 25. Please, I beg you. Let’s don’t go back to 

that day when we only vaccinate those kids living in dorms. Meningitis doesn’t stop at the dorm 

room door. Thank you so much for your work and your kindness. 

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Dr. Stanley Plotkin 

Vaccine Consultant 

I have absolutely no conflict of interest with respect to Pfizer or Novartis. I just want to make 

that clear. One specific point and one general point. The specific point is, as was said, 29% of 

disease in adolescents occurs in college students. Obviously, that means 71% occurs in noncollege students who are smoking and going to bars, et cetera. So, a recommendation for 

college students is, in a sense, discriminatory. The more general point is one that is an obvious, 

sort of a 400-pound gorilla, but I want to bring it out publicly. And that is, the two companies 

have spent millions of dollars to develop vaccines against what might be called a “minor 

disease” in terms of incidence. If these vaccines are not recommended, then this puts a pall on 

vaccine development for diseases that are less prevalent than the ones for which we have 

general recommendations. I hope you will keep that in mind for the future, because this has 

great implications for future vaccine development. 

Dr. Carol Baker 

IDSA Liaison to ACIP

Just to add to that, what vaccine-preventable disease in the US causes 10% mortality? I would 

second the comment about age group as opposed to college. Finally, something that I struggle 

with—I certainly struggled with it as Chair of the Meningococcal WG when the quadrivalent was 

recommended, as chair of the ACIP, and I still struggle with it. I don’t have an answer, and I 

know you’re in the hot seat in February, it sounds like. It’s very difficult to know how much 

money we should spend for prevention of rare diseases. I think that this will increasingly trouble 

the CDC, ACIP members, the AAP if it’s a childhood disease, and the ACP if it’s an adult 

disease. It’s very, very difficult given the past history. It’s not so long ago, really little more than 

a decade, when vaccines were cheap for the prevention of childhood diseases. It’s just a 

comment. 

Dr. Paul Offit 

Chief, Division of Infectious Diseases 

Director, Vaccine Education Center 

Children’s Hospital of Philadelphia

You know, I felt like I’ve lived through this once before. When I was on the ACIP and head of 

the Polio Vaccine WG in the late 1990s, we made a decision to move from the oral polio vaccine 

to the inactivated vaccine. We did it because we knew that every year, although we’d 

eliminated wild-type polio from this country, we hadn’t eliminated vaccine-associated paralytic 

polio. Now, to do that, to move from OPV to IPV costs roughly $4 million per case prevented. 

But, we did it because we knew we could and because we believed we could afford it. I think, in 

some ways, the analogy is here. It was six to eight cases there. It’s roughly 50 cases here, but 

I agree with Stan [Dr. Plotkin]. I think narrowing this to just a high-risk recommendation or just a 

college recommendation will cover roughly 50 cases that are occurring. So, I think if we really 

want to prevent a disease that we can prevent, then we need to make a broader 

recommendation. Thanks. 

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Dr. Jonathan Temte 

ACIP Chair 

I really appreciate the last three comments from Dr. Plotkin, Dr. Baker, and Dr. Offit. Just 

reflecting back on Slide #10 from Ms. MacNeil’s presentation, the rate in college students was 

0.07 cases per 100,000 and three times that for the cohort aged 18 through 23. 

 

Introduction 

Barbara Mahon, MD, MPH 

Medical Epidemiologist 

Enteric Diseases Epidemiology Branch 

National Center for Emerging and Zoonotic Infectious Diseases 

Division of Foodborne, Waterborne, and Environmental Diseases 

Dr. Mahon reminded everyone that the current ACIP recommendation for typhoid vaccination 

was published almost 20 years ago, in December of 1994. The objective has been to update 

this recommendation because it is so long out of date. An ACIP WG on typhoid vaccines was 

not convened because the updated statement does not include substantive changes to the 

recommendations. 

The following table shows the three typhoid fever vaccines included in the 1994 ACIP 

statement: 

Vaccine Vaccine Type Mode of Administration No. of Doses

Ty21a vaccine Live, attenuated Oral 4

Vi capsular polysaccharide vaccine Subunit Parenteral 1

Heat-phenol-inactivated vaccine Inactivated 

whole-cell

Parenteral 2

Currently, the oral Ty21a vaccine and the parenteral Vi capsular polysaccharide (ViCPS)

vaccine are still marketed and are available in the US. The heat-phenol-inactivated vaccine, 

which was associated with high rates of fever and other systemic reactions, was discontinued in 

2000.

One of the major changes in the update is the removal of the vaccine that is no longer available 

in this country. In the 1994 recommendation, the statement that either oral Ty21a or parenteral 

ViCPS is preferable was made. This is because of the highly reactogenic nature of the heatphenol inactivated vaccine. Vaccination is indicated for the following three groups, which have 

not been changed in the updated recommendation: 

Typhoid Vaccines

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 Travelers to endemic countries, which continue to be the major group receiving vaccines 

 Household contacts of chronic typhoid carriers 

 Laboratory workers who work frequently with Salmonella serotype Typhi cultures or 

specimens 

In summary, the 1994 ACIP statement is outdated. No substantive changes are proposed in the 

updated recommendations. The updated statement reflects changes in vaccine availability with 

the removal of the whole cell inactivated vaccine that is no longer available and newer data on 

typhoid epidemiology, vaccine efficacy and effectiveness, and vaccine safety. During this 

session, Dr. Brendan Jackson presented information on typhoid fever and typhoid vaccines, and 

a summary of the proposed updates to the typhoid vaccination statement. 

Typhoid Vaccines Update 

Brendan R. Jackson, MD, MPH 

Medical Epidemiologist 

Enteric Diseases Epidemiology Branch 

National Center for Emerging and Zoonotic Infectious Diseases 

Division of Foodborne, Waterborne, and Environmental Diseases 

Because typhoid fever is uncommon in the US, Dr. Jackson began by providing some brief 

background information. The disease is caused by Salmonella enterica serotype Typhi. 

Contrary to most other Salmonella serotypes, humans are the only reservoir. Infection is 

usually acquired from food or water contaminated with human feces. The incubation period is 

relatively long, ranging from about 6 to 30 days. The disease usually has an insidious onset 

with gradually increasing fever, malaise, headache, and anorexia. Typhoid fever can be severe 

and deadly, particularly if untreated. Life-threatening complications include septic shock and 

intestinal hemorrhage and perforation. 

The disease can now be treated with one of several antimicrobial agents, including the 

following: fluoroquinolone, beta-lactam, azithromycin, chloramphenicol, or trimethoprimsulfamethoxazole. However, antibiotic resistance is common and increasing in many parts of 

the world, placing greater importance on prevention tools like vaccines1. The case-fatality ratio 

for untreated disease was previously reported at 10% to 20%2. However, the current casefatality rate is less than 1% with early and appropriate antimicrobial treatment3

 [1Crump and 

Mintz. Clin Infect Dis. 2010; 2Stuart and Pullen. Arch Int Med. 1946; 3Bhan et al. Lancet. 2005]. 

“Enteric fever” is the broader term for both typhoid fever and paratyphoid fever. Paratyphoid 

fever is caused by three non-Typhi Salmonella serotypes: Paratyphi A, B, and C. The most 

common cause of paratyphoid fever is Paratyphi A, which causes disease that is clinically 

indistinguishable from typhoid fever1. It is important to note that current typhoid vaccines 

provide little or no protection against paratyphoid fever [1Maskey et al. Clin Infect Dis. 2006]. 

Globally, there are an estimated 20 million cases of typhoid fever annually, resulting in about 

200,000 deaths per year1. In comparison, there are an estimated 5 million cases of paratyphoid 

fever each year2. However, in some Asian countries, paratyphoid fever caused by serotype 

Paratyphi A is responsible for a growing proportion of enteric fever cases, accounting for half of 

enteric fever cases in some areas2. Multi-drug resistance, defined as resistance to ampicillin, 

chloramphenicol, and trimethoprim-sulfamethoxazole, is common for serotype Typhi. 

Additionally, fluoroquinolone-resistance and extended spectrum β lactamase-producing strains 

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are emerging problems. Growing rates of drug resistance increases the importance of 

vaccination as a preventive measure [1Crump et al. Bull WHO. 2004; 2Crump and Mintz. Clin 

Infect Dis. 2010]. 

There were about 400 cases of typhoid fever reported each year from 2007 to 2011 in the US. 

Approximately 90% of these were travel-associated1. Among the travel-associated cases, 80% 

to 85% involved travel to three countries: Bangladesh, India, and Pakistan. Use of typhoid 

vaccines is thought to be low among travelers, in general, with one study finding that about 20% 

of travelers had received vaccine2. The most up-to-date vaccine recommendations for travel 

can be found at cdc.gov/travel. Currently, typhoid vaccine is recommended for travel to most 

countries in Africa, Asia, and Latin America. Since 2011, typhoid vaccine is no longer 

recommended for travel to certain countries in Eastern Europe and the Middle East3 [1CDC 

Surveillance. http://www.cdc.gov/nationalsurveillance/typhoid_surveillance.html; 2Mahon et al. 

Vaccine. 2014; and 3Johnson et al. J Trav Med. 2011]. 

As noted earlier, two typhoid vaccines are currently available in the US. The first is Ty21a 

vaccine, Vivotif®, which is a live attenuated vaccine administered as oral capsules on four 

alternate days over one week. Vivotif® is approved for persons six years of age and older, and 

is currently recommended every five years if continued exposure is expected. The second is 

ViCPS vaccine, Typhim Vi®, which is given as a single parenteral dose. Typhim Vi® is approved 

for patients two years of age and older, and repeated dosing is recommended every two years if 

continued exposure is expected. No booster effect has been observed for either vaccine. 

Conjugate polysaccharide vaccines are available in a few countries. However, a conjugate 

vaccine is not licensed in the US. 

Both available vaccines have moderate efficacy based on studies conducted in endemic 

countries1. In a recent systematic review and meta-analysis, the Ty21a vaccine had a 2.5- to 3-

year efficacy of 48% based on a single trial. In two excluded trials that did not adjust for the 

cluster design and may have overestimated the protective effect, efficacy was 79% at 5 years 

and 62% at 7 years. In the same systematic review and meta-analysis, the efficacy of the 

ViCPS vaccine was 69% percent at Year 1 and 59% at Year 2. The cumulative 2.5- to 3-year 

efficacy was 55%, based on a single study. No efficacy studies have been conducted among 

US travelers, but a recent study found 80% effectiveness of typhoid vaccination among this 

group. Note that this estimate is for any typhoid vaccination, given that the study was not able 

to differentiate between the two vaccines2 [

1Anwar et al. Cochrane Database Syst Rev. 2014; 

2Mahon et al. Vaccine. 2014]. 

In terms of safety, both vaccines are generally well-tolerated with low rates of adverse events 

based on data from trials and post-marketing studies. In the meta-analysis field trials, two 

events were significantly more common in vaccinees than among placebo recipients: 1) fever, 

with a risk ratio of 1.8; and 2) a combined measure of any mild adverse event, with a risk ratio of 

1.71. 

In an analysis of post-marketing data from VAERS, there were an estimated 0.6 serious events 

reported per 100,000 doses distributed. Serious adverse events were defined as reports of 

death, hospitalization, prolongation of hospitalization, permanent disability, life-threatening 

illness, or congenital anomaly2

. For the ViCPS vaccine, the meta-analysis found that pain and 

swelling at the injection site were significantly more common among vaccinees than among 

placebo recipients, with a risk ratio of 8.0 (95% CI 3.7–17.2) for pain and 6.0 (95% CI 1.1–34.2) 

for swelling at injection site1. In the VAERS post-marketing study, the ViCPS vaccine was also 

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associated with a similarly low rate of serious events as the Ty21a vaccine2 [1Anwar et al. 

Cochrane Database Syst Rev. 2014; 2Begier et al. Clin Infect Dis. 2004]. 

Contraindications for both Ty21a and ViCPS were hypersensitivity to any component of 

vaccine1,2. ACIP’s general recommendations on immunization suggest that live bacterial 

vaccines, like Ty21a, are generally contraindicated in pregnant women3. Additionally, the Ty21a 

vaccine is contraindicated in immunocompromised persons and should not be administered 

during an acute febrile illness1 [1Vivotif Package Insert www.fda.gov/downloads/BiologicsBlood 

Vaccines/Vaccines/ ApprovedProducts/UCM142807.pdf; 2Typhim Vi Package Insert 

www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM142811.pdf; 

3ACIP. General Recommendations on Immunization. 2011]. 

Because the Ty21a vaccine contains live bacteria, persons should avoid taking antimicrobial 

agents if possible three days before and after administration of the vaccine 1. However, certain 

antimalarial prophylaxis medications can be taken at the same time as vaccine2, which is 

relevant, given that many patients are travelers. Also, Ty21a can be co-administered with other 

live vaccines, including the yellow fever vaccines2. The ViCPS vaccine should be given to 

pregnant women only if clearly needed3 [1Vivotif Product Monograph. http://www.crucellvaccines 

canada.com/pdf/vivotif_pm.pdf; 2ACIP. General Recommendations on Immunization. 2011; 

3Typhim Vi Package Insert www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ 

ApprovedProducts/UCM142811.pdf].

Regarding the minor proposed updates to the current ACIP recommendations regarding who 

should receive vaccine, the first statement pertains to travelers. No substantive changes are 

proposed for 1994 recommendation for this group. Readers are directed to the current CDC 

website for the most updated guidance on countries: 

“Travelers to areas in which there is a recognized risk of exposure to Salmonella

serotype Typhi (see cdc.gov/travel/)

 “Risk is greatest for travelers to developing countries (e.g., countries in Latin 

America, Asia, and Africa) who have prolonged exposure to possibly 

contaminated food and drink, although short-term travelers are also at risk.

 “Multidrug-resistant strains of Salmonella serotype Typhi have become common 

in many regions, and cases of typhoid fever that are treated with drugs to which 

the organism is resistant can be fatal. 

 “Travelers should be cautioned that typhoid vaccination is not a substitute for 

careful selection of food and drink. Typhoid vaccines are not 100% effective, and 

vaccine-induced protection can be overwhelmed by large inocula of Salmonella

serotype Typhi.”

