DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION

Advisory Committee on 

Immunization Practices (ACIP)

Summary Report

February 22-23, 2017

Atlanta, Georgia 

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Table of Contents Page

Agenda 4-5 

Acronyms 6-9 

Wednesday: February 22, 2017

Welcome and Introductions 10-13

Dr. Schuchat’s Welcoming Remarks 13-14

Hepatitis Vaccine

 Introduction

 Revaccination for Unprotected Infants Born to Hepatitis B Surface Antigen (HBsAg)-Positive Mothers

 Cost Analysis of Single‐Dose Revaccination for Infants Born to Hepatitis B Surface Antigen (HBsAg)‐

Positive Mothers

 Consideration of Single Dose Revaccination for Unprotected Infants Born to Hepatitis B Surface 

Antigen (HBsAg)‐Positive Mothers

 Public Comment

 Recommendation Vote

 VFC Resolution

15-32

Influenza

 Introduction

 Influenza Surveillance Update

 Vaccine Effectiveness Update

 FluMist® Update

 Afluria® Update

 Fluzone® High-Dose Update

32-61

Herpes Zoster Vaccines

 Introduction

 Safety Summary of Candidate Vaccine, Herpes Zoster Subunit (HZ/su)

 GRADE of HZ/su

 Consideration for Herpes Zoster Vaccine Policy

62-73

Meningococcal Vaccines

 Introduction

 Consideration for MenB Booster Doses in Groups at Increased Risk for Serogroup B Meningococcal 

Disease

 Update on the Epidemiology of Meningococcal Disease and Guidance for the Control of Meningococcal 

Disease Outbreaks in the US

74-91

Global Immunization Updates

 Global Polio Eradication Initiative

 Global Measles/Rubella Elimination Initiative

91-101

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Public Comment 101-102

Thursday: February 23, 2017

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)

102-106

Vaccination Errors 106-115

Mumps Disease and Vaccine

 Introduction

 Mumps Epidemiology and Vaccination Recommendations in the United States

115-125

Dengue Virus Vaccines

 Introduction

 Dengue Epidemiology and Vaccine Development

125-132

Zika Virus Vaccines

 Zika Virus Epidemiology Update

 Zika Vaccines in Development

132-145

Adult Immunization Schedule

 Introduction

 Implementation of Standards for Adult Immunization Practice

145-150

Yellow Fever Vaccine

 Introduction 

 Update on Yellow Fever Vaccine Supply

150-153

Public Comment 153-158

Certification 159

Membership Roster 160-168

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Acronyms

AAFP American Academy of Family Physicians 

AAP American Academy of Pediatrics

ABCs Active Bacterial Core surveillance 

ACIP Advisory Committee on Immunization Practices

ACNM American College of Nurse Midwives 

ACOG American Congress of Obstetricians and Gynecologists

ACP American College of Physicians 

ADE Antibody Dependent Enhancement 

AE Adverse Events

AFI Acute Febrile Illness 

AFIX Assessment, Feedback, Incentives, and eXchange

AIM Association of Immunization Managers 

ANA American Nurses Association 

ASPR Assistant Secretary for Preparedness and Response 

BARDA Biomedical Advanced Research and Development Authority 

BIO Biotechnology Innovation Organization 

BLA Biologics License Application 

BLS Bureau of Labor Statistics 

BPL β-Propiolactone 

CDC Centers for Disease Control and Prevention

C. difficile Clostridium difficile

cVDPV Circulating Vaccine-Derived Polioviruses 

CGMPs Current Good Manufacturing Practice

CIRN Canadian Immunization Research Network 

CLD Chronic Liver Disease 

CMS Center for Medicare and Medicaid

CNS Central Nervous System 

COI Conflict of Interest 

COID Committee on Infectious Disease, AAP 

CONUS Continental United States 

COPD Chronic Obstructive Pulmonary Disease 

CRS Congenital Rubella Syndrome 

CWRU Case Western Reserve University’s 

DCD Department of Communicable Diseases Prevention, ERMO

DF Dengue Fever 

DFO Designated Federal Official

DGMQ Division of Global Migration and Quarantine 

DHA Defense Health Agency 

DHF Dengue Hemorrhagic Fever

DNA Deoxyribonucleic Acid 

DoD Department of Defense

DSS Dengue Shock Syndrome 

DtaP Diphtheria and Tetanus Toxoid and Pertussis 

DVA Department of Veterans Affairs

DVBD Division of Vector-Borne Diseases 

DVH Division of Viral Hepatitis 

EAP Expedited Access Pathway 

ED Emergency Department

EHDB Enteric and Hepatic Diseases Branch

EHR Electronic Health Record 

EMA European Medicines Agency 

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EMR Electronic Medical Record 

EMRO Regional Office for the Eastern Mediterranean 

EPHBPP Enhanced Perinatal B Prevention Hepatitis B Prevention Program 

EMA European Medicines Agency

EOCs Emergency Operation Centers 

FDA Food and Drug Administration

GBS Guillain-Barré Syndrome 

GID Global Immunization Division 

GMC Geometric Mean Concentrations 

GPEI Global Polio Eradication Initiative 

GMT Geometric Mean Titers 

GRADE Grading of Recommendation Assessment, Development and Evaluation 

GSK GlaxoSmithKline 

HA Hemagglutinin 

HbeAg Hepatitis B e Surface Antigen 

HBIG Hepatitis B Immunoglobulin

HbsAg Hepatitis B Surface Antigen 

HBV Hepatitis B Vaccine 

HCP Healthcare Personnel 

HCV Hepatitis C Virus 

HD High-Dose

HepB Hepatitis B 

HepB-BD HepB Birth Dose 

HHS (Department of) Health and Human Services

HI Hemagglutination Inhibition 

Hib Haemophilus Influenzae Type B 

HIV Human Immunodeficiency Virus 

HPV Human Papillomavirus

HRSA Health Resources and Services Administration 

hSBA Human Complement Serum Bactericidal Antibody 

HZ Herpes Zoster 

HZ/su HZ Subunit Vaccine 

ICD International Classification of Diseases 

IDSA Infectious Disease Society of America 

IgA Immunoglobulin A

IHB Immunization Healthcare Branch 

IHR International Health Regulations 

IHS Indian Health Services

IIV Inactivated Influenza Vaccine 

ILI Influenza-Like Illness 

IMS Insurance Management Services 

IND Investigational New Drug 

IPD Invasive Pneumococcal Disease 

IPV Inactivated Polio Vaccine

IRB Institutional Review Board

ISD Immunization Services Division 

ITT Intention-To-Treat

ISO Immunization Safety Office

JAMA Journal of the American Medical Association 

JE Japanese Encephalitis

JID Journal of Infectious Diseases

LAIV Live Attenuated Influenza Vaccine 

LID Laboratory of Infectious Diseases 

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LPN Licensed Practical Nurse 

LTCF Long-Term Care Facilities 

MenACWY Quadrivalent Meningococcal Conjugate Vaccine

MenB Serogroup B Meningococcal Disease

MI Myocardial Infarction 

MMR Measles, Mumps and Rubella 

MMRV Measles, Mumps, Rubella, and Varicella

MMWR Morbidity and Mortality Weekly Report

MSM Men Who Have Sex With Men 

mRNA Messenger RNA 

NA Neuraminidase 

NACCHO National Association of County and City Health Officials 

NAIIS National Adult and Influenza Immunization Summit 

NAIP National Adult Immunization Plan 

NCAI National Coalition of Adult Immunization 

NCEZID National Center for Emerging and Zoonotic Infectious Diseases 

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

NCHS National Center of Health Statistics 

NCIRD National Center for Immunization and Respiratory Diseases 

NEJM New England Journal of Medicine

NFID National Foundation for Infectious Diseases 

NHANES National Health and Nutrition Examination Survey 

NHIS National Health Interview Survey 

NHP Non-Human Primates 

NIAID National Institute of Allergy and Infectious Diseases 

NIH National Institutes of Health

NIP National Immunization Plan

NMA National Meningitis Association

NNDSS National Notifiable Diseases Surveillance System 

NNT The Number-Needed-to-Treat 

NHs Nursing Homes 

NVAC National Vaccine Advisory Committee 

NVP National Vaccine Plan 

NVPO National Vaccine Program Office 

NYC New York City 

OMB Office of Management and Budget 

OPHPR Office of Public Health Preparedness and Response 

OPV Oral Polio Vaccine 

PAHO Pan American Health Organization 

PHBPP National Perinatal Hepatitis B Prevention Program 

PhRMA Pharmaceutical Research and Manufacturers of America 

pIMDs Potential Immune Mediated Diseases

PHN Post Herpetic Neuralgia 

Poly-A Polyadenosine

PRN Pertactin 

PT Pertussis Toxin 

PVST Post-Vaccination Serologic Testing

QIV Quadrivalent Influenza Vaccine 

qPCR Real-Time Polymerase Chain Reaction 

R&D Research and Development 

RCT Randomized Controlled Trial

RN Registered Nurse

RNA Ribonucleic Acid

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RSV Respiratory Syncytial Virus 

RT-PCR Reverse Transcriptase Polymerase Chain Reaction

S. aureus Staphylococcus aureus

SAEs Serious Adverse Events 

SAGE Strategic Advisory Group of Experts on Immunization 

SIA Supplementary Immunization Activities 

sBLA Supplemental Biologics License Application 

SCR Seroconversion Rate 

SD Standard-Dose

SES Socioeconomic Status 

SME Subject Matter Experts 

SRTI Systemic Respiratory Tract Infection 

TB Tuberculosis

TBE Tick Borne Encephalitis 

Tdap Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis

TDOC Sodium Tauro Deoxycholate 

TIV Trivalent Influenza Vaccine

UF Undifferentiated Fever 

UK United Kingdom

UN United Nations 

URI Urinary Tract Infection 

US United States

UTR Untranslated Region 

VAERS Vaccine Adverse Event Reporting System

VE Vaccine Efficacy

VFC Vaccines for Children

VICP Vaccine Injury Compensation Program 

VistA Veterans Information Systems and Technology Architecture 

VLP Virus-Like Particle 

VRBPAC Vaccines and Related Biological Products Advisory Committee VRBPAC

VSD Vaccine Safety Datalink

VZV Varicella Zoster Virus 

VTEU Vaccine and Therapeutic Evaluation Units 

WG Work Group

WGS Whole Genome Sequencing 

WHO World Health Organization

WNV West Nile Virus

WPV Wild Poliovirus 

WRAIR Walter Reed Army Institute of Research 

YF Yellow Fever

ZIP Zika in Infants and Pregnancy Study

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Call To Order / Welcome 

Nancy Bennett, MD, MS

ACIP Chair

Dr. Bennett called the February 2017 Advisory Committee on Immunization Practices (ACIP) 

meeting to order and welcomed those present.

 

Overview / Announcements 

Amanda Cohn, MD

Executive Secretary, ACIP / CDC

Dr. Cohn welcomed everyone to the February 2017 ACIP meeting. She indicated that the 

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

Web, and welcomed those who could not attend the meeting in person. She then recognized 

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

assist with various meeting functions: Ms. Stephanie Thomas, Ms. Natalie Greene, and Mr. 

Chris Caraway.

She 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 after being made visually accessible to all viewers, including the visually disabled. 

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

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

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

to contact Ian Branam, located at the press table, for assistance in arranging interviews. 

The next ACIP meeting will be convened at the Centers for Disease Control and Prevention 

(CDC) on Wednesday and Thursday, June 21-22, 2017. Registration for all meeting attendees 

is required. The registration deadline for Non-US citizens is May 22, 2017 and for US citizens, 

registration closes June 7, 2017. Registration is not required for webcast viewing. As a 

reminder for non-United States (US) citizens attending ACIP meetings, completion of several 

forms is required for each meeting at the time of registration. It is important that these forms are 

submitted within the required time frame. Stephanie Thomas, the ACIP Committee 

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

Dr. Cohn reported the following member substitutions during this meeting:

Liaison Representatives

 Dr. Corey Robertson is representing Pharmaceutical Research and Manufacturers of 

America (PhRMA)

 Dr. Bonnie Maldonado is representing the Committee on Infectious Diseases (COID) of the 

American Academy of Pediatrics (AAP)

Call To Order, Welcome, Overview / Announcements, & Introductions 

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 Dr. Alexandra Woodward is representing Biotechnology Innovation Organization (BIO)

 Carol Hayes will be representing American Nurses Association (ANA) in addition to her own

organization

 Dr. Bill Schaffner will be representing Infectious Disease Society of America (IDSA) in

addition to his own organization

Regarding public comments, Dr. Cohn indicated that topics presented during ACIP meetings 

include open discussion with time reserved for public comment. She explained that time for 

public comment pertaining to topics on the agenda was scheduled following the end of the day’s 

sessions, and that time for public comments also would be provided prior to each vote by ACIP 

to enable these comments to be considered before a vote. Registration for public comments is 

solicited in advance of meetings. People who planned to make public comments were 

instructed to visit the registration table at the rear of the auditorium where Ms. Stephanie 

Thomas would record their name and provide information on the process. People making public 

comments were instructed to provide three pieces of information: name, organization if 

applicable, and any conflicts of interest (COI). Registration for public comment also was 

solicited in advance of this meeting through the Federal Register. Given time constraints, each 

comment was limited to three minutes. Participants unable to present comments during this 

meeting were invited to submit their comments in writing for inclusion in the meeting minutes.

To summarize COI provisions applicable to the ACIP, as noted in the ACIP Policies and 

Procedures manual, members of the ACIP agree to forgo participation in certain activities 

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

potentially enhance a member’s expertise while serving on the committee, CDC has issued 

limited COI waivers. Members who conduct vaccine clinical trials or serve on data safety 

monitoring boards (DSMBs) may present to the committee on matters related to those vaccines, 

but these members are prohibited from participating in committee votes on issues related to 

those vaccines. Regarding other vaccines of the concerned company, a member may 

participate in discussions, with the proviso that he/she abstains on all votes related to the 

vaccines of that company. It is important to note that at the beginning of each meeting, ACIP

members state any COIs. 

Applications for ACIP membership are due no later than August 1, 2017 for the 4-year term 

beginning July 1, 2018. 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: www.cdc.gov/vaccines/acip/index.html

Nominations: 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

Dr. Jean Clare Smith at jsmith2@cdc.gov

Recommendations and immunization schedules can be downloaded from the ACIP website. 

ACIP has a policy that every three to five years each recommendation is reviewed, and then 

renewed, revised, or retired. During every meeting, an update is provided on the status of ACIP

recommendations. There have been four ACIP publications since February 2016, which are 

reflected in the following table:

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Visitors / Farewells / Roll Call

Nancy Bennett, MD, MS

ACIP Chair

Dr. Bennett introduced the following guests attending this ACIP meeting:

 Dr. Rana Hajjeh, Director, Department of Communicable Diseases Prevention & Control 

(DCD), Regional Office for the Eastern Mediterranean (EMRO)

 Dr. C. Irtaza Ahmad, Technical Officer, Vaccine Preventable Diseases & Immunization, 

DCD, EMRO

She then wished a fond farewell to three ACIP members:

 

Dr. Bruce Gellin

Dr. Gellin has been the Ex-Officio representative at the ACIP for the last 15 years in his role as 

Director of the National Vaccine Program Office (NVPO). He will be leaving NVPO at the end of 

the month to take on a new role as President of Global Immunizations at the Sabin Vaccine 

Institute. ACIP honored Dr. Bruce Gellin for his many years of service and thanked him for his 

constant support and insight for the ACIP over the years, and is thrilled that he will continue to 

work in immunization at a global level. Dr. Bennett emphasized that he would be sorely missed 

and thanked him for his service.

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Dr. Richard Gorman

Dr. Richard Gorman has been serving as the National Institutes of Health (NIH) Ex-Officio

representative for the last 8 years. He has been a constant source of insight and support to 

ACIP. Dr. Bennett personally thanked him because he frequently answers the questions she 

forgets to ask.

Dr. Ian Gemmill

Dr. Ian Gemmill has been serving as the Liaison Member for the National Advisory Committee 

on Immunization (NACI) for Canada as he completes his term as Chair of that committee. He 

also has brought important insights to ACIP, often clarifying the limitation of the committee’s 

vision. By having the opportunity to hear about another country’s approach, ACIP learns a great 

deal.

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

ACIP members had COIs. The following COIs were declared:

 Robert Atmar receives research support from Takeda Vaccines

 Dr. Romero has a non-research related conflict with Merck and will not be voting on the 

Hepatitis B vaccine

 The remainder of the ACIP members declared no conflicts

Dr. Bennett then requested that the liaison and ex officio members introduce themselves. A list 

of Members, Ex Officio Members, and Liaisons are included in the appendixes at this end of this 

document.

Anne Schuchat, MD (RADM, USPHS)

Acting Director, Centers for Disease Control and Prevention

Acting Administrator, Agency for Toxic Substances and Disease Registry

Rear Admiral, US Public Health Service

Thanks so much. It is a special honor, special feeling, to come back to see you all today in this 

time when I am serving as Acting Director for the agency. It’s an incredible privilege to be 

Acting Director, and you are such a special group of people doing such an incredibly difficult 

ACIP February 23, 2017: Dr. Schuchat’s Welcoming Remarks

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and incredibly important work for the nation. So, I was pleased when Amanda asked me to stop 

by.

My main message is to thank you. I want to thank the members of the committee and Dr. 

Bennett for her chairing of the committee in such a professional and efficient way. You take 

time out of incredibly busy schedules to do very complex and tedious work, and the nation really

thanks you for it. I want to thank the liaisons. I know that we have quite a few here who are 

representing all kinds of professional expertise, and bringing that programmatic and 

professional input into our guidelines helping us avoid what Dr. Frieden used to call the “eyerolling” that happens when CDC issues guidance. You are the no “eye-rolling” contingency 

here—you around the central group. I also want to thank the ex officios who are helping us be 

one extremely coordinated federal vaccine enterprise. I appreciate what each of you do and 

want to make special reference to Bruce Gellin, who is going to be retiring soon from 15 years 

of service at the National Vaccine Program Office (NVPO). A real treasure to have you there for 

those years, and a great partner to us at CDC. I also want to thank the public for the voices that 

you bring to ACIP, both in the room and between meetings—the letters that you send and the 

public comments that you make. You make sure that the meeting is serving the nation at all 

times.

Personally, as you know, I was the National Center for Immunization and Respiratory Diseases 

(NCIRD) Director for a decade and during that period and since then, the ACIP has made 

extraordinary improvements. The process was good and it has gotten even better with 

integration of GRADE (Grading of Recommendation Assessment, Development and Evaluation) 

to the deliberations, so we have a very transparent and systematic way that evidence is 

reviewed, including values being considered. The webcasting has opened these meetings up 

even wider. The public can see these meetings not just by traveling to Atlanta, but from 

anywhere in the world. The major changes that you all have made: the votes that you have 

taken that have added vaccines, that have increased doses when we needed a booster and 

taken doses away when they were not essential, such as the HPV for younger teens and I 

guess the hepatitis B deliberation that you had yesterday for infants; the review of the schedules 

every single year looking at new information on efficacy or effectiveness, on safety signals, on 

performance over time with waning immunity, and the attempt to harmonize with the 

professional groups so that clinicians have clear and consistent advice whenever possible; the 

meetings themselves, which regularly review the critical vaccine issues from each working 

group (WG), as well as key outbreaks that may have implications for future recommendations; 

and the regular review of safety for any kind of signals that may have occurred.

This process is not easy, and there is uncompensated time that each of you gives, and the staff 

who support you for the logistics of the meeting, as well as the technical and superb scientific 

program inputs to the working groups. So, this is a process that I think the nation can be very 

proud of and I am personally very proud of. I know how much experience is at this table, and on 

this committee, and around the world, and I just want to tell you how grateful I am for what you 

do every day and particularly in preparation for these meetings. You know, the nation depends 

on CDC and we depend on you and so thank you so much for all that you are doing for us and 

for letting me talk to you this morning. Thanks.

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Introduction

Art Reingold, M.D. Hepatitis Vaccines Work Group

Dr. Reingold reminded everyone that in October 2016, ACIP approved new hepatitis B (HepB) 

vaccination recommendations. Currently, the recommendations are in CDC clearance and will 

be published as a comprehensive summary of previously published recommendations from 

ACIP and CDC for the prevention of hepatitis B virus (HBV) infection in the US. 

He indicated that this session would include a presentation on revaccination for unprotected 

infants born to hepatitis B surface antigen (HBsAg)-positive mothers who do not respond to the 

initial hepatitis B vaccination series, as well as a cost analysis presentation on single-dose 

revaccination for infants born to HBsAg-positive mothers. The presentations would be followed 

by a vote, including a VFC vote, for approval of permissive language for single-dose 

revaccination followed by post-vaccination serologic testing (and completion of the 2nd series 

followed by post-vaccination serologic testing, if necessary) for infants born to HBsAg-positive 

mothers. 

The next topic to be addressed by the HepB Work Group (WG) will be an update to the ACIP 

recommendations for hepatitis A (HepA) vaccine, proposed for presentation during the June 

2017 ACIP meeting.

Revaccination for Unprotected Infants Born to HBsAg‐Positive Mothers

Noele Nelson, MD, PhD, MPH

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

Centers for Disease Control and Prevention

Dr. Nelson reminded everyone of the current recommendation for revaccination of infants born 

to HBsAg‐positive mothers: 

Current Recommendation

 Providers should order post-vaccination serologic testing (PVST), consisting of hepatitis 

B surface antigen [HBsAg] and antibody to HBsAg [anti-HBs], for infants born to HBsAgpositive mothers at age 9–12 months (or 1–2 months after the final dose of the vaccine 

series, if the series is delayed)1 

 HBsAg-negative infants with anti-HBs levels ≥10 mIU/ml* are protected and need no 

further medical management2

 HBsAg-negative infants with anti-HBs levels <10 mIU/mL* should be revaccinated with a 

second 3-dose series and retested 1–2 months after the final dose of vaccine2

1

Schillie S, et. al. MMWR Morb Mortal Wkly Rep. 2015 Oct 9;64(39):1118-20. 

2

 Mast EE, MMWR Recomm Rep. 2005 Dec 23;54(RR-16):1-31. 

*Anti-HBs ≥10 mIU/mL, when following a complete Hepatitis B vaccine series, is serologic correlate of protection 

 (Jack et al., J Infect Dis 1999) 

Note: Available data do not suggest a benefit from administering additional hepatitis B vaccine doses to infants who have 

not attained anti-HBs ≥10 mIU/mL following receipt of two complete hepatitis B vaccine series.

Hepatitis Vaccines

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Considerations

 Some infants may need only a single revaccination dose to achieve protective antiHBs levels

 Single dose revaccination may conserve public health resources by shortening the 

duration of case management 

 For some infants, providing case management services through 

completion of a 2nd hepatitis B (HepB) vaccine series is difficult (e.g., 

infant moves out of the country)

To set the stage for the remaining presentations regarding what the WG was proposing, Dr. 

Nelson showed the following comparison of the existing language to the proposed revised 

language:

Existing Language

 HBsAg-negative infants with anti-HBs levels <10 mIU/mL 

should be revaccinated with a second 3-dose series and 

retested 1–2 months after the final dose of vaccine.1,2 

Revised Language (Proposed)

 HBsAg-negative infants with anti-HBs levels <10 mIU/mL 

should be revaccinated with a second three-dose HepB 

series and postvaccination serologic testing (PVST) 

performed 1-2 months after the final dose of vaccine. 

 Alternatively, these infants may be re-vaccinated 

with a single dose of HepB vaccine and retested 1-2 

months later. Infants whose anti-HBs remains <10 

mIU/mL following single dose revaccination should 

receive two additional doses of HepB vaccine, 

followed by testing 1-2 months later. 

 Available data do not suggest a benefit from 

administering additional HepB vaccine doses to infants 

who have not attained anti-HBs ≥10 mIU/mL following 

receipt of two complete HepB vaccine series. 

1

Schillie S, et. al. MMWR Morb Mortal Wkly Rep. 2015 Oct 9;64(39):1118-20. 2 Mast EE, MMWR Recomm Rep. 2005 Dec 23;54(RR-16):1-31.

 

Two strategies are depicted in the following algorithm:

In terms of background, the perinatal HepB prevention program was established in 1990 and 

was funded by CDC Immunization Cooperative Agreements (Section 317 funding). There are 

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programs in 64 jurisdictions (50 states, 6 cities, 5 territories & 3 freely associated island nations)

that work collaboratively with NCHHSTP’s Division of Viral Hepatitis (DVH). Each year, all 

Perinatal Coordinators from this program are surveyed. In terms of the outcomes from 2014, 

the number of infants enrolled was 11,157. Based on modeling, this number was expected to 

be approximately 18,807 as a lower limit or a point estimate of 26,236. These estimates are 

being evaluated currently and are anticipated to be published in 2017. Therefore, the remaining 

data are reported as percentages and not actual numbers. The percent of all enrolled infants 

with PEP within 1 calendar day of birth was about 97%. The percent with HepB immunoglobulin 

(HBIG) and series complete by 8 months was about 74%. The percent of all enrolled infants 

with post-vaccination serologic testing (PVST) results was about 64%. The percent of all 

enrolled infants with HBsAg-positive results was about 0.4%. The percent of all enrolled infants 

with protective levels of anti-HBs, after three doses of vaccine, was about 95%. The percent of 

all enrolled infants that need revaccination was 2%, while those with indeterminant results was 

about 2%. Considering that potentially 4% of infants enrolled in the program require 

revaccination, that is about 450 infants pertaining to the recommendations under consideration.

Dr. Nelson presented some studies that were used to inform the economic model to be 

presented during this session. With regard to the proportion of infants protected after the initial 

vaccination series, a study by Ko et al of HepB vaccine response using data from the Enhanced 

Perinatal B Prevention Hepatitis B Prevention Program (EPHBPP) found about a 95% response 

rate among infants who completed a 3- or 4-dose HepB vaccine series.

1 A cost-effective 

analysis of a perinatal HepB by Barbosa et al included results from a Cochrane Review; a 

clinical trial of infant outcomes among HBsAg-positive infants born to HBsAg-positive mothers 

found a 92% efficacy for infants who received HBIG + the birth dose of HepB vaccine and the 

remaining doses on time.2 Another study by Schillie et al, also looking at EPHBPP data 

evaluated factors associated with infection status in infants born to HBsAg-positive mothers and 

found that 99% of infants were negative after receipt of ≥3 vaccine doses.

3 [1Ko et al., Hepatitis 

B vaccine response using data from the Enhanced Perinatal B Prevention Hepatitis B 

Prevention Program (EPHBPP); 2Barbosa et al., Efficacy of vaccine and HBIG by time of 

administration and completion of vaccination series; 3Schillie et al., EPHBPP data, factors 

associated with infection status among infants born to HBsAg-positive mothers].

No studies specifically considered the proportion of individuals who do not respond to the initial 

HepB vaccine series who are seroprotected after one additional dose which was a key question 

of the analysis. However, two studies from Thailand assessed infants who were vaccinated with 

four doses at a time point after each vaccine dose. In the Lolekha et al study, in Schedule A, 

infants who received vaccine at birth, 1, and 6 months had a 92% response at 9 months (3 

months after the last dose) and about an 89% response at 13 months (about 7 months after the 

last dose). In Schedule B, infants who received vaccine at birth, 1, 2, 12 months had an 86.5% 

response at 9 months and a 94.4% response at 13 months. In Schedule A, the decline is not 

surprising since it is known that the antibody declines over time.1 A similar study by 

Assateerawatt et al assessed two groups of infants born to positive mothers with a somewhat 

higher birth weight of ≥2500g. Group A received HBIG + vaccine at 0 and vaccine at 1, 2 and 

12 months. Group B received no HBIG and vaccine at 0, 1, 2 and 12 months.

2 There was no 

significant difference among the groups. In Group A, there was a 96% seroconversion rate at 

12 months and 100% at 13 months. In Group B, there was a 95.2% seroconversion rate at 12 

months and 95.7% at 13 months after the fourth dose [1Lolekha S, et al., Vaccine 2002; 20(31-

32): 3739-43; and 2Assateerawatt A, et al., Asian Pacific journal of allergy and immunology 

1993; 11(1): 85-91].

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Ko et al specifically assessed the question regarding what percent of infants who do not 

respond to the initial hepatitis B vaccine series are protected after a complete second vaccine 

series. The study found that of non-responder infants who completed a second vaccination 

series at the time of analysis in the study, 95% demonstrated a response after the second 

series [Ko et al., Vaccine 2014; 32(18): 2127-33].

In terms of the limitations, these studies were not designed specifically to evaluate response to 

single dose revaccination in initial infant non-responders. There was variability among the 

studies with regard to maternal HBsAg status, HBIG administration, schedule, HBeAg status,

and infant birth weight (<2000g vs. ≥2000g). In general, limited data are available on this topic.

Data also were considered from three sites that are part of the Perinatal HepB Prevention 

Program. The records were reviewed for infants born to HBsAg-positive mothers from 2012

through 2016 in Georgia, Michigan, and New York City (NYC) who received 3 doses of hepatitis 

B vaccine and PVST with anti-HBs <10 mIU/mL, followed by single dose revaccination with antiHBs measurement. Of the 15 infants found, 14 (or 93%) had anti-HBs ≥10 mIU/mL after single 

dose revaccination. This provides further evidence that most infants who do not respond to the 

initial vaccine series do respond after a single dose revaccination.

Cost Analysis of Single Dose Revaccination for Infants Born to HBsAg-Positive Mothers 

Eric Hall, MPH

Rollins School of Public Health

Emory University

Mr. Hall presented on assessing the cost-effectiveness of a single-dose of HepB revaccination 

among infants not responding to the initial vaccine series and born to HAV-infected mothers. 

The motivating study question for this analysis was, “Is a one-dose HepB revaccination strategy 

among infants born to HepB-infected mothers who do not respond to the initial vaccine series 

cost-effective compared to the current recommended three dose strategy?” The analysis used 

a societal perspective, considered direct and indirect costs, and considered a one-dose 

revaccination strategy. A one-year intervention timeframe and a one-year analytic horizon were 

used. Discounting was not included due to the one-year horizon. Any costs that differ between 

these two strategies occur during the revaccination process. Here is a diagram of the proposed 

intervention strategy:

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The top part in blue is the first vaccine series for an infant born to a mother who tested positive 

to HBsAg, who then goes on to receive HBIG and a three-dose HepB vaccine series. The infant 

goes on to receive PVST. If the antibody levels are > 10 mIU/mL, the infant is considered to be 

protected. If the antibody levels are <10 mIU/mL, the infant is indicated for revaccination. 

Infants who are not protected after dose 2a go on to receive doses 2b and 2c, which mirrors the 

current 3-dose revaccination strategy. Therefore, the cumulative risk of hepatitis B infection is 

the same in both strategies and health outcomes were assumed to not differ between the 

current strategy and the proposed strategy.

The two strategies were assessed through a decision tree model utilized to assess the cost per 

person in the 1-dose and 3-dose revaccination strategies. The costs per person equaled the 

sum of direct and indirect costs associated with each vaccine dose and each PVST. These 

comparisons were made under a variety of epidemiologic scenarios identified as A, B, and C. In 

terms of health outcomes, the model estimated the number of protected and unprotected 

individuals under each epidemiological scenario. The number of protected individuals and 

cumulative risk of infection are assumed to be the same for each strategy. There is not a 

difference in health outcomes between the two strategies. The decision tree diagram used for 

this analysis is shown below:

On the far left is a cohort of infants who were born to mothers who tested positive with HBsAg 

and received the initial dose of the 3-vaccine series, received the first PVST, and had antibody 

<10 mIU/mL. The blue square is the decision node. The top portion of this diagram represents 

the proposed 1-dose revaccination strategy and the bottom portion represents the current 3-

dose strategy. The green circles are chance nodes. Associated probabilities are attached with 

each chance node that determine which series of branches an individual will follow. Key 

variables are boxed in red and blue and represent infants that were previously protected and 

previously unprotected. This composite variable was used to set the different epidemiologic 

scenarios mentioned earlier. The motivation for creating these different scenarios came from 

the work Dr. Nelson mentioned that was done by their colleagues at DVH. That work indicated 

that if a vaccinated infant had a PVST that was delayed beyond the recommended time frame, 

antibody levels could wane below 10 mIU/mL even though they are actually protected.

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This diagram depicts the various scenarios:

A portion of the infants with delayed PVSTs can be indicated for revaccination even though they 

actually have previous protection. The investigators created different scenarios that represent a 

different proportion of the cohort in which that is the case. At the bottom of the diagram are the 

different variables and inputs that create scenarios A, B, and C. In these, the efficacy of the 

initial vaccine series is varied, as are the proportion of the infants who received a delayed 

PVST, the proportion of infants whose antibody levels waned below 10 mIU/mL and were 

indicated for revaccination, and the resulting proportion of the total cohort indicated for 

revaccination who actually did have previous protection. The red and blue boxes are the infants 

indicated for revaccination. They go into the corresponding red and blue boxes from the 

previous diagram.

Here are the table of probabilities and parameters and costs associated with each PVST that 

were input into this model:

 

 

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A few sensitivity analyses were conducted on some of these variables. The first one, and 

perhaps one of the most important, was a univariate threshold analysis of the proportion 

protected by a single dose of revaccination (Dose 2a). While there is an estimate of what that 

parameter might be, it is based on very limited data. The researchers opened up the range in 

this sensitivity analysis from 0.0 to 0.9 to determine what level would be needed to favor one 

strategy over the other. Secondly, a tornado diagram was constructed in which all probability 

and cost parameters were considered. Finally, a two-way sensitivity analysis looked at the 

efficacy of dose 2a and the composite variable that represents the proportion of infants 

indicated for revaccination who actually previously were protected.

Across all three scenarios, the 1-dose revaccination strategy was a lower cost option. The 

results assume that every single vaccination visit occurred as a previously unscheduled visit, so 

each one included an additional trip to the clinic. The researchers also considered scenarios in 

which 1, 2, or 3 of those revaccination visits occurred during a previously scheduled well-child 

visit. Those visits did not include the added cost of the caregiver taking time off work to travel to 

the clinic, because they were assumed to be previously scheduled visits. The 1-dose 

revaccination strategy remained the lower cost option across the board. Here is a figure of the 

two-way sensitivity analyses:

The added protection from the single revaccination dose ranges from 0.0 to 0.9, with the 

proportion indicated for revaccination who were previously protected ranging from 0.0 to 0.5. 

The blue area in this figure represents the combinations where the 1-dose revaccination 

strategy is the lower cost option. The key point to notice from this is where the curve intersects 

the X axis at 0.45. Basically, for any scenario under any value for the proportion of infants with 

previous protection, the 1-dose revaccination strategy will be the lower cost option as long as 

the efficacy for Dose 2a is 0.45 or higher.

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Here is a tornado diagram that displays the difference in cost per person between the 3-dose 

and 1-dose strategy:

The X axis is the difference in cost per person between the two strategies. The blue vertical line 

represents that differences under the base case scenario that was presented in the earlier table 

of results. If the variables on the Y axis individually took on the most extreme values in their 

possible ranges, the diagram shows how they would affect the individual results in difference in 

cost per person between the 3-dose and 1-dose revaccination strategies.

To summarize the findings, a 1-dose revaccination strategy reduces costs compared to the 

current 3-dose strategy across a wide array of scenarios. The 1-dose revaccination strategy is 

a lower cost option under the assumption that 1, 2, or 3 of the vaccinations occur during a 

previously scheduled well-child visit.

There are a few assumptions and limitations to this analysis. The assumption was made that 

the risk of infection was the same in 1-dose and 3-dose revaccination strategies. This 

assumption was dependent on the proposed structure of the 1-dose revaccination strategy in 

which individuals who were not protected after Dose 2a went on to receive Doses 2b and 2c, 

thus having the same experience as everybody in the current 3-dose revaccination strategy. 

Dropout was assumed to be the same in both strategies. Also assumed was that infants born to 

mothers infected with HepB were correctly identified and that they received the initial vaccine 

series and PVST.

In terms of how this work relates to other studies, a recent study assessed the costeffectiveness of the National Perinatal Hepatitis B Prevention Program (PHBPP) and concluded

that the program is a cost-effective use of resources.1 The authors advocate for an expansion of 

the program to ensure that it reaches all children born to HepB-infected mothers. In 2015, it 

was recommended that initial PVSTs occur 1 to 2 months after completion of the initial vaccine 

series (9 through 12 months of age) for infants born to hepatitis B-infected mothers to ensure 

PVST test results are representative of protection.5 Implementing this 1-dose revaccination 

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strategy also will help correctly identify protected individuals without them having to undergo a 

full 3-dose revaccination series [1Barbosa, C., Smith, E. A., Hoerger, T. J., Fenlon, N., Schillie, 

S. F., Bradley, C., & Murphy, T. V. (2014). Cost-effectiveness analysis of the national Perinatal 

Hepatitis B Prevention Program. Pediatrics, 133(2), 243-253. doi:10.1542/peds.2013-0718; 

5Schillie, S., Murphy, T. V., Fenlon, N., Ko, S., & Ward, J. W. (2015). Update: Shortened Interval 

for Postvaccination Serologic Testing of Infants Born to Hepatitis B-Infected Mothers. MMWR 

Morb Mortal Wkly Rep, 64(39), 1118-1120. doi:10.15585/mmwr.mm6439a6].

Both this report and this presentation underwent a peer review in accordance with the ACIP 

Guidance for Health Economic Studies.14 One question from that review was, “Why weren’t 

revaccination using 2-doses and no-revaccination considered as strategies?” After giving two 

additional doses, it is more practical to continue with a third dose rather than include another 

PVST after Dose 2b and possible continued non-response. Single-dose revaccination is most 

consistent with other recommendations (e.g., for health-care personnel). A non-intervention (no 

revaccination) strategy was not included because it would be unethical to leave infants who do 

not respond to the initial vaccine series unprotected [14Centers for Disease Control and 

Prevention (CDC). (2017). Advisory Committee on Immunization Practices: Guidance for Health 

Economics Studies. Retrieved from 

https://www.cdc.gov/vaccines/acip/committee/guidance/economic-studies.html].

Discussion Points

Dr. Walter applauded the group for looking at ways to simplify the revaccination regimen. 

Noting the recommendation to perform a blood draw after receiving two series of vaccines, he 

wondered whether there were any actionable items if the test is negative and the infant is not 

seroprotected. 

Dr. Nelson responded that the evidence suggests that it does not make sense to then proceed 

with a third revaccination series. At that point, the parent or family would have to be counseled 

that their infant is at high risk for infection and should be followed accordingly.

 

Dr. Schillie (SME) added that there is language to that effect in the draft recommendations. 

There also is a separate table for management following discreet exposures for unprotected 

persons, so that would also be applicable to infants who do not develop protective anti-HBs 

following appropriate vaccination.

Ms. Pellegrini asked to what extent the practitioners in the group thought the second series 

aligned with well-child visits. It appeared that the third dose of the initial series was in the 9- to 

12-month range, while the return for confirmatory testing would be in the 11- to 14-month 

timeframe depending upon on when the third dose was administered. When restarting the 

series, she wondered whether this would align with the 15-, 18-, 24-month period or if these 

families would have to attend extra visits.

Dr. Moore responded that if everything is done on time, the PVST would be done around 9 or 10 

months of age. In general, the minimum age for the PVST is 9 months. If they needed to 

restart, they could do so potentially at their 1-year visit unless they went in early for the first 

dose. It roughly aligns. She said she could hear all of the Perinatal HepB Coordinators 

cheering, because the 1-dose option is a huge step forward in terms of being able to close out 

the follow-up of these children much more efficiently. The most common scenario is the child 

does not have their PVST done in a timely manner, so many who were protected will wind up 

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having a 3-dose series and additional visits although only 1 dose would be needed to 

demonstrate protection.

Dr. Schillie (SME) indicated that the current recommendation for post-vaccination testing is 9 to 

12 months of age, because there are two well-child visits at those points. The recommendation 

also states that infants who are delayed in vaccine series completion should be tested 1 to 2 

months after the final dose of the vaccine series.

Dr. Hunter asked if it would be possible to have an option in the recommendation stating that 

the testing can be done at 7 to 8 months if the child happens to present at that time, which 

should result in fewer children falsely testing negative.

Dr. Messonnier pointed out that some of the details are what Perinatal Hepatitis Coordinators 

need to know when they implement the recommendations. They can try to differentiate the 

language of the recommendation verses the practical implementation guidance.

Dr. Sun (FDA) asked whether in the WG’s review of the literature there were any studies on the 

population of infants who received the higher dose who essentially failed the first series and had 

to receive another series of vaccinations.

 

Dr. Nelson replied that she was not aware of those studies in the published literature. Some 

studies have been conducted, which are unpublished, that assessed differences in what the 

total actually was and how that might indicate how the baby might respond. She did not believe 

that any of the published studies assessed higher vaccine doses.

Dr. Schillie (SME) added that the majority of infants who receive a full second re-dose series 

respond at the standard dose.

As Dr. Hunter understood it, for the cost analysis to be correct, an assumption had to be made 

that 45% of the children who received the extra single dose after they were negative for the 

antibody hepatitis converted to positive.

Mr. Hall confirmed that this interpretation was correct. The estimate for that was based on a 

couple of smaller studies. It was estimated at about 0.78, with a wide range of variability.

Dr. Duchin (NACCHO) asked whether anything was known about the risk factors for failure to 

respond to the first series, if the large proportion of infants born to infected mothers who are not 

ascertained might have higher or lower risk of failure to respond, and whether that would impact 

the cost-effectiveness calculations.

Dr. Schillie (SME) replied that low birth weight and pre-term birth are influential factors. 

Prematurity is a risk factor for non-response, and some limited data suggest that male infants 

might have a slightly lower response than female infants.

Dr. Nelson added that there may be other factors they are unaware of. They used wide ranges 

in the sensitivity analysis down to 0.0 in some cases.

Dr. Thompson asked whether the WG had an opinion as to which of the three scenarios is the 

true scenario, or how those scenarios should be interpreted in the context of what the evidence 

suggests.

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Mr. Hall responded that they tried to create three very drastic scenarios. The initial scenario, A, 

assumes a very high efficacy of the first initial series and that everybody receives their PVST on 

time. That scenario has the highest threshold value for Dose 2a. That is where the 0.45 comes 

from. Scenario B assumptions were made to be more realistic using data about the proportion 

of infants in the perinatal HepB prevention program who have a delayed PVST, and the 

proportion of those who do have antibodies. He would say that Scenario B is probably the most 

reflective of what would be expected. Scenario C had a very low initial efficacy level of that first 

vaccine series that basically incorporated all infants who were not receiving the initial vaccine 

series. It assumed that a lot of them had an initial delayed PVST, and that a similar proportion 

of those had waned antibodies.

Revaccination for Unprotected Infants Born to HBsAg‐Positive Mothers

Noele Nelson, MD, PhD, MPH

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

Centers for Disease Control and Prevention

Dr. Nelson reported that the WG convened for two teleconference meetings on this topic and 

reached consensus regarding the proposed update to the hepatitis vaccine statement regarding 

single-dose revaccination for infants born to HBsAg-positive mothers. They considered the pros 

and cons of single-dose revaccination verses 3-dose revaccination. The pros of the single 

vaccine dose are that there are fewer vaccine doses for most infants, there is a short duration of 

case management, and it is less costly overall. The cons are that those infants who do not 

respond to the single dose vaccination would need an additional blood draw, and 

provider/parent decision-making would be necessary because there would be two options (1-

dose revaccination and 3-dose revaccination). The existing language states that, “HBsAgnegative infants with anti-HBs levels <10 mIU/mL should be revaccinated with a second 3-dose 

series and retested 1–2 months after the final dose of vaccine” [1 Schillie S, et. al. MMWR Morb 

Mortal Wkly Rep. 2015 Oct 9;64(39):1118-20; Mast EE, MMWR Recomm Rep. 2005 Dec 

23;54(RR-16):1-31]. She then presented the revised language presented for a vote as follows: 

 HBsAg-negative infants with anti-HBs <10 mIU/mL should be re-vaccinated with 

a single dose of hepatitis B series and postvaccination serologic testing should 

be performed 1 to 2 months after the final dose of vaccine.

 

 Alternatively, these infants may be revaccinated with a single dose of hepatitis B 

vaccine and retested 1 to 2 months later. Infants whose anti-HBs remains <10 

mIU/mL following single dose revaccination should receive two additional doses 

of HepB vaccine, followed by testing 1 to 2 months later.

 Available data do not suggest a benefit from administering additional hepatitis B 

vaccine doses to infants who have not obtained anti-HBs levels >10 mIU/mL 

following receipt of two complete hepatitis B vaccine series.

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Discussion Points

Dr. Romero made a motion to accept the language as proposed, which Dr. Moore seconded. 

The discussion then continued.

Dr. Belongia was unclear about the benefit of having two options. One of the cons mentioned 

was that parents/providers would have to decide between two options, and the costeffectiveness analysis made the assumption that the outcomes would be the same for the two 

strategies. The only difference is a cost issue not an outcome issue. The proposed option 

incorporates the 3-dose series because if the infant is below 10 mIU/mL, the 3-dose series 

would be given anyway. As stated, the first bullet of the proposed language added complexity 

without any additional benefit.

Dr. Kempe concurred, emphasizing that this is likely to be confusing to providers. They should 

have a blood draw anyway after the second 3-dose series, so this is not necessarily causing 

another blood draw.

 

Dr. Nelson clarified that an additional blood draw would be required for infants who are 

revaccinated with one dose but still do not respond. That is the primary con.

 

Dr. Walter asked if the suggestion was to flip the bullets in the alternate language.

Dr. Nelson asked for clarity regarding whether that meant the revised language would simply 

state that they should be revaccinated with a single dose of hepB vaccine and retest at 1 to 2 

months later. Basically, the second bullet would replace the first.

Dr. Bennett called on Dr. Reingold to comment on the thinking of the WG in bringing this 

statement forward in its current form, and whether there were any specific objections to making 

this a recommendation.

Dr. Reingold replied that it was basically viewed as an evolution and providing two options 

rather than a stark change.

 

Dr. Nelson added that there were no specific objections. However, the WG did not specifically 

address the alternative of only single-dose revaccination. It was not presented as such in the 

WG calls.

Dr. Moore proposed that the preferred option be the single revaccination dose, followed by 

PVST, with an alternate option to give the 3-dose series if the single revaccination strategy is 

not chosen. Dr. Kempe seconded the motion.

Dr. Bennett repeated the amendment on the floor to reverse the proposed revised language 

such that the primary strategy would be single-dose, with an alternative of the full 3-dose series.

 

Dr. Riley asked for clarification regarding whether the pediatric outcomes were the same for 

both strategies in the cost-effectiveness analysis.

Dr. Schillie (SME) replied that they would receive 6 doses regardless, so there would not be any 

reason at all to think that the outcomes would be different.

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Dr. Nelson added that there is always a risk of infection if the infant does not respond, but that is 

not expected to differ between the two scenarios. If they respond after 1 dose, they will be less 

likely to be infected than if they take 3 more doses to respond.

Dr. Atmar thought the initial discussion pertained to including only what was in the second bullet 

and not even having the first bullet as an alternative.

 

Dr. Moore clarified that her motion was to leave the 3-dose series as an alternative as part of 

the evolution of the strategy, versus recommending a sharp change in the recommendation. 

For example, a family may prefer to avoid a blood draw as they are quite difficult on the child 

and the family. A back-up strategy is not inferior in any way, and still should be considered 

acceptable.

Dr. Romero clarified that some parents might object to an additional blood draw on their infant 

and, therefore, would prefer a straightforward 3-dose series. That has to remain as an option 

for those parents who have very strong feelings about the number of invasive procedures done 

to their child.

Dr. Walter pointed out that there also may be logistical issues in terms of getting the blood draw, 

such as actually getting the child there.

Dr. Byington (AAP) indicated that the AAP would favor the single-dose as the preferred option. 

Only if that fails would they support the 3-dose option. This would be easier for families overall.

Dr. Nelson presented the following revised language for a vote:

 HBsAg-negative infants with anti-HBs <10 mIU/mL should be re-vaccinated with 

a single dose of HepB vaccine and receive postvaccination serologic testing 1-2 

months later. Infants whose anti-HBs remains <10 mIU/mL following single dose 

revaccination should receive two additional doses of HepB vaccine, followed by 

PVST 1-2 months after the last dose.

 

 Based on clinical circumstances or family preference, HBsAg-negative 

infants with anti-HBs <10 mIU/mL may instead be revaccinated with a 

second, complete 3-dose series, followed by postvaccination serologic 

testing (PVST) performed 1-2 months after the final dose of vaccine.

 

 Available data do not suggest a benefit from administering additional HepB 

vaccine doses to infants who have not attained anti-HBs ≥10 mIU/mL following 

receipt of two complete HepB vaccine series. 

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Public Comment

Christina Hildebrand

A Voice for Choice

I am glad to see a reduction of vaccines given to babies. I know that previously there was a 3-

dose series. I assume, but I can’t assume that the—well, I should go back. The information 

that was presented today was based on the efficacy of the vaccine as well as the cost of the 

vaccine, but it didn’t go into the risks of the vaccine or look at the outcome of the babies who 

were not given these doses and what happened in those families. So, I just want to make 

sure—I just want to comment that, you know, the risk piece of this is also an important piece. 

The other piece which I find disturbing, which I mentioned the last time I was here, is the fact 

that this is based on very, very small base sizes. So, you know, you’ve got 15 babies that you’ve 

looked at and you haven’t looked at a larger sample size. And I would hope that any 

recommendation is based on more than 15 people, or 15 babies, and that, you know, I 

understand that you’re voting on this today, but in the future, I would hope you would look at a 

larger base size. I understand that the percentage of outcome is very high, and so being a 

statistician, I understand that that would likely replicate and it would likely, you know, be a 

positive outcome and come to the same conclusion. But, having small base sizes is something 

that, you know, as a statistician you don’t do anything with 15 people other than qualitative 

responses. You don’t base decisions on that. That was my public comment. Thank you.

Vote: Hepatitis B Vaccine Recommendation

Dr. Romero initially made a motion to accept the revised Hepatitis B Vaccine Recommendation 

language as presented for a vote by Dr. Nelson. Dr. Moore seconded the motion. The motion 

carried unanimously with 13 affirmative votes, 0 negative vote, and 1 abstention. The 

disposition of the vote was as follows:

13 Favored: Atmar, Belongia, Bennett, Ezeanolue, Hunter, Kempe, Moore, Pellegrini, 

Reingold, Riley, Stephens, Szilagyi, Walter

 0 Opposed: N/A

 1 Abstained: Romero

Vote: Amended Hepatitis B Vaccine Recommendation

Although an initial vote was made on the above motion, following additional discussion, Dr. 

Moore motioned to approve the Hepatitis B Vaccine Recommendation as amended such that 

the preferred option would be the single revaccination dose, followed by PVST, with an alternate 

option to give the 3-dose series if the single revaccination strategy is not chosen. Dr. Kempe 

seconded the motion. The motion carried unanimously with 13 affirmative votes, 0 negative 

vote, and 1 abstention. The disposition of the vote was as follows:

13 Favored: Atmar, Belongia, Bennett, Ezeanolue, Hunter, Kempe, Moore, Pellegrini, 

Reingold, Riley, Stephens, Szilagyi, Walter

 0 Opposed: N/A

 1 Abstained: Romero

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VFC Resolution

Dr. Jeanne M. Santoli

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Santoli indicated that the purpose of this resolution was to clarify recommendations related 

to dosing intervals and revaccination. The eligible groups are all children and adolescents from 

birth through 18 years of age.

The tables below list the acceptable vaccination schedules for children and adolescents from 

birth through 18 years of age, for which there is no change:

Table 1, Part I: Infants

Single antigen vaccine Single-antigen1 and combination 

vaccine2,3

Birth 

weight

Maternal 

HBsAg status 

Dose Age Dose Age

≥2000 g Positive 1 Birth (≤12 hrs)1 1 Birth (≤12 hrs )1

2 1-2 months 2 2 months

3 6 months 3 4 months

4 6 months

Unknown 1 Birth (≤12 hrs)1 1 Birth (≤12 hrs)1

2 1-2 months 2 2 months

3 6 months 3 4 months

4 6 months

Negative 1 Birth (< 24 hours)1 1 Birth (< 24 hours)1

2 1-2 months 2 2 months

3 6 -18 months 3 4 months

4 6 months

Table 1, Part 2: Infants

<2000 g Positive 1 Birth (< 12 hrs)1 1 Birth (< 12 hrs)1

2 1 month 2 2 months

3 2-3 months 3 4 months

4 6 months 4 6 months

Unknown 1 Birth (≤12 hrs)1 1 Birth (≤12 hrs)1

2 1 month 2 2 months

3 2-3 months 3 4 months

4 6 months 4 6 months

Negative 1 Age 1 month or at hospital 

discharge1

1 Age 1 months or at hospital 

discharge1

2 2 months 2 2 months

3 6 -18 months 3 4 months

4 6 months

Table Notes:

1. Only a single antigen hepatitis B vaccine (ENGERIX-B® or RECOMBIVAX HB®) can be given at birth. 

2. Pediarix® [DTaP-IPV-HepB] is licensed for children 6 weeks through 6 years of age. 

3. Use of brand names is not meant to preclude the use of other comparable US licensed vaccines. 

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Table 2: Children and Adolescents 

Age Schedule1, 6

Children (1 through 10 years) 0, 1, and 6 months2

0, 2, and 4 months2

0, 1, 2, and 12 months2,4 

Adolescents (11 through 18 years) 0, 1, and 6 months2

0, 1, and 4 months2

0, 2, and 4 months2

0, 12, and 24 months2

0 and 4-6 months3

0, 1, 2, and 12 months2,4

0, 7 days, 21-30 days, 12 months5

Table Notes 

1. Children and adolescents may be vaccinated according to any of the schedules indicated, except as noted. Selection of a 

schedule should consider the need to optimize compliance with vaccination. 

2. Pediatric/adolescent formulation. 

3. A two-dose schedule of Recombivax-HB Adult Formulation is (10 micrograms) is licensed for adolescents aged 11 through 15 

years. When scheduled to receive the second dose, adolescents aged > 15 years should be switched to a three-dose series, with 

doses 2 and 3 consisting of the pediatric formulation administered on an appropriate schedule. 

4. A four-dose schedule of Engerix B® is licensed for all age groups. 

5. Twinrix® can be administered to persons 18 years of age before travel or any other potential exposure on an accelerated 

schedule at 0, 7, and 21-30 days, followed by a dose at 12 months. 

6. Use of brand names is not meant to preclude the use of other comparable US licensed vaccines. 

This clarification is added to address confusion related to single antigen versus combination 

vaccine schedules. In some cases, more than 3 doses are administered:

Interrupted schedules and minimum dosing intervals

 When the HepB vaccine schedule is interrupted, the vaccine series does not need to 

be restarted. If the series is interrupted after the first dose, the second dose should 

be administered as soon as possible, and the second and third doses should be 

separated by an interval of at least eight weeks. If only the third dose has been 

delayed, it should be administered as soon as possible. 

 The final dose of vaccine must be administered at least eight weeks after the second 

dose and should follow the first dose by at least 16 weeks; the minimum interval 

between the first and second doses is four weeks. Inadequate doses of hepatitis B 

vaccine or doses received after a shorter-than-recommended dosing interval should 

be re-administered, using the correct dosage or schedule.

 Vaccine doses administered ≤4 days before the minimum interval or age are 

considered valid. Because of the unique accelerated schedule for Twinrix®, the 

four-day guideline does not apply to the first three doses of this vaccine when 

administered on a 0 day, 7 day, 21-30 day, and 12-month schedule.

 In infants, administration of the final dose is not recommended before age 24 weeks 

(164 days). 

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This update reflects the discussion ACIP just participated in related to single dose revaccination:

Revaccination

Revaccination (i.e., booster dose, challenge dose, or revaccination with a complete 

series) is not generally recommended for persons with a normal immune status who 

were vaccinated as infants, children, or adolescents. Revaccination when anti-HBs is 

<10 mIU/mL is recommended for the following:

 Infants born to HBsAg-positive mothers

 HBsAg-negative infants with anti-HBs <10 mIU/mL should be revaccinated with a single dose of HepB vaccine and receive post 

vaccination serologic testing 1-2 months later. Infants whose anti-HBs 

remains <10 mIU/mL following single dose revaccination should receive 

two additional doses of HepB vaccine, followed by PVST 1-2 months after 

the last dose. 

• Based on clinical circumstances or family preference, HBsAgnegative infants with anti-HBs <10 mIU/mL may instead be 

revaccinated with a second, complete 3-dose series, followed by 

post vaccination serologic testing (PVST) performed 1-2 months 

after the final dose of vaccine. 

 Hemodialysis patients. For hemodialysis patients, the need for booster doses 

should be assessed by annual anti-HBs testing. A booster dose should be 

administered when anti-HBs levels decline to <10 mIU/mL. 

 Other immunocompromised persons. For other immunocompromised persons 

(e.g., HIV-infected persons, hematopoietic stem-cell transplant recipients, and 

persons receiving chemotherapy), the need for booster doses has not been 

determined. When anti-HBs levels decline to <10 mIU/mL, annual anti-HBs 

testing and booster doses should be considered for persons with an ongoing risk 

for exposure.

 Persons with postvaccination serologic testing results that do not demonstrate 

protection. This includes children and adolescents through age 18 years who are 

chronic hemodialysis patients, HIV-infected, otherwise immunocompromised 

(e.g., hematopoietic stem-cell transplant recipients or persons receiving 

chemotherapy), or sex partners of HBsAg-positive persons. Persons in these 

groups found to have anti-HBs concentrations of <10 mIU/mL after the primary 

vaccine series should be revaccinated. 

Recommended Dosage

Refer to product package inserts.

Contraindications and Precautions

Contraindications and Precautions can be found in the package inserts available at 

http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833

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Statement Regarding Update Based on Published Documents

[If an ACIP recommendation regarding Hepatitis B vaccination is published within 12 months 

following this resolution, the relevant language above (except in the eligible groups sections) will 

be replaced with the language in the recommendation and incorporated by reference to the 

publication URL.]

Vote: Vote: VFC Resolution for Hepatitis B Vaccine Recommendation

Dr. Hunter motioned to approve the VFC resolution for the Hepatitis B Vaccine 

Recommendation. Ms. Pellegrini seconded the motion. The motion carried unanimously with 

13 affirmative votes, 0 negative vote, and 1 abstention. The disposition of the vote was as 

follows:

13 Favored: Atmar, Belongia, Bennett, Ezeanolue, Hunter, Kempe, Moore, Pellegrini, 

Reingold, Riley, Stephens, Szilagyi, Walter

 0 Opposed: N/A

 1 Abstained: Romero

Introduction

Chip Walter, MD

Chair, Influenza Work Group

Dr. Walter reminded everyone that during the October 2016 meeting, there were two sessions, 

including an influenza epidemiology and surveillance update and a summary of the clinical data 

for AFLURIA® Quadrivalent vaccine in adults, which was licensed for persons 18 years of age 

and older in August 2016.

Since the October 2016 ACIP meeting, the WG has engaged in calls twice a month. The 

following is a list of highlights from the calls:

 Updates from MedImmune regarding investigations and planned studies related to the lower 

than expected effectiveness observed with FluMist® against H1N1pdm09 strains during the 

2013-2014 and 2015-2016 seasons in the US

 Updates from Seqirus regarding their pediatric development program for AFLURIA® 

Quadrivalent implications for use in children





Their current trivalent vaccine is licensed in the US for those 5 years of age and 

older

During the 2010-2011 timeframe, ACIP recommended that the vaccine be given only 

to those 9 years of age and older, given that higher rates of fever and febrile seizure 

were observed in children in Australia during the 2010-2011 season

 Ongoing discussions regarding the effectiveness of Fluzone® High-Dose (HD)

Influenza

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The topics for the February 2017 session included an influenza surveillance update, influenza 

VE update, AFLURIA® Quadrivalent vaccine update, and a FluMist® update. 

Influenza Surveillance Update

Lynnette Brammer, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

During this session, Ms. Brammer provided a brief update on influenza activity for the 2016-

2017 season. As of the week ending February 11, 2017, the peak influenza positivity so far was 

during Week 6 at 24.2% positive. This level is similar to the peak for last season. Thus far from 

clinical laboratories, 83% of the viruses have been influenza A. Data from public health 

laboratories show that influenza A (H3N2) viruses are the predominant virus this season. So 

far, 88% of the viruses tested by the public health laboratories have been influenza A viruses. 

Among those that were subtyped, 98% were H3N2 viruses. There have been some reports of 

influenza B, which seemed to be increasing as would be expected for this point in the season. 

Cumulatively for the season, 56% of the influenza B viruses that have had lineage testing 

performed have been from the B Yamagata lineage. Prior to the start of 2017, B Victoria 

viruses had been predominant.

In terms of genetic information on the viruses circulating, the vast majority of viruses have been 

H3N2. In terms of the breakout of those viruses genetically, 96% tested by public health 

laboratories were in the 3C.2a genetic group, which is the same genetic group that the vaccine 

strain belongs to (A/Hong Kong/4801). The remaining 4% were in the 3C.3a group. 

A/Switzerland, last year’s virus, is a representative of that group. All of the H1pmd09 were in 

the 6B.1 genetic group, all of the B Victoria were in the V1A genetic group, and all of the B 

Yamagata were in the Y3 genetic group.

In terms of the antigenic characterization of the viruses, all 74 of the A(H1N1)pdm09viruses

tested using ferret post-infection antisera were A/California/07/2009-like, the H1N1 component 

of the 2016-2017 vaccine. Among the A(H3N2) viruses, 311 of the 322 (96.6%) were 

antigenically characterized as A/Hong Kong/4801/2014-like, the H3N2 component of the 2016-

17 vaccine. Among the B/Victoria linage viruses, 71 of 78 (91%) were antigenically 

characterized as B/Brisbane/60/2008-like, which is included in both quadrivalent and trivalent 

influenza vaccines for the 2016-2017 season. Among the B/Yamagata lineage, all 67 were 

antigenically characterized as B/Phuket/3073/2013-like, an influenza B virus included in the 

quadrivalent influenza vaccines for the 2016-2017 season. 

Regarding influenza-like illness (ILI) as reported through outpatient surveillance, 5.2% of visits 

during the week ending February 11th were for ILI. This is well above the baseline of 2.2%. All 

10 HHS regions were above their region-specific baselines. For that week, all regions except 9 

and 10 (West Cost) continued to increase. The following map shows ILI activity level for states:

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Numerous states were reporting high ILI activity, including 28 states and New York City at high 

activity and another 7 in Puerto Rico at moderate activity. The Western portion of the US was at 

a lower activity level, which likely reflects the fact that many of those states, particularly in the 

Northeast, may already have experienced peak activity and may be declining.

In terms of hospitalization data report through FluSurv-NET, which covers about 9% of the US 

population, the overall laboratory-confirmed associated hospitalization rate was 29.4/100,000

cumulative through the week ending February 11th. That rate was highest for people 65 years 

of age and older at 136.6/100,000 followed by people 50 to 64 years of age at 28.5/100,000.

Based on data from the National Center of Health Statistics (NCHS) mortality surveillance 

system as of the week ending January 28th, 7.8% of deaths filed had pneumonia or influenza 

listed on the death certificate. This is above the epidemic threshold of 7.5% for that week and 

was the fourth week above that threshold. This is considered to be excess influenza-associated 

mortality. Thus far, 29 influenza-associated laboratory-confirmed pediatric deaths have been 

reported.

Regarding the schedule for vaccine strain selection for the 2017-2018 influenza season, the 

WHO Consultation on the Composition of Influenza Virus Vaccines for Use in the 2017-2018 

Northern Hemisphere influenza season was scheduled for February 27-March 1, with their 

announcement of their decision anticipated on March 2nd. The FDA’s Vaccines and Related 

Biological Products Advisory Committee (VRBPAC) was scheduled to meet on March 9, 2017 to 

make the US-specific vaccine strain decision.

In summary, influenza A(H3N2) viruses have predominated during the 2016-2017 season. 

However, influenza B activity may be starting to increase as would be anticipated late in the 

season. So far, influenza activity has been moderate but may not have peaked yet. The

majority of circulating stains are similar to those contained in the 2016-2017 vaccine. Vaccine 

virus recommendations for the 2017-2018 influenza season should be made in the next two

weeks. 