The second statement focuses on those with intimate exposure (e.g., household contacts). 

Changes to the 1994 recommendation for household contacts are for the carrier to be specified 

as “chronic” and for chronic carriage to be defined as excretion >1 year. The purpose of this 

change is so that the recommendation is not misconstrued as applying to close contacts of any 

person with typhoid fever and not just chronic carriers: 

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“Persons with intimate exposure (e.g., household contact) to a documented Salmonella

serotype Typhi chronic carrier (defined as excretion of Salmonella serotype Typhi in 

urine or stool for >1 year)”

The third statement regards microbiologists and laboratory workers, with a change to the 1994 

recommendation of “Microbiology laboratorians who work frequently with S. typhi”:

“Microbiologists and laboratory workers who work with cultures of Salmonella serotype 

Typhi or with specimens that contain this organism or who work in laboratory 

environments where these cultures or specimens are handled.”

No substantive changes are proposed regarding the choice of vaccine. As in the 1994 

statement, no preference is given between the ViCPS and oral Ty21a vaccines. The inactivated 

whole-cell vaccine that is no longer available has been deleted from the recommendation. 

In summary, the current 1994 typhoid vaccine statement is outdated. No substantive changes 

are proposed to the recommendations are proposed. The updated statement was presented 

during this session for an ACIP vote. It reflected a change in vaccine availability, with the 

whole-cell vaccine being removed, new data on typhoid epidemiology, and newer data on 

vaccine effectiveness and safety. 

Discussion Points

Dr. Temte thanked Drs. Mahon and Jackson for a very succinct presentation. He reminded 

everyone that ACIP strives to review, renew, reaffirm, retire, or revise its statements every 5 

years. This statement is now 20 years old. The biggest changes include the elimination of one 

vaccine and some minor wording. There was some discussion regarding whether this 

recommendation should be subjected to a formal GRADE review. Given the Ebola situation, 

there has been a shortage of time within CDC over the last few months. In addition, nothing has 

really changed from the original recommendation. Systematic reviews have strongly suggested 

that there is efficacy as previously stated, and the safety profile has not changed. 

Dr. Schaffner (NFID) noted that 90% of the cases are travel-associated. Of those, 80% to 85% 

are among travelers to Bangladesh, India, or Pakistan. He was curious to know who these 

travelers are, and was thinking analogous to malaria. That is, are these people who were born 

in the US who are traveling to these countries? Or, are many of them people who were born in 

these countries, moved to the US, and returned to visit family? This is very important because if 

it is the latter, perhaps a sentence or two might be included to emphasize that those are also 

individuals at risk. Similarly, many people do not take malaria chemoprophylaxis when visiting 

their country of origin. 

Dr. Mahon replied that most of the travelers are people who are visiting friends and relatives, 

but who were not necessarily born in those countries. 

Dr. Messonnier pointed out that the attempt to clarify the recommendation for laboratory 

workers was itself confusing. She wondered whether the intent was to recommend vaccination 

for laboratory researchers who work with this organism, or local clinical laboratories who may 

receive specimens from returning travelers. If the intent was local laboratorians, she asked 

whether the potential number of people who would be impacted had been quantified. The 

recommendation potentially could include a large number of people. 

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Dr. Jackson indicated that this was recently revisited. There is a concern that making such a 

broad recommendation may apply to more people than initially intended. A few cases continue 

to occur among laboratory and clinical laboratory workers. Perhaps the wording could be 

revised to include the word “frequently” such that the statement would read “who work 

frequently with cultures of Salmonella serotype Typhi.”

Dr. Fryhofer (AMA/ACP) asked whether the oral vaccine still needs to be refrigerated. Dr. 

Jackson replied that it does. 

Dr. Pickering pointed out that children are often exposed to people who have traveled to these 

areas of the world when they return. The returning travelers may be asymptomatic, but the 

children who are exposed to them may develop typhoid fever. 

Dr. Belongia noted that there seem to be relatively few cases coming from Latin America, so he 

wondered whether the epidemiology had changed and the risk decreased in Latin America. 

Dr. Mahon replied that while she did not recall the exact percentages, and she had read that 

overall the incidence has been decreasing, there are travel-associated cases reported to CDC 

from travel to Latin America. A number of cases are also seen among travelers from the 

Caribbean. Therefore, vaccines are still recommended for travelers to those areas. 

Dr. Jean Smith was struck by the fact that only 20% of travelers are receiving vaccine. Her 

daughter went to India and Nepal last summer, so she paid about $50 for the oral typhoid series 

at Publix. She wondered whether cost and/or lack of awareness are issues. 

Dr. Mahon responded that they do not have this information, but would like to acquire it. She 

suspects that as Dr. Schaffner pointed out, central to the issue of low vaccination rates is that 

people do not think about it. When traveling to these countries to visit friends and relatives, it 

feels like going home. Efforts to reach those groups would be the most effective way of 

decreasing rates of typhoid in this country. CDC knows whether people are traveling to visit 

friends and relatives because that is reported as part of the enhanced surveillance for typhoid in 

this country. She shared an anecdote from a colleague who is of Indian descent with whom she 

was discussing this session earlier in the week. With a startled look on his face he said, “You 

know, my father is visiting India right now and it never occurred to me to tell him to get 

vaccinated.”

Given that the oral vaccine is live attenuated, Dr. Loehr asked whether the same 28-day rule 

applied as for other live attenuated vaccines. If so, he suggested pointing that out in the 

recommendation. 

Dr. Jackson said he would review this information. As he recalled, the language in the 2011 

general recommendations on immunization from ACIP states that there is not a contraindication 

to administering live vaccines together with typhoid vaccine. 

Dr. Loehr clarified that simultaneously is fine, but if one is given, there must be 28 days before 

another live attenuated vaccine. 

Dr. Mahon said that the difference may be because it is administered orally. The biology is 

different with parenterally-administered live viral vaccines. 

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Dr. Kroger clarified that with respect to the 28-day rule for non-simultaneous vaccination of live 

vaccines, the general recommendations apply to injectable and intranasal vaccines but not oral 

vaccines, so it would not apply in this case. 

Ms. Pellegrini was puzzled over the precaution that the vaccine should be given to pregnant 

women only if “clearly needed.” She was trying to think about cases in which it might be 

indicated but not “clearly needed.” She wondered if, for example, they were thinking of a 

pregnant woman going on a cruise with ports of call in these countries. 

Dr. Jackson replied that the statement came directly from the current FDA-approved vaccine 

label, with no changes to that. Further consideration can be given to how this should be 

interpreted. 

Dr. Mahon added that the scenario suggested by Ms. Pellegrini would be the type of situation 

that would apply. The risk-benefit balance would differ for someone traveling to a location with 

limited access to clean food and water for a prolonged period of time during pregnancy versus a 

pregnant woman traveling by cruise ship to ports of call in these countries where they would not 

have prolonged exposure. 

Dr. Decker (Sanofi Pasteur) emphasized that the pregnancy language is regulatory and is 

prescribed by the Code of Federal Regulations, so it needs to be interpreted with that in mind. 

Vote: Typhoid Vaccine Recommendation 

Dr. Reingold made a motion to approve the Typhoid Vaccine Recommendation as proposed, 

including the minor changes suggested during the discussion. Dr. Rubin seconded the motion. 

The motion carried with 13 affirmative votes, 0 negative votes, and 0 abstentions. Two 

members were absent. The disposition of the vote was as follows: 

13 Favored: Bennett, Belongia, Bocchini, Harrison, Karron, Kempe, Pellegrini, Romero, 

Reingold, Riley, Rubin, Temte, and Vazquez 

 0 Opposed: N/A

 0 Abstained: N/A 

 2 Absent: Campos-Outcalt, Harriman 

Tom Shimabukuro, MD, MPH, MBA 

Immunization Safety Office 

Centers for Disease Control and Prevention (CDC) 

During this session, Dr. Shimabukuro presented an overview of the proposed changes to the 

VAERS reporting form. As a reminder, VAERS is a national spontaneous reporting system for 

adverse events after US-licensed vaccines. In recent years, VAERS has received 

approximately 30,000 US reports annually. VAERS accepts reports from healthcare providers, 

Vaccine Safety

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manufacturers, and the public. Signs and symptoms of adverse events are coded using 

Medical Dictionary for Regulatory Activities (MedDRA) terms and are entered into the database. 

VAERS is jointly administered by CDC and FDA, and was authorized by the National Childhood 

Vaccine Injury Act (NCVIA) of 1986. 

Currently, there is a secure online submission process for VAERS. Approximately 30% of 

reports in recent years have been submitted using this process. Most reports are received as 

mailed or faxed hardcopies in paper form. In rare instances, reports are made via telephone 

through a VAERS customer service representative if someone has no other way to submit a 

report. Reporter types overall include vaccine providers (36%), vaccine manufacturers (34%), 

patients/parents (15%), and others (15%). There is variability among individual vaccines. 

The current VAERS-1 report form is a paper form that has been in use since 1990. It must be 

downloaded, printed, and completed by hand. Forms are mailed or faxed to the VAERS 

contractor, and manual processing and data entry procedures are required and are fairly 

resource-intensive and time-consuming. Hardcopies are scanned and uploaded to the VAERS 

image database, so there is a traditional research-type database and an image database of the 

actual report. The online reporting tool has the same fields as VAERS-1 form in a different 

presentation. The preference is that the online reporting be used to submit forms. The online 

interface will time out for security reasons after a period of inactivity, so reports cannot be 

saved. That is, reports must be completed in a single setting. 

The objectives for the proposed VAERS 2.0 form are to: 

 Create a fillable/savable electronic reporting form 

 Update data fields to address current vaccine safety information needs and changes in 

vaccination practices over time (e.g., pregnancy, types of facilities, race/ethnicity) 

 Modernize the appearance and format of the VAERS form 

 Modernize reporting procedures (implement electronic document upload capability with the 

VAERS 2.0 form) 

 Ensure data collected on the VAERS 2.0 form allows for comparisons to be made with older 

data (i.e., historical comparisons between VAERS-1 and VAERS 2.0 data) 

There are several reasons for revising the VAERS form. Some fields on the current VAERS 

form, VAERS-1, have limited public health and/or regulatory value. That was determined by 

meeting with ISO staff who work with VAERS data on a daily basis, as well as CDC’s 

colleagues at the FDA who use VAERS data for regulatory purposes. Other important 

information is not being collected. Some fields are no longer relevant due to changes in the 

immunization program. The language in some fields is confusing and needs clarification. Fields 

used in paper reporting and for manual processing will no longer be necessary (e.g., 

manufacturer fields after the transition to the ICH E2B(R3) message standard). New fields, 

such as pregnancy, are needed because of new recommendations and patterns of vaccine 

uptake. Handwritten mailed and faxed paper reporting is an inefficient way to conduct vaccine 

safety surveillance. Paperless reporting using an electronic form would eliminate most manual 

processing and much data entry, mitigate problems with poor handwriting and non-standard 

reporting, take advantage of smart features (auto-population, drop down menus, programmed 

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check boxes, pop-up instructions/reminders, logic checks), allow for standardized data elements 

(dates and times), and address the complaint of getting timed out on the online reporting tool 

(i.e., would offer an electronic alternative to using the online reporting tool). Manufacturers are 

transitioning to fully electronic reporting using the ICH E2B(R3) message standard, so it makes 

sense to transfer non-manufacturer reporting to electronic reporting. 

A number of actions have already occurred in the VAERS 2.0 form development process. Initial 

internal development, review, and revision have been done by CDC, FDA, and VAERS 

contractor staff. Review and revision are ongoing. External review has been done by 

immunization partners (e.g., CDC immunization program, NVPO, HRSA, DoD, ACIP liaison 

representatives, state immunization program officials, and other partners). Cognitive interviews 

have been conducted with potential reporters (e.g., physicians, nurses, pharmacist, parents, 

and patients) and revisions have been made based on the results of those interviews. Cognitive 

interviews are commonly used to validate questions in surveys. The form has been presented 

to the federal Immunization Safety Task Force (ISTF). Follow-up interviews have been 

conducted with a sample of individuals who completed the cognitive interviews to test the 

revised form. The form has been presented to the ACCV and NVAC. The contractor conducted 

computer testing of a “smart” form with potential reporters, and revisions have been made 

based on that testing. The form was presented at the FDA Electronic Postmarket Safety 

Reporting Updates meeting. 

The proposed reporting method would be for the reporter to download the VAERS 2.0 form from 

the VAERS website. The reporter would complete a VAERS 2.0 form on a computer. The form 

is a fillable/savable PDF document. The reporter would save the VAERS 2.0 report as an 

electronic document in a local environment, and would upload the report to the VAERS 

contractor through the VAERS website. The VAERS contractor would then electronically extract 

the data from the VAERS 2.0 report into the VAERS database (also reviews, redacts and 

performs Q&A on data), and would generate an individual report for the VAERS image 

database. There will still be options for manual reporting such as faxing and mailing, at least in 

the short-term, until technology and connectivity catch up. A full scale VAERS 2.0 report was 

included in the members’ binders.

The next steps are to solicit public comments through the Federal Register, make final 

revisions, develop the platform to accept electronic VAERS 2.0 submissions and update the 

online reporting tool to reflect new data elements, implement the VAERS 2.0 form, and evaluate 

the completeness and quality of VAERS data (pre-post comparison). 

Discussion Points 

Dr. Temte asked whether there will be any forced answers on the new form, and whether there 

would be any verification of the incoming information and the information provided by the 

contractor. 

Dr. Shimabukuro replied that there are no forced answers on the new form. If someone enters 

an illogical answer, there will be a pop-up reminder cautioning them that the answer may be 

incorrect or that they may want to reconsider. However, the reporter always has the option to 

override that or leave anything blank that they wish. If an answer is left blank, there will be 

reminders, but there is never a hard stop on the form. Currently, the VAERS report intake 

processing and data entry are done by a contractor. There will be no difference in the process 

for the current form versus the new form, except that now instead of the paper forms being 

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mailed or faxed to the contractor, the hope is that most of the forms will be uploaded to the 

contractor electronically. 