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Vaccine Effectiveness Update

Brendan Flannery, PhD 

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Flannery reported interim estimates of 2016–2017 seasonal influenza VE against medically 

attended influenza from the US Flu VE Network. The interim estimates were published in the 

Morbidity and Mortality Weekly Report (MMWR) on February 17, 2017. These data come from 

five US Flu VE Network. The sites and principal investigators are as follows:

 Baylor Scott and White Health (Manju Gaglani) 

 Group Health Cooperative (Mike Jackson, Lisa Jackson) 

 Marshfield Clinic Research Foundation (Ed Belongia, Huong McLean) 

 University of Michigan (Arnold Monto, Emily Martin) 

 University of Pittsburgh (Rick Zimmerman, Tricia Nowalk) 

The methods are the same as have been used for estimates in the past. The system enrolls

outpatients 6 months of age and older with acute respiratory illness defined as having acute 

respiratory illness with cough of less than 7 days duration. These data include enrollment from 

November 28, 2016 through February 4, 2017. One of the sites started as early as November, 

with others starting in January. These data come from a test-negative design. Vaccination 

odds are compared among influenza reverse transcriptase polymerase chain reaction (RT-PCR) 

positive cases and RT-PCR negative controls. Vaccination status for the interim estimates is

receipt of at least one dose of any 2016–2017 seasonal influenza vaccine according to medical 

records, immunization registries, and/or self-report. One site has medical records in registries 

only for this interim estimate, two sites have a mixture of medical records and self-report, and 

two sites that use self-report; whereas, for the end of season estimates, it is documented or 

plausible self-report. The analysis uses a logistic regression of (1 – adjusted OR) x 100% for 

VE. The variables used to adjust odds ratios include study site, age, self-rated general health 

status, race/Hispanic ethnicity, interval (days) from onset to enrollment, and calendar time. 

Similar to the surveillance data, the majority of cases for patients enrolled in the network were 

H3N2. Overall, 24% (744) of the 3144 patients enrolled during the time period of the interim 

analysis tested RT-PCR positive and 76% (2400) tested influenza RT-PCR negative. There 

was some B/Yamagata predominantly among the B lineage seen for patients enrolled. About 

30% of those enrolled were positive for influenza in more recent weeks.

The overall estimate for all influenza A and B includes all ages. The percentage vaccinated was 

45% among the influenza positives and 55% among the influenza negatives. The VE was 48% 

(CI 37% to 57%). Dr. Flannery stressed that it was too early at this stage to make much of the 

differences in some of the point estimates by age, though they hope to have better estimates to 

determine whether VE differs by age group as has been observed in some previous seasons in 

the end of season estimates. The estimates also were available by H3N2 specifically, which 

was very similar to the overall estimate. The adjusted VE against H3N2 for all ages was 43% 

(CI 29% to 54%). There was some variability in the point estimates by age, but only two of the 

age groups were statistically significant at this point, the 6 months through 8-year-old group at 

53% and the 50 through 64-year-old group at 50%. Overall for all ages against influenza B, the 

VE was 73% (CI 54% to 84%].

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In summary, the interim results for 2016–2017 season through February 4, 2017 indicate VE of 

48% against medically attended influenza. This interim estimate is similar to previous seasons 

when vaccine was well-matched to circulating influenza viruses. There was significant 

protection against circulating influenza A(H3N2) and B viruses (predominantly B/Yamagata), but 

VE was not estimated against H1N1pdm09 or B/Victoria due to the small number of cases. 

Enrollment continues, so end-of-season VE estimates may differ from interim estimates. VE 

was 43% against A(H3N2), similar to antigenically matched H3N2 viruses. VE was 39% in both 

2011-2012 and in 2012-2013. Both of those seasons were judged to be antigenically matched, 

although in 2012-2013 it was noted that there were egg adaptations in H3N2 viruses that may 

have affected the VE.

However, a meta-analysis1 of test-negative VE studies similar to this study looking at VE over a 

number of seasons found an H3N2 VE weighted average of 33% (26% - 39%). The 43% 

estimate can be said to be similar to those estimates of H3N2 effectiveness over multiple 

seasons, which suggests that there is a problem for VE against H3N2 in relation to slightly 

higher effectiveness than seen against A(H1N1)pdm09, which was an average of 61% in the 

same meta-analysis, and B viruses with an average of 54%.

1 It is not clear why there is a 

problem with H3N2 viruses specifically. There are more frequent updates to the H3N2 

component, which reflects more rapid antigenic change among H3N2 viruses. Also noted is 

that the candidate A(H3N2) vaccine viruses are more often affected by egg-adapted changes 

that result in antigenic difference after the adaptation to growth in eggs. CDC is working on 

methods and approaches to improve VE against A(H3N2) viruses and better candidate viruses 

[

1 Belongia et al. Lancet Infect Dis, 2016].

Discussion Points

Regarding the change in the antigenic nature of the vaccine virus in the egg as possibly being a 

reason that H3N2 VE is lower, Dr. Hunter asked whether there were any data about vaccines 

administered that have not been produced in egg to know whether they work better against 

H3N2.

Dr. Flannery responded that there are not yet enough data to be able to have an estimate of VE 

of either the recombinant or the cell-based vaccine from the CDC network. CDC is dependent 

on uptake of those vaccines, which has not reached a level at which they have been able to 

estimate the effectiveness of those vaccines. End-of-season estimates will include vaccinespecific or vaccine type estimates, but being able to get a VE will still be dependent upon 

uptake.

Dr. Reingold asked whether there were any estimates of vaccine coverage for this season in 

various groups.

Dr. Flannery replied that estimates through November were published and are included in the 

MMWR on VE. The key question regards the live attenuated influenza vaccine (LAIV) 

recommendation and effective coverage in children. It is too early to know. The Immunization 

Services Division (ISD) is doing some work on that. The point estimate for young children is 

slightly lower than it was in November for the previous season by about 5 percentage points at 

about 40%.

Dr. Messonnier added that there are some newer data, which would be presented later in the 

session.

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Dr. Duchin (NACCHO) asked whether any assessment is being done of sequence differences 

between the vaccine strain selected and the strain produced after egg manufacturing as a way 

to determine what might explain the reduced VE.

Dr. Katz replied that in the US, the FDA does not require that information. However, in Europe 

there is a pilot study to examine the sequences after the viruses have been propagated during 

the vaccine manufacturing process. The regulatory requirements are different in the US and are 

very stringent. The FDA does an antigenic analysis of the seed virus that goes into the 

manufacturing process, and that can be passaged only one or two more times. They ensure 

that the egg propagated vaccine seed virus is antigenically similar within 2-fold to the candidate 

vaccine virus that the manufacturers receive. They send their seed that they have passaged 

several times to optimize yield back to the FDA, and the FDA compares the two. This is with 

ferret antisera raised to the vaccine virus. There are different approaches in Europe.

AFLURIA® Update

Gregg C. Sylvester, MD, MPH

Head of Medical Affairs

SeqirusTM A CSL Company

Dr. Sylvester reviewed the comprehensive investigation on 2010 AEs in the Southern 

Hemisphere CSL 2010 SH trivalent influenza vaccine (TIV), as well as the staged clinical 

development program for AFLURIA®. The four trials in the staged clinical development program 

for AFLURIA® include the following, though Dr. Sylvester focused only on the first and third trials 

during this presentation given that they were the ones germane to the discussion earlier in the 

morning pertaining to fever rates:

 Children 5 years <9 years of age: Modified TIV Safety Phase IV

 Adult ≥18 years of age: QIV Immunogenicity & Safety Phase III

 Children 5 years of age to <18 years of age: QIV Immunogenicity & Safety Phase III

 Children 6 months of age to 59 months of age: QIV Immunogenicity & Safety Phase III

AFLURIA® is a purified, inactivated, split virion influenza vaccine. It has been manufactured in 

Parkville, Australia for the last 40 years. There are two formulations, a thimerosal-free 0.5mL 

pre-filled syringe and a thimerosal-containing 5mL multi-dose vial. It has an interesting 

licensure history. In November 2007, CSL was granted approval for the TIV in those ≥18 years. 

In 2010-2011 season, there was a licensure down to 6 months of age and above. The vaccine 

was never brought into the US, so in December 2011, the FDA revised the licensure and now it 

is licensed for the TIV for those 5 years of age to <18 years of age. The FDA approve QIV in 

those ≥18 years of age in August 2016, which Dr. Sylvester presented on to ACIP in October 

2016. A Supplemental Biologics License Application (sBLA) has been submitted to the FDA for 

use of QIV in those 5 years of age to <18 years of age.

The prescribing information for AFLURIA® is that it is not to be used in children less than 5 years 

of age. However, ACIP recommends that other age-appropriate influenza vaccine should be 

used in children through the age of 8 years. There is a different in the licensure versus the 

recommendation, which is due to the fact that there was an unexpected increase in reports of 

fever and febrile seizures primarily in children less than 5 years of age compared to previous 

seasons in the Southern Hemisphere using the CSL 2010 SH TIV. Also noted was that there 

were increased reports of fever in children 5 years of age to less 9 years of age.

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Dr. Sylvester described three discrete programs looking at a systematic and comprehensive 

investigation:

 Clinical Safety Review











Characterize the AEs

Identify risk factors and at-risk populations

 Manufacturing & Quality Review

Assessment of safety and manufacturing process

Assessment of quality (purity and potency)

 Scientific Research Investigation

Explore potential indirect surrogate measures (in vivo and in vitro tests)

The safety review examined the unexpected increase in fever and febrile seizures observed in 

the Southern Hemisphere in 2010. It would be rare to see a febrile seizure over the age of 5 

due to the stage of hypothalamic development in young children. Febrile seizures typically 

occur in children between the ages of 6 months and 5 years of age. The peak age is about 24 

months of age, and they can occur up to 5 years of age. In the Southern Hemisphere, 5 to 

9/1000 children vaccinated had a febrile seizure. More than 80% occurred within the first 12 

hours of receiving the vaccine. The average duration following seizure onset was 2.5 minutes, 

with a range from 1 to 6 minutes. In the US, this occurred in a predominance of males at 2/3 

compared to 1/3 in females. The highest fever recorded was 40.8o C but the mean was 39o C. 

There also were increased fever reports in children 5 to less than 9 years of age. Within a 

month of this investigation, the regulatory agency in Australia, the recommending body in 

Australia, and the company CSL withdrew the vaccine but continued post-marketing 

surveillance throughout the entire season. At that time, FDA, CDC, and ACIP were notified. As 

early as July 2010, the recommendation was made on AFLURIA®. 

Dr. Sylvester showed the following schematic of the CSL manufacturing process, asking 

everyone to focus on the two arrows:

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After the whole virus is grown in egg, there is an inactivation state, the β-propiolactone (BPL) 

treatment. That inactivates the vaccine, creating the virion in the middle, which contains the 

fragmented ribonucleic acid (RNA). The splitting agent is created by sodium tauro deoxycholate 

(TDOC), which creates the lipid/RNA complexes. Dr. Sylvester focused further on the TDOC 

and the lipid RNA complexes.

A detailed review was made of all manufacturing aspects starting at the seed all the way to fill 

and finish, including raw materials, facilities, utilities, and processes. No deviation or change

was found from previous seasonal formulations. All batches met specification and there was no 

evidence of batch-specific issues. Laboratory testing ruled out chemical contamination, 

bacterial contamination, and viral contamination. There was no evidence of agglomeration as a 

contributing factor. However, there was one major change of note. The WHO had 

recommended three new virus strains for inclusion in the 2010 influenza vaccines for the 

Southern Hemisphere. There was a complete strain change for TIV in 2009. The strains for 

those two years were:

TIV 2009

 A/Brisbane/59/2007 (H1N1) – Like 

 A/Uruguay/716/2007 (H3N2) – Like 

 B/Florida/4/2006 – Like

TIV 2010

 A/California/7/2009 (H1N1) – Like 

 A/Perth/16/2009 (H3N2) – Like 

 B/Brisbane/60/2008 – Like 

The scientific investigation was then performed. An attempt was made to find an animal model 

that could create febrile seizures. Non-human primates, ferrets, rabbits, and newborn rats were 

considered. However, febrile seizures were not induced in any of the in vivo models examined

with any TIV. Therefore, assays were created for in vitro models. The published literature 

suggested that increased cytokine levels were observed after febrile seizures. Thus, cytokine

and chemokine models were explored as correlates of in vivo pyrogenicity. Mapping these 

cytokines and chemokines in vitro may act as an indirect surrogate measure of the reactogenic 

potential of the TIVs. CSL 2010 SH TIV was found to stimulate the release of cytokines and 

chemokines in whole blood assays more robustly than previous CSL TIVs or other 

manufacturers’ TIVs. The difference between the CSL 2010 SH TIV and other TIVs suggested 

that the manufacturing process may have played a role. The difference between the CSL 2010 

SH TIV and previous CSL TIVs suggested that the new influenza strains may have played a 

role. 

The investigation revealed that the CSL manufacturing process resulted in more residual lipid 

and RNA complexes with the CSL 2010 SH TIV than other licensed influenza vaccines. These 

complexes induced a stronger than expected inflammatory signal. It turned out that the splitting 

agent, or TDOC, plays a key role in the number of lipid/RNA complexes. The higher 

concentration of TDOC and lower reduction of lipid/RNA complexes resulted in lower reduction 

in the assays or in the signal. By increasing the concentration in TDOC levels, CSL showed 

that there was a significant reduction in the inflammatory response, shown in these two graphs: 

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The two graphs represent two assays. The standard TIV was split for A(H1N1) at 0.9%, H3N2 

at 1.5%, and B at 0.5%. The inflammatory signal can be seen on both of the above assays. 

H1N1 was then increased to 1.5% and H3N2 and B were left the same (New #1). That resulted 

in a reduction in the pyrogenicity. Then H1N1 was 0.9% and H3N2 and B were 1.5% (New #2), 

which resulted in a marked reduction. There was a belief that B was creating the AEs. Then all 

three were assessed at the concentration of 1.5% (New #3) within the manufacturing process 

allowance, which showed an even further reduction. These in vitro models demonstrated that 

lipids and degraded RNA fragments “preserved by the standard TDOC manufacturing process” 

as well as the three new strains were the contributing factors of the CSL 2010 SH TIV pediatric 

AE profile. The investigation demonstrated that increasing the levels of TDOC attenuated the 

pro-inflammatory signals in vitro. These conclusions led to the staged approach for a new 

clinical development program for AFLURIA®. 

The Pediatric Phase 4 Safety Study focusing on children 5 years to <9 years of age was 

modified within registered conditions because the B strain was split at 1.5% TDOC. There were 

400 subjects in whom safety and tolerability were evaluated. Hopefully, the results will inform 

the QIV pediatric clinical development program and can be used as an indirect comparison with 

historical data and comparator QIV. The comparator QIV is a licensed US vaccine. This study 

showed an overall fever rate for the CSL TIV modified vaccination in children 5 years of age to 

<9 years of age was 8.2%, with the vast majority being mild or moderate at <39o C compared to 

the reference QIV, which was 9.2%. The confidence intervals overlap and the fever rates are 

similar to the licensed QIV product. By increasing the TDOC in the B strain, the point estimates 

are now much lower than the historical TIV as well as the comparator QIV. The confidence 

limits do overlap. In terms of severe fever rates, fever intensity of >39o C, the point estimates 

hover at about 2% and once again, below the comparator QIV and historic TIV from past 

experience at CSL.

The conclusion was that the CSL TIV fever rates observed in this study were similar to the 

comparator QIV vaccine in children 5 years of age to <9 years of age. Due to this, the TDOC 

concentrations are now incorporated for splitting all A and B strains. This informed the staged 

approach for the QIV program. As mentioned earlier, the FDA has already approved the 

licensure for the QIV in those ≥18 years. The Phase III Study for those 5 years to <18 years of 

age has been submitted to the FDA, with the hope that it will be licensed in 2017. The Phase III 

Study in those 6 months to 59 months of age is now an ongoing study.

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The trial in children 5 years to <18 years of age was an immunogenicity as well as a safety trail, 

and all 8 co-primary endpoints were met. AFLURIA® QIV demonstrated non-inferior 

immunogenicity for all strains to the comparator QIV (Fluarix® QIV) in children 5 years to <18 

years of age. Descriptive secondary immunogenicity endpoints overall, and by age subgroups 

(5 years to <9 years, and 9 years to <18 years inclusive) were robust and were consistent with 

expectations for these age groups, and this is similar with the comparator QIV. 

 

AFLURIA® QIV following vaccination were similar to the comparator QIV in both age groups, 

with 5 years to <9 years of age at 4.5% (95% CI: 3.2, 6.1) compared to 3.6% (95% CI: 1.8, 6.6), 

and in 9 years to <18 years at 2.1% (95% CI: 1.3, 3.4) compared to 0.8% (95% CI: 0.1, 2.7). 

The vast majority of fever in both vaccines were mild to moderate. In terms of historical fever 

rates, the point estimates are even lower than the TIV study with 400 subjects and historical 

TIV. For severe fever, AFLURIA® QIV hovers just over 1% for >90o C and slightly higher than 

the comparator, but well within the same confidence limits.

In summary, AFLURIA® TIV and QIV safety profiles in those 5 years to <18 years of age is 

acceptable. Fever rates for those 5 years to <9 years of age are similar to the comparator and 

less than historical vaccines. Both AFLURIA® TIV and QIV will be offered in the US during the 

2017-2018 influenza season. As mentioned, the sBLA for the 5 years of age through 18 years 

of age was submitted in 2016 and is anticipated to be licensed before the end of the year.

Discussion Points

Dr. Belongia asked whether TDOC is routinely used for split virus vaccines across 

manufacturers, and what kind of guidance the FDA provides to manufacturers in terms of the 

TDOC concentration.

Dr. Sylvester replied that every vaccine manufacturer has different proprietary methods. TDOC 

is used only for AFLURIA® and not in other influenza vaccines.

Dr. Sun said that he had nothing to add, but that if the other manufacturers wished to comment 

on their splitting agents, they may do so.

Dr. Stephens noted that it raised the question about mechanism. He wondered if Dr. Sylvester 

could offer any more specificity about how they are modifying the immune response by 

increasing the TDOC and changing the lipid and RNA fragment concentrations.

Dr. Sylvester responded that that what they do know is that when TDOC was at 0.5% for the B 

strain, there was a lot of residual lipid that was connected to the messenger RNA (mRNA). 

Increasing the TDOC clears out much of the lipid component that was believed to be causing 

much of the AEs and leaves the RNA, and there is still nice immunogenicity.

Dr. Walters asked whether there were plans to continue the assessments on an ongoing basis 

as vaccines are produced and differ annually.

Dr. Sylvester replied that the two assays they created have been validated and are now part of 

the manufacturing process, so that as the four strains are created, they are tested throughout 

the system and at the end product to ensure that the reactogenicity is much lower than 

previously.

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Based on the data, Dr. Foster (APhA) asked whether the WG was considering removing the 

recommendation for those 5 years of age to <8 years of age.

Dr. Cohn indicated that a summary of the WG discussion would be presented later in the 

session.

Fluzone® High-Dose (HD) Update

Stefan Gravenstein, MD, MPH, CMD

Professor of Medicine 

Director, Center for Geriatrics and Palliative Care

University Hospitals and Case Western Reserve University

Adjunct Professor of Medicine, Brown University

Clinical Director, Healthcentric Advisors

Dr. Gravenstein presented results from a Fluzone® HD versus standard-dose (SD) cluster 

randomized trial in US long-term care facilities (LTCF). He said that as a geriatrician, he would 

frame this around the way he thinks about older patients and the value of vaccines as 

distinguished from children. A study by Smeeth examined first heart attack or first stroke after 

an inflammatory event, in this case systemic respiratory tract infection (SRTI) or urinary tract 

infection (URI). The study showed that in the weeks and months following the inflammatory 

event, there is an increased risk for first heart attack or first stroke that is 2- to 4-fold higher. 

That increased risk persists out for a few months [Smeeth, L. et al. N Engl J Med 2004; 351:

2611-2618].

When Dr. Gravenstein talks about this with his health staff, he talks about inflammation and the 

risk of vaso-occlusive event. In this case, it is framed as thrombosis, and he uses a 

“thrombometer” that he contrived to help explain this:

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When people are born and are young, the inflammatory mediators or markers of inflammation 

are relatively low. On the Thrombometer, young people would be at low-risk for propensity to 

clot. With increasing age, inflammatory markers start rising and the propensity to clot increases 

as well. If underlying diseases (obesity, diabetes, arthritis, vascular disease, dementia, chronic 

obstructive pulmonary disease (COPD)) are added on top of that, the markers increase further 

and the propensity to clot is even higher. In terms of the risk for complications from infectious 

events, vaso-occlusive risk rises with age and disease. Add to that infections (bladder, 

respiratory), the risk goes even higher. One outcome that might be expected with 

administration of an effective vaccine that reduces the amount of inflammation with an infectious 

event such as influenza or pneumococcal disease is a reduction in these types of events. Older 

individuals become immune senescence, have a lessor immune response that is more 

permissive for infection and often more permissive for severe infection that can result in 

hospitalization. This also lowers the vaccine response, so better vaccines are needed to 

overcome declining response. This also slows recovery from infection and changes symptom 

presentation with age [Lambert Nathaniel D et al. Understanding the immune response to 

seasonal influenza vaccination in older adults: a systems biology approach. Expert Rev. 

Vaccines. 2012 August; 11(8): 985-994; and Taub D, Longo D. Insights into thymic aging and 

regeneration. Immunol Rev. 2005;205(1):72-93. (Abstract only)].

Studies with HD compared to SD influenza vaccine have been presented to ACIP previously. In 

an RCT published by DiazGranados and colleagues of an elderly population of approximately 

32,000 people showed a 25% reduction in laboratory-confirmed influenza and a 30% reduction 

in hospitalizations.1 A meta-data analysis study published by lzurieta and colleagues in 

collaboration with CDC, NIH, and FDA examined individuals diagnosed and treated for influenza 

and observed a similar reduction in these diagnoses (22%) and hospitalizations (22%) with an 

influenza diagnoses2 [1Carlos A. DiazGranados, M.D., Andrew J. Dunning, Ph.D., Murray 

Kimmel, D.O., Daniel Kirby, B.Sc., John Treanor, M.D., Efficacy of High-Dose versus StandardDose Influenza Vaccine in Older Adults, N Engl J Med 2014; 371:635-645|August 14, 2014|DOI: 

10.1056/ NEJMoa1315727; 2Slzurieta HS, Thadani N, Shay DK, Lu Y, Maurer A, Foppa IM, 

Franks R, Pratt D, Forshee RA, MaCurdy T, Worrall C, Howery AE, Kelman J., Comparative 

effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged 65 

years and older from 2012 to 2013 using Medicare data: a retrospective cohort analysis, Lancet 

Infect Dis 2015 Mar;15(3):293-300. doi: 10.1016/S1473-3099(14)71087-4. Epub 2015 Feb 9].

What these studies did not answer are questions about the people who are the sickest and least 

likely to respond to vaccine and whether a benefit can still be achieved in this group, such as 

the group that is in the long-term care setting. Case Western Reserve University’s (CWRU) 

approach to this was a pragmatic large-scale cluster RCT on comparative effectiveness of HD 

versus SD influenza vaccine in long-term care specifically in the long-term care setting. Two 

studies were conducted. The first was a pilot/feasibility study undertaken in 39 nursing facilities 

for the 2012-2013 predominantly A/H3N2 influenza season. The second was the full cluster 

RCT of HD influenza vaccine versus SD influenza vaccine in 823 nursing homes (NHs) for the 

2013-2014 predominantly A/H1N1 influenza season. 

Of the 39 facilities enrolled in the pilot study, 19 were in the HD group and 20 were in the SD 

group. Approximately 12,000 people were admitted to these facilities during the influenza 

season. As of October 1, 2012, there were 4400 residents living in the facilities. Of those, 3800 

were over the age of 65 who qualified for the analytic group and 3000 were in the long-stay 

population. The long-stay population had to have been living there for at least three months. 

Those were the analytic samples with roughly an even split of just under 1500 in each of the HD 

and SD group. There was no difference in the outcome of death for this season. There was a 

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30% reduction in hospitalization, which was the primary outcome and satisfied the investigators 

that this was feasible to do in a long-stay population. The absolute hospitalization rate between 

the two groups for ever being hospitalized during the season was just under 21% for the SD and 

13.5% for the HD. This gave the signal to move forward to the large trial.

For the pragmatic cluster RCT of HD versus SD influenza vaccine in NHs, NHs were recruited in 

areas adjacent to 122 cities in the CDC influenza surveillance system. Federally mandated 

nursing home resident Minimum Data Set (MDS) assessment to identify permanent NH 

residents with selected demographic and functional characteristics and to measure the 

outcomes. Medicare Fee-For-Service (FFS) resident hospital claims were used to measure the 

outcome of hospitalization for influenza cardiovascular exacerbations of influenza. 

Facilities were recruited within 50 miles of CDC cities. Facilities were excluded that already 

were using HD as standard of care, had fewer than 50 permanent residents, were hospitalowned NHs, or in which >20% of residents were under 65 years of age.

Individual residents could still decline vaccine or ask for a different vaccine, and the facility could 

do whatever they typically would do as its standard of care. If a facility had already been 

offering HD as its standard of care, they were excluded to the study. Facilities had to be 

indifferent to the type of vaccine that was going to be given to their residents.

The facilities were randomly assigned to 4 groups: 

 High-Dose for NHs residents 





Free Staff Vaccine

No Free Staff Vaccine

 Standard Dose for NHs residents 





Free Staff Vaccine

No Free Staff Vaccine

Provision of free or no free vaccine for staff did not affect any outcomes. Facility staff were 

educated on influenza and the study procedures. There were some 200,000 hits to the video 

for this education. Facility data were linked to the Online Survey Certification & Reporting 

System (OSCAR) that nursing homes submit to describe themselves; the federally required 

MDS, which includes demographic information and information about the facility; and Medicare 

Part A data for the FFS and diagnoses; MDS discharge data, which indicates where someone 

leaving the NH went (hospital, other setting); and vital status files to determine who died. 

Vaccination data reports were collected directly from the facilities. The facilities faxed these to 

the investigators monthly, and the investigators conducted an onsite audit. Patient eligibility 

was at least 3 months of residency, over 65 years of age on November 1, 2013, and Medicare 

FFS. 

The first analysis examined all-cause hospitalization per person-year, which is all that can be 

acquired out of the MDS; mortality; and functional decline. The qualifying period was through 

September, the vaccination period until November, and the outcome period from November 

through March. The pre-specified primary outcome for FFS was the risk of hospitalization due 

to pulmonary and influenza-related illness defined by these International Classification of 

Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes: 460–466, 480–488, 490–

496, 500–518. 

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The 823 participating facilities across the country are relatively well-distributed, as shown in the 

following map (yellow = HD vaccine facilities; red = SD vaccine facilities): 

Within the 50-mile radius, there are 9200 facilities of which 10% were screened. Of those, 166 

were excluded leaving 823. About half were HD and half were SD. In that allocation, there 

were approximately 45,000 residents in each of the HD and SD facilities. There were 

approximately 54 to 60 residents per NH in the analytic sample for the MDS, leaving 

approximately 25,000 residents per group.

Based on the OSCAR and Medicare claims data, the facilities were relatively similar between 

the groups with about 118 residents per home, 80% of residents vaccinated, 78% long-stay 

residents, about 86% of the long-stay residents vaccinated, about 55% of staff vaccinated 

across all facilities, about the same number of patients on Medicaid, about the same ratio of 

Registered Nurse (RN) or RN plus Licensed Practical Nurse (LPN) staffing, and about the same 

level of functional disability.

Approximately 92,000 residents were living in the study NHs on October 1, 2013. 

Approximately 76,000 of these were over the age of 65; about 53,000 were long-stay; about 52, 

000 were in the MDS analytic sample; and about 38,000 were in the FFS sample. The MDS 

sample included all-cause hospitalizations and all residents were included in that. The FFS 

sample included only those who were on Medicare FFS, which reduced the sample by about 

20%. In terms of the demographics of the individual residents, the groups were similar by age, 

gender, ethnicity, and underlying conditions.

The influenza season during the study timeframe was predominantly A/H1N1, with a little 

A/H3N2. It was an interesting season because it often is said that A/H1N1 is not such a big 

deal in older people. The unit of analysis for the analytic approach was individual residents, 

which was adjusted for clustering by NHs using robust variance estimates. Multivariable 

logistic, Poisson, and Cox regressions were used. The initial model assessed interaction 

between treatments, and was adjusted for pre-specified NH- and resident-level covariates. The 

analysis was Intention-To-Treat (ITT), so the 15% who were not vaccinated were still included. 

The Number-Needed-to-Treat (NNT) was also calculated.

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Based on a seasonal index of hospitalizations by month from November 2013 through May 

2014, about 20% of the population was hospitalized. There were more hospitalization in the SD 

group versus the HD group in all months except May. Because these are index hospitalizations, 

the typical epidemic curve expected is not seen because this includes only the first 

hospitalization for any one individual.

This is the calculation for the NNT:

NNT = 1/ARR where ARR* = CER – EER 

1/(0.2090-0.1967) = 81.3 (CI: 53, 182)

*Using unadjusted event rates

There was a 21% hospitalization rate in the SD and a 19.67% in the HD. That 1.2% difference 

generates a NNT to prevent hospitalization of about 81. With the adjusted numbers, it is a little 

higher than that at 82.6.

For the unadjusted Medicare FFS data diagnosis-related hospitalizations of a smaller population 

of only 38,000), all-cause hospitalizations was 7.4% relative difference or an absolute difference 

of about 280 hospitalizations from any cause. Looking at the diagnoses with which people were 

diagnosed, if cardiac or cerebrovascular was in any position, there was about a 10% difference. 

If a cardiac diagnosis of heart attack, heart failure, atrial fibrillation, or a respiratory diagnosis 

was in any position, it was about a 10% difference. Cardiac, cardiovascular, or respiratory can 

account for the entire difference in the all-cause hospitalization. If a respiratory condition is by 

itself in any position, it only accounts for about 10% difference or two-thirds. If the discharge 

diagnosis is required to be a cardiac condition in the first position, it also accounts for about twothirds of hospitalizations. In the case of respiratory in the first position, it is a difference of 92 or 

about 12%, so about one-third have a diagnosis with a respiratory condition in the first position. 

With pneumonia in the first position, it is a difference of 31 or only 10% of the total difference 

seen in all-cause. As the numbers get smaller, the statistical and clinical meaningfulness is 

less. While there was a 70% lower likelihood of having an influenza diagnosis, only 27 people 

had an influenza diagnosis in these claims. Of those, 6 received HD and the remainder 

received SD. This is a frequency plot, not an adjusted plot.

In terms of the unadjusted and adjusted marginal Poisson regression analysis outcomes 

accounting for clustering by NHs, a nearly 7% reduction was observed for all-cause 

hospitalization in the MDS cohort. In the smaller FFS cohort (N=~38,000), in the adjusted group 

all-cause, there was a similar size reduction estimated of about 8.5%. For hospitalization for 

respiratory issue, there was a 12.5% reduction in hospitalizations.

To summarize, hospitalization reductions by diagnoses listed at discharge were as follows:

Unadjusted

 Any cause: 7.4%

 Any cardiac or cerebrovascular event: 9.7%

 Any heart failure, heart attack, atrial fibrillation or respiratory diagnosis: 9.7%

 Any respiratory diagnosis: 10.3%

 As primary diagnosis, a cardiac condition heart attack, heart failure or atrial fibrillation: 9.0%

 As primary diagnosis, a respiratory condition: 11.8%

 Pneumonia: 26.2%

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Adjusted 

 All cause: 8.5 %

 Respiratory first: 12.7%

The following offers some context between the two study years:

 

In the bottom left is the pilot year, during which there was a large hospitalization rate that was 

almost twice as high is the top right, which is the full study year. The year that followed the full 

study year was much higher. There was a relatively light influenza season compared to the pilot 

year or the year after.

In summary, HD vaccine has been shown to reduce laboratory confirmed influenza among 

outpatient elderly. NH residents have higher event rates (e.g., hospitalization) than other

settings, which enables health services impact studies; cluster-randomized approach; and 

overcomes selection biases such as access. All residents had equal access to vaccine. The 

2013-2014 season is of special interest because it offers a conservative estimate of relative 

benefit in this population. It was an A(H1N1) predominated season, and the relative benefit of 

HD vaccine for this strain in a NH population has yet been unknown. It was a relatively mild 

season compared to other seasons, so the opportunity for greater effect is also not seen, but is 

suggested by the pilot study. The FFS claims differences are consistent with the biologic 

plausibility of effect on hospitalization-based diagnoses and the cardiorespiratory outcomes.

To recap the primary findings, the pilot and full study support the idea that HD influenza vaccine 

reduces hospitalization risk for institutionalized elderly compared to standard dose. In the pilot

among nearly 3000 people divided between HD and SD, 197 (13.5%) versus 302 (20.2%) were 

hospitalized, or an adjusted RR of 0.701 (0.543-0.905), in an A/H3N2 predominant season. In 

the full study among approximately 53,000 people divided between HD and SD, 5239 (19.7%) 

versus 5517 (20.9%) were hospitalized, or an ARR of 0.933 (0.884-0.985) in an A/H1N1 

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predominant season. The differences in hospitalization rates can be largely accounted for by 

differences in cardiorespiratory event diagnoses. 

These estimates may be conservative due to the severity of the influenza season, the ITT 

approach with nearly 15% residents not being vaccinated, and the type of influenza virus 

circulating (A/H1N1), and the assessment only of reduced hospitalization which likely 

underestimates the net benefits to nursing home residents’ health outcomes. When 

approximately 20% of the population is hospitalized, even a 1% absolute reduction in 

hospitalization can be cost-effective (e.g., 81 vaccines at ~$30/vaccine = $2430, or less than the 

average cost of hospitalization). 

There are some limitations of the study. There are no laboratory data to confirm influenza. The 

HD:SD relative benefit on A(H1N1) may underestimate difference when other strains dominate, 

such as A(H3N2). The relative difference to no vaccine was not estimated, though it could be 

larger.

Discussion Points

Dr. Atmar observed that other studies that have examined this population have shown that 

vaccination of the healthcare workers in these facilities has a greater effect than vaccinating the 

residents. He found it disappointing that only 26% of the workers in these facilities were 

vaccinated. He wondered whether they examined the effect of higher versus lower vaccination 

acceptance within facilities on outcomes and, if so, how that compared to HD versus SD.

Dr. Gravenstein responded that they wondered if by offering free vaccine they would see a skew 

in vaccine uptake to prospectively settle the question of whether vaccinating staff could reduce 

risk. By offering free vaccine, nothing was skewed. Therefore, it is not possible to tell whether 

there was a difference in HD versus SD based on staff vaccination from a randomization 

perspective. The hazard of the other studies that assessed staff vaccination, though he 

believes them to reflect truth, is that the percentages of facilities with the highest staff 

vaccination often are making many other efforts that help the residents potentially do better. It 

is hard to know for sure how much the difference is, because the facilities are just better. 

Facilities that have higher uptake among the residents are more likely to have higher uptake 

among the staff, have infection control policies in place, have an Infection Preventionist to 

implement isolation, and other types of measures. It is difficult to speak specifically to whether 

staff vaccination would actually help in this case.

Dr. Kempe asked whether any self-selection was involved in residents who chose to get the HD 

vaccine in those facilities.

Dr. Gravenstein replied that there is not. In any facility, when residents are asked what vaccine 

they got for anything, they typically do not know. The 10% of residents who refuse may be the 

subset who might know what they are getting. This is an unblended study allocated at the 

facility level, but even the nursing staff do not know what they gave three weeks later. 

Expecting that the residents are skewing the results is unlikely.

Dr. Reingold pointed out that Dr. Gravenstein had not mentioned anything about pneumococcal 

vaccine coverage in these NHs. He was curious as to whether that information was available, 

and if it made any difference.

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Dr. Gravenstein responded that they do not have that information, and he was not sure whether 

the information available to them through the MDS record is reliable. In terms of whether it 

would be in the administrative data, this would have to go back five years and they were looking 

at the data only for one year.

Dr. Messonnier asked who funded the study.

Dr. Gravenstein replied that Sanofi Pasteur funded the study.

Dr. Duchin asked whether there was any information about medications that patients were 

taking, such as statins or others with an anti-inflammatory effect.

Dr. Gravenstein responded that they did not yet have the Part D claims, but they do plan to 

examine this in the future.

Dr. Schmader (AGS) said it struck him that perhaps the name “pilot” should be removed for the 

pilot study. He found both studies to be equally valuable. There were positive findings for 

H3N2 in the pilot, so it was adequately powered. There is no Type 2 error there. The study is 

even positive against the obstacles of a weak season with H1N1, so the results are impressive.

Dr. Thompson (NVAC) suggested examining cost in a more significant way. In reality, the cost 

savings could be quite significant.

Dr. Gravenstein indicated that they have begun the cost-effectiveness work.

Dr. Maldonado (AAP) asked whether it was possible to examine AEs with HD, which has been 

raised as an issue in the past.

Dr. Gravenstein replied that because this was a standard of care, they used the VAERS 

reporting system, and there were no differences in the reports.

FluMist® Update

Helen Bright, PhD

Raburn Mallory, MD

MedImmune

Drs. Bright and Mallory presented an update of the 2015-2016 vaccine effectiveness data, 

including recently published data on the effectiveness of LAIV against pediatric influenza 

hospitalization. In addition, they provided an update on the non-clinical root cause investigation, 

and work that MedImmune has been doing to help optimize the A/H1N1 strain selection for the 

2017-2018 vaccine formulation, and insights into ongoing clinical studies and timelines for data 

availability. 

Revisiting the data from the 2015-2016 influenza season, Dr. Bright reminded everyone that the 

data from this outpatient setting showed six vaccine effectiveness studies with a consolidated 

estimate. Looking across the studies, the point estimates are generally similar. The 

consolidated estimate is 48% for LAIV and 60% for IIV. For the B strains, there is an additional 

dataset from a test negative study published last year. LAIV has a consolidated vaccine 

effectiveness point estimate of 66%, while IIV is 49%. [1. Ambrose C. Presented at Advisory 

Committee on Immunization Practices Meeting; June 22, 2016; Atlanta, GA 2. Flannery B. 

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In terms of LAIV and IIV effectiveness estimates for A/H1N1pdm09 strains for the 2015-2016 

influenza season1,2 in the outpatient setting from the US and the rest of the world, the 

consolidated overall VE was 32%, demonstrating low but significant effectiveness. The IIV 

effectiveness was 72% [1Caspard H et al. Abstract accepted for presentation at: Pediatric 

Academic Societies Meeting; May 6-9, 2017; San Francisco, CA; 2Helmeke C et al. [poster]. 

Presented at: European Scientific Conference on Applied Infectious Disease Epidemiology; Nov 

28-30, 2016; Stockholm, Sweden.

Despite overall low effectiveness against the predominating circulating H1N1 strain outpatient 

setting, there are data from the same season which demonstrate moderate to good VE in the 

inpatient setting. Data on the impact of LAIV use on inpatient hospitalization due to influenza 

was recently published on the 2015-2016 influenza season in the UK. These data 

demonstrated meaningful endpoints for the reduction of severe disease resulting in 

hospitalization. Effectiveness in the prevention of laboratory-confirmed influenza hospitalization 

in children was 55% in England and 63% in Scotland. These are both populations in which 

LAIV is almost exclusively used [1 Peabody R et al. Euro Surveill. 2017; 22(4):pii=30450.

2 Health Protection Scotland. http://www.hps.scot.nhs.uk/resourcedocument.aspx?id=5529. 

Accessed 16 February 2017]. 

Turning to the progress made in the non-clinical root cause investigation, this investigation is 

currently focused on two potential hypotheses. The first is reduced replicative fitness of 

H1N1pdm09 LAIV strains in human cells, and the second is vaccine virus interference in the 

quadrivalent formulation. Studies to address the second hypothesis are currently ongoing. 

During this session, Dr. Bright presented an update on the first hypothesis. The approach has 

been to characterize and define the biological profile of the effective vaccine strains and 

compare these to recent H1N1 strains that had lower than expected VE. This presentation 

focused on a comparison between the following pdm09 H1N1 strains: 

Pre-Pandemic Strains Post-Pandemic Strains

New Caledonia 1999 

(NC99)

California 2009 (CA09)

South Dakota 2007 (SD07) Bolivia 2013 (BOL13)

Slovenia 2015 (SOLV15) 

Pandemic (pdm)

Presented at Advisory Committee on Immunization Practices Meeting; June 22, 2016; 

Atlanta, GA 3. Caspard H et al. Presented at International Society for Influenza and 

Other Respiratory Virus Diseases (ISIRV) Options IX for the Control of Influenza 

Conference; August 25, 2016; Chicago, IL. 4. Nohynek H et al. Euro Surveill. 

2016;21(38):pii=30346. 5. Pebody R et al. Euro Surveill. 2016;21(38):pii=30348. 6. 

Helmeke C et al. http://www.verbraucherschutz.sachsen-anhalt.de/fileadmin/Bibliothek/

Politik_und_Verwaltung/MS/LAV_Verbraucherschutz/hygiene/influenza/

Effektivitaet_der_Influenzaimpfstoffe_2015-16.pdf 7.Caspard H. Abstract Accepted for 

Publication PAS, May 6-9, 2017; San Francisco, CA].

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NC99 is particularly relevant as it was in the vaccine for many years and has a high level of 

efficacy and effectiveness of clinical data. MedImmune has profiled its LAIV strains through the 

influenza virus life-cycle and also developed a novel primary human nasal cell model in which 

their performance can be evaluated. An important feature of their LAIV strains is that they only 

differ biologically in their external surface glycoproteins, hemagglutinin (HA) neuraminidase 

(NA). These are taken from the wild-type circulating strain each year, and they provide the 

antigenic match to the vaccine. The remaining internal components of the vaccine virus remain 

the same every year and provide the attenuated phenotype. The HA protein is responsible for 

cell binding and cell fusion of the virus, while NA is responsible for virus release and spread. 

The physiological role of HA is to help the virus enter the cell. At a pH of approximately 5.5, the 

HA changes its shape and allows the virus to uncoat its genome. However, high temperature 

from the external environment can also have an effect on the HA shape and this could reduce 

virus infectivity. Initial findings with the California strain in the 2013-2014 vaccine indicated an 

HA protein at a lower than expected stability. Based on this, Bolivia was selected as it 

demonstrated higher HA thermostability, which is much more similar to previous H1N1 LAIVs. 

However, this may have made the HA too acid-stable. The Bolivia strain has a much lower 

activation period in terms of the pH at which HA changes it shape. This can result in a 

prolonged uncoating stage for the virus, which would also impact virus replication fitness.

HA is also responsible for the binding of the virus to the cell. Assays have been developed to 

compare binding of the viruses to α2-6 human cell receptors. These studies indicate that the 

pandemic CA09 and BOL13 strains may have decreased binding to the human receptor 

compared to NC99.

The late stage of viral replication was also evaluated, which affects cellular release and spread. 

This was done by comparing replication using two assays. The Fluorescent Focus Assay (FFA)

measures a single cycle of replication. The Tissue Culture Median Infectious Dose (TCID50)

measures multiple rounds of replication and relies on proficient release of the virus and efficient 

spread. For the pre-pandemic H1N1 viruses, the two assays gave similar results. However, for 

the pandemic09 strains, there is a discrepancy between the FFA titer and the TCID50 titer. This 

suggests that H1N1pdm09 viruses are less able to support multiple rounds of replication. Postpandemic H1N1 LAIV strains have reduced replication in primary human nasal epithelial cells. 

Regarding the update on A/H1N1 strain selection for 2017-2018 season, as was the case for all 

previous effective vaccine strains, A/California and A/Bolivia were selected based on 

characteristics and characterization data from a range of assays. This culminated in 

immunogenicity studies in ferrets. However, based on the lower than expected vaccine efficacy 

seen with these two strains, several new assays have been added into the strain selection 

process. Using these assays, a lead H1N1 candidate was identified, A/Slovenia 2015 for 

inclusion in the 2017 vaccine.

The preliminary data show that A/Slovenia has improved HA properties. It has an activation 

period that is very similar to the pre-pandemic H1N1 strain and to other effective vaccines 

strains. Preliminary receptor binding data suggest that A/Slovenia has improved receptor 

binding compared to Bolivia. Measuring A/Slovenia’s replication by FFA and TCID50, the assay 

values are very similar. Again, this profile matches vaccine with previous effective LAIV strains. 

When evaluated in the primary human nasal cell model, the new A/Slovenia strain showed 

significantly improved replication kinetics compared to the previous A/Bolivia vaccine strain, 

though not quite to the level of NC99.

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To summarize the non-clinical dataset, the initial findings indicated that there was reduced 

replicative fitness with H1N1pdm09 viruses. The underlying mechanism for this is likely to be 

multi-factorial (e.g., HA stability, HA activation pH, receptor binding, NA). MedImmune has 

identified a lead H1N1 candidate, A/Slovenia, for inclusion in its 2017-2018 LAIV composition. 

A/Slovenia has no deficiency with multiple rounds of replication. Its FFA and TCID50 titers 

match, and it is much more similar in this regard to previous LAIVs. It has a higher HA 

activation pH compared with A/Bolivia, and looks much more similar to previous effective LAIVs. 

It has a much higher replication in the primary human nasal epithelium model versus the

A/Bolivia strain. Investigation is ongoing and is now focusing on cell and ferret studies 

evaluating interference and formulation. There is a planned clinical study with the 2017-2018 

LAIV. 

Dr. Mallory described a planned pediatric study to further characterize the A/Slovenia strain that 

likely will be included in the vaccine for the 2017-2018 influenza season, and to further compare 

the new A/Slovenia strain to the previous A/Bolivia strain that was previously included in the 

vaccine. This will be a randomized, double-blind, study that plans to enroll approximately 200 

children 24 to <48 months of age. Subjects will be randomized with approximately 65 subjects 

per group at a 1:1:1 ratio to receive two doses of one of the following vaccines:

 LAIV4 2017-2018 

(A/H1N1 Slovenia strain)

 LAIV4 2015-2016 

(A/H1N1 Bolivia strain)

 LAIV3 2015-2016 

(A/H1N1 Bolivia strain)

Having trivalent and quadrivalent versions of the 2015-2016 will allow for evaluation of what 

interference might be occurring between these two strains. This issue is being addressed with 

the A/Bolivia strain because it has reduced replicative fitness compared to the A/Slovenia strain, 

and these results will be more likely to show this. The primary endpoint of the study is HAI 

antibody seroconversion rates after each dose. The secondary endpoints include neutralizing 

antibody seroconversion rates after each dose, mucosal immunoglobulin A (IgA) increases after 

each dose, shedding after each dose, and safety. 

In terms of the timelines for data availability from ongoing studies, final 2017-2018 H1N1pdm09 

A/Slovenia strain characterization and 2016-2017 VE H3N2 data (UK, Finland, Canada) should 

be available for presentation during the June 2017 ACIP meeting. Data should be available on 

US pediatric shedding/immunogenicity from the new H1N1pdm09 strain and from the Japan 

2016-2017 pediatric efficacy study data on A/H3N2 for presentation during the October 2017 

ACIP meeting.

In conclusion, LAIV demonstrated overall effectiveness in most studies conducted in 2015-2016. 

However, H1N1 effectiveness was more variable and lower than IIV in all studies. Effectiveness 

against influenza hospitalization has been published recently. Initial findings from the 

investigation indicate that post-pandemic strains have reduced replicative fitness compared to 

pre-pandemic strains. Based on the findings of the investigation, new assays were introduced 

into the strain selection process. A replacement A/H1N1 Slovenia strain has been selected for 

2017-2018 that has characteristics similar to pre-pandemic strains. Final non-clinical strain 

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characterization data for the new A/Slovenia strain are expected to be available by the end of 

the second quarter in 2017. 

Discussion Points

Dr. Reingold asked whether the prior vaccination histories will be known for the participants in 

the US and Japan, and if they believe it matters whether they have been primed with IIV.

Dr. Mallory replied that for the Japan study, that is being conducted by MedImmune’s marketing 

partner, they will be collecting five years of vaccination history. In the study MedImmune plans 

to conduct, vaccination history will be collected on the 2 to 3-year-old children.

Dr. Walter noted that in the pediatric study, children will receive two doses of vaccine. He asked 

whether blood draws would be done after the first dose on all of those children. Referring to 

Slide 6, he also asked what was driving the consolidated estimate. It seemed to be the data 

from Finland. The confidence interval for all of the effectiveness for LAIV crosses zero for every 

other study but the Finland study and the consolidated estimate.

Dr. Mallory replied that immunogenicity blood draws will be done at baseline, 28 days after the 

first dose, and 28 days after the second dose. The second dose is an attempt to assess 

vaccine shedding after the second dose to determine whether there is a reduction in shedding 

after the second dose compared to the first dose. In terms of what was driving the consolidated 

estimates, he said he thought in general with the consolidated estimates was that there are 

more subject cases, the confidence intervals are narrow in general. He deferred to Dr. Caspard

who is conducting the study for more details.

Dr. Atmar asked which of the countries used LAIV3 versus LAIV4.

Dr. Mallory reported that for 2015-2016, all countries were using LAIV4.

Referring to slide 22, Dr. Savoy (AAFP) said she thought the CA09 strain was the reason the 

US stopped offering LAIV in the US. It appeared that the new strain is somewhat better, but 

was pretty much the same as the SLOV15 line. It was not clear to her how that would help to 

make a decision about LAIV in the US.

Dr. Mallory replied that these are in vitro data. They proposed the pediatric study, which will be 

examining pediatric data on the shedding and immunogenicity of that strain. That study will be 

able to directly compare the previous BOL13 strain that was in the vaccine with the new strain to 

determine whether there are differences in immune responses in the shedding of that strain.

Dr. Gorman (NIH) asked whether all of the children in the proposed pediatric study will be naïve 

to influenza vaccine when they begin, or if previously vaccinated children will be accepted.

Dr. Mallory replied that the goal for the proposed pediatric study is for about half of the children 

to be naïve to previous vaccination.

Dr. Hunter asked whether the A/Bolivia strain was used in the MedImmune vaccine and that 

was why it was emphasized so much.

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Dr. Mallory clarified that the A/Bolivia vaccine strain was in the 2015-2016 influenza season, for 

which there are all of the H1N1 effectiveness estimates. It is in the vaccine this year. However, 

because H3N2 has been circulating predominantly, there are no effectiveness estimates for that 

strain for this year. The vaccine strain was selected primarily on improved stability properties 

compared to the previous California strain. Effectiveness has still been lower than IIV, which is 

what they are attempting to solve now.

Dr. Kempe observed that if half of the 200 children to be included in the proposed pediatric 

study are naïve and half are primed, it seems like the study would be underpowered to examine 

the issue of whether this was related to priming.

Dr. Mallory clarified that overall the study has the power to detect difference around 20% to 25% 

in either shedding rates or immune responses. The power will be lower for the subgroup 

analysis. They struggled with which type of subjects to enroll because they also want a subject 

population that is somewhat representative of the people who would be receiving the vaccine.

Dr. Bennett said she remained somewhat confused about the interference issue. It appears that 

the only way this will be addressed is in the study of children, some of whom will receive 

trivalent versus quadrivalent.

Dr. Bright indicated that they have been using an optimized ferret model to compare mono, 

versus trivalent, versus quadrivalent with Bolivia and the NC99, which was a very effective 

vaccine strain. NC99 was given only as a trivalent, so now it is being compared to determine 

how it would have performed had it been in a quadrivalent. In addition to pre-clinical ferret 

models, they have some assays using and are using the primary human nasal epithelial cell 

model as well for pre-clinical to determine whether these models can translate into the clinic for 

future use.

Dr. Byington (AAP) said she shared some of the concerns and confusion of others. She still 

had not heard stated directly what MedImmune believes the definitive mechanism to be for the 

failure, and the focus on the thermal and pH stability. The lack of emphasis on human trials for 

interference and priming make her believe that MedImmune eliminated those or that they do not 

think those are viable causes for the failure.

While the study is ongoing, Dr. Mallory emphasized that the data presented during this session 

show that the post-pandemic strains have reduced replicative fitness compared to the prepandemic strain, and that a strain has been selected that looks better in that regard. There are 

extensive ongoing ferret studies to try to elucidate whether interference may also be playing a 

role. That also will be assessed using the human nasal epithelial cells. Some information will 

be collected from the clinical study as well. In terms of prior immunity, the previous 

effectiveness studies conducted did not show an effect of prior immunity in lowering vaccine 

effectiveness estimates. In terms of whether prior immunity is completely eliminated, additional 

data will be available from the ongoing studies. Throughout the development of FluMist®, 

effectiveness has been examined in different age groups of people exposed to either 

vaccination or wild-type influenza, prior immunity has not shown an impact on VE in children. 

Slide 31 shows that the VE estimates in children immunized previously did not change 

compared to those who were not.

Referring to slide 22, Dr. Romero said his understanding was that the TCID50 represented multicycle replication and the FFA represents single cycle replication. He wondered how the two 

could be compared.

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Dr. Bright said that both values were given as a titer or as a log value. FFA is an infectivity 

assay that tells how much virus is getting into a single cell, and it has to be tittered out. TCID50

relies on the NA efficiently working. It is a 6-day assay that requires multiple rounds of 

replication and amplification. If those two titers do not match, it suggests that while some 

viruses can get in quite efficiently and start the replication cycle, what they are not able to do so 

efficiently is multiple rounds of replication and amplification over a number of days. That is 

when the pandemic H1N1s struggle. This offers a clue to the biology of the virology behind 

these strains that says something about the difference between the pandemic H1N1 strains 

compared to the seasonal influenza viruses they have worked with previously. It gives them 

clues as to what might be mechanistically happening. Because only the HA and NA differ each 

year, it has to be something about what the HA and NA are doing.

Dr. Decker (Sanofi Pasteur) questioned whether the response earlier that the Y axis scale on 

the right half of slide 22 was linear arithmetic logarithmic. On the left hand side there is 108 and 

109 TCID50, while on the right-hand side there was 2 to 8. Not 102, but simply 2.

Dr. Bright replied that it is a log scale.

Dr. Moore said she still hears concerns about repeated use of LAIV year over year and whether 

that would contribute in any way to the US results being lower than some of the others observed 

elsewhere. She wondered whether any of the studies assess not only prior season use of 

vaccine, but also year over year use of LAIV as seen in the US.

Dr. Mallory replied that they do not have those data readily available. What will be interesting 

are the data that come out of the UK for the past season, because children in the UK are 

enrolled in a vaccination program year after year. So, they are beginning to look more like US 

children in terms of their prior vaccination history. The other data that can address this will be 

from the Japan efficacy study. Those children will have up to five years of vaccination history, 

so it will be possible to assess VE in heavily vaccinated children compared to VE in less heavily 

vaccinated children.

Ms. Pellegrini noted that she had not seen anything to account for the geographic variation 

observed during that season, and she wondered whether there were theories that would 

account for variation in VE from country to country during that season.

Looking at the overall data for A and B strains, Dr. Mallory pointed out that there was less 

variation from country to country than there actually is within the US. In the B strain data, there 

is some variation but the confidence intervals are very wide because there was not a lot of B 

strain circulating in the 2015-2016 season. There are not clear explanations for the differences 

that occurred in the US and in other countries. MedImmune is doing some work with CDC to 

combine the data from the MedImmune study and the CDC study to determine whether some of 

the differences can be further elucidated. The differences were observed in the US and other 

countries, so this is not a US-specific finding.

Dr. Bennett asked whether there was any explanation for why the Finland data, which is the 

outlier, looked different.

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Dr. Mallory responded that the Finland study was a cohort study while the rest of the studies 

were test-negative. In addition, a limited age group was enrolled in Finland of children 2 years 

of age.

Dr. Walter requested clarification about what additional strain characterization data will be 

presented during the June 2017 ACIP meeting.

Dr. Bright replied that in June, they will present ferret data from their interference studies.

Dr. Mallory added that they presented the data on the A/Slovenia strain with the expectation that 

that strain will be selected at the March WHO meeting and the subsequent VRBPAC meeting. If 

a different strain is selected, they will present final data on the new strain. Most of the strain 

characterization data from the in vitro assays has been presented, but there will be some 

additional in vivo ferret data.

Regarding the effect or prior immunity, Dr. Belongia emphasized that it is important to recognize 

that the VE studies do not have the ability to assess children under 4 years of age. They 

typically assess children 2 years to 17 years of age, which perhaps could be stratified down to 2 

years to 8 years of age, but there are a lot of children in that analysis who are older who 

certainly have been previously infected. In the trial, there will be children under 48 months of 

age. Thus, he would not rule out the possibility that they will see priming effects or differences 

between those children who have been previously vaccinated and those who have not. If those 

effects are present, then they will be down to stratification with perhaps 30 to 35 children in each 

group. If both of those effects are operating, this could be very difficult to tease out.

Dr. Duchin (NACCHO) added that there are some data in adults with IIV that suggested that 

repeat vaccination with the same vaccine strains results in reduced VE against a drift strain. In 

the context of previous vaccination, he wondered if MedImmune was considering the impact of 

the vaccine strains that a child was vaccinated with in previous seasons and the specific strain 

that is circulating that season to draw conclusion about the impact of prior vaccination.

Dr. Mallory replied for the proposed study the children will be young and the investigators will 

know which vaccines they received and thus which strains are in them. In the Japan study, 

there will be five years of vaccination history, so they should be able to assess the specific 

effects to the extent that they are powered to do that. On the question of prior immunity, this 

seems to be more specific to the A than the B strains if it is occurring. B strain effectiveness 

continues to look good. If it is occurring for the A strain, it may be in the setting of reduced 

replicative fitness for that particular strain.

Dr. Bennett emphasized that what she was hearing from the ACIP was that they have concerns 

about the power calculations and whether they will be able to tease out the impacts.

 

Dr. Mallory replied that they struggled to enroll very young children to receive a vaccine that is 

not approved for use in the US.

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Influenza Summary and WG Considerations

Lisa Grohskopf, MD, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Regarding plans for the 2017-2018 ACIP influenza recommendations that will be published 

sometime during the summer, Dr. Grohskopf indicated that no new policy language was

proposed for consideration at the time of this meeting. The 2017-2018 statement will reiterate

the core recommendation that annual influenza vaccination is recommended for all persons 

aged 6 months of age and older who do not have contraindications.

In terms of the vaccines discussed during this session, the WG had the opportunity to hear 

presentations on AFLURIA® Quadrivalent pre-licensure data for adults prior to the October 2016 

meeting. The WG presented to ACIP on these data during the October meeting. Since that 

time, the WG has heard data on the safety evaluation presented during this session and prelicensure data for children 5 years of age and older. At this time, the WG has proposed no 

change in the language for AFLURIA® Trivalent specifically related to the issue of children 5 

years of age and older versus 9 years of age and older and awaits licensure of a quadrivalent 

for an age ≥5 years. 

Regarding WG discussion about Fluzone HD® and because there are related vaccines (Fluad®

and Flublok®) that have been examined specifically for this high-risk group of 65 years of age 

and older, the WG had an opportunity to listen in and ask questions about the Gravenstein longterm care facility data presented during this meeting. Currently, two vaccines are licensed 

specifically for age ≥65 years. Data heard previously by ACIP include Fluzone HD® data that 

were noted to have superior VE to standard-dose IIV3 against protocol-defined ILI-associated 

with laboratory-confirmed influenza in a two-season RCT of almost 32,000 persons age ≥65 

years. ACIP also recently heard data for Fluad®, which is the adjuvanted IIV3 that was shown 

to have superior VE to unadjuvanted IIV3 against lab-confirmed influenza in an analysis of 227 

participants in a one-season observational study of persons age ≥65 years. 

In addition to that and although it is not licensed for 65 years of age and older, ACIP previously 

heard data from a 2014-2015 season randomized trial of Flublok® Quadrivalent, which was 

licensed by the FDA last fall but is not available this season. These data compared Flublok® 

Quadrivalent to IIV4 in a randomized study of subjects 50 years of age and older, and noted 

superiority over IIV4 during that season. During that season, there was notable drift. There 

have not been any direct comparisons of these vaccines with one another. Currently, ACIP 

expresses no preference for one vaccine over another. The WG proposes no change in 

language, and looks forward to further discussion of the efficacy and effectiveness data for 

these vaccines in this high-risk population. Data for vaccines for this population will be 

summarized in upcoming 2017-2018 ACIP Influenza Statement. 

In terms of influenza vaccine coverage among children, CDC has updated early season 

influenza vaccination coverage estimates from NIS-Flu to evaluate potential impact of the 

recommendation to not use LAIV for the 2016-2017 season. The preliminary estimates reflect 

reported vaccinations received by the end of December 2016. Coverage among children ages 

6 months through 17 years increased from 37% by early November to 50% by the end of 

December. This end of December coverage was similar to coverage through December last 

season, which was 51%. Comparing by age group, there was no statistically significant 

differences for 2016-2017 compared to the 2015-2016 season. The differences in the various 

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age groups ranged from 2.7% for ages 13 through 17 years to -2.8% for ages 5 through 12 

years. As in past seasons, coverage was higher in younger children at 66% for ages 6 through 

23 months, 56% for ages 2 through 4 years, 50% for ages 5 through 12 years, and 40% for 

ages 13 through 17 years. In past seasons, influenza vaccination of children continued to be 

reported past December. For 2015-2016, coverage increased from 52% by the end of 

December 2015 and 59% by end of May 2016. It is important to note that these are very new 

data.

To summarize influenza division activities related to VE and more specifically to LAIV, there 

continues to be ongoing evaluation of vaccine effectiveness via the US Influenza Vaccine 

Effectiveness Network, which Dr. Flannery presented data from at the beginning of the session. 

There is also discussion of an intra-seasonal waning and decision tree analysis regarding timing 

of vaccination, as well as research studies ongoing to assess immunologic effects of repeat 

vaccination. Regarding specific LAIV activities, the division has embarked on a systematic 

review of the literature and meta-analysis of efficacy and effectiveness of LAIV since 2010-

2011, the first season post-pandemic, as well as a combined US individual patient-level LAIV 

effectiveness analysis that will include CDC, DoD, and MedImmune data. In addition, data 

continue to be gathered for review and publication of the annual ACIP influenza statement. 

In terms of WG considerations regarding FluMist®, the best evidence to support 

recommendation for use would be effectiveness data for LAIV containing a new H1N1 

component against H1N1 viruses. Anticipated data timelines include the 2016-2017 

effectiveness data for H3N2 from the US, UK, and Finland by June 2017; and efficacy data on 

H3N2 from Japan and US pediatric shedding/immunogenicity by October 2017. That said, this 

is a predominantly H3N2 season, so effectiveness against H1N1 cannot be assessed from the 

current season’s data in any of these countries. Unfortunately, it is not possible to predict when 

the next H1N1-predominant season will occur. Therefore, it could be several years before there 

is an H1N1-specific season so that effectiveness/efficacy data would be available.

In the absence of effectiveness/efficacy data for FluMist® with a new H1N1 component, the 

following would be reassuring: 1) Demonstration that the new virus exhibits improved fitness in 

animals (ferrets), and particularly in human shedding and immunogenicity studies; and 2) 

Demonstration that performance (e.g., replicative fitness) is similar to that of pre-pandemic 

H1N1 viruses, which were demonstrated to be effective in previous studies.

A caveat, there is no adequate correlate of protection for LAIV against influenza viruses. 

Shedding and antibody levels do not always correlate with effectiveness. Shedding is an 

indication of replicative fitness and vaccine “take.” However, lack of shedding has not always 

correlated with poor effectiveness. Therefore, there is inherent difficulty in interpreting a 

negative (poor shedding) result. However, the human shedding and antibody (immunogenicity) 

data anticipated by October 2017 are probably the most constructive data that can be collected 

within a 1- to 2-season timeframe. The question regards whether the ACIP feels that these data 

will be sufficient to re-consider whether to recommend LAIV. 

Discussion Points

In terms of the immunological effects of repeat vaccination, Dr. Kempe wondered whether the 

data exist to allow them to examine priming and repeated LAIV versus IIV adequately.

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Dr. Grohskopf reminded everyone that the Japan study would have five years of data collected, 

which could potentially address this. However, the current season is predominantly H3N2. If 

there is a differential effect, it will be more difficult to determine if the problem is H1N1-related.