Dr. Temte observed that there likely would be less variability with the new form and uploading 

process. 

Dr. Riley expressed gratitude for the inclusion of pregnancy-specific information in the VAERS-2 

form. She noted that Box #8 states “If pregnant, yes” but states in parenthesis that pregnancy 

information goes into Box #18, but then it never comes up again to put the pregnancy 

information in there. The problem with the form and trying to figure out what to do with the 

information is that the due date or gestational age are almost never known, so it is not possible 

to time when a vaccination was given. She thought reporters should be forced to include the 

due date in Box #8, given that this is a critical element. Otherwise, pregnancy information from 

this form is useless. The point is to try to draw conclusions about vaccines and pregnancy, and 

the vaccines that are given in the third trimester do not cause birth defects. The rest of the 

information about pregnancy can go in Box #18. 

Dr. Shimabukuro replied that in previous iterations of the form, there was much more detail on 

pregnancy. Initially the thought was that including checkboxes or questions for specific 

information would be helpful, but the cognitive testing challenged a lot of the preliminary 

assumption. The feedback received about the form in general was to simplify it and have 

reporters fill in information in the text box. Three of the physicians interviewed were OBGYNs. 

There are instructions below the question on Box #8. Perhaps they could figure out the most 

important items and include them at the front of the instructions. Many reasonable suggestions 

were made about the form, but may not appear due to space considerations or not testing well 

in the cognitive interviews. However, he thought the concern about estimated due date or 

gestational age could be addressed. 

Dr. Loeher (AAFP) suggested adding to Box #18, “If pregnant, due date.”

Dr. Shimabukuro noted that one problem with putting pregnancy in Box #18 is that it is amazing 

what people will write about if they are tipped off to write about something. Box #18 previously 

included much more descriptive language. However, in the cognitive interviews, many 

physicians suggested saying “Describe the event” and leaving it to reporters to enter 

information. Based on the research conducted in revising this form, sometimes the more details 

asked, the more potential problems or unintended consequences created. 

Dr. Hayes (ACNM) wholeheartedly and completely supported Dr. Riley’s statement that without 

an actual estimated date of delivery, the data are absolutely useless. 

Dr. Belongia found VAERS-2 to be a nice improvement; however, it still involves filling out a 

form completely. It is just that this will be done on line instead of in hardcopy. For VAERS-3, he 

suggested taking advantage of the computer technology that allows for branching points. Not 

everybody has to see the entire form. They see whatever is relevant for what they are filling 

out. There could be a different pathway for someone who is pregnant that includes variables 

that others do not see, because they go down a different pathway. 

Dr. Shimabukuro replied that while that may be an option for the online reporting tool, the PDF 

“smart” form is limited in its smartness. 

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Jane Zucker (New York City Immunization Program) indicated that New York City has a fairly 

robust registry, which currently has an adverse event reporting module that takes the 

information from a reported event. That is, it automatically pulls out the vaccine information 

(e.g., type of vaccine, lot number, demographics on the child, et cetera) and a VAERS form is 

generated and faxed. Having the electronic online system will be great, because New York City 

will transition to electronic submission, again, pulling all of the information from the reported 

event. She emphasized the importance of remembering that immunization information and 

program managers are also stakeholders, because they will actually take the information and 

specifications form the online form and build those into registries to try to improve reporting of 

adverse events as well as the quality of the data submitted. 

Dr. DeStefano commented that data gathering does not stop when the form is received. In 

particular, pregnancy has been a high priority for the ISO office for a few years. That means 

that when reports of pregnancy are received, additional detailed information is obtained about 

the pregnancy (e.g., date of delivery, expected date of conception, delivery, birth outcomes, et 

cetera). 

Introduction 

Joseph A. Bocchini, Jr, MD 

Chair, ACIP HPV Vaccine Working Group

Dr. Bocchini reminded everyone that the HPV Vaccine WG has been preparing for licensure of 

9-valent HPV vaccine, with potential licensure anticipated in December 2014. The WG is also 

continuing to review data on 2-dose schedules. As a reminder, Dr. Markowitz reviewed the 

available data on 2-dose schedules for both of the licensed vaccines during the June 2014 

meeting. 

In terms of background, the investigational 9-valent HPV vaccine is an L1 VLP vaccine similar to 

quadrivalent HPV vaccine. It targets 5 additional high risk types (31, 33, 45, 52, and 58). The 

BLA was submitted to FDA in December 2013 for females 9 through 26 years of age and males 

9 through 15 years of age. The trials submitted were conducted with a 3-dose schedule. The 

data on males 16 through 26 years of age were not part of the BLA submitted in 2013. However, 

the data from that study are now available and will be presented to ACIP during this session. 

The HPV Vaccine WG is reviewing data and considering policy options for presentation to ACIP. 

Presentations given to ACIP previously regarding investigational 9-valent HPV vaccine include 

an overview of investigational 9-valent program in October 2013; burden of cancers and cervical 

pre-cancers attributed to HPV types in the US and 9-valent HPV vaccine pivotal efficacy and 

immunobridging trials in February 2014; and 9-valent HPV vaccine concomitant use trials, 

safety data, revaccination study, and policy questions in June 2014. As noted for the 2-dose 

schedules, a comprehensive review of the data was presented to ACIP in June 2014 on bivalent 

and quadrivalent HPV vaccines. There was a discussion of the WHO decision regarding the 2-

dose schedules for young girls up to the age of 14. At the same time, it was recognized that 

there is an intersection between consideration of a 2-dose schedule for HPV2 and HPV 4 

vaccines with considerations being made as a result of the potential licensure of the 9-valent 

Human Papillomavirus (HPV) Vaccines

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HPV vaccine. No data are available for the 9-valent HPV vaccine in a 2-dose schedule; 

however, a study is underway that is expected to provide data within about a year comparing 

immunogenicity of a 3-dose to a 2-dose schedule. 

Program Summary and New 9-Valent HPV Vaccine Trial Data

Alain Luxembourg, MD, PhD 

Director, Clinical Research

Merck & Company, Inc. 

Dr. Luxembourg reminded everyone that 9vHPV vaccine is the investigational 9-valent HPV 

vaccine and qHPV vaccine is the licensed quadrivalent HPV vaccine, known as Gardasil®. 

The epidemiology of 9vHPV has been covered in great detail in terms of the relative contribution 

of HPV types in 9vHPV vaccine to cervical cancers worldwide. Adding the five additional 

oncogenic types (HPV 31, 33, 45, 52 and 58) to those already in the licensed vaccine increased 

the potential to prevent additional disease (from 70% to 90% for cervical cancer from 30% to 

80% for CIN2/3, and from 25% to 50% for CIN1) . These figures may be slightly different by 

country because these are worldwide figures, but every country will benefit. Overall, coverage 

could be 85% to 95% worldwide depending on the type of cancer. 

The qHPV vaccine is based on VLP and contains an aluminum-based adjuvant. The 9vHPV 

vaccine is manufactured the same way, using the same VLP as the qHPV plus five additional 

VLP types and the same adjuvant. The dosage of antigen and adjuvant has been adjusted to 

insure comparable immunogenicity to the qHPV vaccine. 

As a reminder, the key goals of the 9vHPV vaccine clinical program included the following: 

 Demonstrate that 9vHPV provides a similar level of protection as qHPV vaccine against 

infection/disease due to HPV 6/11/16/18 

 Demonstrate that 9vHPV is highly protective against infection/disease due to HPV 

31/33/45/52/58 

 Prove non-inferior immunogenicity in adolescents versus young women (immunobridging) 

 Prove non-inferior immunogenicity in young men versus young women (immunobridging) 

 Demonstrate an acceptable safety and tolerability profile 

 

These goals were accomplished with four pivotal studies. The data for three of these pivotal 

studies were presented to ACIP in February 2014 (the results of the fourth pivotal study, 

Protocol 003, immunobridging in young men, are presented at this meeting): 

 Protocol 001: Efficacy study in young women 

 Protocols 002 and 009: Immunobridging studies in adolescents 

All efficacy and immunogenicity objectives were met for Protocols 001, 002, and 009. Noninferiority was demonstrated with respect to the 4 original types in the qHPV vaccine. 

Non-inferior immunogenicity with respect to HPV 6, 11, 16, and 18 was demonstrated in young 

women who received 9vHPV vaccine compared with women who received qHPV vaccine. 

There were very few cases of HPV 6-, 11-, 16- 18-related disease in subjects followed for three 

to four years, and there was no statistical difference in terms of incidence rates between the 

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9vHPV and qHPV vaccine groups. Assessment of the HPV 6/11/16/18 disease endpoints for 

Protocol 001 showed that the 9vHPV disease numbers were very low compared to the historical 

placebo for Gardasil. This offers supportive evidence that the two vaccine products protect 

similarly against disease for the original 4 types. 

Approximately 97% protection was documented against HPV 31-, 33-, 45-, 52-, and 58-related 

disease. For these 5 types, there was high efficacy for all the key efficacy endpoints at 96% to 

97%. There was also substantial risk reduction in terms of procedures (e.g., biopsy and 

definitive therapy). 

Non-inferior immunogenicity was demonstrated in boys and girls versus young women. The AE 

profile was similar to that of the qHPV vaccine, except that there were more injection site AEs 

that were mostly mild to moderate in intensity. The safety profile was also very similar for the 

two vaccines, the only difference being higher incidence of injection site AEs for 9vHPV vaccine. 

These injection site AEs were primarily mild to moderate in intensity. 

The following supportive studies have been completed, the results of which were presented to 

ACIP in June 2014: 

 Protocols 005 and 007: Concomitant use studies 

 Protocol 006: Study in prior qHPV vaccine recipients 

 Integrated summary of safety for Protocols 001, 002, 005, 006, 007, and 009 

All immunogenicity objectives were met for supportive studies 005, 006, and 007. These 

studies showed that 9vHPV vaccine can be administered concomitantly with Menactra®

(meningococcal vaccine: A, C, Y, W-135), Adacel® (Tdap vaccine), and Repevax® (Tdap-IPV 

vaccine, licensed in the EU). 9vHPV vaccine was highly immunogenic in prior qHPV vaccine 

recipients. 

Evaluation of the integrated safety data for all six studies (001, 002, 005, 006, 007, and 009) 

demonstrated that the 9vHPV vaccine was generally well-tolerated in over 13,000 subjects. The 

AE profile was generally comparable across age, gender, race, and ethnicity. The AE profile 

was similar to that of qHPV vaccine. There were more injection-site adverse events with 

9vHPV, but these were mostly mild to moderate in intensity. 9vHPV was generally welltolerated in prior qHPV vaccine recipients. 

All of the data previously presented were part of the original FDA filing. Protocol 003 the 

women-men immunobridging study, was not included in the filing, but was presented at this 

meeting. The study was designed to include 1100 young women 16 through 26 years of age, 

1100 heterosexual men (HM) 16 through 26 years of age, and 300 men having sex with men 

(MSM) 16 through 26 years of age. Vaccination was administered as a 3-dose regimen (Day 1, 

Month 2, and Month 6). This was an open label study in which all subjects received 9vHPV 

vaccine. The key endpoints for immunogenicity were anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 

58 titers at Day 1 and Month 7. The key endpoints for safety were Vaccination Report Card 

(VRC)-aided surveillance and SAEs for Day 1 through Month 12. 

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The key objectives for Protocol 003 were as follows: 

Immunogenicity 

 To demonstrate non-inferior immunogenicity of 9vHPV vaccine in men (HM) 16 through 26 

years of age versus women 16 through 26 years of age 

 To summarize 9vHPV vaccine immunogenicity in MSM 

– Rationale: Though not fully understood, the immunogenicity of qHPV vaccine 

was lower in MSM than in heterosexual men (secondary objective; results not 

included in this presentation in the interest of time) 

Safety

 To evaluate the safety/tolerability of the 9vHPV vaccine in young men and young women 16 

through 26 years of age 

The study showed that non-inferior immunogenicity was demonstrated in young heterosexual 

men versus young women for all 9 vaccine HPV types. These data support bridging of efficacy 

findings in young women 16 through 26 years of age to men 16 through 26 years of age. In 

terms of safety, the vaccine was generally well-tolerated in young men and young women, with 

a lower frequency of AEs in young men versus young women. This is similar to the previous 

safety findings for qHPV vaccine. 

In summary, the clinical studies for the 9vHPV vaccine showed that: 

 The immune response for the 9vHPV vaccine was non-inferior response with respect to the 

original types compared to the qHPV vaccine. 

 Approximately 97% protection was demonstrated against HPV 31, 33, 45, 52, and 58-

related disease. 

 Non-inferior immunogenicity was demonstrated in boys and girls versus young women, and 

in young men versus young women. 

 9vHPV vaccine was generally well-tolerated, and the AE profile was similar to that of the 4-

valent vaccine. There were more injection-site AEs with the 9vHPV vaccine, but most were 

mild to moderate in intensity. Over 15,000 subjects received 9vHPV vaccine. 

 9vHPV vaccine can be co-administered with Menactra® and Adacel® 

 9vHPV vaccine is generally well-tolerated, and is highly immunogenic in prior qHPV vaccine 

recipients. 

The 9vHPV vaccine is still an investigational product under review by the FDA. 

Cost-Effectiveness of 9-Valent HPV Vaccination

Dr. Marc Brisson 

Canadian Research Chair Modeling Infectious Diseases 

Associate Professor, Université Laval 

Dr. Brisson’s presentation focused on the impact and cost-effectiveness of the 9-valent 

compared to the 4-valent HPV vaccine in the US. The modeling team that produced these 

results is from Canada, the UK, and CDC. He thanked the CDC internal peer reviewers for 

valuable comments to this presentation, and indicated that the model was funded by a variety of 

sources from Canada, the US, the EU, and the UK. 

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The study question for the model was, “From the societal perspective, what is the additional 

impact and cost-effectiveness of the 9-valent compared to 4-valent (quadrivalent) HPV vaccine 

in the context of an established 4-valent HPV vaccine program in the US?” The objective was 

to evaluate the additional population-level effectiveness and incremental cost-effectiveness of 

switching from the 4-valent to the 9-valent HPV vaccine in the US. 

To achieve this objective, an individual-based transmission-dynamic model known as HPVADVISE was used. This model takes into account the direct effects of vaccination on 

vaccinees, as well as herd immunity effects. This model was developed to answer policy 

questions in Canada, but has also been used to assess 2-dose HPV vaccination in the UK and 

for the WHO. The model included six components: demographics, sexual behavior HPV 

transmission, natural history of disease, vaccination, cervical screening and treatment, and 

economics. The population is open and stable, meaning that the number of individuals who 

enter the population is equal to the number of people who die of natural causes. Age-specific 

mortality was based on US data. For HPV infections, 18 genotypes were modeled individually, 

including: 6/11/16/18/31/33/45/52/58. Also modeled were HPV-related diseases, including 

anogenital warts (AGW); cervical cancer (SCC and adenocarcinoma); and cancers of the anus, 

oropharynx, penis, vagina, and vulva [Van de Velde et al. JNCI 2012 104(22):1712-23].

The more complex these models become, the more they look like a video game. For them to be 

really worthwhile for a public health decision, the model has to be calibrated and confronted to 

actual data to find the appropriate parameters to represent the epidemiology and behavior of a 

population. An extensive calibration process is used that includes three steps. For all of the 

parameters in the model, a systematic review of the literature to find the minimum and 

maximum value of each of the parameters (Step 1). After hundreds of thousands of 

combinations of these parameters are sampled (Step 2), the parameter sets are put through the 

model to find those parameter sets that actually fit the US data (Step 3). Fitting is done to a lot 

of highly stratified data, such as the following: 

 Sexual and screening behavior (stratified by gender and age) 

 HPV prevalence (stratified by HPV type, gender, age, and sexual activity) 

 Incidence of AGW, cervical lesions, cervical cancer and other HPV-related cancers 

(stratified by HPV type, gender, and age) 

In total, the model was fit to 826 data points. The result was 200,000 different combinations of 

parameters that were sampled from the prior parameter distributions. From these, 50 

parameter sets were found that produced a very good fit to the 826 pre-specified data target 

points. They were then run again through the model with vaccination to get effectiveness. Dr. 

Brisson showed illustrations of the model fits for sexual behavior model, HPV prevalence in 

women, screening, and squamous cell carcinoma (SCC). 

Once the model fit the situation in the US, the next step was to determine the impact of HPV 

vaccination. To do this, vaccine efficacy parameters are needed. There were two scenarios for 

4-valent efficacy because in a systematic literature review Dr. Brisson’s team conducted, the 4-

valent vaccine was found to protect against the types in the vaccines in addition to having some 

cross-protection to the other types in the clinical trial. Whether this is true cross-protection or 

how long it will last are unknown, so all of the predictions were done with two scenarios: one 

with cross-protection and the other without. Obviously, this assumption can have an impact on 

the additional gains from the 9-valent vaccine. It was assumed that the 9-valent vaccine is as 

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effective as the 4-valent vaccine against the 4-valent types and that it is 95% effective against 

the five additional types. 

The economic analysis is from the societal perspective. All direct medical costs were included. 

The primary outcome measure was cost per quality adjusted life years (QALYs) gained. 

Discounting of 3% was used for costs and benefits over a 70-year time horizon. The cost of the 

vaccine with administration was assumed to be $145/dose for the 4-valent vaccine and 

$158/dose for the 9-valent vaccine. These numbers were based on a Merck presentation at the 

29th International Papillomavirus Conference in 2014 on the cost-effectiveness of the 9-valent 

vaccine. 

In terms of predictions, it is important to model the US program as closely as possible. 

Therefore, vaccination was introduced in 2007 in females only with the quadrivalent vaccine. In 

2011, gender-neutral vaccination with the 4-valent vaccine was added. Now in 2014, decisions 

can be made either to continue with the 4-valent gender-neutral strategy or to switch the 

program to a 9-valent scenario. Two scenarios were modeled, one in which the US vaccinates 

girls only with 9-valent vaccine and maintains 4-valent use for boys or one in which there is a 

complete switch from the 4-valent gender-neutral vaccination to the 9-valent gender-neutral 

vaccination. 

To model the situation in the US as appropriately as possible, 3-dose vaccine coverage was 

used from the NIS. Age-specific 3-dose uptake rates were used (e.g., the annual percent of 

vaccinated individuals with 3 doses among those who had not previously received 3 doses). 

For 2007 through 2013, observed uptake rates were used. From 2014 on, uptake rates were 

assumed to be constant at 2013 levels. This means that in 2013 the data were produced for the 

coverage of 13 through 17 year olds, which was about 39% for girls and about 14% for boys. If 

vaccine uptake rates remain constant, vaccine coverage increases slightly until 2017 due to age 

and time cohort effects. 

In terms of the potential for additional cancer prevention due to use of 9-valent HPV vaccine, 

most of the cancers are due to 16/18, which are already targeted by the 4-valent vaccine. 

However, there are opportunities for additional gains. In assessing cost-effectiveness and the 

impact of a vaccination program, it is necessary to determine the number of cases per year that 

could be prevented. The greatest gain from the 9-valent vaccine would be by additional 

prevention of cervical cancer. 

In a scenario of 4-valent vaccination of girls and boys compared to a 9-valent gender-neutral 

vaccination under the base case assumptions and assuming no cross-protection for the 4-

valent, with the 4-valent vaccine there would be substantial reductions in CIN 2/3 to about 61% 

and cervical cancer to about 65%. By switching to a 9-valent vaccine, there would be an 

additional 19% reduction in CIN 2/3 and 14% reduction in cervical cancer. In the same scenario 

but with cross-protection, the additional benefits of the 9-valent are reduced from 19% to 12% 

for CIN 2/3 and from 14% to 10% for cervical cancer. There are still substantial gains, even if 

cross-protection is assumed. Another strategy regards moving from a 4-valent gender-neutral 

strategy to a to a 9-valent gender-neutral strategy. Most of the benefit of this type of switch 

would be from vaccination of girls with the 9-valent vaccine. 

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There are other benefits to the vaccine in addition to CIN 2/3 and cervical cancer, including 

oropharyngeal cancer and anogenital warts. The additional benefits of the 9-valent are 

somewhat smaller for these outcomes, which is to be expected. In the model, there was no 

difference in impact on anogenital warts between the 4-valent and the 9-valent because it was 

assumed that the 4-valent and 9-valent had the same efficacy for anogenital warts. For 

oropharyngeal cancer, there was a slight increase in benefits by vaccinating with the 9-valent 

vaccine. This added benefit is quite similar to the other cancer sites. 

There are different ways of looking at the overall impact of vaccination. In terms of the health 

outcomes prevented over 70 years for the different scenarios modeled, the added benefit of 

moving from a vaccine program with no cross-protection to a 9-valent girls and boys strategy 

would be an additional 87,000 cancers prevented over 70 years. This would relate to a number 

needed to vaccinate (NNV) of 1000, meaning that 1 additional cancer case would be prevented 

for every 1000 individuals switched from the 4-valent to the 9-valent vaccine. The model also 

predicts that an additional 26,000 cancer deaths would be prevented by switching to the 9-

valent vaccine. The additional benefits of the 9-valent vaccine are lower when cross-protection 

is assumed for the 4-valent vaccine. When cross-protection is assumed for the 4-valent, the 

NNV increases and the additional number of cases prevented by the 9-valent vaccine is 

reduced, so the model predicts 47,000 cancer cases prevented and 14,000 deaths prevented. 

The added benefit in switching from 9-valent in girls and 4-valent in boys to 9-valent in girls and 

boys is quite small. 

In terms of cost-effectiveness, the primary outcome for benefit is QALYs gained. The primary 

benefit of QALYs gained of vaccinating with the 4-valent vaccine is prevention of cervical cancer 

and other HPV-related cancers. The incremental benefits of switching girls to 9-valent vaccine 

and continuing to vaccinate boys with 4-valent vaccine are smaller, but that is understandable. 

The primary benefit in this scenario is in the prevention of cervical cancer. The incremental 

benefits of switching from a strategy of 9-valent in girls and 4-valent boys to 9-valent girls and 

boys is small. Regarding incremental healthcare costs saved from vaccination, the primary 

savings using a 4-valent vaccine strategy is in costs related to cervical screening. Comparing 9-

valent vaccine in girls and 4-valent boys to 4-valent girls and boys, the main primary saving is 

due to costs related to cervical screening. There are very few gains in averted healthcare costs 

when switching from a strategy of 9-valent in girls and 4-valent boys to 9-valent girls and boys. 

Regarding cost-effectiveness assuming no cross-protection for the 4-valent vaccine, the 4-

valent vaccine compared to no vaccination is estimated to be highly cost-effective at $6,400 per 

QALY gained. A scenario with 9-valent vaccine for girls and 4-valent vaccine for boys is costsaving. Switching to a 9-valent program would be cost-saving, and the majority of these cost 

savings would be in the prevention of the costs related to cervical screening. The incremental 

costs are quite low in a gender-neutral 9-valent scenario (compared to a scenario with 9-valent 

vaccine for girls and 4-valent vaccine for boys), though the cost-effectiveness ratio is still about 

$31,000 per QALY. However, there is a lot of uncertainty around that cost-effectiveness ratio, 

which goes from very cost-effective to not cost-effective at all. Whereas there is considerable 

uncertainty in the cost-effectiveness of a 9-valent gender-neutral strategy compared to a 

strategy of 9-valent vaccine for girls and 4-valent vaccine for boys, there is much less 

uncertainty in the cost-effectiveness of a 9-valent gender-neutral strategy compared to a 4-

valent gender-neutral strategy. When using a 4-valent gender-neutral strategy as the 

comparator, the cost-effectiveness of a 9-valent gender-neutral strategy is not particularly 

sensitive to assumptions about cross-protection of the 4-valent vaccine. 

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In order to determine how robust these results were to changes in key parameters, sensitivity 

analyses were performed varying certain parameters to assess their impact. The model and 

predictions were very robust to the sensitivity analyses. Varying the duration of efficacy did not 

make a major difference on the results. Vaccine coverage was changed to higher coverage, 

and a scenario was assessed in which a high proportion of 13-year old girls and boys would be 

vaccinated at 13 instead of the older ages. Also assessed was a scenario with minimum cost to 

the healthcare system, meaning that costs related to screening would be very low. Even in that 

scenario, the switch to the 9-valent vaccine was cost-saving. In the base case, primary cervical 

cancer screening was modeled as cytology-based screening. To determine what might happen 

with changes to screening guidelines, an alternate scenario was modeled in which HPV cotesting was incorporated into cervical cancer screening. Even with HPV co-testing in women 30 

through 65 years of age, the switch to the 9-valent vaccine was cost-saving. Even when 

assuming cross-protection of the 4-valent vaccine, the results for the 9-valent vaccine were very 

insensitive to changes in key parameter values. One parameter that is very important is the 

cost of the intervention. The base-case assumption was that the cost difference between the 9-

valent and 4-valent vaccine was $13 per dose. At a difference of $13 per dose and when 

assuming no cross-protection of the 4-valent vaccine, 9-valent vaccine was cost-saving in all of 

the scenarios. In the cross-protection scenario, 9-valent vaccine was cost-saving in most of the 

scenarios examined. However, as the additional cost per dose increases beyond $13, the cost 

per QALY gained by 9-valent vaccine increases. 

In all modeling and cost-effectiveness exercises, there are many limitations. Dr. Brisson pointed 

out three main limitations. The first is that duration of 4-valent and 9-valent vaccine efficacy and 

future vaccination coverage in the US remains unknown. However, duration of protection and 

vaccination coverage were varied and these parameters had no real impact on the conclusions. 

Cytology-based screening and HPV co-testing were also modeled, but screening may change in 

the coming years. For example, primary HPV testing might be considered. If the changes to 

screening result in less costly and/or more effective cervical cancer prevention, the incremental 

cost-effectiveness of the 9-valent vaccine may become less favorable. The cost-effectiveness 

of the 9-valent versus the 2-valent vaccine was not presented because that is not the strategy 

being used in the US. However, the HPV-ADVISE model suggested that in Canada, the 2-

valent vaccine was less cost-effective than the 9-valent and 4-valent scenarios. 

In summary of population-level effectiveness predictions, the current US 4-valent girls and boys 

strategy is expected to reduce HPV-related diseases substantially. A 61% reduction in CIN2/3 

and 65% reduction in cervical cancer are anticipated after 70 years, assuming that there is no 

cross-protection. One HPV-related cancer would be prevented for every 250 vaccinated 

individuals. Switching to a 9-valent girls and boys strategy is expected to further reduce precancerous lesions and cervical cancer, with relatively less additional impact on other HPVrelated outcomes. A 19% additional reduction in CIN2/3 and 14% additional reduction in 

cervical cancer are anticipated after 70 years, assuming no cross-protection of the 4-valent. 

One additional HPV-related cancer would be prevented for every 1000 vaccinated individuals 

with the 9-valent instead of the 4-valent vaccine. Vaccinating girls with the 9-valent vaccine 

provides the great majority of benefits of a 9-valent girls and boys program. 

To summarize cost-effectiveness predictions, the current US 4-valent girls and boys HPV 

vaccination program is highly cost-effective. Switching to a 9-valent girls and boys program is 

likely to be cost-effective and cost-saving. Vaccinating girls with the 9-valent vaccine provides 

the majority of cost savings and QALYs gained of a 9-valent girls and boys program. The 

results are robust across a range of plausible assumptions, including cross-protection or no 

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cross-protection of the 4-valent vaccine, price, duration of protection, health care costs, and 

burden of illness. 

Discussion Points 

Dr. Orenstein (NVAC) noted that one question that will likely arise in policy-making deals with 

what to do with persons who are already fully vaccinated against the 4 types. He wondered 

whether the cost-effectiveness of vaccinating these individuals with 9-valent had been modeled. 