Dr. Reingold asked whether there was an expectation of having effectiveness data from other 

countries and, if so, is it possible that they will be useful in the US context in terms of number of 

prior doses, priming, and other potential issues.

Dr. Grohskopf indicated that this has been a common theme of discussion. For example, the 

European data have differed from the US data even for H1N1. Although it does appear 

consistently that generally, the inactivated vaccine has done better. CDC will continue to 

communicate with colleagues overseas to find out what they are observing. There is always 

going to be a question about comparability, given the fact that the US has routinely 

recommended vaccination for the entire pediatric population since 2008. This is relatively new 

in other countries. Granted US coverage is not perfect, but pediatric vaccination was phased in 

age stepwise between 2003 and 2008. That is a longer period of time than most other countries 

have been vaccinating healthy children annually on a routine basis. They will just have to try to 

determine how comparable the data are to the best extent they can.

Dr. Bennett added that not only is it important to understand the context in which the studies are 

conducted, but also it is important to understand the study methods. Because there are 

significant differences, ACIP would like to hear about the methods in some detail.

Dr. Belongia noted that there is consideration of a human challenge study with H1N1. While 

there are differing opinions about whether that would be helpful, because by necessity it would 

have to be done in adults. Adults are different from children and may respond differently. 

However, if it did work in adults, there might be reasonable inference to say that it is likely to 

work in children as well. Since it looks like that is not planned, they will be left with the data 

from the proposed study. He expressed his hope that the results would be clear and 

conclusive, at least in terms of shedding and serologic response, to give ACIP sufficient 

confidence. If it is more equivocal, it could be a tough decision.

Dr. Riley recalled that when this was discussed previously, one of the concerns when this was 

removed as an option regarded whether a major decrease would be observed in the number of 

children being vaccinated. This made her think that something is better than nothing if only 20% 

of children will be vaccinated. The fact that it is 50% versus 51% made her think that if there 

was not a significant decrease in the number of children being vaccinated, it certainly is 

important to ensure that what they are being given works.

Dr. Hunter said he was not familiar with the methodologies of the various countries for which VE 

for H1N1 was presented. He was curious to know whether there was something about the 

methodology used by CDC that would explain why it is so much lower than everyone else.

Dr. Grohskopf replied that the majority of studies are test-negative case-control designs. The 

Finland study was a cohort design. The definitions of infection are not universal across all of the 

studies.

Dr. Flannery added that the short answer is that there is no explanation for the difference in the 

point estimates. There are wide confidence intervals around the estimates from the CDC data. 

There is some heterogeneity in the point estimates, but there are overlapping confidence 

intervals. Except for the Finland study, the studies all included zero for the H1N1-specific 

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effectiveness in 2015-2016. All of the studies except Finland used a test-negative design. 

CDC’s inclusion criteria are slightly more sensitive. They do not include ILI specifically. It is 

acute respiratory illness. It is helpful that the MedImmune also showed the B estimates, which 

were different, but the heterogeneity was less. It is expected that if there was a methodological 

problem, it would not just apply to H1N1 over several seasons. Other than that, there is no 

explanation for why CDC’s estimate seems to be the lowest point estimate by far.

Dr. Moore emphasized that the virus does continue to drift. It could be that in just one more 

season, it will be necessary to move on from A/Slovenia to something else. She asked whether 

in the future the ACIP could anticipate that MedImmune would perform these same pH, 

thermostability, and replication studies and present them to the committee in order to be able 

evaluate future strains. Because that question arises, she wondered if it would be valuable to 

assess those same studies on the past H3N2 strains that have been effective so that future 

changes in H3N2 strains also could be assessed in the same type of way, given that there are 

not good laboratory correlates of protection.

Dr. Bresee replied that MedImmune is planning to conduct these replicative fitness studies with 

the assays they used to understand these strains better each year going forward. As the strains 

and antigens change, they will understand replicative fitness going forward and will make sure 

that it does not drift back again to the A/Bolivia phenotype.

Dr. Mallory indicated that the new assays described by Dr. Bright described to their strain 

characterization on an ongoing basis, and they will be assessing H3N2 and B strains with these 

assays. There is ongoing work to assess past H3N2 strains that were known to work. The 

priority is to examine the new A/Slovenia strain and H1N1, but data are being gathered for the 

H3N2 strains.

Dr. Gemmill (NACI) reported that there are numerous studies underway in various centers in 

Canada on VE for influenza vaccine. He is certain that those data will be available through the 

Canadian Immunization Research Network (CIRN) as part of their collaboration. He shared 

Canada’s frustrations with trying to get a handle on influenza vaccine. Fifteen years ago, there 

was one vaccine. Now there are many vaccines and everyone is trying to figure out how they 

compare to each other. VE seems to be a “moving target” as well. A think tank was planned for 

February 24, 2017 to consider how best VE can be used to make recommendations. This has 

been a terrible frustration for them. A silver lining for Canada of the recommendation by ACIP in 

June 2016 not to use LAIV in America was that it gave Canada the ability to pull back from its 

preferential recommendation on LAIV in Canada for young children. He was not confident that 

he could make a preferential recommendation for any of the vaccines. When one looks 

somewhat better, they are using statements such as “If you use this vaccine, it is expected that 

you may have better protection.”

Dr. Gellin (NVPO) asked how long MedImmune would continue, given that it is unknown how 

long before the season would be right to develop VE data.

Dr. Mallory responded that MedImmune and AstraZeneca place the highest priority on patient 

health and the overall impact of its products to public health. They remain committed to 

FluMist® as they believe it provides an important option for vaccination and for pandemic 

preparedness. They are committed to investigation and to providing FluMist® as an option for 

patients.

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Dr. Walter pointed out that the WG seemed to be struggling with what level of data they need to 

bring before the ACIP in order to help make a decision (in vitro, in vivo, effectiveness, efficacy, 

which season).

Dr. Kempe emphasized that there are some very large issues immunologically here that 

probably cannot be answered by MedImmune or a company. There are natural experiments 

comprised of cohorts of people who have received yearly LAIV for four to five years and other 

children who have received none. It seemed to her that some basic science would be helpful in 

answering portions of this that should be funded other than by the companies. Portions of this 

should not be related to a particular vaccine, but that are important for ACIP to understand in 

the context of how they consider each new vaccine.

Dr. Atmar expressed concern about potentially having to withdraw a recommendation again if 

they recommend LAIV based on the data that are or will be available, but then it still did not 

demonstrate effectiveness in the US. This could lead to loss of confidence in this group. 

Without really understanding the reason for the lack of effectiveness, despite some good 

hypotheses, he urged ACIP to have VE data for H1N1 going forward though it probably would 

have to be developed in other countries.

Ms. Pellegrini pointed out that the issues raised during this session were not exclusive to 

influenza. The same types of issues are being observed with the inability to get to a vaccine for 

Ebola and Zika as strains or viruses burn themselves out, abruptly reemerge, and disappear 

again. This field as a whole is going to have to continue grappling with the idea of what kind of 

data is acceptable at different points in an epidemic or the natural rise and fall of these viruses.

Dr. Stephens would like to see effectiveness data, given that it is most powerful in human 

populations. This may not be available for a while. He said that he was troubled that the in vitro

studies were proposed to be a correlate based on some of the discussion about slides 20 and 

22 and the new A/Slovenia strain. Even those data were not very convincing to him at this 

point.

Dr. O’Leary (PIDS) noted that in some of the data from other countries, VE was still less than 

IIV. Some questions for the WG and ACIP is: What is the threshold? Is it better than zero? Is 

it overlapping confidence intervals? If they had good VE studies, what would be the threshold 

for consideration of another recommendation?

Dr. Atmar said he did not know whether a threshold could be defined at this point, but he 

reminded everybody that LAIV was superior to IIV in many of the early studies. He still believes 

that this is potentially an important vaccine, particularly for young children. Understanding why 

it did not work in the US for the three seasons it did not is important so that this can be 

overcome and it can be used again. It is a valuable tool even if IIV is accepted by parents and 

children in this age group.

Ms. Stinchfield (NAPNAP) said that anecdotally in clinical settings in hospitals, clinics, and 

school-based influenza programs, they did not see a lot of rejection of the injectable vaccine this 

year. There was initial sadness without having intranasal vaccine, but people dealt with that 

and went on. Those who wanted to be vaccinated were taking the injectable.

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Introduction

Edward Belongia, MD

Chair, Herpes Zoster Work Group

Dr. Belongia reminded everyone that the primary objective of the Herpes Zoster (HZ) WG is to 

develop evidence-informed vaccine policy for the use of herpes zoster vaccines. The WG will:

 Consider vaccine and programmatic performance of currently licensed vaccine (Zostavax®) 

 Consider the efficacy, safety and duration of protection of HZ/subunit (HZ/su) vaccine that is 

currently in review at FDA

 Identify programmatic options for both vaccines that incorporate cost effectiveness analyses 

and impact on disease burden

Recently, the WG reached consensus on important and critical outcomes to consider pertaining 

to vaccination for HZ, received presentations by manufacturers and researchers on the safety 

and immunogenicity of HZ vaccines, and considered the body of evidence supporting HZ/su

vaccine.

ACIP received presentations during the October 2016 meeting on HZ epidemiology and

Zostavax® performance and coverage, and Phase III efficacy studies of HZ/su vaccine (ZOE-50 

& ZOE-70). During this session, there were presentations on the safety summary of HZ/su 

vaccine by GSK; and Grading of Recommendation Assessment, Development and Evaluation 

(GRADE) of HZ/su vaccine and considerations for policy by CDC. In June 2017, presentations 

are anticipated on a cost-effectiveness analysis, Zostavax® GRADE, and considerations for 

policy. A vote is anticipated in October 2017.

Safety Summary of Candidate Vaccine HZ/su

Romulo Colindres, MD, MPH

Global Medical Affairs Lead, Zoster

GSK

Dr. Colindres noted that he would be presenting on behalf of a very large team at GSK and 

many study investigators across the world on the safety summary for GSK’s adjuvanted HZ/su 

vaccine candidate. To place this presentation into context, he reminded everyone that ZOE-50 

and ZOE-70 results were previously presented at ACIP sessions in 2015 and 2016, and also 

have been published in the NEJM. ZOE-50 and ZOE-70 are the Phase III clinical trials that 

enrolled subjects greater than 50 years of age and greater than 70 years of age respectively, 

and demonstrated a remarkable VE of greater than 90% independent of age, even in those 

greater than 70 years of age and 80 years of age who are most at risk for zoster disease. GSK 

is also pleased because this efficacy has been demonstrated to last at least 4 years postvaccination. The presentation during this session focused on a broad overview of HZ/su 

vaccine safety.

Herpes Zoster Vaccines

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During this session, Dr. Colindres presented information on the vaccine composition; the 

adjuvant used in HZ/su vaccine; the incidence of solicited local and systemic events, including 

some new data on frequency of reactions between doses; detailed safety analyses and 

conclusions; and new data on 9-year immunogenicity for HZ/su vaccine. 

The following graphic illustrates the composition of the non-live, adjuvanted subunit vaccine:

On the left in turquois is the antigen, which is 50 μg of recombinant glycoprotein E. This is the 

most abundant protein found on the envelope of VZV, which elicits a specific cellular and 

humoral immune response. On the right is the adjuvant system, which is ASO1B. ASO1B is a 

liposome-based adjuvant system that contains immunostimulants MPL and QS-21. MPL 

enhances cellular and humoral immunity, which QS-21 stimulates Th1 cell-mediated immunity 

as well as cytotoxic T- lymphocyte activity. Synergistically, when MPL and QS-21 are 

combined, there is an enhanced proinflammatory response or innate immunity, as well as 

cellular and humoral response increases. Overall, this results in a faster, stronger, and longer 

lasting immune response [Dendouga et al. Vaccine 2012;30:3126–35; Garçon et al. 

Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam: Elsevier; 

2011; chapter 4: p89–113; Dendouga et al. Vaccine 2012;30:3126–35; Grunewald et al. 

Science 2003;302:1396–8; Mata-Haro et al. Science 2007;316:1628–32].

AS01 was chosen for the zoster program because of its ability to increase both humoral and 

cellular response to the co-administered antigen. This is important in the context of zoster 

because of the VZV-specific cellular decline that can lead to increased susceptibility of zoster

disease in individuals over 50 years of age. AS01 works by inducing a local and transient 

inflammatory response similar to other adjuvants in licensed vaccines. This transient 

inflammation, while often associated with local or systemic symptoms, promotes a faster, 

stronger, and longer lasting VZV-specific response1,2 [1Didierlaurent et al, J. Immunol, 2014;. 

Didierlaurent et al, Exp Rev Vac, 2016. 2Leroux-Roels G, et al. Clin Immunol. 2016 May 

25;169:16–27].

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There is now a large amount of clinical experience with AS01 covering a wide range of 

populations with several antigens in over 40,000 subjects. Of course, the largest experience is 

with the HZ/su vaccine candidate in which over 28,000 adults have been exposed. The second 

largest population is greater than 12,000 infants and toddlers who received AS01E, a smaller 

dose of the same adjuvant, together with a malaria antigen. There is a series of other vaccines 

in earlier phase development such as tuberculosis (TB), human immunodeficiency virus (HIV), 

and hepB in which the adjuvant has been combined with the antigen and applied to several 

populations such as children, adolescents, and adults. Importantly, all of these vaccines have 

been well-tolerated with no major safety concerns. Additionally, independent of antigen 

adjuvant combination, AS01 has been shown consistently to stimulate a strong T-cell response.

The safety data presented during this session were drawn from a large pooling of over 14,000 

subjects from the ZOE-50 and ZOE-70 Phase III clinical trials which were conducted at multiple 

sites across 18 countries. A comparative analysis was performed between the vaccine group 

and a placebo group, including all of the safety endpoints: local and systemic reactions, SAEs 

and potential immune-mediated diseases (pIMDs). 

In terms of how safety data were collected in these clinical trials, subjects received 2 doses of 

either vaccine or placebo at a 2-month interval. Solicited local and systemic symptoms were 

proactively collected via diary cards for 7 days post-each dose. SAEs were collected for up to 

12 months post-second dose. SAEs considered related to vaccination by the investigator, any 

fatalities, and pIMDs were tracked for the entire time of the study, which had a mean follow-up 

of 4.1 years. As a note, because of the potential concern between adjuvanted vaccines and 

autoimmune diseases, GSK closely monitors pIMDs in all clinical trials with adjuvanted vaccine.

Turning to the results for solicited local symptoms of any grade post-vaccination in a 

comparison between the vaccine and placebo group, the solicited local symptoms were more 

common among vaccine than placebo recipients as might be expected with an adjuvanted 

vaccine. Pain was by far the most common solicited local symptom. The majority of these 

symptoms were reported as moderate to mild in intensity and had a median duration of 2 to 3 

days. Looking specifically at Grade 3 solicited local symptoms reported during the 7 days postvaccination, Grade 3 is defined as “redness and swelling at the injection site were scored as 

grade 3 for those more than 100 mm. All other symptoms were scored as 3 for preventing 

normal activity.” Subjects experienced 8% or less Grade 3 reactions for local symptoms, and 

these were still more common among vaccine than placebo recipients. The median time for 

these Grade 3 reactions was 1 to 2 days.

In terms of solicited systemic symptoms of any grade 7 days post-vaccination, for any grade 

fatigue, headache, myalgia, and shivering were the most common. All symptoms occurred 

more frequently in vaccine compared to placebo recipients. Most of these were mild to 

moderate in intensity, with a median duration of 1 to 2 days. Grade 3 solicited systemic 

symptoms 7 days post-vaccination were reported in 6% or less of study subjects and were still 

more frequent in the vaccine versus placebo group specifically for fatigue, headache, myalgia, 

and shivering. The median duration for these symptoms was 1 to 2 days.

Regarding some new data from an ad hoc analysis of systemic and local reactions by dose, 

GSK sometimes receives the question, “What is the frequency by grade between Dose 1 and 

Dose 2?” This analysis attempted to answer these questions. Looking at subjects’ intensity of 

reaction at Dose 2 for those individuals who had a Grade 0 or 1 reaction at Dose 1, 3650 

subjects reported having a Grade 0 or Grade 1 pain following the first dose. Approximately 85% 

of the 3650 subjects had a similar Grade 0 or Grade 1 reaction following the second dose. If 

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this is extended to look at the remaining systemic symptoms, the trend is similar with the 

proportion of subjects who had a Grade 0 or Grade 1 specific symptom at Dose 1 experiencing 

a similar intensity of reaction for the same symptom at Dose 2 ranges between 85% and 92%. 

A similar analysis looked specifically at Grade 3 reactions at Dose 1 to determine what occurred 

with Dose 2. There were 155 subjects who reported Grade 3 pain on the first dose. 

Approximately two-thirds of the 155 subjects experienced Grade 2 or less reaction on the 

second dose. Extending to the other systemic symptoms, the trend is similar with the proportion 

of subjects who had a Grade 3 specific symptom at Dose 1 experiencing a lower intensity of 

Grade 2 for the same symptom at Dose 2 ranging from 66% to 76%.

Regarding 2-dose compliance, 96% of subjects complied with the second dose in ZOE-50 

among vaccine and placebo recipients. For ZOE-70, 94% and 95% received a second dose 

respectively for the vaccine and placebo groups. Overall in these clinical trials, there was very 

high second dose compliance. In terms of the impact of a Dose 1 reaction on Dose 2 

compliance, of the 268 subjects ZOE-50 and ZOE-70 who experienced a first-dose Grade 3 

local reaction, 23 received Dose 1 only and 245 (91%) received both Dose 1 and Dose 2. Of 

the 251 subjects who experienced a first-dose Grade 3 systemic reaction, 27 received Dose 1 

only and 224 (89%) received both Dose 1 and Dose 2. While Dose 1 reaction may be a factor 

in subjects not receiving the second dose, the large majority of subjects in this study, including 

those who had a Grade 3 reaction on the first dose, still received the second dose.

Shifting to the main safety analysis, in the first 30 days post-last vaccination there was no 

difference between the vaccine and placebo groups for SAEs, fatalities, or pIMDs. At 1 year 

post vaccination, SAEs were well-balanced between the vaccine and placebo groups with a 

frequency of 10.1%. There also were no differences between groups for deaths or pIMDs, with 

pIMDs having an incidence of 0.7% in both groups. The most frequent SAEs by preferred term 

were cardiac conditions such as atrial fibrillation and myocardial infarction (MI), as well as 

infections such as pneumonia. These frequencies are as would be expected for the study 

population. More importantly, for the individual rates of these frequent SAEs, there was no 

difference between the vaccine and placebo groups.

Regarding fatal SAEs by time period, for all time periods evaluated, there were no differences 

between the vaccine or placebo group. The majority of the deaths occurred greater than 1 year 

post-last vaccination. In terms of the most frequent fatal SAEs during the whole postvaccination time period overall, cardiac conditions, infections of the respiratory track, and 

neoplasms were common. This aligns with the most frequent causes of death among this aged 

population. Once again, these most frequent fatal SAEs were equally balanced between the 

vaccine and placebo groups. As expected, fatal SAEs were more common in subjects 70 years 

of age or older.

For all time periods evaluated, the pIMDs were seen in equal frequency among the vaccine and 

placebo groups, with a frequency of 1% for the entire study period in both groups. 

Approximately half of the pIMDs were reported greater than one year after the last vaccination. 

The most frequent pIMDs in the entire study were polymyalgia rheumatic, rheumatoid arthritis, 

psoriasis, and autoimmune thyroiditis. These are some of the most frequently reported pIMDs 

in the general population. There were no differences for these between the vaccine and 

placebo groups.

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In conclusion for local and systemic solicited symptoms, as may be expected with an 

adjuvanted vaccine, local and systemic solicited symptoms were higher in the HZ/su vaccine 

versus placebo group. However, the majority of symptoms were mild to moderate intensity and 

of short duration of 1 to 3 days. In an ad hoc analysis, it was observed that subjects with Grade 

3 reaction at Dose 1 were likely to experience a lower grade reaction at Dose 2 for the same 

symptom. Compliance for the second dose was quite high overall at 95%, and ≥ 89% even 

among subjects who had Grade 3 reaction at Dose 1. With regard to general safety 

conclusions, a large safety database with over 14,000 subjects with greater than 60,000+ 

person years of active follow-up was available for the evaluation of the safety of HZ/su 

candidate vaccine. Safety data from the HZ/su vaccine clinical program has not detected any 

safety concern. The overall incidence of SAEs, deaths, and pIMDs is equal between the 

vaccine and placebo groups. Based on the data available, the current benefit/risk profile for this 

vaccine remains positive.

The new data on the 9-year immunogenicity of HZ/su vaccine come from the Zoster-060 study, 

which is an extension to a Phase II immunogenicity and safety study (Zoster 003). Subjects in 

the original study received 2 doses of HZ/su vaccine at a 2-month interval. A subset of subjects 

from this original study were followed through 6 years post-vaccination, and these data were 

published previously. Zoster-060 included 70 subjects for evaluation of immune response at 

year 9 post vaccination. The endpoints assessed included antigen-specific humoral and cellmediated immune response. 

The 70 subjects received 2 doses of HZ/su vaccine and had a mean age of 72.3 at the time of 

the initial vaccination. The mean age 9 years later is 81.3 with the oldest subject in the study 

being 90 years of age. There was a predominance of female subjects and all subjects were 

White-Caucasian, which is not surprising considering that the study was conducted in Germany, 

Sweden, and the Czech Republic. 

In terms of the sustained cellular immune response overall 9-years post-vaccination, the cellular 

immune response persists well above pre-vaccination baseline values. At month 108, or 9 

years post-vaccination, there was a 3.4-fold increase over pre-vaccination. This fold increase 

was sustained since month 48, or 4 years post-initial vaccination. Similar results were observed 

when stratified by age categories of subjects 60 through 69 years of age and 70 years of age or 

older. Independent of age and including the subjects who were 70 years of age or greater at 

initial vaccination, there was a modest decrease in immune response during the first few years 

that seems to have plateaued by Year 4 and remained stable through Year 9, still above the 

pre-vaccination levels. Looking at sustained humoral immune response for the same two age 

categories, the trends for humoral immunity closely followed those of cell-mediated immunity 

with persistent immune response at Year 9 well-above baseline levels, a larger fold than the 

cell-mediated immune responses. The humoral immune response also remained stable 

between Year 4 and Year 9 and applied to all age groups, including those individuals 70 years 

and older at initial vaccination.

In conclusion, 9 years post-vaccination, immune responses to HZ/su vaccine were above 

baseline values (median 3.4-fold increase) in healthy older adults. Stable, persistent immune 

responses were observed between Year 4 and Year 9. Immune responses were maintained in 

the oldest age cohort (> 70 years). Additional Year 10 data will be available in the first quarter 

of 2018. 

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In summary, the HZ/su candidate vaccine has a well-characterized safety profile with no 

concerns observed to date. The majority of local and systemic reactions were of mild to 

moderate intensity and of short duration. As might be expected with an adjuvanted vaccine, 

these were higher among HZ/su vaccine than placebo recipients. However, this same adjuvant 

in combination with the gE antigen contributes to robust immunogenicity, persisting through 9 

years post-vaccination. The unique combination of adjuvant and antigen in HZ/su vaccine has 

led to unprecedented VE of greater than 90% independent of age, largely overcoming the 

natural decline in cell response that can lead to increased zoster in older adults. This VE 

extends at least 4 years post-vaccination and may very well last for much longer.

Discussion Points

Dr. Reingold asked whether there were any studies of immunogenicity and safety data in people 

who have previously received another zoster vaccine, and whether GSK would be seeing an 

indication for use in that population.

Dr. Colindres responded that GSK is currently conducting a revaccination study among subjects 

65 years of age and older who received or did not receive the currently licensed vaccine. This 

study will evaluate immunogenicity and safety, and the results should be available in the 

upcoming months.

In terms of the 4% to 5% who did not return for the second dose, Dr. Hunter asked how hard the 

research assistants worked to get them to come back. He wondered how this would work in 

actual practice outside of a research setting.

Dr. Colindres replied that the reasons for not returning were quite varied, but as expected in 

most clinical trials. The number one reason was withdrawal of consent not due to an AE. Other 

reasons included loss to follow-up, moving from the area, unsolicited AEs, SAEs, pIMDs, and 

protocol violations. While there are no real-world data yet, in the clinical trial settings in the US, 

at the lowest percentile of compliance in individual sites, the lowest 2-dose compliance was 

85%. Worldwide, the lowest compliance was approximately 68%. GSK is currently working 

with its own health economic teams as well as health economic teams at CDC to determine how 

to best estimate 2-dose compliance in a real-world setting.

Dr. Walter observed that about 5% to 6% of participants had Grade 3 reactions per event, and 

wondered what total percentage had a Grade 3 reaction.

Dr. Colindres replied that for specific symptoms, 8% or less experienced Grade 3 injection site 

symptoms and 6% or less experienced Grade 3 systemic symptoms. It is about 8% to 9% for all 

of the symptoms combined. An analysis is being performed now to interpret what exactly is the 

experience of a patient with a Grade 3 reaction. By definition a Grade 3 for most of the 

symptoms was preventing daily activity. A Grade 2 was interfering with daily activity and a 

Grade 1 was tolerable.

Dr. Duchin (NACCHO) asked whether there was any variability in the incidence AEs or SAEs 

according to the race or ethnicity of the subjects.

Dr. Colindres responded that the patterns of safety and reactogenicity among minority 

populations, such as African Americans or Hispanics, did not differ significantly from the general 

population as a whole. Of the North America subjects, 8% were African American. Based on 

the US Census data from 2016, African Americans above 50 years of age is about 10%. They 

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realized that they were modestly below the representation of the general population, but GSK 

always strives to have a diverse population in its studies.

Dr. Decker (Sanofi Pasteur) asked whether they had followed the Zoster 003 population over 

time to look at zoster-free survival curves.

Dr. Colindres replied that the current plan for the Zoster-060 study as an extension of the Zoster 

003 study is to follow those subjects through Year 9. Currently, the only subjects still being 

followed are the 70 presented during this session. The placebo recipients have not been 

followed. 

GRADE of HZ/su Vaccine

Kathleen Dooling, MD, MPH

Medical Epidemiologist

Division of Viral Diseases

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Dooling presented the results from the GRADE analysis of HZ/su vaccine. She reminded 

everyone that the GRADE process is to develop policy questions, consider critical outcomes, 

review and summarize evidence of benefits and harms, evaluate quality of evidence, assess 

population benefit, and evaluate values and preferences. The subsequent steps involving the 

review of health economic data, considerations for formulating recommendations, and GRADE 

category will be presented during a future meeting.

The policy question for consideration is, “Should HZ/su vaccine be routinely used to prevent 

herpes zoster?” The population of interest is immunocompetent adults aged 50 years or older. 

The intervention of interest is a 2-dose series of HZ/su vaccine consisting of the current 

formulation of 50 μg gE and the adjuvant AS01B administered intramuscularly at 0 and 2 

months. The WG looked for studies that compared this intervention to placebo or no vaccine. 

The outcome the WG considered most important included the following:

 HZ

 Post herpetic neuralgia (PHN)

 Duration of protection against HZ

 SAEs 

 Reactogenicity (Grade 3)

Outcomes included in the evidence profile can be divided into both benefits and harms. The 

benefits of prevention of HZ and PHN were deemed critical and duration of protection 

considered important. The harm category of SAEs was deemed critical and reactogenicity was

considered important.

The WG completed a systematic review of studies from PubMed, Embase, CINAHL, Cochrane, 

Scopus, and clinicaltrials.gov in any language. Efforts also were made to obtain unpublished or 

other relevant data. Initial search terms included: “herpes zoster” and “subunit,” or “HZ su ADJ5 

subunit,” or “HZ su,” or “GSK 1437173A.” Articles were included if they presented data on the 

HZ/su vaccine and involved the relevant population of immunocompetent adults aged 50 years 

or older, included data for the relevant intervention, included data relevant to the outcome 

measures being assessed, and reported primary data. 

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Working with an expert in Library Sciences, the WG identified 116 references via database 

searches. An additional 32 references were identified from clinicaltrials.gov. Title and abstracts 

were then screened for all 148 references, and records were excluded if there was no primary 

data or if the study did not include the population or intervention of interest. Following that step, 

29 full text articles were reviewed and 19 were excluded because either the study was still 

ongoing, the reference was a duplicate, the population under study was immunocompromised, 

or multiple vaccines were co-administered as an intervention. Ultimately, 10 studies were 

included in this GRADE analysis.

For reference, the evidence types outlined in the GRADE process are as follows:

Initial Evidence Type Study Design

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

Outcome #1 was the incidence of HZ. Two manuscripts were included for assessment. Lal et 

al reported an RCT in adults 50 years of age and older, also known as ZOE-50. This Phase III 

clinical trial compared HZ/su vaccine to placebo and reported vaccine efficacy against HZ. 

Cunningham et al reported an RCT in adults 70 years of age and older known as ZOE-70, 

which also reported vaccine efficacy against HZ compared to placebo. These GSK-funded 

studies were performed in parallel at the same study sites in 18 countries. After enrollment in 

the study, participant 70 years and older were randomized either to ZOE-50 or ZOE-70. Study 

protocols were consistent in both study arms. While the results were reported separately, for 

GRADE purposes these were considered as one study.

For HZ, the estimates of effect were as follows: For adults over 50, VE was 96.6%. For adults 

in their 60s, it was 97.4%. For adults 70 years of age and older, VE was 91.3%. The type of 

evidence supporting the prevention of HZ is Type 1. ZOE-50 and ZOE-70 are considered one 

RCT with an initial evidence level of 1. The WG determined that there was no serious risk of 

bias. As there was only one study, inconsistency could not be assessed between studies. 

There were no serious concerns regarding indirectness of the study with respect to the central 

policy question, and no concerns regarding imprecision of the study.

Outcome #2 was the incidence of PHN. Cunningham et al described previously pooled data 

from pooled data from ZOE-50 and ZOE-70 studies to report VE against PHN. Regarding 

incidence of PHN, the estimates of effect were as follows: For adults 50 years of age and older, 

VE was 91.2%. For adults in their 50s and 60s, there actually were no cases in the vaccinated 

group. Thus, there was a VE of 100% with wide confidence intervals. The study was powered 

to assess PHN in adults 70 years of age and older. For this group, VE was 88.8%.

The type of evidence supporting incidence of PHN is type 1. ZOE-50 and ZOE-70 are 

considered one RCT with an initial evidence level of 1. The WG determined that there was no 

serious risk of bias. As there was only one study, inconsistency could not be assessed between 

studies. There were no serious concerns regarding indirectness of the study with respect to the 

central policy question, and no concerns regarding imprecision of the study.

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Next, the WG considered outcome #3, duration of protection against HZ. Again, Cunningham et 

al was the only manuscript to report on this outcome and was derived from pooled ZOE-50 and 

ZOE-70 data. For the duration of protection against HZ, estimates of effect in adults 70 years of 

age and older were as follows: During the first year following vaccination, VE was 97.6%. In 

the second, third, and fourth years, VE was 92.0%, 84.7%, and 87.9%, respectively.

The type of evidence supporting the duration of protection against HZ is type 1. ZOE-50 and 

ZOE-70 are considered one RCT with an initial evidence level of 1. The WG determined that 

there was no serious risk of bias. Inconsistency was not applicable. There were no serious 

concerns regarding indirectness of the study with respect to the central policy question, and no 

concerns regarding imprecision of the study.

Turning to the evidence for potential harms, outcomes #4 and #5 were SAEs and reactogenicity. 

Four studies were included. Cunningham and Lal were discussed earlier in this presentation. 

Chlibek et al in the Journal of Infectious Diseases (JID) in 2013 was an RCT that included adults 

50 years and older and compared HZ/su vaccine to placebo and assessed SAEs as well as 

reactogenicity. Another study by Chlibek et al published first in 2014 and then followed up in 

2016 was an RCT that compared HZ/su vaccine to an unadjuvanted glycoprotein vaccine. 

Poder, Leroux-Roels, and Vink were RCTs in the target population that administered HZ/su 

vaccine but did not have a non-vaccine comparison group. Godeaux and Lal 2013 were not 

randomized, nor did they have an adequate comparison group. All studies assessed SAEs as 

well as reactogenicity, and all were funded by GSK.

Outcome #4 was SAEs. Among the over 29,000 participants followed through the entire study 

period, almost equal numbers of SAEs were observed in the placebo and vaccine groups. This 

was true for all SAEs as well as AEs considered by the independent safety committee to be 

possibly related to vaccination. The remaining 7 studies that administered HZ/su vaccine to a 

total of 616 participants found no SAEs related to vaccination. The type of evidence for SAEs is 

type 1. There were two RCTs with an initial evidence level of 1. The WG determined that there 

was no serious concerns regarding risk of bias, inconsistency, indirectness, or imprecision. The 

four RCTs with no placebo group and the two non-randomized trials were non-blinded, openlabel trials and therefore were downgraded for risk of bias and indirectness. They were 

downgraded for indirectness because they did not have a comparison group. The two nonrandomized studies started at a lower initial evidence type. Given that the top two listed RCTs 

contributed type 1 evidence and the other studies were consistent with their findings, the 

evidence type assigned to this outcome is type 1.

Outcome #5 was reactogenicity, specifically Grade 3 reactions. In ZOE-70 studies, symptoms 

were solicited from almost 10,000 participants for 7 days following vaccination. Any Grade 3 

reaction was noted in 3.1% of the placebo and 16.5% of the vaccinated group for a difference of 

13.4%. Grade 3 reactions at the injection site showed 9.1% excess in the vaccinated group, 

and Grade 3 systemic reactions showed an excess of 8.4% in the vaccinated group. Four 

additional studies reported any solicited Grade 3 reactions after vaccination among participants 

who received HZ/su vaccine. Those estimates are 3.4% (Godeaux, 2017, n=96), 9.3%

(Chlibek, 2013, n=150), 11.5% (Poder, 2016, n=119), and 40% (Lal, 2013, n=10). The 

remaining three studies that administered HZ/su vaccine to a total of 241 participants reported 

Grade 3 reactions by symptom and had findings consistent with the previous studies. The type 

of evidence for reactogenicity was type 1. There were two RCTs with an initial evidence of type 

1. The WG determined that there was no serious risk of bias in these studies and there were no 

concerns about inconsistency, indirectness, or imprecision. The four RCTs with no placebo 

group were non-blinded, open-label trials and were downgraded for risk of bias and 

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indirectness. The two non-randomized studies had an initial evidence level of 2 and were 

downgraded for risk of bias and indirectness. Given that the two RCTs contribute type 1 

evidence and that the other studies are consistent with those findings, the evidence type 

assigned to this outcome was also type 1.

There were limitations to the ZOE-50 and ZOE-70 study as with any study. Reactogenicity of 

the vaccine itself may have resulted in effective un-blinding of some vaccine recipients, leading 

to opportunities for bias in reporting of AEs and possibly case ascertainment. With regard to 

generalizability, only 18% of the participants were from North America and only 1% of overall 

participants were black. The study excluded those with a history of HZ, previous Zostavax®

recipients, and those taking immunosuppressant or immuno-modifying drugs. 

In summary, the critical outcomes of HZ, PHN, and SAEs are all supported by at least one good 

quality, large RCT. To recap, the findings were that HZ/su vaccine is significantly efficacious in 

preventing HZ and PHN. No differences were detected between the vaccinated and placebo 

groups for SAEs. Grade 3 reactions were more commonly reported in vaccinated groups 

compared to placebo. Overall, HZ/su vaccine was significantly efficacious in preventing HZ 4 

years following vaccination. The overall evidence type supporting the critical outcomes is 1. In 

other words, the WG’s level of certainty of the estimate of effect for these outcomes is high.

Consideration for HZ Vaccine Policy

Kathleen Dooling, MD, MPH

Medical Epidemiologist

Division of Viral Diseases

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Dooling emphasized the importance of considering vaccine policy in the context of the 

epidemiology in the US. The annual rate of HZ is approximately 4 cases per 1000 population or 

roughly 1 million cases annually1,2. The incidence increases with age, ranging from <1 

case/1000 children to >15 cases/1000 population 80 years and older2,3. For adults 50 years 

and older with HZ, 10% to 18% will go on to develop PHN. Similar to HZ, the incidence 

increases with age3. The incidence of HZ is decreasing in children, increasing in younger 

adults, and has plateaued in adults ≥65 yrs4 [1Jumaan et al., JID, 2005, 191:2002-7; 2Yawn, et 

al., Mayo Clin Proc. 2007; 82:1341-9; 3Insinga et al., J Gen Intern Med. 2005, 20:748-53; 

4Hapaz et al, IDWeek 2015].

Zostavax®, a live attenuated vaccine for the prevention of HZ, was recommended by ACIP in 

2008 for immunocompetent adults ≥60 years. Phase III clinical trials demonstrated a VE of 51% 

against HZ and 67% against PHN5. The duration of protection against HZ5,6 was 62% in Year 1,

45% by Year 4, and 7% by Year 9. In terms of AEs following immunization5, there was no 

significant difference between placebo and vaccine. However, non-serious AEs were seen 

more frequently in the vaccinated group. In 2015, 31% of adults ≥60 years had been vaccinated 

with Zostavax7 [5Oxman et al. 2005, NEJM, 6Morrison et al. 2015, CID; 7CDC 2015 Adult 

Vaccination Coverage General Population Report. 

Therefore, the key factors to consider when formulating policy recommendations can be 

summarized as thus: The evidence type for both harms and benefits is evidence type 1. In 

terms of balance between benefits and harms, HZ and PHN were significantly less frequent in 

the vaccinated group. That finding persisted 4 years following vaccination. SAEs occurred at 

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similar rates in vaccinated and placebo groups. Grade 3 reactions occurred more frequently in 

vaccine recipients. Ultimately, the WG concluded that benefits of disease prevention outweigh 

harms of reactogenicity. With respect to values, the WG placed high value on prevention of HZ 

and PHN. Studies have shown that community members also place high value on prevention of 

HZ and PHN8. Patients who had experienced herpes zoster consistently placed the highest 

value on avoidance of the disease8 [8Lieu, Pharmacoeconomics 2009]. Of course, costeffectiveness will be an important factor to consider. That analysis is ongoing.

The WG has identified a number of information gaps for policy-making. For example, 2-dose 

compliance was 95% in Phase III clinical trials. It is not known what 2-dose compliance will be 

under real world conditions, or whether non-completion of the series will have an effect on 

vaccine effectiveness and/or duration of protection. The protection that HZ/su vaccine can 

provide beyond 4 years is not clear. Though no data are yet available to assess vaccine 

efficacy in immunocompromised persons, fortunately Phase III trials of 2 vaccines, HZ/su and 

V212, are ongoing. The efficacy and safety data from these trials will inform vaccine policy in 

this high-risk group. Importantly, there are no head-to-head comparisons of VE between HZ/su 

and Zostavax®. 

Based on the review of the evidence for critical and important outcomes, the WG’s interpretation 

is that the vaccine is safe, efficacious, and maintains high protection against HZ 4 years 

following vaccination among immunocompetent adults aged 50 years and older. The issues 

under active consideration by the WG are as follows:

 Should recommendations for routine vaccination start at age 50 or age 60? The substantial 

disease burden in the 50 through 59-year-old cohort must be weighed against increasing 

disease incidence with age, possible waning of immunity, and incremental cost/benefit.

 Should persons previously vaccinated with Zostavax® be revaccinated with HZ/su and if so, 

when? As mentioned earlier, Zostavax® recipients account for over 30% of the population 

60 years of age and older. The known waning of immunity of Zostavax® must be considered 

and the forthcoming safety and immunogenicity studies that address revaccination. More 

information will be presented on this during the June ACIP meeting.

 What policy recommendations may prevent the greatest burden of HZ and PHN if 2 licensed 

vaccines are available for use? Given the differing VEs, duration of protection, 

reactogenicity profiles, and dosing regimens, how can we prevent the most disease? 

 What is the most cost-effective vaccine program? The price of HZ/su vaccine is not yet 

known, but that will factor into each of the above considerations. ACIP will hear costeffectiveness analyses during the June and October 2017 meetings.

Next steps for the WG include cost-effectiveness analyses for HZ/su in the context of the 

current vaccine program, as well as a GRADE for Zostavax®. Forthcoming data for 

consideration include co-administration of HZ/su with other adult vaccines and expanded dosing 

schedules, immunogenicity and safety in adults who have previously received Zostavax®, and 

immunogenicity and safety in Zostavax® versus HZ/su. 

To recap and review the intended timeline, after today’s review of safety and GRADE HZ/su, in 

June 2017 ACIP will hear a GRADE review of Zostavax®, as well as safety and immunogenicity 

data that will compare HZ/se and Zostavax® and revaccination. Cost-effectiveness and 

considerations for policy also will be presented in June. In October 2017, summaries of 

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GRADE, cost-effectiveness, and policy considerations will be presented. With that in mind, she 

asked whether there are additional data that would be helpful to ACIP to inform a

recommendation for the use of HZ/su in immunocompetent adults. 

Discussion Points

Dr. Hunter thought there were times when there were lower quality evidence that would diminish 

higher quality evidence, such that the final quality score would be lower.

Dr. Dooling clarified that within any individual outcome, the GRADE level applied is not 

necessarily the arithmetic average of the GRADEing of the studies. In fact, if there is strong 

level 1 evidence, that carries the most weight. For the outcomes she presented, the lower 

quality of evidence showed similar effect sizes as the higher quality of evidence; therefore, the 

higher quality of evidence prevailed.

Dr. Hunter asked which would have prevailed if the higher and lower quality of evidence had not 

agreed, and if there is ever a decrease in the final quality score of the evidence when there is 

only one study from one source.

Dr. Dooling replied that the overall quality of evidence would have been downgraded for 

inconsistency. Therefore, the highest quality would not have been assigned to any outcome 

that demonstrated inconsistency of estimates. In terms of only one study, one of the areas of 

assessment is heterogeneity or inconsistency between studies. With only one study, that 

particular parameter cannot be assessed. This raises a good philosophical point in terms of 

whether it should count against the body of evidence that there is only one large study. So far, 

the guidance has been to not downgrade if there is one well-done, large RCT.

Dr. Patricia Whitely-Williams (NMA) asked if the group discussed whether having additional data 

on the use of zoster vaccine in a more heterogeneous population, particularly African 

Americans, would be beneficial. The disparity gap is large for this vaccine and is probably even 

worse for some of the other vaccines. Not that they could predict that there would be an 

adverse health outcome. However, if there is, it is important to avoid having any other more 

negative effect or reasons for African Americans not to become immunized, particularly as the 

population ages.

Dr. Dooling responded that the WG agrees that diversity in the population under the study is 

extremely helpful and essential to be able to generalize the results to the entire American 

population for whom ACIP would be making recommendations. Worldwide, it was only 1% of 

the study population. Specifically within the US population, the percentage was greater as was 

previously indicated by Dr. Colindres. Could the study populations achieve better diversity to 

reflect the populations for whom we want to make public health recommendations? Absolutely. 

The WG has consistently reinforced that in its discussions and has asked for specific ethnicityor race-based breakdowns of safety.

Dr. Bennett asked whether there were any additional data that would be helpful to the ACIP. No 

other data were requested.

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Introduction

David S. Stephens, MD

Chair, Meningococcal Work Group

Dr. Stephens reported that the Meningococcal WG has been engaged with a number of 

activities, including reviewing newly available data for meningococcal B (MenB) vaccines, 

including antibody persistence and response to a booster dose, considering booster doses of 

MenB vaccine for persons at increased risk, and recently hearing an update on the 

discontinuation of the meningococcal polysaccharide vaccine Menomune® (MPSV4). 

The policy option under consideration pertains to booster doses of MenB vaccines for persons 

at increased risk, which states that:

 Booster doses of MenB vaccine should be administered every 5 years throughout life to 

persons aged ≥10 years in each of the following groups:









Persons with persistent complement component deficiencies including persons 

taking eculizumab

Persons with anatomic or functional asplenia

Microbiologists routinely exposed to isolates of Neisseria meningitidis (as long as 

exposure continues)

 Booster doses of MenB vaccine should be administered to persons identified as at 

increased risk because of a serogroup B meningococcal disease outbreak if it has been 

≥6 months since their last MenB dose

When multi-year or prolonged outbreaks occur, CDC should be consulted and 

recommendations for additional booster doses will be considered on a case-bycase basis

The agenda for this session focused on considerations for MenB booster doses in groups at 

increased risk for serogroup B meningococcal disease; and an update on the epidemiology of 

meningococcal disease and guidance for the control of meningococcal disease outbreaks in the 

US. 

As mentioned, Sanofi Pasteur is discontinuing production and supply of the meningococcal 

polysaccharide vaccine A, C, Y, W Menomune® (MPSV4) in the US. The last remaining lots will 

expire in June through September 2017. Letters to health care providers were sent on February 

8, 2017. 

The updated guidance for use of meningococcal vaccines in persons aged ≥56 years is as 

follows:

 Meningococcal vaccines that are licensed for use in persons aged ≥56 years are not 

currently available in the United States

Meningococcal Vaccines

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 Persons aged ≥56 years who are recommended meningococcal vaccination because 

they are at increased risk for meningococcal disease should receive MenACWY 

conjugate vaccine





This includes, meningococcal vaccine-naïve persons aged ≥56 years who 

anticipate requiring only a single dose of meningococcal vaccine (e.g. travelers 

and persons at risk as a result of a community outbreak)

And persons who were vaccinated previously with MenACWY conjugate vaccine 

and are recommended for revaccination or for whom multiple doses are 

anticipated (e.g., persons with asplenia, HIV, and microbiologists)

A Policy Note regarding the updated recommendations for the use of MenB-FHbp (Trumenba®) 

is soon to be published in the MMWR. 

Considerations for Serogroup B Meningococcal (MenB) Vaccine Booster 

Doses in Persons at Increased Risk for Serogroup B Meningococcal Disease

Jessica MacNeil, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Ms. MacNeil presented the WG’s considerations for MenB vaccine boosters in persons at 

increased risk for serogroup B meningococcal disease. As a reminder, MPSV4 polysaccharide 

vaccine was first recommended for groups at increased risk in 1980. MenACWY conjugate 

vaccine was recommended for persons 11 through 55 years of age at increased risk when 

licensed in 2005, which was the original age indication for licensure. Recommendations for 

children 2 through 10 years of and infants at increased risk were then made as the licensed 

indication expanded. However, during this time, MPSV4 was available for use in persons at 

increased risks who were outside of the licensed age indication of the conjugate vaccine. In 

2010, booster doses of MenACWY conjugate vaccine were added for certain groups who 

remain at increased risk for meningococcal disease.

The rationale for ACIP recommending booster doses of MenACWY for persons at increased risk 

included that persons at increased risk for meningococcal disease represent small targeted 

groups with a demonstrated increased risk for meningococcal disease. There is evidence of 

waning functional antibody 3 to 5 years after a single dose of MenACWY and evidence of a 

booster response to revaccination. There is a low-risk for SAEs following additional doses of 

meningococcal conjugate vaccine, and vaccination is the accepted standard of care for high-risk 

groups. Based on these considerations, ACIP recommended booster doses of MenACWY 

every 5 years throughout life for certain persons who remain at increased risk for 

meningococcal disease. 

In 2014 and 2015 two MenB vaccines were licensed in the US for persons aged 10 to 25 years

of age. MenB-FHbp (Trumenba®, Pfizer) contains two components. It can be administered 

either as a 3-dose series administered at 0, 1–2, and 6 months among persons at increased risk 

for serogroup B meningococcal disease or as a 2-dose series at 0 and 6 months when 

administered to healthy adolescents who are not at increased risk. MenB-4C (Bexsero®, GSK)

contains four components and is administered as a 2-dose series at 0 and ≥1 month of age. 

MenB-4C is also licensed in a number of other countries for use in persons ≥2 months of age. 

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Shortly after the licensure of the MenB vaccines, in 2015 ACIP recommended routine use of 

MenB vaccine for persons aged ≥10 years at increased risk for serogroup B meningococcal 

disease. During its February 2015 meeting, ACIP recommended routine MenB vaccination for 

persons with complement component deficiencies, persons with anatomic or functional 

asplenia, microbiologists routinely exposed to isolates of Neisseria meningitidis, and persons 

identified as being at increased risk because of a serogroup B meningococcal disease outbreak. 

In June 2015, ACIP recommended that adolescents and young adults 16 through 23 years of 

age may receive a MenB vaccine to provide short-term protection against most strains of 

serogroup B meningococcal disease. To date, ACIP has not discussed or made 

recommendations for booster doses of MenB vaccine.

It is known that certain people, including the groups outlined above, who are increased risk for 

meningococcal disease are likely to remain at increased risk throughout their lifetime. Further 

available data suggest waning of antibodies shortly after vaccination with MenB vaccines

among healthy subjects. There are currently limited data available on the immunogenicity of the

MenB primary series among immunocompromised subjects, the duration of protection of MenB 

vaccines, and the efficacy of MenB booster doses among persons at increased risk. It is 

unlikely that more data for these groups will become available. However, there is a need to 

optimize protection for persons at increased risk for meningococcal disease. 

During this presentation, Ms. MacNeil reviewed the groups at increased risk for serogroup B 

meningococcal disease who are currently recommended MenB vaccination, and discussed the 

WG’s interpretation of the available data on immunogenicity of MenB-4C among 

immunocompromised subjects and data on the antibody persistence and response to a booster 

dose following a primary series with MenB-FHbp (Trumenba®) or MenB-4C (Bexsero®) among 

healthy subjects. In addition, she reviewed the proposed policy option for MenB booster doses 

among persons at increased risk for serogroup B meningococcal disease.

In terms of the groups at increased risk for serogroup B meningococcal disease currently 

recommended for MenB vaccination, persistent or genetic deficiencies in the complement 

pathway are well-known to increase risk for meningococcal disease. Individuals with persistent 

complement component deficiencies are at up to 10,000-fold increased risk for developing 

meningococcal disease often develop recurrent infections. Complement component 

deficiencies are rare and only affect about 0.03% of the US population1. Complement 

component deficiencies are often recognized as a result of a meningococcal infection or 

recurrent meningococcal infection. In the US, it is estimated that between 7% and 25% of 

meningococcal cases have a complement component deficiency2 [1Densen R. Clin Exp 

Immunol. Oct 1991; 86(Suppl 1): 57-62; 2Figueroa JE. Clinical Microbiology Reviews. July 1991; 

4(3):359-95].

Persons who take eculizumab (Soliris®), which is a monoclonal antibody that is indicated for 

treatment of atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal 

hemoglobinuria (PNH) are also at elevated risk for developing meningococcal disease. This is 

because the monoclonal antibody binds to C5 and inhibits the terminal portion of the 

complement cascade. Data presented to the FDA Drug Safety and Management Advisory 

Committee showed that 16 cases of meningococcal infection occurred among persons taking 

eculizumab during 2007–2014, including one death.1 These 16 cases occurred out of 5200 

person years of eculizumab exposure, which means that these patients have 2000 times the 

occurrence of meningococcal disease when compared to the general US population. Among 

those 16 cases, 1 was serogroup B, 2 were serogroup C, and 2 were serogroup Y. In 11 cases, 

the serogroup was unknown1. All of the patients had been vaccinated with a MenACWY

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vaccine.1 Additionally, the first known MenB vaccine failure was recently reported in the UK in a 

person taking eculizumab.

2 The number of patients taking eculizumab is unknown, but both 

aHUS and PNH are rare conditions [1http://www.fda.gov/

downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManag

ementAdvisoryCommittee/UCM423031.pdf; 2Abstract O54: http://neisseria.org/ipnc /2016/

IPNC2016 AbstractBook.pdf; 3http://atypicalhus.ning.com/page/what-is-ahus; 4http://imgjp1.

pnhsource.jp/Downloads/pdf/UnderstandingPNHBrochure.pdf].

Asplenic persons are also at increased risk for invasive infection caused by many encapsulated 

bacteria, including Neisseria meningitidis. The asplenic population is quite heterogeneous and 

notably includes patients with sickle cell disease which affects ~100,000 persons of all ages1. 

Importantly, people with asplenia have a higher case-fatality ratio when they do develop 

meningococcal disease (40%–70%)2 compared to the US population.3 In one study from the 

UK, persons with asplenia were shown not to respond as well to 1 dose of MenC vaccine4

[

1http://www.cdc.gov/ncbddd/sicklecell/data.html; 2MMWR. January 28,2011; 60(3): 72-76; 

3Cohn AC. Clin Infect Dis 2010;50:184-91; 4Balmer P. Infection and Immunity, Jan 2004, 332-

337].

Microbiologists are also at increased risk of developing meningococcal disease, with an attack 

rate that was found to be 13/100,000 among those who work with Neisseria meningitidis

compared to 0.1 to 0.2/100,000 among the general US population. Microbiologists have been 

shown to have a higher case fatality ratio, possibly due to exposures to higher concentrations of 

the organism or to highly virulent strains. However, the majority of cases that have occurred in 

clinical microbiologists occurred in those who were not using respiratory protection at the time of

the exposure [Sejvar JJ. Journal of Clinical Microbiology. Sept 2005;43(9):4811-14].

Meningococcal disease outbreaks are rare and only account for 2% to 3% of US cases.1

However, when they do occur, they cause significant anxiety and are devastating for the 

communities in which they occur. There were 5 serogroup B meningococcal disease outbreaks 

on college campuses during 2008–2014. During those outbreaks, students were found to be at 

between 200- and 1400-fold increased risk for meningococcal disease during the outbreak 

period. In 2015 and 2016, there have been an additional 6 serogroup B meningococcal disease 

outbreaks on college campuses [1National Notifiable Diseases Surveillance System].

In the US, data on the number of cases that occur among persons in these groups at increased 

risk are limited. Through the Active Bacterial Core surveillance (ABCs) system, information was 

collected on two of these groups, persons with anatomic or functional asplenia and complement 

component deficiencies. ABCs is an active laboratory- and population-based surveillance 

system that operates in 10 states and covers approximately 43 million persons, or 13% of the 

US population. ABCs collects data information from the medical record for all meningococcal 

cases reported in the surveillance area, and has collected information on whether cases had 

asplenia or sickle cell disease since 1995 and complement component deficiencies since 2005. 

One limitation that is of particular relevance for the information on the diagnosis of complement 

component deficiencies is that these deficiencies may not be diagnosed until after 

hospitalization for meningococcal disease and therefore may not be captured in ABCs during 

the medical record review for the acute meningococcal hospitalization.

In terms of the estimated number of people and the reported number of cases reported in each 

group, approximately 270,000 individuals fall into three groups of people at increased risk for 

meningococcal disease. Although only a handful of cases have been documented in ABCs or 

the published literature, these groups are known to be at increased for meningococcal disease 

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and are currently recommended to be vaccinated with both MenACWY conjugate vaccine and 

MenB vaccine. Looking at the outbreak at-risk populations, approximately 180,000 students 

attend the universities where the 11 serogroup B university outbreaks occurred during 2008-

2016. This translates into approximately 20,000 students at risk per year or 16,000 students at 

risk on average per outbreak. During these outbreaks on college campuses, a total of 50 cases 

of serogroup B meningococcal disease and 3 deaths were reported.

In summary, persons at increased risk for serogroup B meningococcal disease represent small 

targeted groups with a demonstrated increased risk for meningococcal disease. For persons 

with complement component deficiencies or anatomic or functional asplenia and most 

microbiologists, the increased risk for meningococcal disease is ongoing. For persons at 

increased risk because of a serogroup B meningococcal disease outbreak, the risk period may 

be more limited. 

In terms of the immunogenicity among immunocompromised subjects for MenB-4C vaccine, 

Bexsero®, the only available data for MenB vaccine response in immunocompromised persons 

comes from a study that looked at the immunogenicity of a 2-dose series of MenB-4C among 

subjects with complement component deficiency or asplenia compared to healthy controls. This 

study was a Phase IIIb, open label, controlled, multi-center study that evaluated the safety, 

tolerability, and immunogenicity of 2 doses of MenB-4C administered to 152 subjects 2 through 

17 years of age with complement deficiency or asplenia compared to 87 healthy controls. 

Subjects received vaccine at 0 and 2 months.

Immunogenicity was assessed as the proportion of subjects who achieved an hSBA titer >1:5 

using an exogenous complement source for each of the 4 selected serogroup B strains tested. 

An exogenous complement source means that a complement derived from healthy adult sera is 

added during the hSBA assay. When comparing baseline to post-dose 2, after receiving 2 

doses of MenB-4C, there was an increased immune response to all 4 strains tested in subjects 

with complement deficiency and asplenia. However, the response was generally lower in 

subjects with complement deficiency compared to subjects with asplenia or healthy controls.

Immunogenicity was also assessed as an hSBA titer ≥1:4 using an endogenous complement

source for each of the 4 selected serogroup B meningococcal strains tested. Endogenous 

complement means that the source of the complement for the hSBA assay is the test serum 

itself. After receiving 2 doses of MenB-4C, all three groups had an increased response. 

However, the hSBA responses were lower among those with complement deficiency when an 

endogenous complement source is used.

Subjects with complement deficiency were broken down into 3 separate groups, including 7 

subjects who were taking eculizumab, 4 subjects with terminal complement deficiencies, and 27 

subjects with other deficiencies compared to 85 healthy controls. After receiving 2 doses of 

MenB-4C, there was an increased response among all three groups, but the subjects taking 

eculizumab had the lowest response.

In summary, in the only available data assessing immunogenicity of a 2-dose series of MenB4C among persons 2 through 17 years of age at increased risk of for meningococcal disease, 

there was an increase in hSBA responses in subjects with complement component deficiency 

and asplenia, and in subjects receiving eculizumab after two doses of MenB-4C. Comparable 

responses were observed in healthy subjects and subjects with asplenia. The lower responses 

were reported in subjects with complement component deficiencies, especially if endogenous 

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complement was used in the hSBA assay. Subjects receiving eculizumab showed an increase 

in hSBA titers, but had the lowest response. 

Regarding MenB antibody persistence and response to a booster dose among healthy subjects, 

based on the available data, for healthy adolescents, antibody persistence and booster 

response data are available up to 48 months for MenB-FHbp and up to 11 through 24 months 

for MenB-4C. Among children 4 through 7 and 8 through 12 years, there are antibody 

persistence and booster response data for MenB-4C up to 24 to 36 months.

In terms of the persistence of hSBA responses ≥1:4 against 4 selected serogroup B 

meningococcal strains up to 48 months in adolescents aged 11 through 18 years following 

completion of a 2- or 3-dose series of MenB-FHbp, 1 month post-completion of the primary 

series for persons who completed both the 2- and 3-dose series, there was an initial increase in 

the percentage of persons with hSBA titers ≥1:4. However, the percentage of subjects with 

protective antibodies dropped sharply at 12 months post-completion of the primary series and 

then remained stable through 48 months post-vaccination.

Regarding antibody persistence up to 48 months in adolescents 11 through 18 years of age 

after completion of either the 2- or 3-dose of primary MenB-FHbp series and hSBA responses to 

a booster dose at 48 months post-primary series, for each strain tested there was an initial 

increase in the percentage of persons with hSBA titers ≥1:4 at 1 month post-primary series. 

This was followed by a decline at 48 months post-completion of the primary series, then 

followed by another increase in the percentage of persons with hSBA titers ≥1:4 1-month postbooster dose.

Looking at the percentage of adolescents with hSBA titers ≥1:4 or ≥1:5 1 month after a 2-dose 

primary series of MenB-4C, between 99% and 100% of adolescents had an hSBA titer of ≥1:4 

or ≥1:5 1 month after a 2-dose primary series of MenB-4C. At 11 months or 18 through 24 

months for each of the strains tested, antibody persistence declined over time.

Among children 4 through 7 years of age and 8 through 12 years of age who received a primary 

series of MenB-4C, there was an initial increase in the percentage of persons who had hSBA 

titers ≥1:4 1 month post-primary series, followed by a decline at 24 to 36 months postcompletion as a primary series, followed by another increase in the percentage of persons with 

hSBA titers ≥1:4 at 1 month post-booster dose at 24 to 36 months.

The WG anticipates reviewing one additional study before the June 2017 ACIP meeting. Fouryear antibody persistence and booster response data for adolescents from Canada and 

Australia after completion of primary series of MenB-4C are anticipated within the next few 

months. Data are anticipated to be available for ACIP to review during the June 2017 meeting.

 

The WG also reviewed the available safety data for both the primary series and a single booster 

dose for the MenB vaccines. As described to ACIP previously, MenB vaccines are more 

reactogenic than other vaccines given during adolescence, with the most common AE reported

being pain at the injection site. However, the overall safety and tolerability profiles are similar 

for the primary series and one additional booster dose. 

In summary, the available data demonstrate that there is evidence of waning antibody for both 

MenB vaccines as early as 12 months after completion of the primary series. However, different 

waning rates were observed for antibodies to each vaccine antigen or strain tested. The data 

from the two MenB vaccines are not directly comparable, as each was evaluated against 

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different strains at different intervals following the primary series, and in subjects of different 

ages. These data also demonstrated that there is evidence of a booster response to 

revaccination among previously vaccinated subjects at intervals varying from 24 to 48 months, 

and there is a low-risk for SAEs following additional MenB doses.

Overall, the WG’s interpretation of the data presented during this session is that persons at 

increased risk for serogroup B meningococcal disease represent small targeted groups with a 

demonstrated increased risk for meningococcal disease. MenB vaccines are immunogenic in 

persons at increased risk for meningococcal disease. Waning of antibody is observed as early 

as 12 months post-vaccination, and booster response is observed in previously vaccinated 

subjects following one additional MenB dose. 

Similar to the rationale behind the recommendations for booster doses of MenACWY conjugate 

vaccine, the WG supports MenB booster doses among persons at increased risk because 

persons at increased risk for meningococcal disease represent a small targeted group with a 

demonstrated increased risk for meningococcal disease. Evidence of waning antibody is 

observed as early as 12 months after MenB vaccination, and there is evidence of a booster 

response to revaccination. There is also a low-risk for SAEs following additional doses of MenB 

vaccine, and vaccination is the accepted standard of care for high-risk groups. 

The WG discussed the appropriate timing or interval for MenB booster doses extensively for 

persons who remain at increased risk for serogroup B meningococcal disease and in the setting 

of an outbreak. There is a desire to harmonize the timing of the booster recommendations with 

MenACWY for persons who remain at increased risk if possible to improve compliance with 

booster doses of both vaccines, and to ensure that some level of protection is maintained over 

time in these individuals. There was recognition that there is evidence of waning antibody as 

early as 12 months after the MenB primary series. However, the WG felt that harmonization of 

the booster doses made sense at the time given the currently available data. Outbreaks 

represent quite a different scenario, and there may be additional benefit to an individual if a 

booster dose is given at a shorter interval to a person previously vaccinated to ensure that 

antibody and potential protection is maximized during the outbreak period. 

The overall consensus of the WG was to support routine MenB booster doses for persons at 

increased risk of serogroup B meningococcal disease, and to harmonize the timing of the 

booster doses with MenACWY boosters for groups at prolonged increased risk for 

meningococcal disease. In outbreak settings, the WG supported providing booster doses if it 

has been at least 6 months since their last MenB dose. Based on this, the WG proposed the 

following policy option:

 Booster doses of MenB vaccine should be administered every 5 years throughout life to 

persons aged ≥10 years in each of the following groups:







Persons with persistent complement component deficiencies including persons 

taking eculizumab

Persons with anatomic or functional asplenia

Microbiologists routinely exposed to isolates of Neisseria meningitidis (as long as 

exposure continues)

 Booster doses of MenB vaccine should be administered to persons identified as at 

increased risk because of a serogroup B meningococcal disease outbreak if it has been ≥6 

months since their last MenB dose

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 When multi-year or prolonged outbreaks occur, CDC should be consulted and 

recommendations for additional booster doses will be considered on a case-by-case 

basis

A GRADE evaluation of the evidence supporting MenB booster doses is currently underway and 

will be presented to the ACIP in June 2017. In addition, an ACIP vote will be proposed during 

the June 2017 on routine MenB booster doses in persons aged ≥10 at increased risk for 

serogroup B meningococcal disease. 

Ms. MacNeil posed the following questions on which the WG desired feedback:

 Are there additional data that ACIP would like to review?