Dr. Brisson responded that the cost-effectiveness of revaccinating 13 through 17 years old 

females who have already received 3 doses of the 4-valent vaccine was assessed in 

exploratory analyses. The incremental cost-effectiveness ratio was $88,000. The range was 

from $52,000 to $300,000 so there was a lot of variability in this. It is important to note that 

simplifying assumptions were made that biased the results in favor of revaccination and that in 

reality the cost-effectiveness of revaccination would likely be less favorable. Revaccinating older 

women or revaccinating boys would be even less cost-effective than revaccinating females 13 

to 17 years old. 

Dr. Temte asked whether that would be administering 3 additional doses of 9-valent for those 

who already received 3 doses of 4-valent. 

Dr. Brisson confirmed that the assumption was 3 doses of 9-valent vaccine given to those who 

already received 3 doses of 4-valent. 

Referring to the cost-effectiveness table, Dr. Loehr (AAFP) said he was unclear what was meant 

by the 1 versus 0 and 3 versus 2 columns. 

Dr. Brisson clarified that it was to explain what the comparator was. 

Thomas Weiss (Merck) emphasized that the Merck model mentioned earlier that was presented 

at a recent HPV Congress and to the ACIP WG showed similar results and reached similar 

conclusions. 

Dr. Temte asked how likely the price used in the modeling is to be what is observed in the 

future. 

Thomas Weiss (Merck) indicated that this has not yet been determined, but will be announced 

at the time of licensure. 

Dr. Schuchat indicated that the price announced at licensure may not be the price over time. 

The VSD prices are posted on CDC’s website, which are updated when the price changes. The 

price has not been stable since the original licensure. 

Dr. Belongia asked whether the prices generally go down afterward. 

Dr. Schuchat replied that the price has increased annually. 

Dr. Sun (FDA) asked whether the modeling took into account the potential indirect effects or 

herd immunity. 

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Dr. Brisson responded that this model did take herd protection into account. The model takes 

into account all partnership formation and separation. Sexual behavior, transmission of HPV, 

and the indirect effects of preventing someone from being infected are modeled. If a woman is 

prevented from having HPV, she is also not transmitting the HPV to her male partner or 

partners. 

Dr. Kinsinger (DVA) asked whether the drop in screening costs referred to the initial screening, 

or if Dr. Brisson was suggesting that the costs were lower due to less abnormal lesions that 

need to be followed. 

Dr. Brisson replied that the screening costs being saved would be primarily due to less cost to 

follow-up and management of abnormal lesions. 

Dr. Reingold wondered how practical having different vaccines for girls and boys would be for 

practitioners in terms of storage, confusion, et cetera. 

Dr. Temte inquired as to whether Merck would continue to make both vaccines, or if it would be 

akin to the move from PCV7 to PCV13. 

Julie McCafferty (Merck) indicated that Merck anticipates that there will be demand for both 

products in the US, and intends to supply both products until there is a time when the 

indications for Gardasil® and the 9-valent vaccine match. Time would then be allowed for series 

completion. Merck will also still manufacture 4-valent for outside the US. 

Dr. Markowitz suggested that this be further discussed during the Policy Options presentation 

and discussion. 

GRADE for 9-Valent HPV Vaccine

Emiko Petrosky, MD, MPH

EIS Officer

Epidemiology and Statistics Branch 

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

Centers for Disease Control and Prevention 

Dr. Petrosky reported that the HPV WG used GRADE to review data related to the 9-valent HPV 

vaccine. As a reminder, the 9 steps of GRADE are to: 

 Develop policy questions 

 Consider critical outcomes 

 Review and summarize evidence of benefits and harms 

 Evaluate quality of evidence 

 Assess population benefit 

 Evaluate values and preferences 

 Review health economic data 

 Considerations for formulating recommendations 

 ACIP recommendations and GRADE category 

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The previous presentations included an assessment of the population benefit and a review of 

the health economic data for the 9-valent vaccine. Dr. Petrosky’s presentation covered the first 

4 steps in GRADE. The remaining steps will be completed and presented during the next ACIP 

meeting in February 2015. 

The first step in GRADE is to develop the policy questions. The questions Dr. Petrosky 

addressed during this session included: 

 Should the 9-valent vaccine be recommended routinely for 11 through 12 year olds? 

 Should the 9-valent vaccine be recommended for females aged 13 through 26 years and 

males aged 13 through 21 years who have not been previously vaccinated? 

The next step in GRADE is to consider critical outcomes. The following table shows the 

outcomes the WG identified and ranked, and whether they were included in the evidence profile 

for GRADE. The benefits are listed separately for females and males, and the harms are listed 

jointly: 

In red are the outcomes not included in the evidence profile. Definitive therapies were not 

included since they are represented by cervical pre-cancer and cervical cancer, or 

oropharyngeal cancer as there are no data for this outcome from any HPV vaccine study. For 

simplicity, vaginal/vulvar cancer and anal cancer were not included in the evidence profile for 

females, instead focusing on the most prevalent outcomes in women: cervical pre-cancer, 

cervical cancer, and anogenital warts. For males, anal cancer and anogenital warts were 

assessed. For harms in both females and males, SAEs and anaphylaxis were assessed. 

The next step in GRADE is to review and summarize the evidence of benefits and harms, which 

were performed after reviewing published and unpublished data relevant for the 9-valent 

vaccine. Before presenting the data, Dr. Petrosky mentioned a few considerations. Both the 9-

valent and quadrivalent vaccines are recombinant HPV virus-like particle (VLP) vaccines with 

the same manufacturing process, and both contain HPV 6/11/16/18 VLPs, the 4 original types. 

The 9-valent vaccine contains 5 additional VLPs. The 9-valent vaccine program compared the 

9-valent vaccine to the quadrivalent vaccine as the active comparator. However, because the 

quadrivalent vaccine has high efficacy, there were few disease endpoints due to the 4 original 

types in the comparator cohort, and the efficacy of the 9-valent vaccine for the 4 original types 

could not be directly assessed. Instead, the 9-valent vaccine was immunobridged to the 

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quadrivalent vaccine to demonstrate non-inferior immunogenicity and comparable efficacy. 

Because of this, data from the quadrivalent vaccine trials were considered for the 4 original 

types for GRADE of the 9-valent vaccine. Of note, neutralizing antibody is considered to be the 

mechanism of protection for HPV vaccination. Vaccines induce high antibody titers; however, 

no minimum level of protective antibody has been identified. 

The following table shows the quadrivalent phase 2 and 3 efficacy RCTs submitted for 

quadrivalent vaccine licensure that were considered for GRADE of the 9-valent vaccine for the 4 

original types. In females, there were 3 RCTs and in males 1 RCT comparing the quadrivalent 

vaccine to placebo: 

Per Protocol Population Protocol Outcomes

Females aged 16–26 years 007, 013, 015 CIN 2/3 or AIS

Anogenital warts

Males aged 16–26 years 020 AIN 2/3

Anogenital warts

As mentioned earlier, the 9-valent vaccine was immunobridged to the quadrivalent vaccine. All 

of the data examined for GRADE involved the per protocol population from these studies. Of 

note, although the age groups in these studies do not completely correspond to the age groups 

in the policy questions, they do closely overlap. Protocol 001 is the pivotal efficacy study that 

compared the quadrivalent vaccine to the 9-valent vaccine in females aged 16 through 26 

years. Protocol 002 compared the 9-valent vaccine in females aged 16 through 26 years to 

females and males aged 9 through 15 years. Protocol 003 compared the 9-valent vaccine in 

females aged 16 through 26 years to males of the same age group. Protocol 009 compared the 

quadrivalent vaccine to the 9-valent vaccine in females aged 9 through 15 years. Protocol 005 

and 007, the concomitant use studies, provided additional supportive evidence of 9-valent 

vaccine immunogenicity and safety. 

Dr. Petrosky reviewed and summarized the evidence of benefits, first focusing on the population 

of females aged 13 through 26 years. The intervention is the 9-valent vaccine and the 

comparison group is the quadrivalent vaccine. The outcomes were examined by vaccine type, 

the 4 original types and the 5 additional types. She presented the evidence in older females 

first, as vaccine efficacy can only be demonstrated in older age groups. Efficacy findings are 

then immunobridged to the younger age groups. The quadrivalent vaccine trials showed high 

efficacy. In females, the vaccine demonstrated greater than 98% efficacy in preventing CIN 2/3 

or AIS due to the 4 original types and greater than 98% efficacy for anogenital warts. 

Regarding data from the study immunobridging the quadrivalent vaccine to the 9-valent vaccine 

in females, (Protocol 001) for outcomes due to the 4 original types, the 9-valent vaccine 

demonstrated comparable efficacy in preventing cervical pre-cancer and anogenital warts. For 

the 5 additional types, the 9-valent vaccine demonstrated greater than 96% efficacy in 

preventing cervical pre-cancer. The absolute risk difference was 4 fewer cases per 1000 and 

the number needed to vaccinate (NNV) was 250. Based on the dynamic model of HPV 

vaccination shown previously by Dr. Brisson, 1 case of CIN 2/3 due to the 5 additional types is 

prevented for every 51 to 76 females vaccinated with the 9-valent vaccine instead of the 

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quadrivalent vaccine over a period of 70 years. Protocol 001 found greater than 99% 

seroconversion after vaccination with the 9-valent vaccine. There was no difference for the 4 

original types compared to the quadrivalent vaccine. For the 4 original types, the 9-valent 

vaccine induced non-inferior GMTs compared with the quadrivalent vaccine. For the 5 

additional types, GMTs were superior compared with the quadrivalent vaccine. 

The next step in GRADE is to evaluate the quality of evidence. As a reminder, the evidence 

type ranking used for GRADE is as follows: 

1. Randomized controlled trials (RCTs) or overwhelming evidence from observational studies 

2. RCTs with important limitations, or exceptionally strong evidence from observational studies 

3. Observational studies, or RCTs with notable limitations 

4. Clinical experience and observations, observational studies with important limitations, or 

RCTs with several major limitations 

For GRADE of the 9-valent vaccine, all of the evidence types begin with 1 based on starting with 

either the RCT of the quadrivalent vaccine or the RCT of the 9-valent vaccine. 

The evidence type for the benefits due to the 4 original types in older females are shown in the 

following table: 

Because the 9-valent vaccine was immunobridged to the quadrivalent vaccine for the 4 original 

types, the quadrivalent vaccine trials data were graded and data from the 9-valent studies were 

considered as supportive evidence. The quadrivalent vaccine trials were RCTs without notable 

limitations, so each outcome began with an evidence type of 1. Starting with cervical precancer, the evidence was downgraded by 1 for indirectness due to the use of immunobridging to 

the quadrivalent vaccine, resulting in an evidence type of 2. For cervical cancer, the evidence 

was downgraded again for indirectness due to the use of cervical pre-cancer as a surrogate 

marker for cervical cancer, resulting in an evidence type of 3. For anogenital warts, the 

evidence was downgraded by 1 for indirectness, again for the use of immunobridging data, 

resulting in an evidence type of 2. 

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For the 5 additional types, Protocol 001, the RCT that compared the 9-valent vaccine to the 

quadrivalent vaccine in older females was graded as this study was able to demonstrate 9-

valent vaccine efficacy for the 5 additional types. For cervical pre-cancer, there was no 

downgrade for any of the criteria, which kept the evidence type at 1. For cervical cancer, there 

was a downgrade of 1 for indirectness due to the use of cervical pre-cancer as a surrogate 

marker for cervical cancer, resulting in an evidence type of 2. This is shown in the following 

table: 

Dr. Petrosky then discussed the younger population, females aged 11 through 12 years. Similar 

to older females, the outcomes were examined separately for the 4 original types and for the 5 

additional types. In the interest of time, for this and the remaining populations, Dr. Petrosky did 

not present the data for the benefits as these were previously presented to ACIP. She instead 

focused on the process used to GRADE the evidence and explain the approach for evidence 

type ranking. 

Protocols 002 and 009 were the supportive studies considered for GRADE for the 9-valent 

vaccine in younger females. Protocol 002 was an immunobridging study that showed the 9-

valent vaccine induced non-inferior seroconversion and higher GMTs in younger females, which 

supports the bridging of efficacy findings in older females to younger females. Protocol 009 

showed that the 9-valent vaccine induced non-inferior seroconversion and GMTs compared with 

the quadrivalent vaccine in younger females, which supports the bridging of efficacy findings 

from the quadrivalent vaccine to the 9-valent vaccine. For the younger females, the WG started 

with the evidence type for the older females and did not downgrade for any of the criteria, 

keeping the evidence type the same. This is because of the high seroconversion rates and 

higher GMTs in the younger females compared to the older females, and because the efficacy 

data were from the per protocol population. 

Dr. Petrosky next summarized the evidence for the 9-valent vaccine in males, first in the 

population of males aged 13 through 21 years. Only the outcomes due to the 4 original types 

were assessed because of the low burden of disease due to the 5 additional types in males. In 

protocol 020, the quadrivalent vaccine efficacy trial in males, the quadrivalent vaccine 

demonstrated greater than 74% efficacy for prevention of AIN 2/3 and greater than 89% efficacy 

for prevention of anogenital warts. For the studies considered for GRADE for the 9-valent 

vaccine in older males, the WG started with the quadrivalent vaccine trial in males and 

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considered the data from the 9-valent trial, protocol 003, as supportive evidence. Of note, 

GRADE for the quadrivalent vaccine in males was presented to the ACIP in 2011. Based on 

protocol 020, efficacy for prevention of anal cancer had been ranked an evidence type of 2 and 

anogenital warts an evidence type of 1. There is no study in older males immunobridging the 9-

valent vaccine to the quadrivalent vaccine. Instead, there is Protocol 003, which 

immunobridged the 9-valent vaccine in older females to older males. The 9-valent vaccine 

induced non-inferior seroconversion and GMTs in older males, which supports the 

immunobridging of outcome findings in older females to older males. 

The following table shows the evidence type for the benefits of the 9-valent vaccine in older 

males: 

Starting with the evidence type of 2 for anal cancer and 1 for anogenital warts, both outcomes 

were downgraded for indirectness due the use of immunobridging data, resulting in an evidence 

type of 3 for anal cancer and 2 for anogenital warts. 

Focusing on the population of males aged 11 through 12, similarly to older males, the WG only 

assessed the outcomes due to the 4 original types. One of the supportive studies was Protocol 

002, which immunobridged the 9-valent vaccine in older females to younger males. The 9-

valent vaccine induced non-inferior seroconversion and higher GMTs in younger males, which 

supports the bridging of efficacy findings from older females to younger males. In addition, the 

WG compared the GMTs in younger males from this study with GMTs from older males in 

Protocol 003. The younger males had higher GMTs compared with the older males, which 

supports immunobridging from older males to younger males. Thus, for the younger males, the 

WG started with the evidence type for the older males and did not downgrade for any criteria, 

keeping the evidence type the same. This is because the younger males had high 

seroconversion rates and higher GMTs than the older males, and because the efficacy data was 

from the per protocol population. 

Switching to harms, the outcomes under consideration were SAEs, which were examined as 

days 1 through 15 after vaccination and any time during the study period, and anaphylaxis, day 

1 through 15, after vaccination. The harms were examined by older and younger age groups. 

First focusing on harms in older females and males, 1 RCT (Protocol 001) and 2 observational 

studies (Protocols 002 and 003) assessed harms in the older age group. The adverse events 

were similar for the 9-valent vaccine and the quadrivalent vaccine. There were few cases of 

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vaccine-related SAEs in either group, and only 1 case of anaphylaxis with the 9-valent vaccine, 

which was determined to be due to a non-study medication. In terms of the evidence type for 

the harms due to the 9-valent vaccine in older females and males, the WG started with an 

evidence type of 1 due to inclusion of an RCT. For both SAE and anaphylaxis, only imprecision 

was downgraded due to the small sample size, resulting in a final evidence type of 2. 

For the younger age group, 1 RCT (Protocol 009) and 3 observational studies (Protocols 002, 

005, and 007) assessed harms. Once again, the adverse events were similar for the 9-valent 

vaccine and the quadrivalent vaccine. There were few cases of vaccine-related SAEs in the 9-

valent vaccine group and, for the younger age groups, no cases of anaphylaxis in either group. 

The evidence types for harms of the 9-valent vaccine in younger females and males were 

similar to the older age groups. The initial evidence type was 1 due to inclusion of an RCT, and 

for both SAE and anaphylaxis, only imprecision was downgraded due to the small sample size, 

resulting in a final evidence type of 2. 

Dr. Petrosky then summarized the findings and the overall quality of evidence for the 9-valent 

vaccine by the populations just presented, beginning with the older females. The quadrivalent 

vaccine trials showed high efficacy for the quadrivalent vaccine, and the 9-valent vaccine 

demonstrated non-inferior immunogenicity and comparable risk for the outcomes due to the 4 

original types. For the 5 additional types, the WG graded the RCT comparing the 9-valent 

vaccine to the quadrivalent vaccine, which showed a decreased risk for the outcomes due to the 

5 additional types. For harms, there were few SAEs and no vaccine-related anaphylaxis. 

Taking into consideration the evidence types for all 9 types combined and the supportive 9-

valent vaccine studies, the overall evidence for benefits and harms in older females was given a 

final ranking of 2. In younger females, the 9-valent vaccine demonstrated non-inferior 

immunogenicity, and the evidence types were the same as for older females. For harms, there 

were no SAEs and no cases of anaphylaxis. 

In older males, the quadrivalent vaccine trial showed high efficacy for the quadrivalent vaccine, 

and the 9-valent vaccine demonstrated non-inferior immunogenicity for the 4 original types. The 

harms were the same as for the older females. For older males, because there is no 

immunobridging study comparing the quadrivalent vaccine to the 9-valent vaccine in males, the 

overall evidence type for the benefits and harms was given a ranking of 3. In younger males, 

the 9-valent vaccine demonstrated non-inferior immunogenicity, and the evidence types were 

the same as for older males. The harms were the same as for the younger females. 

In conclusion, the overall evidence type for older and younger females was 2, indicating 

moderate confidence. For the older and younger males, the evidence type was 3, or of low 

confidence. 

Discussion Points 

In terms of the indirectness of the data from CIN to cervical cancer, Dr. Gorman (NIH) asked 

whether there were natural history studies that could provide the percentage of those with CIN 

who progress and those who resolve spontaneously that could eliminate the downgrading 

factor. The natural history studies were in the late 1990s and led to the recommendations for 

the present therapeutic interventions for those. The decision was made that treatment is 

needed for those because of the percentage that progressed and regressed. 

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Dr. Markowitz added that they were being very conservative in counting those as indirectness. 

Downgrading was not done for prevention of the pre-cancerous lesions themselves. They have 

been very conservative in considering pre-cancer a surrogate for cancer. That is generally what 

has been considered by regulatory agencies and worldwide. 

Policy Options and Discussion 

Lauri Markowitz, MD

HPV Vaccine Working Group 

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

Centers for Disease Control and Prevention 

Dr. Markowitz reviewed the issues and considerations for HPV vaccine recommendation options 

that have been discussed by the HPV vaccine WG. Policy decisions over the next year will be 

impacted by the expected licensure of the 9-valent HPV vaccine and the status of data available 

on 2-dose schedules. For both of these issues, consideration will have to be given to the 

evidence base, programmatic considerations, and regulatory issues. Dr. Markowitz began with 

an overview of the current data on vaccine coverage in the US, provided a brief overview of 

data presented to ACIP at the June 2014 meeting regarding 2-dose schedules, and discussed

recommendation considerations and options discussed by the ACIP WG. 

Based on the latest National Immunization Survey-Teen (NIS-Teen) national vaccination 

coverage levels among adolescents aged 13 through 17 years from 2006 through 2012, Tdap 

and MCV4 coverage increased to approximately 80%. In contrast, while HPV coverage 

increased initially somewhat in parallel with those vaccines, coverage has plateaued for at least 

1-dose and 3-dose coverage. There was an increase between 2012 and 2013, but this was 

small. At least 1-dose coverage was 57% in 2013 and 3-dose coverage was 38%. Coverage in 

boys increased after 2011 when the recommendation was made for routine vaccination. 

Overall, about 70% of those who start the series complete all three doses. Based on estimates 

of at least 1-, at least 2-, and at least 3-dose coverage in the US, the drop-off between 1 and 2 

and 2 and 3 is similar. At 3-dose coverage was 57%, at least 2 dose coverage was 47% in 

2013, and at least 3-dose coverage was 38% [MMWR 2014:63;625-33].

There are ongoing efforts to try to increase coverage in the US, including materials to assist 

providers. There has also been special funding awarded to many project areas to assess 

communication, education, elimination, and missed opportunities. In addition, there have been 

partnerships with other organizations. 

Since NIS data for 2014 will not be available until sometime next year, to get an idea of what is 

happening in 2014, cumulative doses distributed in the US were assessed for 2012, 2013, and 

2014. Of note, the number of doses administered is not known. This is just to show distributed 

doses. There was an increase between 2012 and 2013, mirroring the 3.5% increase observed 

in NIS-Teen between those years. Through August 2014, doses distributed in 2014 were 

similar to 2013. 

Earlier in this session, there was a review of 9-valent HPV vaccine data and GRADE. A review 

of information on 2-dose schedules was presented to ACIP during the June 2014 meeting. This 

included data from trials on 2-dose schedules, regulatory approvals and recommendations, 

countries using 2-dose schedules, and considerations for the US. 

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Most of the data on 2-dose schedules are from immunogenicity studies. These studies have 

shown very high seroconversion rates with 2 doses, and GMTs that are non-inferior after 2 

doses given at 0 and 6 months in females 9 through 14 years of age compared to 3 doses in 

females 16 through 26 years of age who received the traditional 3-dose schedule. There are 

also data from a post-hoc analysis of a 3-dose RCT of the bivalent vaccine that found high 

efficacy for 2 doses. There are a variety of data from post-licensure effectiveness studies. In 

general, these found lower effectiveness for 2 versus 3 doses for a variety of outcomes. 

However, these studies have many limitations, one of which is that the 2-dose recipients did not 

receive a 0, 6 months schedule. They were persons who were supposed to receive a 3-dose 

schedule but did not complete it. Second, there could have been confounding in these studies 

due to differences between the 2-dose and 3-dose recipients. 

The following table shows immunogenicity studies of bivalent and quadrivalent vaccine 

comparing 2 and 3 doses. The top 3 are bivalent vaccine trials and the bottom 2 are 

quadrivalent vaccine trials. To date there are two published studies for bivalent vaccine and 1 

of quadrivalent: 

 

The Romanowski and Puthanakit studies were included in the licensure submissions that GSK 

submitted for the bivalent vaccine. The Dobson study was included in the submission for the 

quadrivalent vaccine in some countries. Because the US is primarily using the quadrivalent 

vaccine, Dr. Markowitz further described the Dobson study. The Dobson study was a 2- versus 

3-dose immunogenicity trial. One experimental group received 2 doses at 0 and 6 months and 

9 to 13 years. Two comparison groups received 3 doses, one group of 9 through 13 year old 

girls and one group of 16 through 26 year old women. The primary analysis was a comparison 

of the 2-dose 9 through 13 year old group with the 3-dose 16 through 26 year old group. In this 

comparison, non-inferior criteria were met and the antibody response was higher in the 2-dose 9 

through 13 year old group. In the analysis comparing the 2-dose and 3-dose schedules in the 9 

through 13 year old group, non-inferiority was lost for HPV 18 by 24 months and for HPV 6 by 

36 months. 

HPV2 and HPV4 have regulatory approval for use as 2-dose schedules from the European 

Medicines Agency (EMA) and a variety of countries. WHO changed the recommendations in 

2014. A 2-dose HPV vaccination schedule is recommended if vaccination is initiated before 15 

years. The minimal interval between doses is 6 months. A 3-dose schedule remained 

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recommended if vaccination initiated on or after 15 years. A 3-dose schedule (0, 1-2, 6 months) 

remains recommended for immunocompromised individuals, including those known to be HIVinfected. Several countries recommended 2-dose schedules before the WHO recommendation 

and regulatory approvals, and more are changing to 2-dose schedules. 

In the US, there have been no submissions to FDA for 2-dose schedules. There are no plans 

for submissions to FDA for the bivalent or quadrivalent vaccines. For the 9-valent vaccine, 

there are no data on 2-dose schedules in the BLA currently under consideration by FDA. A trial 

comparing 2-dose and 3-dose schedules has been initiated by the manufacturer. This trial 

started in December 2013 and the last patient is scheduled to complete the study in July 2015. 

There are 5 study arms, with 3 experimental 2-dose schedule arms in 9 through 14 year olds. 

Two comparison groups are receiving a 3-dose schedule in the standard 0,2,6 month schedule. 

One of the comparison groups includes 9 through 14 year olds, and the other includes 16 

through 26 year olds [Clinicaltrials.gov identifier NCT01984697].

Given the expected licensure of 9-valent HPV vaccine and the status of data on 2-dose 

schedules, options for recommendations have been discussed by the WG. There two basic 

approaches that could be taken by ACIP. One is to consider HPV9 as a 3-dose schedule and to 

wait to consider 2-dose schedules when data are available from the ongoing 2- versus 3-dose 

trial for 9-valent vaccine. The other option is to consider 2-dose schedules now for HPV2 and 

HPV4 based on available data. 

To review some considerations for 9-valent vaccine (HPV9) that pertain to both options, in the 

BLA submitted to FDA in December 2013, there are data from 3-dose schedule in females 9 

through 26 years of age and males 9 through 15 years of age. In contrast to the situation with 

PCV7 and PCV13, HPV4 likely will continue to be available for 12 to 18 months after HPV9 is 

licensed. This differs from the situation with the PCV7 to PCV13 transition and impacted the 

WG’s proposed wording. The WG considered HPV9 for currently recommended ages in the 

US. However, because of the age groups included in the original BLA, HPV9 is expected to be 

licensed first for females 9 through 26 years of age and males 9 through 15 years of age. Use 

in males older than age15 would be off-label initially. Immunogenicity data in males 16 through 

26 years of age were presented to ACIP earlier in this session. These data would be used to 

support licensure in the older aged males. The WG also considered that HPV9 would provide 

little additional benefit for males compared with HPV4. However, programmatic issues were 

considered by the ACIP WG, such as stocking different vaccines and the need to have different 

HPV vaccines for different age groups or sexes. 

The first option is to consider HPV9 as a 3-dose schedule and to consider 2-dose schedules 

when data are available for this vaccine. In the draft wording that follows, the first two bullets 

are the same as the current recommendations and state the vaccination ages. The third bullet 

differs, with HPV9 included as one of the vaccines that can be used for vaccination of females 

or males. The last bullet states the 3-dose schedule: 

Option 1 

 ACIP recommends routine HPV vaccination at age 11 or 12 years for females and 

males. The vaccination schedule can be started beginning at age 9 years. 

 Vaccination is also recommended for females aged 13 through 26 years and for males 

aged 13 through 21 years who have not been previously vaccinated. Males aged 22 

through 26 years may be vaccinated. 

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 Vaccination of females is recommended with HPV2, HPV4 (as long as this formulation is 

available) or HPV9. Vaccination of males is recommended with HPV4 (as long as this 

formulation is available) or HPV9. 

 A 3-dose schedule is recommended with the second dose 1-2 months after the first dose 

and the third dose 6 months after the first dose. 

To conceptualize the recommendations, the following table shows what this recommendation 

would look like. It is essentially the current recommendation with HPV9 as one of the options 

for vaccination for females and males. At the bottom is a note about what part of this 

recommendation is off label: 

Many other parts of the recommendation would need to be drafted. The following example 

shows some of the additional proposed wording that would be included for any option: 

 HPV2, HPV4 and HPV9 all protect against HPV types 16 and 18, types that cause about 

66% of cervical cancers and the majority of other HPV-attributable cancers in the United 

States. HPV9 targets 5 additional cancer causing types, which account for about 15% of 

cervical cancers in the United States. HPV4 and HPV9 also protect against HPV types 6 

and 11, types that cause genital warts. 