 Does ACIP agree with the proposed policy option language and timing for booster doses in 

persons with complement component deficiencies, asplenia, and microbiologists?

 Does ACIP agree with the proposed policy option language and timing for booster doses in 

outbreak settings?





For persons previously vaccinated who later are in an outbreak? 

For persons within a prolonged outbreak scenario?

Discussion Points

Dr. Atmar requested further information about the relative risk of MenB disease in high risk 

groups versus the groups involved in outbreaks at a population level.

Ms. MacNeil replied that increased risk varies for each group. For complement deficient people, 

it is up to a 10,000-fold increased risk, and is also extremely high for eculizumab. For asplenics, 

the risk is primarily for streptococcus pneumoniae, though there is also increased risk for 

Neisseria meningitidis. The primary risk for that group is increased mortality when they do 

become infected. For microbiologists, it is 13/100,000 and in outbreaks there is about a 200- to 

1400-fold increased risk.

Dr. Atmar observed that the recommendation was for outbreak, which on a population-based 

level seemed to have a lower risk than the total complement deficient patients. Boosting at a 

shorter interval seemed like it should be the other way around, or it should be a shorter interval 

for all of them. He questioned the 5-year interval. While he understood that this made it easier, 

it would potentially leave more than 75% to 80% at risk during that 5-year period if immunity is 

waning by a year.

Ms. MacNeil indicated that the WG discussed this extensively and felt that based on the data 

available, it made sense to harmonize with the MenACWY recommendation for the groups at 

increased risk. There remains a question for the outbreak setting about whether the appropriate 

interval is 5 years or a shorter period.

Dr. Szilagyi requested additional information about the extent of waning after the booster dose.

Ms. MacNeil replied that there are data for only 1-month post-booster dose currently, but it is 

hoped that there will be additional data eventually. 

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Dr. Kempe requested a reminder about the duration of immunity after ACWY, which she 

recalled was in the 4- to 5-year range.

Ms. MacNeil indicated that the vaccine begins to wane within a few years after vaccination. The

waning curve is slightly different for ACWY in that it wanes somewhat more slowly. Decreases 

were observed in protection in the hSBA and effectiveness data as early as a few years after 

vaccination with only a single dose.

Dr. Messonnier noted that routine revaccination was included on the same slide with the 

outbreaks, but routine revaccination of people with complement deficiency is every 5 years 

across their entire lifespan as opposed to the outbreak recommendation which has occurred 

once a year in a limited population. This is the question faced from a public health perspective 

when a university calls CDC in the middle of an outbreak and is trying to decide what to do. 

Putting them together on the slide mixed the messages. Those on eculizumab are a small 

number of people, but they are at exceedingly high risk. However, the data with at least one 

vaccine do not look reassuring. She asked whether there was certainty that vaccination would 

help them, or if there is any other information that would help to make a data-based 

recommendation for that group of people.

Ms. MacNeil responded that the data reviewed so far suggested that vaccine may not protect 

these individuals. The WG is considering whether there are additional measures that should be 

used in this population to ensure protection. The WG felt that vaccination should be 

recommended for this group based on the chance that there would be some protection since the 

risk is so high. However, other interventions probably should be considered for that group as 

well.

Regarding Dr. Atmar’s comments, Dr. Moore reported that there was not consensus about this 

issue among the WG members and there was a lot of concern about the 5-year benchmark 

because they recognized that the evidence of waning immunity showed that they would not be 

protected for a good portion of that time. While there was not an agreement, what people were 

weighing and the dilemmas they faced included the fact that there was a concern about people 

not getting the vaccine at all if it was recommended at a high frequency and also concern about 

trying to understand cost-benefit or the cost per case prevented among these high-risk 

populations, acknowledging that the population is very small and the absolute case count 

among that population is very small. It is very difficult to get a sense of how much would have 

to be spent and how many doses would have to be administered in that population to prevent a 

single case of MenB. There was a tension in those issues of trying to harmonize with the 

schedule that exists and how frequently doses would have to be given in order to provide 

consistent MenB protection at the highest level, and whether it would be worth it in terms of the 

potential for cases prevented. She did not believe the WG concluded with a firm answer on 

that, and would like to have ACIP’s input into that dilemma.

Dr. Stephens added that it is unclear what will happen with a subsequent booster. It could 

provide a much longer period of protection, but those data are not available at this point in terms 

of making a specific recommendation. Regarding the terminal complement component inhibitor, 

these are people at very high risk. There is previous experience with polysaccharide and 

conjugate vaccine in complement deficient individuals. Even though ESBT cannot be boosted, 

which is what the data are based on, some protection is observed even though they persistently 

have complement deficiency. So, there may be other advantages to optimization of other 

components that may be simulated by a vaccine that would not necessarily be reflected in an 

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SBA type of assay in that instance. There may be other considerations for this particularly very 

high-risk group that they need to focus on.

Regarding the question about additional data, Ms. Pellegrini pointed out that typically when 

discussing meningitis, ACIP hears data on cases and deaths. It is known that for the people 

who survive, there are often dramatic and life-altering, lifelong health consequences. It would 

be helpful in the future to capture some of that nuance, because it would help ACIP get a 

clearer picture of cost-benefit in that there is more than preventing just death. There are 

disabilities and other issues involved.

Dr. Thompson (NVAC) Requested clarity about the term “microbiologist” regarding how the WG 

was using it and how that might be interpreted with respect to laboratory personnel, more 

broadly, and routinely or just in the context of an outbreak.

Ms. MacNeil reminded everyone that two years ago when the recommendation was made, the 

WG engaged in considerable discussion about how to define that group. The original language 

was kept, which was that employee health or microbiologists will have to determine who fits that 

category. The research microbiologists who routinely work with Neisseria meningitidis clearly 

fit. The clinical microbiologists are somewhat more challenging to define. Those who work on 

outbreaks should be vaccinated already, because those who routinely work with Neisseria 

meningitidis would be in a public health or in a clinical laboratory. The WG has not discussed 

microbiologists in that setting in particular.

It was not clear to Dr. Savoy (AAFP) what data the WG reviewed to make them feel comfortable 

to spread out the timeframe for a booster to 5 years, when the vaccine wanes in a year. She 

values harmonization because family doctors have to deal with so many things already, but not 

at the risk of someone’s life. Given that this pertains to a very small number of people, the cost 

cannot be that much.

Dr. Romero pointed out that exposure by clinical microbiologists is not uncommon. His 

institution had an exposure this year, and it has happened at three times in the 10 years he has 

been at his institution. They are not cavalier. These people are very careful in what they are 

doing, but there are exposures in the clinical laboratory.

Dr. Hunter suggested that perhaps ACIP should say they cannot make a change because there 

are no data to support doing so.

Dr. Messonnier pointed out that the way the language is currently written, a dose is 

recommended every 5 years for the rest of one’s life. This requires a lot of investment and 

decision-making. She suggested that the WG think about the short-term versus obliging 

something for which there are no data across the lifespan. The recommendation already states 

that duration of protection is not known after one booster dose.

Dr. O’Leary (PIDS) expressed confusion about the process situation since the most someone 

could have had since the vaccine has been in use in the US is 2 years. With only 2 years of 

data, it was unclear to him why they were talking about 5 years. He suggested waiting a few 

years before deciding on a 5-year booster.

Dr. Reingold inquired as to what the current policy is in the military in terms of revaccination for 

people who are living in a barracks for 20 years, and if there are any data from the DoD that 

might be accessed.

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A DoD representative indicated that for regular inductees, this has not been included.

Dr. Moore asked what additional information the WG might consider to make a different 

recommendation, such as the concept of a range.

 

Dr. Stephens replied that it is known that there is significant waning at 12 to 18 months with the 

primary series. For individuals at risk, it is because of that waning that the WG is 

recommending the booster dose. The other question pertains to what should be done after that, 

and there are no data for that. Perhaps as Dr. Messonnier suggested, the recommendation 

should be narrowed in the hope of hearing additional data on persistence after the booster dose 

for future recommendations.

Dr. Atmar noted that an economic analysis had been alluded to, and it may be beneficial to see 

what the cost would be with various assumptions that might inform the WG’s deliberations. He 

agreed with the suggestion to consider 1.5 to 2 years, but even for that an economic analysis 

could be beneficial.

Update on the Epidemiology of Meningococcal Disease and 

Guidance for the Control of Meningococcal Disease Outbreaks in the US

Sarah Meyer, MD, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Meyer described the epidemiology of meningococcal disease and outbreaks in the US, 

reviewed the current guidance for the evaluation and management of meningococcal disease 

outbreaks, described the proposed updates to CDC’s meningococcal disease outbreak 

guidance, and discussed the next steps.

Since the late 1990s, a sustained decline in the incidence of meningococcal disease has been 

observed in the US, decreasing from 1.3 to 0.12 cases per 100,000 population from 1996 to 

2015. This decline in incidence began prior to the introduction of a quadrivalent meningococcal 

conjugate, or MenACWY, vaccine in adolescents or the availability of serogroup B, or MenB, 

vaccines. Incidence has decreased in all three primary disease-causing serogroups, B, C, and 

Y, shown in the blue, purple, and green lines in the graph below, with incidence of serogroup W 

and other serogroups remaining stably low:

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Incidence and serogroup distribution vary by age group. The highest incidence is observed in 

children aged less than 2 years and adults aged greater than 85 years. A peak in incidence is 

also observed among adolescents and young adults aged 16-25 years. Serogroup B is the 

predominant serogroup in children aged less than 5 years. In children and adolescents aged 5

through 20 years, serogroup B accounts for approximately half of cases, and in adults aged 

greater than 20 years, serogroups C, W, or Y cause the majority of disease.

Although information on outbreak-associated cases is collected through the National Notifiable 

Diseases Surveillance System (NNDSS), reporting is likely incomplete. In 2014, CDC and state 

health departments conducted a retrospective review of all meningococcal disease cases from 

2009-2013 to identify and characterize clusters/outbreaks. For the purpose of this analysis, 

clusters were defined as 2 cases of the same serogroup within 3 months. Outbreaks were 

defined according to the current outbreak threshold as 3 or more cases of the same serogroup 

with an attack rate of >10 cases/100,000 population within 3 months. Clusters and outbreaks 

were classified as either organization-based in which there is a common affiliation other than a 

shared geographic space, or community-based in which there is no affiliation other than a 

shared geographic space. From 2009-2013, among the 3,683 cases reported to NNDSS, 195 

primary cases from 41 clusters that met criteria were identified.

Regarding the epidemiologic features of these clusters, among the 41 clusters or outbreaks, 22 

were community-based and 19 were organization-based. Among the community-based clusters 

or outbreaks, 2 occurred among men who have sex with men (MSM) during this time period.

Compared to other community clusters or outbreaks, these clusters had higher cumulative 

attack rates. The other community-based clusters or outbreaks generally had low attack rates, 

with a median of 1 case per 100,000 population, with only 2 of 38 clusters meeting the outbreak 

threshold. Among the 19 organization-based clusters, 9 occurred among university populations 

and 10 occurred among other organizations such as a correctional facility, health-care facility, 

high school, et cetera. In general, organization-based outbreaks had high cumulative attack 

rates. Cases associated with organization-based clusters and outbreaks are primarily due to 

serogroup B; whereas, those associated with community-based clusters are primarily serogroup 

C. In contrast, sporadic cases are primarily due to serogroups B and Y, followed by serogroup 

C.

Dr. Meyer examined in more detail two commonly reported cluster or outbreak types in the US: 

serogroup B organization-based clusters among university populations and serogroup C 

community clusters among MSM. 

From 2008-2016, 11 serogroup B university-based clusters or outbreaks were reported in the 

US. The epidemiology of these clusters or outbreaks varies, with duration lasting from a few 

days to nearly 3 years, with a cluster size of 2 to 13 cases and undergraduate university sizes 

ranging from 4,000 to 35,000 students. MenB vaccine was first used in response to a 

serogroup B university outbreak in 2013 prior to licensure of the vaccine in the US. Since that

time, 7 of 8 universities implemented MenB vaccination in response to a cluster or outbreak of 

meningococcal disease.

Since 2010, 5 clusters or outbreaks of serogroup C meningococcal disease among MSM have 

been reported. To date, these clusters have ranged in duration from 4 months to two and a half 

years, with 3 to 22 cases reported. MenACWY vaccination has been implemented in four of 

these clusters or outbreaks.

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In summary, rates of meningococcal disease have declined from approximately 1 to 0.1 cases 

per 100,000 population in the past 20 years, with a decline seen in all serogroups, including 

serogroup B. Each cluster or outbreak is unique, with a range in number of cases, population 

size and characteristics, and duration. This creates challenges in applying guidance for the 

control of meningococcal disease outbreaks that is applicable to a wide variety of outbreak 

situations. In recent years, several serogroup B outbreaks in universities and serogroup C 

outbreaks among MSM have been reported.

Regarding the current guidance for the evaluation and management of meningococcal disease 

outbreaks and proposed updates to this guidance, guidance was originally developed in 1997 

and updated in 2013 in Appendix B of the ACIP “Prevention and Control of Meningococcal 

Disease” statement. Interim guidance was developed in 2014 for the control of serogroup B 

outbreaks in organizational settings prior to the licensure of serogroup B vaccines in the US, 

specifically to guide use of unlicensed serogroup B vaccines under a CDC-sponsored 

Investigational New Drug (IND) program [Centers for Disease Control and Prevention. 

Prevention and Control of Meningococcal Disease; Recommendations of the Advisory 

Committee on Immunization Practices (ACIP). MMWR 2013;62(No. RR-#2): 1-28].

The key components of these meningococcal disease outbreak guidance documents include

the following: 

 Cases to be included in the case count for vaccine decision-making,

 The affected population, classified as organization or community-based

 Outbreak thresholds and the decision to vaccinate

 Defining the vaccination group

 The role of molecular genotyping

 Other control measures, such as mass chemoprophylaxis

The current guidance was originally developed under a different epidemiologic context and prior 

to the availability of conjugate MenACWY or MenB vaccines. Several recent outbreaks have 

identified challenges in managing outbreaks using the current guidance. As a result, state and 

local health departments expressed a need for updated guidance better adapted to the current 

situation.

The objective of the revised guidance is to update and harmonize guidance for the investigation 

and public health management of suspected outbreaks of meningococcal disease due to all 

serogroups, accounting for the changes in the epidemiologic situation and available outbreak 

response measures. To develop this guidance, subject matter experts (SMEs) were consulted 

from September 2015 to March 2016 to review the current guidance and available data, and 

discuss challenges in managing outbreaks using the current guidance. A review of the literature

also was conducted to describe the use and impact of meningococcal vaccines in outbreak 

settings.

CDC, with input from SMEs, reviewed all components of the current guidance previously 

mentioned. However, this presentation focused on a few key areas: cases to be included in the 

case count for vaccine decision-making, outbreak thresholds and the decision to vaccinate, and 

the role of molecular genotyping as it pertains to defining outbreak-related cases. Two 

additional topics were added to the updated guidance document: serogroup B vaccine selection 

based on expected vaccine coverage against an outbreak strain, and re-evaluation of outbreak 

status. 

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Regarding the cases to include for vaccine decision-making and the role of molecular 

genotyping, this presentation was limited to the discussion on the role of genotyping in terms of 

its application in defining outbreak-related cases. In the current guidance, only primary cases of 

the same serogroup are included in the case count for vaccine decision-making, as primary 

cases indicate ongoing transmission within a population. A primary case is defined as a case 

that occurs in the absence of previous known close contact with another patient. Co-primary 

and secondary cases are those that occur among close contacts of a primary case, with coprimary cases occurring within 24 hours of the primary case and secondary cases occurring 

more than 24 hours after the primary case.

There are several challenges to the current guidance. Determining whether cases had close 

contact may be challenging in some populations, such as homeless or MSM populations. In 

addition, there are differences in the community versus public health perception of what 

constitutes an outbreak. It may create confusion and communication challenges when some 

cases “don’t count.” In some situations, serogroup alone may not be sufficient to determine 

whether cases are related. New tools for molecular typing are available. Whole genome 

sequencing (WGS) provides the highest resolution for determining relatedness of strains. The 

role of WGS is becoming increasing important, particularly with the availability of serogroup B 

vaccines. However, there will continue to be cases in whom an isolate is not available for WGS.

In the updated guidance, cases will no longer be classified as primary, co-primary, or 

secondary. In addition, evidence of related or identical strains by WGS will not be required for 

inclusion of cases in the case count. However, if sequencing demonstrates that a case is 

unrelated to others in the outbreak, this case should not be included. Thus, in the proposed 

guidance, all cases of meningococcal disease of the same serogroup are included in the case 

count unless there is evidence of genetically distinct strains by WGS. 

In terms of the outbreak thresholds and the decision to vaccinate, in the published guidance, the 

outbreak threshold is 3 cases of the same serogroup with an attack rate of greater than 10 

cases per 100,000 population in 3 months. In the interim guidance, which applies only to 

serogroup B organization-based outbreaks, the outbreak threshold is 2 cases of the same 

serogroup in a population of less than 5000, and 3 or more cases of the same serogroup in a 

population of greater than or equal to 5,000 in 6 months. 

There are many challenges to the current guidance. Meningococcal outbreaks are not “one size 

fits all.” There is a need for flexibility in the guidance to evaluate each outbreak on a case-bycase basis. The threshold of 10 cases per 100,000 population is a hundred times higher than 

the current US national incidence. However, in the absence of data, it is difficult to define a 

more appropriate threshold. This creates challenges in situations in which the outbreak 

threshold is not reached despite a clear need for intervention, such as in the 2016 serogroup C 

outbreak in Southern California in which 21 cases among MSM were reported but the 

cumulative attack rate reached only 6 cases per 100,000 population. In addition, there is little 

tolerance for additional cases that are viewed as preventable, and many communities and 

health departments are not comfortable with watchful waiting for additional cases. Finally, 

attack rates are challenging to calculate in community outbreaks and those occurring among 

special populations due to difficulty in defining the denominator.

While calculation of an attack rate is useful for comparison against baseline trends in the 

affected population, in the proposed guidance, the threshold for vaccination would not be 

determined through a specified attack rate. Rather, each outbreak should be evaluated on a 

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case-by-case basis to determine the appropriate threshold for implementing vaccination. 

General guidance includes the following:

 For organization-based outbreaks: 2 to 3 cases of meningococcal disease of the same 

serogroup within 3 months

 For community-based outbreaks: Incidence of meningococcal disease of the same 

serogroup that is above expected in the affected community during a 3-month period.

The guidance will provide some flexibility in how an increase above expected is defined, such 

as comparison against a historical baseline in the community or, in the event that the community 

baseline is 0 cases, a comparison against national incidence. Considerations for vaccine 

decision-making include the size of the population, the ability to define a target group for 

vaccination, whether ongoing transmission is likely, or rather, if cases likely represent a single 

transmission event (for instance, among household contacts, roommates, boyfriend/girlfriend), 

the feasibility of a vaccination campaign, and timing of potential vaccination in relation to cases.

Currently there is no guidance related to selection of MenB vaccines for use during an outbreak, 

as no MenB vaccines were available at the time of writing. Unlike conjugate MenACWY 

vaccines which target the polysaccharide capsule, MenB vaccines induce an immune response 

to subcapsular proteins, which vary by strain. While WGS can identify the presence of MenB 

vaccine antigens in the outbreak strain, it cannot determine expression of the antigen or 

expected coverage by MenB vaccines. Furthermore, there are challenges to conducting 

additional testing to determine coverage of a MenB vaccine against the outbreak strain in realtime during an outbreak. Thus, in the proposed guidance, identification of MenB vaccine 

antigens by molecular characterization should not drive the choice of MenB vaccine during an 

outbreak of meningococcal disease at this time. No vaccine preference is stated for outbreak 

control; however, the recommended schedule will be 2 doses if MenB-4C is used and 3 doses if 

MenB-FHbp is used.

Regarding re-evaluation of outbreak status, there currently is no guidance on when to declare 

an outbreak as being “over.” Meningococcal disease epidemiology is dynamic and 

unpredictable, with outbreak-associated cases sometimes reported months after the last known 

case. Nevertheless, public health officials need guidance on how long to continue vaccination 

and other interventions following the declaration of an outbreak. For instance, after vaccinating 

undergraduates at a university with MenB vaccine, do incoming freshman the following year 

need to be vaccinated? Prematurely declaring an outbreak as being “over” can erode public 

trust if further cases are identified.

Because of the unique epidemiology of meningococcal disease outbreaks, it is difficult to predict 

the course of the outbreak and risk of further cases. Thus, the proposed guidance does not 

provide criteria for determining when to declare an outbreak as being over. However, for public 

health decision-making, after one year without any new reported cases, the risk of 

meningococcal disease likely returns to baseline.

In summary, all cases of meningococcal disease of the same serogroup are included in the 

case count for vaccine decision-making unless there is evidence of genetically distinct strains by 

WGS. Each outbreak should be assessed on a case-by-case basis to determine the threshold 

for implementing vaccination, though in general organization-based outbreaks are defined as 2 

to 3 cases of meningococcal disease of the same serogroup within 3 months. Communitybased outbreaks are defined as incidence of meningococcal disease of the same serogroup 

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above expected in the affected community during a 3-month period. No preference is stated for 

MenB vaccine selection at this time, regardless of molecular typing results. After one year 

without any new cases, the risk of meningococcal disease likely returns to baseline.

The next steps are the finalization of the CDC guidance document for control of meningococcal 

disease outbreaks.; publication of the updated guidance document on CDC’s website, to 

replace current guidance in Appendix B of ACIP’s Prevention and Control of Meningococcal 

Disease” statement and the interim guidance for MenB outbreaks; and continued efforts to 

improve reporting and collection of epidemiologic data of meningococcal disease outbreaks.

Discussion Points

Dr. Szilagyi requested further information about how “community” is defined for a communitybased outbreak, and noted that the incidence above a baseline is 1 case.

Dr. Meyer replied that defining “community” was probably the topic with the most discussion 

among WG members while trying to revise these guidance documents. A community would be 

defined as the geographic area and cases in space and time that are related. That would be 

defined at the local level. Typically, this would include the smallest area for which a border 

could be drawn around the cases. That could be a neighborhood, town, or county and depends 

upon the epidemiology of the cases. With the incidence of disease being so low in the US, 

many communities will not have had any cases of meningococcal disease in recent years. This 

is where the idea to compare against other sources such as national incidence to offer an 

example of where that has been applied recently. In some of the MSM outbreaks that have 

occurred in communities, often it is pretty difficult to compare against a baseline because data 

are just starting to be collected in those populations. The incidence of disease among adult 

men has been used as the baseline comparison to help health departments make those 

decisions. That is why there is an emphasis on making these decisions on a case-by-case 

basis, because the situations are all unique, especially in terms of the community outbreaks. 

One case would not be considered an outbreak. 

Dr. Moore added that in thinking about organization- or community-based outbreaks, in the past 

the organization or community has not been considered if the cases were clearly 

epidemiologically linked one to another (girlfriend/boyfriend, household contact). Having a 

secondary case in a household contact would not define the organization within which that 

household resides as an organization-based outbreak. It is the identification of cases that are 

matched where epidemiologic links are lost.

Dr. Meyer responded that this was discussed while revising the guidance. In a lot of cases, it 

was communicated that it is sometimes difficult to define epidemiological links in real-time, 

especially among certain populations where it is not clear whether there were any 

epidemiological links. For the purposes of broad general guidance, in expert consultations and 

through various outbreaks, it was felt that having this extra layer of classification of cases often 

can create confusion and may not be necessary, but describing a sample situation could be 

helpful. For example, if two roommates both had meningococcal disease and there were no 

other cases, that would not necessarily prompt a 30,000-student university to launch a multidose MenB vaccination campaign. This is where the flexibility in the guidance and some of the 

considerations for vaccine decision-making should be taken into account.

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Dr. Reingold asked what the implications would be upon declaring that an outbreak is over (no 

longer vaccinating, no further chemoprophylaxis), and how the WG arrived at 1 year.

Dr. Meyer replied that the purpose of having something in the guidance document is for vaccine 

decisions and public health interventions. The goal is not necessarily to be able to announce 

this or for communication messaging. This is especially relevant in university or community 

outbreaks when trying to determine when to stop, and whether vaccine should be given to new 

people entering the population. Regarding how the WG arrived at the 1 year cut point, the 

epidemiology of all of the outbreaks of which CDC is aware were assessed. Things varied by 

outbreak, but this conservative approach was taken to feel relatively confident that the risk has 

decreased to baseline. The intent was not to say that an outbreak is over, because there can 

be additional cases.

Dr. Kempe asked whether based on that, the recommendation invariably would be to vaccinate 

all incoming Freshmen.

Dr. Meyer responded that this type of decision is typically arrived at after consultation with CDC, 

and that type of language would be included in the guidance document to maximize flexibility. 

Vaccinating all incoming Freshmen has occurred in some situations.

Dr. Even (ACHA) pointed out that one issue which arises is media and media requests and how 

to address those, because there is a lot of interest in whether an outbreak is ongoing. The 

distance between cases in a meningococcal outbreak can make it appear like there is 

something new happening when it may be part of the same situation. Being able to say that an 

outbreak is back to baseline helps to clarify the decision about advanced preparation for 

immunization for incoming students, whether it is incoming Freshmen or students who are new 

to a campus. This helps to have some frame of reference for outbreak activity.

Ms. Hayes (ACNA & ANA) asked for clarification about the risk factor that is linked to being a 

gay man and getting this disease, as she was grappling with why this is not occurring among 

other people who are having sex.

Dr. Meyer replied that this is an area CDC is still trying to understand better. There have been a 

couple of clusters in the US, and sporadic cases among MSM. HIV is believed to play a role, 

and there is a growing belief that HIV creates an increased risk for meningococcal disease. 

That does not explain the whole picture. CDC is actively investigating this area, but has not yet 

identified risk factors. It is known that meningococcal disease is spread through close contact, 

which is often observed with people sharing close spaces, going to clubs, smoking, all of which 

increase risk. Therefore, it could be assumed that some of that plays a role. This area is still 

being investigated.

Ms. Hayes (ACNA & ANA) asked whether a specific questionnaire has been developed to be 

used specifically to collect data on these outbreaks among MSM, and what risk factors are 

being examined.

Dr. Messonnier recalled that there was a discussion about this a couple of ACIP meetings ago. 

There was a 20-minute presentation from the WG specifically on this issue.

Dr. Sun (FDA) pointed out that both of the available vaccines were licensed based on 

immunogenicity, and that it is still conceivable that for a particular outbreak, one vaccine may be 

better than the other in terms of bactericidal activity. He wondered whether consideration had 

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been given to examining this type of evidence, and selection of a particular vaccine for a 

specific outbreak.

Dr. Meyer said the reason they were saying that molecular genotyping should not drive vaccine 

selection at this time is because they do recognize that more work is ongoing to try to correlate 

identifying vaccine antigens by WGS with immunologic responses. These data are not currently 

available to make recommendations in this guidance, but that work is ongoing. Molecular 

genotyping is used in the management of these outbreaks, but they are saying that this should 

not drive vaccine selection at this time. As new data become available, consideration will be 

given to whether that data can be used.

Dr. Gorman (NIH) asked whether there is any role for nasal carriage surveillance after an initial 

case to inform vaccine decision making for an outbreak, or if data are being collected for the 

isolated cases to see if they are surrounded by people who carry even if they do not have the 

disease.

Dr. Meyer responded that this is not part of current public health practice. In general, there are 

logistical challenges and utility issues that play into that. One is that the priority is to provide 

chemoprophylaxis to persons who are close contacts of patients. Swabbing them for carriage 

delays the whole process. Also, carriage is dynamic and transient. Someone could have been 

a carrier, but by the time they are swabbed they could no longer be a carrier or at the time of 

swabbing, was not a carrier, only to subsequently become a carrier. This has not been identified 

as being very useful for active public health management during an outbreak.

Dr. Hahn (CSTE) said that as a state epidemiologist, she like the proposed language and 

thought it would be a very helpful tool.

Dr. Stephens indicated that WGS is being used as an approach, but it is not necessarily 

predictive based on the sequence data in terms of what the immune response is going to be 

and what will be protective. Work is ongoing and they will continue to learn more about the 

relationship between the antigens present, whether they are expressed or not, and 

immunogenicity.

Global Polio Eradication Initiative

Abhijeet Anand, MBBS, MPH

Polio Eradication Branch

Global Immunization Division

Centers for Disease Control and Prevention

Dr. Anand presented a status update on polio eradication, reviewing the four key objectives as 

described in the endgame strategic plan. The objectives are: 1) detection and interruption, 

which is essential to the core set of eradication objectives; 2) oral polio vaccine (OPV2) 

withdrawal, inactivated polio vaccine (IPV) introduction, immunization system strengthening; 3) 

containment and global certification; and 4) legacy planning. 

Global Measles/Rubella Elimination Initiative

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The following map and the table lay out the number of cases that have been observed in the 

three endemic countries where there is polio transmission (Nigeria, Pakistan/Afghanistan, 

Laos). The table lists the number of cases in 2016 and 2017:

The total case count in 2016 was down to the lowest point ever seen. In Afghanistan, there 

were 13 cases and in Nigeria there was 1 case of Wild Poliovirus Type 1 (WPV1). There were 3 

cases of circulating vaccine-derived polioviruses 1 (cVDPV) in Laos in 2016. There were more

cases in 2015. In Nigeria, there was one cVDPV Type 2 case reported in 2016 and another 

was reported much later. In Pakistan, there was 1 cVDPV Type 2 case. The key message is 

that in 2016, the only type seen was Type 1. The last time Type 3 virus was seen was in 

November 2012.

There has been a tremendous amount of progress in Pakistan and Afghanistan, with the lowest 

number of cases that have been seen. There has been a dramatic reduction in the total number 

of cases for Type 1 virus, which is unprecedented in terms of the total number of cases that 

have been seen in Pakistan. It is not only a reduction in the total number of cases, but also a 

reduction in the geographical distribution of these cases. The number of districts that have 

been affected is much lower, the genetic diversity of the virus is reduced, and there has been an 

improvement in the program quality in the transmission zones in Pakistan, which has essentially 

led to the virus being seen outside of the core transmission districts in Pakistan. There are 

clearly gaps that still exist in the country for population immunity as well as surveillance, which 

has led to a few viruses that have emerged and ongoing transmission that has been seen 

outside of the core transmission zones and a reduced transmission in the core transmission 

zones.

Afghanistan has shown similarly remarkable progress in program implementation. In 2016, the 

total number of Type 1 cases reported in Afghanistan was 13. More than half of those cases 

came essentially from one province in the Southeast part of the country, Paktia Province. Most 

of those cases came from one small district, Bannu District, with a total population of about 

100,000 people. Essentially, that district had vaccine refusals and security issues. Two cases 

have been reported in 2017 in Kandahar, with another reported in Helmand, which is the 

adjoining province.

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Afghanistan and Pakistan are treated as one epidemiological block. The political borders 

between the countries is just an artificial line drawn on the land, but there is free movement of 

people from known and not so known points of crossing, which facilitates transmission. Three 

corridors of active transmission link reservoirs on both sides of the border: 

 Nangarhar/Kunar: Khyber/Peshawar

 Paktika: FATA / Bannu

 Kandahar/Helmand: Balochistan (Quetta block)

Overall, these two countries have shown improvements in surveillance quality and 

supplementary immunization activities (SIAs) quality, and a decrease in the number of polio 

cases and environmental positive samples. There has been progress in the highest risk areas 

of Peshawar, FATA and Quetta, with a reduction in intensity of transmission and genetic 

diversity of circulating virus. There is strong coordination between the countries, with new 

National Emergency Action Plans (2016-2017) endorsed by TAGs. Emergency Operation 

Centers (EOCs) are now operational in Kabul and the 3 high-risk Afghanistan regions. 

However, there have been some concerning developments. There is continued viral 

transmission in South KP/FATA and adjoining South Eastern Afghanistan (Paktika Province), 

and recent positive environmental samples from Pishin (Quetta Block, Balochistan). The 

common themes that unite the countries are the issues of accessibility, conflict, and security. 

While these issues complicate program management, they do not rise to the same level that 

has been seen in other countries such as Nigeria.

Turning to Nigeria and Lake Chad, the last set of cases of Type 1 were seen in Nigeria in 2013. 