 For protection against genital warts in addition to cancer causing HPV types, vaccination 

is recommended with HPV4 or HPV9. When HPV4 is no longer available, HPV9 can be 

used to complete a series begun with HPV4. 

The second option is to consider 2-dose schedules for HPV2 and HPV4 in 9 through 14 year 

olds based on available data. If this is considered, there are three options for HPV9 if that 

vaccine is licensed. The WG considered the first suboption. For the second suboption, the WG 

felt that there are no data, but a trial is ongoing and data will be available in less than one year. 

Regarding the third suboption, to postpone a recommendation for HPV9 until data from 2-dose 

trial, the WG had concerns about delay in vaccination waiting for HPV9 availability if this 

approach was taken. 

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Following is the second option considered by the WG, which is a 2 dose schedule for HPV2 and 

HPV4 in 9 through 14 year olds and a 3-dose schedule for HPV9. For this recommendation, the 

first part of recommendation would be the same as the current recommendations. As in Option 

1, HPV9 would become one of the recommended vaccines. The second bullet addresses the 

different schedules. If the vaccination series is started with HPV2 or HPV4 before age 15 years 

a 2-dose schedule (0,6 months) is recommended. If the vaccination series is started with HPV9 

before age 15 years, a 3-dose scheduled is recommended (0,2,6 months). If the vaccination 

series is started with any HPV vaccine at 15 years or older a 3-dose schedule is recommended 

(0,1-2 and 6 months): 

Option 2 

 Vaccination of females is recommended with HPV2, HPV4 (as long as this formulation is 

available) or HPV9. Vaccination of males is recommended with HPV4 (as long as this 

formulation is available) or HPV9. 

 If the vaccination series is started with HPV2 or HPV4 before age 15 years a 2-dose 

schedule is recommended (0,6 months). If the vaccination series is started with HPV9 

before age 15 years, a 3-dose scheduled is recommended (0,2,6 months). 

 If the vaccination series is started at age 15 years or older with any HPV vaccine a 3-

dose schedule is recommended (0,1-2 and 6 months). 

It is important to note that the 9 through 14 year old age group is the age group included in the 

bivalent trials of 2 doses. The one study available for HPV4 included girls 9 through 13 years, 

but the ongoing 9-valent trial includes girls 9 through 14 years. 

A variation of Option 2 would be to recommend HPV9 in a delayed 3-dose schedule so that the 

first and second doses would be similar to the 2-dose schedule. As was presented to the WG in 

June 2014, for HPV2 and HPV4, 3-dose schedules with longer intervals between doses have 

been found to be non-inferior to the currently recommended schedule. The following show 

Options 2 and 2a in table format: 

 

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There are pros and cons to each of these options. The WG felt that Option 1 was the simplest, 

given that there would be less confusion for providers and the public. Reconsideration can be 

given to 2-dose schedules when the 2-dose trial data are available for HPV9. In terms of Option 

2, there is general interest in 2-dose schedules. These could facilitate delivery and decrease 

resources. This might also increase initiation, although there are no data on this issue. In the 

current situation, there is concern about potential for confusion for providers if there are different 

recommendations for different vaccines and frequent changes in recommendations. There is 

the remaining question about differences in duration of protection for 2 versus 3 doses. In 

addition, a 2-dose schedule would be off-label for HPV2 and HPV4 and manufacturers have no 

plans for submission to FDA for these. 

In conclusion, Dr. Markowitz posed the following questions: 

 Are there other recommendation options that ACIP members want to consider? 

 What other data would ACIP members want to see before February 2015 or during the 

February 2015 ACIP meeting? 

 Which option do ACIP members prefer?

Discussion Points 

Dr. Vazquez asked about revaccination of individuals who are fully vaccinated with quadrivalent 

vaccine. 

Dr. Markowitz replied that the WG is not enthusiastic about revaccination recommendations. 

They are still exploring some of the cost-effectiveness issues. As shown by Dr. Brisson, it does 

not appear that this would be cost-effective in the most favorable scenario. The WG also feels 

that resources should be spent on vaccinating more people. Therefore, the decision was made 

not to make a specific recommendation for revaccination at this time. 

Dr. Harrison liked the simplicity of Option 1. 

Dr. Kempe also like the simplicity of Option 1. She pointed out that it would be extremely 

difficult to ignore the 9-valent vaccine and not make a recommendation about that. If that is the 

case, it means potentially 3 different vaccines with different dosing patterns. That will be very 

difficult. 

Dr. Bennett agreed with the simplicity argument, but expressed concern that if Option 2 was 

selected and the 9-valent study later shows inferior immunogenicity with 2 doses, they would be 

stuck forever. In terms of a pathway, it is important to deal with implementation of the 9-valent 

vaccine and then figuring out the number of doses. 

Ms. Pellegrini thought there would be simplicity in Option 1 in terms of providers, but for families 

there is less simplicity to a 3-dose schedule than a 2-dose schedule. There is also the 

consideration that if ACIP recommends 3 doses, they have to be cognitive of the fact that they 

may have to revise the recommendation a year later to 2 doses. That has implications for how 

people view ACIP’s work.

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Picking up on that point, Dr. Temte said he could see a benefit eventually in leveraging the 

biology of younger people into something that has profound effects. It will send a powerful 

message to parents to tell them that if they begin this series before the age of 15, only 2 doses 

will be needed, but if they begin it after that, 3 doses will be needed. This could result in a 

profound increase in rates. 

Dr. Bennett asked if Ms. Pellegrini and Dr. Temte were saying to make a recommendation “out 

of the box” with only 2 doses for 9-valent. 

Dr. Temte emphasized that he would “eventually” like to see that. They do have to be careful 

not to pre-anticipate the results of studies being conducted. If such results are found, he would 

be very proactive in regard to the benefit for families. 

Dr. Schuchat reminded everyone that the results that might be forthcoming in a year or so 

regarding a 2-dose schedule will be about a 0, 6 month interval not a 0, 2 month interval. In 

addition to whatever sequencing and timing is determined, she does not think the science 

suggests that 0,2 is the same as 0, 6. 

Dr. Kempe agreed that having the option of 2 doses if starting early could be a very strong 

leverage. She also agreed that flip-flopping a lot on recommendations has the potential to 

destroy credibility. That is a strong case for recommending the 3-dose schedule for 9-valent 

vaccine, but making the transition as quickly as possible to 2 doses. 

Dr. Riley’s concern with recommending 2 doses at this point regarded whether that was 

appropriate since they are awaiting completion of the studies. Also, it was not clear to her 

whether there would be any data regarding the length of protection from 2 doses. 

Ms. Pellegrini clarified that making recommendations with little or no evidence would always be 

her last choice, but there was a prospect of having evidence in the near future. She was not 

trying to say that they should presume what the evidence would be, but instead was suggesting 

that they build into the recommendations the recognition of that and strongly telegraph that 

changes may be coming soon. 

Dr. Reingold liked the simplicity of the first option, but pointed out that the duration of protection 

of a 3-dose schedule is also not known. 

When thinking about HPV vaccines, to Dr. Karron there is always the question of what can be 

assumed by inference from 4-valent versus 9-valent. She was not personally convinced that 

they would need to wait for long-term duration data for 2 doses to be able to move to a 2-dose 

schedule. They might be able to use data from the quadrivalent vaccine by inference to think 

about that. She agreed that it would be helpful to have the initial efficacy data from the 2-dose 

schedule for the 9-valent vaccine. 

Dr. Bolongia thought the incremental cost-effectiveness analysis was very helpful, which was 

done on 3 doses. If he recalled correctly, it was not particularly sensitive to the duration of 

protection. While it would be great to go to 2 doses, the science did not seem to support that 

yet. 

Dr. Brisson replied that duration of the protection was assumed to be the same for the 4-valent 

and 9-valent vaccine, and the analysis was not sensitive to that assumption. 

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Dr. Middleman (SAHM) pointed out that it is important to recognize that the majority of those 

who start the HPV vaccination series complete it. She was not sure whether 2 doses versus 3 

doses should become a major issue. More important is how to get people to start the series. 

There was a 2-dose recommendation for a specific age group for the Hepatitis B vaccine for one 

of the products, which she thought became very confusing. It is important to remember the 

historical perspective. 

Dr. Schuchat reminded everyone that in the early days of Hib vaccine, there were different 

vaccines with difference schedules that providers had no problem with because they were so 

enthusiastic about an effective Hib vaccine. 

Dr. Temte pointed out the importance of better understanding why only 50% of potential 

recipients choose to get the first dose. He agreed that once the first dose is given, the series is 

usually completed. However, that is only 1 out of 2 people. He is much more interested in 

having the first dose provided at age 11, 12, or 13 than at age 18, 19, or 20. There are some 

profound effects in terms of how to market this vaccine. While it is not ACIP’s job to market 

vaccines, it is their job to keep in mind what practitioners face on a daily basis in trying to 

implement ACIP’s recommendations.

Regarding off-label use, Dr. Pickering asked whether studies are being conducted to clarify 

whether there would be any data forthcoming on the 2-dose 0,12 months 9-valent vaccine. That 

would fit in nicely with the yearly recommendations adolescents have for their visits. 

Dr. Markowitz replied that the 9-valent trial currently being conducted does have a 0, 12 month 

arm, so there will be data. One of the trials conducted with a bivalent vaccine, which is not 

published yet but has been presented, also had a 0, 12 month arm. That study showed that the 

0,12 month results looked about the same as 0, 6 months. They were both non-inferior to the 

older women. Those data have only been presented at a meeting. Most of the studies have 

been on a 0,6 month schedule. The reason she highlighted in the tables what would be off-label 

was because she wanted to point out for ACIP that in any of the scenarios proposed, there 

would be at least one off-label recommendation. In order for Option 1 not to have an off-label 

component, they will have to recommend the quadrivalent vaccine for 16 through 26 year old 

males until the 9-valent vaccine is licensed in that age group. Even though the simplest 

recommendation will contain an off-label component for older males, that is temporary because 

Merck is going to be submitting the data presented during this session to FDA. However, it will 

take the usual amount of time to be reviewed by FDA. If ACIP recommends bivalent or 

quadrivalent 2-dose schedules, those will remain off-label because the companies are not 

submitting any data to the FDA on the bivalent and quadrivalent vaccines. 

Dr. Temte asked whether the members had given Dr. Markowitz sufficient feedback. 

Dr. Markowitz said they had, but she wanted to understand more about the comment that was 

made regarding giving people some foresight into what is coming and how they recommend 

doing that. 

Ms. Pellegrini said she would be delighted to discuss that offline. 

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Dr. Ault (ACOG) was glad to hear people talk about pragmatic issues. One pragmatic issue that 

gynecologists have to deal with every day is that they are not seeing patients in the earliest teen 

years. If there is a 2-dose schedule, payers will only pay for 2 doses. People will leave the 

office with zero doses if they think they have to pay for the extra third dose. 

Dr. Temte noted that there had been some recent changes on recommendations for annual 

gynecologic exams. He asked Dr. Ault how common it is for women to present every 12 months 

as opposed to sporadic visits in between. He also asked AAFP and AAP to weigh in on their 

abilities to carry out the current 0, 1-2, 6 month schedule versus a 0, 12 month schedule. 

Dr. Ault (ACOG) responded that there are still recommendations about mammographies, breast 

exams, blood pressure checks for people using oral contraceptives, pregnancy planning, et 

cetera that probably got short shrift during the annual exam when the concentration was on the 

Pap smear. The well-woman visit is being reviewed by ACOG. As a specialty, they could 

certainly do a better job with immunizations as well. 

Dr. Loehr (AAFP) responded that logistically he has turned it into a 0, 6-week, and 6-month 

schedule because the two 6s make it easier for his staff and patients to remember. The 6-week 

visit is very easy for people because it is not that far away. The 6-month is much harder and is 

usually caught up at the next well-child check when missed. 

Dr. Kimberlin (AAP) said that clearly 2 visits would be simpler than 3 for an adolescent. That 

said, he believes the AAP would rather wait for the pending data that can drive the discussion 

and decision. 

Dr. Temte concluded that there seemed to be a consensus that a 2-dose schedule is something 

to strive for in the future, but until data and evidence are available, they are hesitant to take that 

leap. While there may be some incrementalism, it should be evidence-based incrementalism. 

Dr. Middleman (SAHM) clarified that SAHM would agree with that process. The concern about 

2 doses for one product at one time is an issue, and she just wanted to make sure that people 

were clear on SAHM’s position on that.

Public Comment 

Dr. William Schaffner 

National Foundation for Infectious Diseases 

On behalf of the National Foundation for Infectious Diseases (NFID), I am pleased to announce 

a new Call to Action from NFID and the Council of State and Territorial Epidemiologists (CSTE) 

that urges healthcare professionals to be stronger advocates for HPV vaccination. A hardcopy 

of the report was included in the packet for ACIP members and liaisons, and additional copies 

are on the handout table outside the room. It is troubling to NFID and to me personally, and I 

hope to all of you, that extremely effective HPV vaccines are available but are still underutilized, 

leaving adolescents vulnerable to HPV-related cancers. The Call to Action is supported by 

many professional organizations. Among its conclusions, healthcare professionals need to 

recommend HPV vaccine with the same strength and conviction that they recommend other 

adolescent vaccines—same day, same way. It is their responsibility to educate themselves and 

everyone in their practice about HPV and the benefits of vaccination so that positive messages 

reach their patients and, of course, parents. Finally, a drum we beat often, they need to make 

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HPV vaccination routine and eliminate missed opportunities. First dose coverage in girls and 

boys 13 through 17 would reach over 90% if they received HPV vaccine at the same time they 

received other recommended vaccines. The Call to Action is available on NFID’s new HPV 

Resource Center. The website is available in the document. The resource center includes tools 

from a range of medical organizations to help healthcare professionals improve HPV vaccine 

delivery. Finally, NFID and CSTE will be hosting a series of webinars, with the first scheduled 

for November 4th, to share the report and its findings. Information about the webinars and a link 

to the register is available at the HPV Resource Center website and on a card, some of which 

may still be on the handout table. Thanks. The link to the HPV Resource Center is: 

http://www.adolescentvaccination.org/hpv-resource-center. 

 

No public comments were offered during this session. 

Day 2: Public Comment

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Upon reviewing the foregoing version of the October 29-30, 2014 ACIP meeting minutes, Dr. 

Jonathan Temte, ACIP Chair, certified that to the best of his knowledge, they are accurate and 

complete. His original, signed certification is on file with the Management Analysis and Services 

Office (MASO) of CDC. 

Certification

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CHAIR 

TEMTE, Jonathan L., MD, PhD 

Professor of Family Medicine 

University of Wisconsin School of Medicine and Public Health 

Madison, WI 

Term: 07/01/2011-06/30/2015 

EXECUTIVE SECRETARY 

PICKERING, Larry K., MD 

Senior Advisor to the Director 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Atlanta, GA 

MEMBERS 

BENNETT, Nancy, MD, MS 

Professor of Medicine and Community and Preventive Medicine 

University of Rochester School of Medicine and Dentistry 

Rochester, NY 

Term: 07/01/2011-06/30/2015 

BELONGIA, Edward, MD 

Director 

Center for Clinical Epidemiology & Population Health 

Marshfield Clinic Research Foundation 

Marshfield, WI 

Term: 07/01/2014-06/30/2018 

BOCCHINI, Joseph A., Jr., MD 

Professor and Chairman 

Department of Pediatrics 

Louisiana State University Health Sciences Center 

Shreveport, LA 

Term: 07/01/2011-06/30/2015 

CAMPOS-OUTCALT, Douglas, MD, MPA 

Medical Officer 

Mercy Care Plan 

Phoenix, AZ 

Term: 07/01/2011-06/30/2015 

ACIP Membership Roster

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HARRIMAN, Kathleen, PhD, MPH, RN 

Chief, Vaccine Preventable Disease Epidemiology Section 

Immunization Branch 

California Department of Public Health 

Richmond, CA 

Term: 07/01/2012 – 06/30/2016 

153

HARRISON, Lee H., MD 

Professor of Medicine and Epidemiology 

Infectious Diseases Epidemiology Research Unit 

University of Pittsburgh 

Pittsburgh, PA

Term: 07/01/2012 – 06/30/2016 

KARRON, Ruth A., MD 

Professor and Director 

Center for Immunization Research 

Department of International Health 

Johns Hopkins Bloomberg School of Public Health 

Baltimore, MD 

Term: 07/01/2012 – 06/30/2016 

KEMPE, Allison, MD, MPH 

Professor of Pediatrics 

Director of Primary Care Fellowship 

University of Colorado School of Medicine 

Director of Research 

Division of General Academic Pediatrics 

Director of Children’s Outcomes Research Program

The Children’s Hospital of Denver

Denver, CO 

Term: 07/01/2013 - 06/30/2017 

PELLEGRINI, Cynthia 

Senior Vice President 

Public Policy and Government Affairs 

March of Dimes 

Washington, DC 

Term: 07/01/2013-06/30/2017 

REINGOLD, Arthur L., MD 

Professor of Epidemiology 

Edward Penhoet Distinguished for Global Health and Infectious Disease 

Associate Dean for Research 

School of Public Health 

University of California 

Berkeley, CA 

Term: 07/01/2013-06/30/2017 

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RILEY, Laura E., MD 

Associate Professor, Obstetrics, Gynecology and Reproductive Medicine 

Harvard Medical School 

Maternal Fetal Medicine 

Massachusetts General Hospital 

Boston, MA 

Term: 07/01/2014-06/30/2018 

ROMERO, José R., MD, FAAP 

Professor of Pediatrics 

Horace C. Cabe Endowed Chair in Infectious Diseases

Director, Pediatric Infectious Diseases Section 

University of Arkansas for Medical Sciences and 

Arkansas Children's Hospital 

Director, Clinical Trials Research 

Arkansas Children's Hospital Research Institute 

Little Rock, AR 

Term: 07/01/2014-06/30/2018 

RUBIN, Lorry, MD 

Director 

Pediatric Infectious Diseases 

Steven and Alexandra Cohen Children’s Medical Center of New York

North Shore-Long Island Jewish Health System 

New Hyde Park, NY 

Professor of Pediatrics, Hofstra-North Shore LIJ School of Medicine 

Hempstead, NY 

Term: 07/01/2012 – 06/30/2016

VÁZQUEZ, Marietta, MD 

Associate Professor of Pediatrics 

Department of Pediatrics 

Yale University School of Medicine 

New Haven, CT 

Term: 07/01/2011-06/30/2015 

EX OFFICIO MEMBERS 

Centers for Medicare and Medicaid Services (CMS)

HANCE, Mary Beth 

Senior Policy Advisor 

Division of Quality, Evaluations and Health Outcomes 

Children and Adults Health Programs Group 

Center for Medicaid, CHIP and Survey & Certification 

Centers for Medicare and Medicaid Services 

Baltimore, MD 

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Department of Defense (DoD)

GEIBE, Jesse, MD, MPH, MBA 

CDR, Medical Corps 

Defense Department Liaison Officer 

Centers for Disease Control and Prevention 

Atlanta, GA 

Department of Veterans Affairs (DVA) 

KINSINGER, Linda S., MD, MPH 

Chief Consultant for Preventive Medicine 

Office of Patient Care Services 

National Center for Health Promotion and Disease Prevention

Durham, North Carolina 

Food and Drug Administration (FDA) 

SUN, Wellington, MD 

Director, Division of Vaccines and Related Product Applications 

Office of Vaccines Research and Review 

Food and Drug Administration 

Rockville, MD 

Health Resources and Services Administration (HRSA) 

HOUSTON, A. Melissa, MD, MPH, FAAP 

Chief Medical Officer 

Division of Vaccine Injury Compensation 

Health Resources and Services Administration 

Rockville, MD 

Indian Health Service (IHS)

GROOM, Amy, MPH 

Immunization Program Manager 

Indian Health Service 

Albuquerque, NM 

National Vaccine Program Office (NVPO) 

GELLIN, Bruce, MD, MPH 

Director 

National Vaccine Program Office 

Department of HHS, Public Health and Science 

Washington, DC 

National Institutes of Health (NIH) 

GORMAN, Richard L., MD 

Associate Director for Clinical Research 

Division of Microbiology and Infectious Diseases/NIAID 

National Institute of Health 

Bethesda, MD 

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LIAISON REPRESENTATIVES 

American Academy of Family Physicians (AAFP) 

LOEHR, Jamie, MD, FAAFP 

Cayuga Family Medicine (Owner) 

Ithaca, NY 

American Academy of Pediatrics (AAP) 

BYINGTON, Carrie L., MD 

Chair, AAP Committee on Infectious Diseases 

H.A. and Edna Benning Presidential Professor of Pediatrics 

Associate Vice President for Faculty and Academic Affairs 

University of Utah Health Sciences Center 

Salt Lake City, UT 

American Academy of Pediatrics (AAP) 

Red Book Editor 

KIMBERLIN, David, MD 

Professor of Pediatrics 

Division of Pediatric Infectious Diseases 

The University of Alabama at Birmingham School of Medicine 

Birmingham, AL 

American Academy of Physician Assistants (AAPA) 

LÉGER, Marie-Michèle, MPH, PA-C 

Senior Director, Clinical and Health Affairs 

American Academy of Physician Assistants 

Alexandria, VA 

American College Health Association (ACHA) 

EVEN, Susan, MD 

Executive Director 

Student Health Center 

University of Missouri 

Columbia, MO 

American College of Obstetricians and Gynecologists (ACOG) 

AULT, Kevin A., MD 

Professor and Division Director, General Obstetrics and Gynecology 

Department of Obstetrics and Gynecology 

Kansas City, KS 

American College of Physicians (ACP) 

FRYHOFER, Sandra Adamson., MD, MACP 

Adjunct Associate Professor of Medicine 

Emory University School of Medicine 

Atlanta, GA 

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American College of Physicians (ACP) (alternate) 

POLAND, Gregory A., MD 

Mary Lowell Professor of Medicine and Infectious Diseases 

Mayo Clinic 

Rochester, MN 

American Geriatrics Society (AGS) 

SCHMADER, Kenneth, MD 

Professor of Medicine-Geriatrics 

Geriatrics Division Chief 

Duke University and Durham VA Medical Centers 

Durham, NC 

America’s Health Insurance Plans (AHIP)

NETOSKIE, Mark J., MD, MBA, FAAP 

Market Medical Executive, CIGNA 

Houston, TX 

American Medical Association (AMA) 

FRYHOFER, Sandra Adamson., MD, MACP 

Adjunct Associate Professor of Medicine 

Emory University School of Medicine 

Atlanta, GA 

American Nurses Association (ANA) 

RITTLE, Charles (Chad), DNP, MPH, RN, FAAOHN 

Assistant Professor, Nursing Faculty 

Chatham University, School of Health Sciences 

Pittsburgh, PA 

American Nurses Association (ANA) (alternate)

HAYES, Carol E., CNM, MN, MPH 

Advanced Practice Nurse 

American Nurses Association 

American College of Nurse Midwives 

DeKalb Board of Health 

Decatur, GA

American Osteopathic Association (AOA) 

GROGG, Stanley E., DO, FACOP 

Associate Dean/Professor of Pediatrics 

Oklahoma State University-Center for Health Sciences 

Tulsa, OK 

American Pharmacists Association (APhA) 

FOSTER, Stephan L., PharMD, FAPhA 

Professor and Vice Chair, Department of Clinical Pharmacy 

University of Tennessee Health Sciences Center, College of Pharmacy 

Memphis, TN 

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Association of Immunization Managers (AIM) 

MOORE, Kelly, MD, MPH 

Medical Director, State Immunization Program 

Tennessee Department of Health 

Nashville, TN 

Association for Prevention Teaching and Research (APTR) 

McKINNEY, W. Paul, MD 

Professor and Associate Dean 

University of Louisville School of Public Health and Information Sciences 

Louisville, KY 

Association of State and Territorial Health Officials (ASTHO) 

DWELLE, Terry L, MD, MPHTM, FAAP, CPH 

State Health Officer 

North Dakota Department of Health 

Bismarck, ND 

Biotechnology Industry Organization (BIO) 

LEWIN, Clement, PhD, MBA 

Head, Medical Affairs and Immunization Policy 

Novartis Vaccines and Diagnostics 

Cambridge, MA 

Council of State and Territorial Epidemiologists (CSTE) 

HAHN, Christine, MD 

State Epidemiologist 

Office of Epidemiology, Food Protection and Immunization 

Idaho Department of Health and Welfare 

Boise, ID 

Canadian National Advisory Committee on Immunization (NACI) 

GEMMILL, Ian MacDonald, MD, CCFP, FCFP, FRCP(C) 

Medical Officer of Health 

Kingston, Frontenac and Lennox & Addington Public Health 

Kingston, Ontario, Canada 

Department of Health, United Kingdom 

Vacant 

Infectious Diseases Society of America (IDSA) 

NEUZIL, Kathleen M., MD, MPH, FIDSA 

Vaccine Development Global Program (PATH) 

Clinical Professor 

Departments of Medicine and Global Health 

University of Washington School of Medicine 

Seattle, WA 

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Infectious Diseases Society of America (IDSA) (alternate)

BAKER, Carol J., MD 

Professor of Pediatrics 

Molecular Virology and Microbiology 

Baylor College of Medicine 

Houston, TX 

National Association of County and City Health Officials (NACCHO) 

ZAHN, Matthew, MD 

Medical Director, Epidemiology 

Orange County Health Care Agency 

Santa Ana, CA 

National Association of Pediatric Nurse Practitioners (NAPNAP) 

STINCHFIELD, Patricia A., RN, MS, CPNP 

Director 

Infectious Disease/Immunology/Infection Control 

Children's Hospitals and Clinics of Minnesota 

St. Paul, MN 

National Foundation for Infectious Diseases (NFID) 

SCHAFFNER, William, MD 

Chairman, Department of Preventive Medicine 

Vanderbilt University School of Medicine 

Nashville, TN 

National Immunization Council and Child Health Program, Mexico 

VILLASEÑOR RUIZ, Ignacio 

Directora del Programa de Atencion da la Salud de la Infancia y la Adolescencia / Director 

General, Child and Adolescent Health 

Centro Nacional Para la Salud de la Infancia Y La Adolescencia / National Center for Child and 

Adolescent Health 

Ministry of Health / Secretaría de Salud 

Mexico 

National Medical Association (NMA) 

WHITLEY-WILLIAMS, Patricia, MD 

Professor and Chair 

University of Medicine and Dentistry of New Jersey 

Robert Wood Johnson Medical School 

New Brunswick, NJ 

National Vaccine Advisory Committee (NVAC) 

ORENSTEIN, Walt, MD 

Chair, NVAC 

Associate Director, Emory Vaccine Center 

Emory University 

Atlanta, GA 

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Pediatric Infectious Diseases Society (PIDS) 

SAWYER, Mark H, MD 

Professor of Clinical Pediatrics 

University of California, San Diego School of Medicine 

San Diego, CA 

Pediatric Infectious Diseases Society (PIDS) (alternate)

ENGLUND, Janet A., MD 

Professor, Department of Pediatrics 

Seattle Children's Hospital

University of Washington 

Seattle, WA 

Pharmaceutical Research and Manufacturers of America (PhRMA) 

BRAGA, Damian A. 

President, sanofi pasteur 

Swiftwater, PA 

Society for Adolescent Health and Medicine (SAHM) 

MIDDLEMAN, Amy B., MD, MSEd, MPH 

Professor of Pediatrics 

Chief, Section of Adolescent Medicine 

University of Oklahoma Health Sciences Center 

Oklahoma City, OK 

Society for Healthcare Epidemiology of America (SHEA) 

WEBER, David, MD, MPH 

Professor of Medicine, Pediatrics, and Epidemiology 

University of North Carolina Schools of Medicine and Public Health 

Medical Director, Hospital Epidemiology and Occupational Health, UNC Health Care 

University of North Carolina 

Chapel Hill, NC 

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