Since then, there has been no known transmission in Nigeria. The biggest setback to the 

program was the transmission in Nigeria in 2013. An environment sample of cVDPV2 was 

observed in March 2016, which was a long-term transmission different from Sabin type. This 

transmission had been missed for a long time. In July 2016, long-term transmission was noted 

for WPV1. This circulation was missed for at least 5 years. Each of the 4 cases that were 

picked up were genetically different from each other by long-term, and represent the “tip of the 

iceberg.” The key issue that defines this challenge is accessibility in Borno. There are 

numerous areas the program and Nigerian Army cannot access, because they are controlled by 

Boco Haram. Boco Haram does not negotiate for safe passage of vaccination teams, so even 

some small areas that have been cleared by the Nigerian Army are not accessible because of 

the necessity to access through Boco Haram-controlled areas. Therefore, they have to be 

accessed by helicopters or mechanisms from other countries to conduct surveillance and 

administer vaccines. The key linchpin here is changing access in Borno. Without improved 

access in this area, transmission cannot be properly controlled. This has been declared as a 

Level 3 health sector emergency by the United Nations (UN). There is also starvation, famine, 

and even a measles outbreak reported in that area.

Lake Chad coordination has been established in N’djamena with partner agencies and 5 

governments. Lake Chad Countries have declared a regional public health emergency, and a 

regional Global Polio Eradication Initiative (GPEI) Coordinator was appointed by WHO/AFRO. 

This has led to a multi-country response in this entire area. The multi-country response plan

includes 5 bOPV SIAs followed by mOPV2; surveillance enhancement, including active case 

search as well as enhanced laboratory capacity; strategies to reach children in inaccessible 

areas; advocacy, communications and social mobilization strategies; and 

strong linkages with humanitarian response. 

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In summary, there has been unprecedented progress with the lowest global case count ever 

observed. Interruption of WPV1 remains challenging. At the same time, there are inaccessible 

areas in Borno, Nigeria. 

At the same time, the Nigeria situation has been a lightning rod for the program and has led the 

program to look deeper into all of the areas associated with conflict and limited access, mapping 

them out, and assessing the risk based on the available data. There also is an understanding of 

the importance of looking beyond the indicators. The traditional polio indicators did not reveal 

the surveillance gaps noted in Borno, so it is important to look beyond these indicators to find 

ways to access these populations. Vaccination teams must be set up in coordination with the 

military, so the teams can move as rapidly as the military moves into an area.

Moving on to Objective 2, withdrawal of OPV and introduction of IPV is essential for achieving 

eradication. SAGE has recommended a phased approach, starting with OPV2. This was 

preceded by introduction of IPV to provide population immunity to Type 2 in 2015-2016, 

followed to a switch from trivalent (tOPV) to bivalent OPV (bOPV) in April-May 2016. 

Eventually, after achievement of certification, OPV use will stop. In April-May 2016, in a period 

of two weeks, all of the countries using tOPV stopped and switched to bOPV. This was a 

remarkable achievement for the program to manage an entire vaccine replacement worldwide. 

Independent monitoring of the switch began two weeks into the switch, with people visiting 

facilities to look for any potential vials of tOPV. Nearly 150,000 facilities were monitored all over 

the world to find tOPV vials. Did this go perfectly? Probably not. Some vials have been 

discovered outside of the areas that were monitored, and this has been published in an MMWR

and also has recently been noted in Nigeria.

The key achievement for removal of tOPV has really been a dramatic decline in the number of 

cVDPVs. Of the total number of cVDPVs reported, cVDPV2 used to account for approximately 

85% to 90% percent of the total. Now there has been a dramatic decline. As noted, the switch 

from tOPV was preceded by introduction of IPV. There was a clear set of criteria from Tier 1 to 

Tier 4 countries of introduction of IPV. A single dose of IPV was recommended by SAGE 

administered by 14 weeks of age. This has been delayed in several countries because of IPV 

supply issues. The supply situation remains bleak and continues to worsen. This led the 

program to rapidly evaluate how to prioritize use of IPV for eradication purposes or routine 

immunization. Introduction has been delayed in 21 Tier 3 and 4 countries. An additional 

approximately 22 Tier 3 and 4 countries will be forced into stock outs. The supply will remain 

constrained into 2018. Countries considered to be at highest risk for cVDPV2 outbreaks are 

currently all receiving IPV. 

In terms of the policy response to this, SAGE developed a new recommendation that was 

published in a WHO Polio Position paper in March 2016 in which SAGE reaffirmed two 

fractional doses of intradermal IPV in lieu of one full-dose intramuscular. Uptake of this has 

been fairly slow. India has replaced two-thirds of its states with fractional IPV. The entire 

country is likely to be using fractional IPV by about the second quarter of 2017. Sri Lanka and 

Bangladesh have switched to fractional IPV. The remaining countries are still using 

intramuscular IPV when available.

In summary of the endgame, the OPV withdrawal and ability of GPEI to introduce IPV

was a success in a short two-week window that has impacted risk. The supply situation clearly 

has an impact on the risk of cVDPV2, and impacts GPEI credibility. There has been slow uptake 

of the SAGE recommendation for 2 fractional IPV doses. Fractional IPV would ease the supply 

situation.

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Moving on to containment and global certification, 23 countries reported hosting 58 designated 

Poliovirus-Essential Facilities (PEFs). These are all of the laboratories that have said they are 

hosting potentially infectious material to OPV2. There are other countries that probably will be 

hosting Sabin Type 2. That depends on the survey. There are countries that are running 

behind schedule on completing the survey to note whether they are holding Sabin 2.

Regarding transition planning, GPEI has learned many lessons on the road towards eradication, 

including the following:

 Accessing insecure and hard-to-reach areas

 Accountability

 Communications

 Social mobilization/community engagement

 Working in complex global partnership

 Achieving and maintaining political commitment

 Global disease surveillance networks

How can these lessons be used for greater benefit? GPEI-funded staff already report spending

more than half of their time on health priorities other than polio, including natural disasters and 

humanitarian response as reflected in this pie chart:

The majority of GPEI staff are in Pakistan, Afghanistan, and Nigeria. Of the endemic countries, 

they have the largest footprint. There were 16 high priority countries that developed transition 

plans for using polio resources for other programs, as well as listing out the polio operations that 

need to continue beyond the presence of the GPEI. Another 14 countries and 5 regional offices 

will be expected to have transition plans prepared by the end of 2016, and 2 countries and 2 

regional offices will be expected to have transition plans prepared within 12 months of 

interruption in the endemics. Specific timelines have been laid out for transition planning. The 

only country that actually has completed its transition plan as of now is India. Other countries

are behind schedule and are expected to complete their transition planning some time in 2017. 

Obviously, there is a greater set of challenges in Afghanistan, Pakistan, and Nigeria which are 

the endemic countries and are focused more on the response at this time.

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In terms of program priorities for the next 6 months, the biggest priority clearly is the Nigeria 

outbreak in all 5 Lake Chad basin countries ensuring that high quality campaigns can be 

achieved. There were no high-quality campaigns for the Nigeria response, but the campaign 

quality has slowly improved. There is a need to continue to support Pakistan and Afghanistan. 

The program has turned around dramatically over the last few years to improve surveillance and 

response, but there now must be a focus on the final set of transmission zones and the weak 

spots in the country. It also is important to recognize transmission so that it is not missed as 

occurred in Borno. Is it possible that transmission has been missed elsewhere, what are the 

other conflict affected areas and how can surveillance quality be improved in those areas? 

There has clearly been a dramatic focus of the program on surveillance quality and 

establishment of new focus and new teams to look at surveillance. This is from the point of view 

of not just noting the existence of missed transmission, but also getting the programs ready for 

certification.

Discussion Questions

Dr. Hunter inquired as to why there is a shortage of IPV.

Dr. Anand replied that this has largely been due to production challenges that the manufacturers 

faced. Some batches of production went bad, which has led to shortages. There also has been 

a large increase in demand for IPV because of increased needs. Promises were made to 

increase the amount of infrastructure that the managers had to increase production, and those 

also have not lived up to the timelines.

Global Measles/Rubella Elimination Initiative

Gavin Grant, MD, MPH 

Global Immunization Division

Center for Global Health

Centers for Disease Control and Prevention

Dr. Grant presented an update on the goals, strategies, and status of measles and rubella

activities, many are coordinated by the Measles and Rubella Initiative (M&RI). The M&RI is a 

collaboration between the American Red Cross, United Nations Foundation, CDC, UNICEF and 

WHO. The Global Measles and Rubella Strategic Plan offers a context of the activities that are 

underway toward measles and rubella elimination.

Global elimination of measles and rubella elimination is important in the US; a great reminder is 

the 2014 Philippines measles outbreak. The graphic below illustrates how quickly measles can 

spread globally when measles is poorly controlled outside of the US: 

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This large outbreak in the Philippines led to multiple importations in the US. Strains could be 

traced to the Philippines based on the sequence information. Most of the viruses that were 

exported were genotype B3, but genotype D9 was circulating in Southern Philippines and was 

imported to the US and is associated with a very large outbreak in Ohio. Another importation is 

very well-known because it was a theme park-associated outbreak after exposure at a Disney 

Land theme park. This outbreak led to multiple importations of measles virus throughout the 

world in addition to the US, including Europe, Australia, and Canada. The point is that trying to 

control measles and rubella on a global level has a direct impact on the US.

A framework to reach measles and rubella elimination was put forth in the Global Measles and 

Rubella Strategic Plan 2012-2020, which was developed by the M&RI partners. The vision for 

that plan is to achieve and maintain a world without measles, rubella, and congenital rubella 

syndrome (CRS). This plan establishes several targets and milestones, which are as follows:

Milestones by 2015

 Reduce annual measles incidence to < 5 cases per million and maintain that level





90% coverage with routine MCV1 nationally and > 80% vaccination coverage in

every district or equivalent administrative unit

95% coverage with M, MR, or MMR during SIAs in every district or equivalent 

administrative unit

 Establish a rubella/CRS elimination goal in at least 1 more WHO Region

 Establish a target date for the global eradication of measles

By End of 2015

 Reduce global measles mortality by at least 95% compared with 2000 estimates

 Achieve regional measles and rubella/CRS elimination goals

By End of 2020

 Achieve measles and rubella elimination in at least five (of the six) WHO Regions

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Key Strategies to Reach Goals

 High population immunity through vaccination with two doses of M and R containing 

vaccines 

 Effective surveillance, monitoring, and evaluation

 Outbreak preparedness and response and case management

 Communication to build public confidence and demand for immunization

 Research and development

In terms of achievement of the goals set forth, from 1980 to approximately 1990, coverage with 

the first dose of measles vaccine increased from 17% to about 70%, and continued to slowly 

increase until 2009, when coverage plateaued, at approximately 85%, and has remained at the 

same level today, globally. Data from 2016 is not presented because these data are the official 

WHO data, which are aggregated annually. The data for 2016 will not be available for several 

more months. The coverage milestone is a national milestone, which shows that 119 (61%) of 

countries have > 90% MCV1 coverage and are maintaining that milestone; however, the 

remaining countries failed to meet that milestone with 42 (22%) of countries having a very low 

measles coverage of < 80% MCV1 coverage. 

In order to fill some of the immunity gaps, campaigns are conducted within countries. In 2015, 

39 countries conducted 66 campaigns. These campaigns reached 180 million children. Of the 

66 campaigns, 40 (61%) attained 95% coverage, which was the target. Because administrative 

coverage is not always accurate, coverage surveys are recommended to be used with many of 

these campaigns. Of the 66 campaigns, 18 (27%) had surveys. Of the 18 campaigns that had 

surveys, 4 surveys documented >95% coverage. These campaigns occurred in various 

countries, but not all countries, as measles campaigns occur intermittently according to the 

epidemiology and they are not expected to take place annually in any country.

The second milestone pertains to measles incidence. There has been a decrease in cases 

since 1980. Since 2000, there also has been a decrease of incidence. The current measles 

incidence is 36 / million, a decrease of 75% since 2000. This is great progress, though it did not 

achieve the milestone of < 5 cases / million population. This decrease has been concurrent with 

the increase in second dose measles campaigns, which have been occurring since the mid1990s that has helped decrease the number of cases and measles transmission globally.

The third milestone is mortality reduction, with a target of a 95% decrease in mortality relative to 

2000. From 2000 to 2015, a 79% decrease has been observed. This did not reach the target of 

95%, but the decrease in mortality is quite significant. Approximately 20.3 million deaths have 

been averted in the past 15 years by measles vaccination, which is a remarkable achievement 

within itself.

Many measles elimination activities are taking place, and the rubella program has taken 

advantage of this opportunity to move rubella elimination forward. Over half the world’s children 

are not vaccinated against rubella. Clearly, some progress needs to be made in order to 

increase global coverage of infants. Rubella vaccination coverage is not equal globally. Some 

regions of the world have very high rubella coverage of over 80%. In the Americas, Europe, 

and West Pacific Regions, there has been introduction of vaccine in all countries in each region. 

The Eastern Mediterranean Region tracks approximately with global coverage, just under 50%

of the infants vaccinated, while the Southeast Asian and African Regions have coverage of < 

20%, primarily because either most countries have not introduced vaccine or countries with very 

large populations have not introduced vaccine.

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Modeling data have provided an estimate of CRS incidence globally. Africa, Southeast Asia, 

and some countries in the West Pacific Region have relatively high incidence of CRS where the 

burden is great. Therefore, it is important to ensure that rubella vaccines are introduced at the 

global level. India delayed introduction of the vaccine until 2017. Overall, 148 (75%) of 

countries have introduced a rubella-containing vaccine, with 11 others expected to introduce 

one this year. It is good to note that also in the next 3 years, 17 countries are expected to 

introduce rubella vaccines. There has been rapid uptake of rubella vaccine. This introduction of 

rubella vaccine is in part supported by additional funds from the GAVI Alliance to support rubella 

introduction in the least developed countries.

Regarding regional progress in terms of the strategic plan, all regions have a measles 

elimination goal. Three regions (Americas, European, and Western Pacific) have rubella 

elimination goals. The Western Pacific Region has agreed on rubella elimination; however, the 

actual year they would like to reach that target has not been agreed upon in the region. Another 

area of note is the Southeast Region has declared a rubella control goal has been established, 

but an elimination goal has not been established.

One of the tools for elimination is establishment of Regional Verification Committees. Each of 

the 6 WHO regions is in the process of developing or utilizing their Regional Verification 

Committees. These committees review the data and evaluate whether elimination has been 

achieved, and also can provide guidance to countries to help with achieving that goal. Two 

regions are currently in the final stages of developing a verification committee for at least 

measles (African and Eastern Mediterranean Regions). However, a committee has not been 

convened in the South-East Asian Region, so they have not noted any elimination. The 

Americas Region has been the most successful in terms of measles and rubella elimination and 

have reached the elimination goal in all 36 countries for measles and rubella. In Europe, 

approximately 40 countries have been validated for measles and 45 countries for rubella. As of 

the last meeting, the Western Pacific Region has verified 7 countries for elimination. They have 

recently established guidelines for evaluating rubella verifications, which will be implemented at 

the coming meeting in 2017.

There also is a regional scorecard that evaluates the progress toward measles and rubella 

elimination. The African region is clearly off track to reach their 2020 goal, and they do not have 

a rubella target within that region. A lot of effort needs to be made to support Africa in reaching 

their targets and goals. The Americas Region has verified elimination of measles and rubella, 

which is a great success. Measles was verified in 2016 and rubella was verified prior to 

measles verification in May 2015. Europe and the Eastern Mediterranean Regions are off track 

to reach their targets as are the South-East Asia and Western Pacific Regions to reach their 

2020 targets.

In terms of the regional situation, different regions have different challenges. Some challenges 

have been encountered in all regions. The Americas have eliminated rubella, but they have a 

risk of importation, so it is important to maintain a strong surveillance system. Rapid response 

to outbreaks of importations will be critical to sustaining their elimination status. In the African 

Region, there are weak immunization and health systems, which has resulted in a reliance on 

campaigns to achieve high population immunity. However, this has challenges for 

sustainability. Reliance on campaigns also increases the risk of mortality from other vaccinepreventable disease as campaigns tend to be much more vertical than the routine program. 

The European Regions have experienced problems with vaccine hesitancy, susceptible adults, 

and variable surveillance quality within the countries. The Eastern Mediterranean Region had 

some countries that were doing very well, but due to security issues that limited access, 

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coverage in some of those countries decreased. Some countries in that region have 

persistently low coverage. In the South-East Asia Region, there are two large federalized 

countries, India and Indonesia, which constitute about 80% of the infants within that region. 

Those two countries have heterogeneous coverage, and they need to strengthen and expand

their case-based surveillance. In the Western Pacific Region, there has been very high 

coverage for several years, but there has been a resurgence of measles in China and the

Philippines, which the region is working to address. All regions have a need for increased 

visibility and political commitment to regional elimination goals. There also are susceptibility 

gaps, including among older children and adolescents who are not commonly targeted for 

measles vaccination, other challenges include a lack of human and financial resources and 

vaccine hesitancy in various populations.

The Measles and Rubella Initiative requested a mid-term review of the strategic plan to 

understand the status, the challenges, and what needs to be done to move forward towards 

elimination. This review found that while a tremendous amount of progress has been made 

since 2001, neither measles nor rubella elimination is on track to achieve the plan’s ambitious 

goals. The basic strategies articulated are sound; however, full implementation has been 

limited by inadequate country ownership and global political will. This is reflected in inadequate 

human and financial resources. It is premature to set a timeframe for measles eradication at 

this point. A determination should be made, not later than 2020, whether a formal global goal 

for measles eradication should be set with timeframes for achievement. Disease incidence is 

the most important indicator of progress. There is an urgent need to strengthen the collection 

and use of surveillance data to better guide program strategy and implementation. 

Strengthening of immunization systems is critical to achieving regional elimination goals. Two 

doses of measles or measles-rubella vaccine delivered through ongoing services is the 

standard for national programs. Regular preventive campaigns should be conducted if 

coverage is insufficient for high population immunity. 

In summary, the US is still at high risk of importation due to ongoing global transmission. 

Effective vaccination strategies exist, resulting in major achievements, but targets have not 

always been met. The mid-term review summary stated, “The basic strategies are sound, 

however, the main impediments to full implementation have been inadequate country ownership 

and global political will, reflected in inadequate resources.” Global efforts to assist countries to 

introduce rubella-containing vaccine are needed. Mid-term review recommendations are being 

implemented to continue progress towards a world without measles, rubella and congenital 

rubella syndrome. 

Discussion Points

Dr. Schaffner (NFID/IDSA) observed that according to the data presented, measles 

immunizations rates are very high in Europe. However, he was under the impression that that 

was not the case. It was not so long ago that there was a huge outbreak of measles in France. 

He wondered whether this had turned around so quickly.

Dr. Grant replied that there are some countries in Europe that do not have very high measles 

coverage. Like the US, countries have outbreaks in populations that are susceptible, but it does 

not necessarily extrapolate to the entire country. There are a lot of advocacy efforts to try to 

make sure these countries move forward, especially in Europe. The Regional Verification 

Committee has gone into Italy to try to advocate for the country to increase their resource 

control. His understanding is that France is working on it, but still has gaps in its program, but it 

may not be a national gap.

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Dr. Belongia emphasized what an accomplishment averting 15 million deaths in 15 years is. He 

asked what level of vaccine coverage is needed to prevent sustained transmission.

Dr. Grant replied that this is close to 95%, which supports the importance of two doses of 

measles vaccine in all of these countries.

Lynn Bozof, President

National Meningitis Association (NMA)

Most of you know that I lost my college age son to meningococcal disease several years ago. 

While NMA applauds the Category B recommendation for serogroup B meningococcal disease, 

I would like to remind the committee of the personal toll of this disease. The average family is

not having a discussion about serogroup B vaccination with their healthcare providers. Over the 

last several months, I have been getting emails and phones calls from families whose college 

age children have come down with serogroup B. Some have died. Others are facing limb 

amputations. The question I always get is, “How did this happen? My son (or daughter) was 

vaccinated.” College campuses are rushing to vaccinate after the fact, after the whole campus 

is in a panic, after all the parents are in a panic. Although the number of cases isn’t high, the 

individual loss and suffering is immeasurable. I hope that in the coming months, these Category 

B recommendations can be readdressed. Thank you.

Christina Hildebrand

A Voice for Choice

I wanted to speak to new research that was done and published in the International Journal of 

Vaccination looking at micro- and nano-contamination. The CDC hasn’t come out with any 

comments that I know of, but it shows that all vaccinations, barring one which was a veterinarian 

vaccination, showed contamination with organic and inorganic particles, particulate matter, 

including tungsten and silver and a whole bunch of others. I can give you the journal article. 

The concern there is that the CDC hasn’t said anything about that. These vaccines, every one 

of them on the CDC schedule, have been contaminated. Some of these particulate matters are 

known to cause cancer. Section 13.1 of every single vaccine package insert states that the 

vaccine has not been tested for carcinogenic, mutagenic, or infertility. It’s really concerning that 

you aren’t doing anything about this, or researching it more, or making it known that you’re 

researching it more. So, I would ask you to look into that because we should not have vaccines 

that are dirty. And then the other piece of it—I guess that was my comment on that. I just ask 

you to do the research and to look into it, because our children should not have these vaccines 

that are dirty going into them. Thank you.

 

Claire Hannon

Association of Immunization Managers (AIM)

We are a membership association whose members direct immunization programs in the 50 

states, 8 territories or federated states, and 6 large cities. I just wanted to share some 

information that we collected in the last week from some of our members about the impact of

Day 1: Public Comment

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the live-attenuated influenza vaccine in this flu season. We had 26 of 64 awardees give us 

some input, 10 who tracked coverage rates in real-time using an IIS and one tracking according 

to vaccine ordering. Of those 11, one reported higher rates currently this season, 6 lower 

coverage rates, and 4 coverage rates were about the same. Twenty-two of those 26 replaced 

an entire LAIV order for an equal amount of QIV, 4 did not. We will follow up with those 22 later 

in the season to see if those replaced doses were all used. Eight reported that the loss of LAIV 

impacted their ability to vaccinate in the same capacity as previous years, 12 reported no 

impact, and 6 were not sure yet. Where we saw the greatest impact was in the school-located 

flu vaccination programs. Of the 18 awardees reporting that school-located programs are 

conducted in their area, 15 reported a reduction in the number of clinics conducted due to the

lack of LAIV, 1 reported a 42% decrease in vaccine, several report schools and counties 

declining to participate, 3 report large counties or entire school districts declining to participate 

when they had previously participated using LAIV, 1 reported 40,000 less doses administered 

this year, 17 awardees reported that their providers are interested in having a non-invasive flu

option available again, and 9 said they did not know, and none said that providers were not 

interested. And then we just asked, “Assuming if it was recommended, and it was added to the 

government contact, and it would be available for second round orders next year, would you 

order?” and 7 say yes they would order, 5 said no, 15 said it would depend on the demand. 

And that’s an order that would come later in the season in October. Just to reiterate the key 

challenges that you all mentioned for a return of LAIV (which many of our programs really rely 

on the LAIV product for their school clinics): the timing of the availability would be very 

important, confidence in the vaccine, and the evidence supporting the vaccine effectiveness. 

Thank you for the opportunity to share the comments.

Centers for Disease Control and Prevention (CDC)

Dr. Messonnier reported that CDC is gearing up for National Infant Immunization Week that will 

take place April 22-29, 2017. Each year, state and local immunization programs, coalitions, and 

partners plan and hold local events to celebrate the positive impact that infant immunizations 

have on babies, families, and communities. These events also offer opportunities for 

communities to focus time and attention on addressing local barriers and challenges to on-time 

immunization. She expressed her hope that everyone would engage locally to help support 

those efforts.

Another issue of importance is lot number differences, which affects the immunization 

community daily in terms of practical issues. Some vaccine manufacturers use different lot 

number patterns on the units of use (vials and syringes) than on the unit of sale (cartons) for 

specific vaccines. This has caused a lot of chaos in provider offices that are using bar codes to 

track use of vaccines, as well as to order vaccines. CDC is working with providers to try to 

resolve these issues, but this could take some time to resolve.

As a follow-up to the discussion on the first day of the meeting concerning polio containment, 

one of the major activities pertains to laboratories that potentially have polio-containing 

materials. A number of steps have been taken domestically. One effort has been to survey any 

laboratory in the US that might have either polio-containing material or potentially poliocontaining material. This is defined broadly as gastrointestinal or respiratory specimens from a 

country that was using oral polio vaccine (OPV). A number of laboratories potentially have 

Agency Updates

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those materials, and containment is the process of making sure that laboratories that wish to 

continue to hold the specimens, do so under a variety of conditions that ensures no one will be 

exposed. In order to support this process, CDC is standing up a new unit under the Office of 

Public Health Preparedness and Response (OPHPR) to address containment. This work will 

begin in the laboratories that know they have polio-containing material.

In conclusion, Dr. Messonnier announced that NCIRD has a new Management Officer, 

Alexander Harrington.

 

Centers for Medicare and Medicaid Services (CMS)

Ms. Hahn reported that the voluntary course on quality measures in the Medicaid program has 

been revised to reflect the new adolescent quality measure that incorporates all of the 

adolescent quality measures into one. The individual HPV quality measure has been retired.

Department of Defense (DoD)

Dr. Deussing reminded everyone that influenza vaccination is mandatory for all uniformed 

personnel, including Active Duty, Coast Guard, Reserve, and National Guard with an 

immunization goal of 90% by mid-December. Influenza vaccination also is mandatory for HCP 

who provide direct patient care in military treatment facilities, and is recommended for all other 

HCP in these facilities. DoD achieved its 90% goal during the 2016-2017 influenza season by 

mid-December, despite using only injectable vaccine. The live intranasal vaccine, which usually 

accounts for 1 million or more doses of DoD’s vaccine allocation each year, was unavailable 

following ACIP recommendations. DoD procured enough injectable vaccine at its military 

treatment facilities for all age groups be immunized against influenza. As of February 9, 2017, 

1.9 million influenza vaccinations were given, with 96% compliance among DoD HCP. 

Regarding Yellow Fever (YF), the Defense Health Agency (DHA) Immunization Healthcare 

Branch (IHB) continues to work with Army, Navy, and Air Force services as well as the 

manufacturer on mitigating strategies to conserve available doses of YF vaccine and continues 

to monitor this situation very closely.

Department of Veterans Affairs (DVA)

Dr. Kim reported that a relationship between the VA and Walgreen’s was established for the 

2016-2017 influenza season to promote access to seasonal influenza vaccination for veterans 

receiving care at the VA. The intent of this relationship is to improve veteran access to 

influenza immunization. More than 77,000 immunizations were administered through this 

program through December 2016. In addition, the VA recently released an electronic decision 

support tool called a “Clinical Reminder” for HPV immunizations in February 2017. This Clinical 

Reminder can be used in the Veterans Information Systems and Technology Architecture 

(VistA), which is the VA EMR. In addition, development has begun on another electronic 

decision support tool for meningococcal immunization.

Food and Drug Administration (FDA)

Dr. Sun reported that the FDA’s legacy is still in transition. They are still waiting on the 

nomination of their new Commissioner, as well as senior leadership guidance to implement the 

21st Century Cure Act. The FDA had a busy year in 2016 in terms of vaccines, with one 

approval of a new original Biologics License Application (BLA) new vaccine, nine major 

approvals of supplements, seven of which involved influenza and two of which involved 

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Trumenba® two-dose and HPV-9 two-dose. On the developmental side, the FDA has been very 

busy in working with other government agencies such as CDC, NIH, the Biomedical Advanced 

Research and Development Authority (BARDA), World Health Organization (WHO), and the 

European Medicines Agency (EMA) on developmental vaccines in areas such as Zika, 

Respiratory Syncytial Virus (RSV), Ebola, and healthcare-associated diseases, such as 

Clostridium difficile (C. difficile), Staphylococcus aureus (S. aureus), and multiply-resistant 

bacterial organisms. 

Health Resources and Services Administration (HRSA)

Dr. Nair shared three updates for the Vaccine Injury Compensation Program (VICP). There 

continues to be an increase in the number of claims. In fiscal year 2016, there were 1120 

claims filed. That is the highest number since the inception of the program in 1988. Of these 

claims, 856 were adjudicated. Of those, 677 were found to be compensable and 179 were 

dismissed. Compensation totaled $250 million for petitioners and their attorney fees. For this 

fiscal year, 219 claims have been filed and approximately $52 million in awards have been paid 

to petitioners and $7 million has been paid in attorney fees. More information about the 

numbers can be obtained from the website. As a result of the 21st Century Cures Act, the VICP 

will now cover vaccines that are recommended for routine use in pregnant women. Previously, 

VICP covered vaccines that were recommended for routine use in children only. Now those 

liability protections for manufacturers and vaccine-administrators are extended for vaccines that 

are recommended for use in pregnant women. The Final Rule that modifies the Vaccine Injury 

Table was published in January 2017. Those changes will go into effect in March 2017.

Indian Health Services (IHS)

Ms. Groom reminded everyone that IHS implemented a mandatory influenza vaccination policy 

for HCP, but had not successfully bargained it with the unions. They were able to only partially 

implement the policy. They now have successfully bargained the policy with the unions, so it 

did go into effect this year. Preliminary data suggest that healthcare vaccine influenza vaccine 

coverage was 89.9% in IHS facilities as of December 2016. IHS is very optimistic that they 

might achieve the Healthy People 2020 goals this year. In terms of clinical decision support, 

IHS included the two-dose HPV vaccine series into its clinical decision support in the IHS EHR. 

They also are working on an algorithm to identify individuals with chronic liver disease (CLD) 

and HepC for the purposes of HepA and HepB vaccine. That reminder should go into effect 

later this year. IHS recently began a collaboration within Johns Hopkins Center for American 

Indian Health to assess maternal immunization in some tribal communities. They have been 

working with communities on messaging and with provider intervention with the hope to create a 

reminder for maternal immunization in the IHS EHR in the future.

National Institutes of Health (NIH)

Dr. Gorman first shared a personnel update. Dr. Francis Collins has been asked to remain as 

NIH’s Director by President Trump. It is unclear at this point from the announcements made 

whether this is a reappointment or, in fact, just an extension for transition. Major General James 

K. Gilman, MD has been named the new Director of NIH’s Clinical Center (CC). He has 35

years of experience commanding virtually every large US Army hospital in the US. He is a 

Cardiologist and highly decorated leader, with rich expertise in commanding the operations of 

numerous hospital systems. “His medical expertise and military leadership will serve the NIH 

Clinical Center well,” said Dr. Collins. Dr. John Gallin, the former Director of the CC, stays on 

as the Associate Director for Clinical Research and the Chief Scientific Officer of the CC. Inside 

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NIAID, Dr. Emily Erbelding is the new Director of Microbiology and Infectious Diseases (DMID). 

She is an Infectious Disease Physician with broad research and clinical experience in both 

government and academic medicine. She has served as the Deputy Director of the Division of 

AIDS at NIAID since 2010. She has been involved in all aspects of scientific program 

management and support, helping to design and implement new initiatives involving basic, 

translational, and clinical research. She has administered complex extramural grant programs 

and complex research infrastructure. Prior to joining NIAID, she spent 14 years on the faculty of 

Johns Hopkins University. As an interesting link, General Gilman and Dr. Erbelding are both 

graduates of a medical school in Indiana. Dr. Catherine Laughlin of the Virology Branch (VB) is 

retiring in March 2017 after 29 years of government service. Dr. Cristina Cassetti has been 

announced as the Acting Branch Chief of the VB. Dr. Clare Schmitt was announced in late 

January 2017 as the Acting Branch Chief for the Enteric and Hepatic Diseases Branch (EHDB). 

Dr. Schmitt is acting in that capacity until a permanent replacement for Frederick Cassels can 

be named. Dr. Gorman also will be retiring in late April 2017 after nine years in government 

service.

Regarding some specific activities of interest, NIH funds additional medical centers to expand 

the Precision Medical Research Program. Four regional centers have been added to clinical 

care, hoping to engage more than 1 million US participants to enable research that will, over 

time, improve the ability to prevent and treat diseases based on individual differences in 

lifestyles, environments, and genetics. The new awardees are the California Precision Medicine 

Consortium, Geisinger Health System, the New England Precision Medicine Consortium, and 

the Trans-American Consortium for the Health Care Systems Research Network. 

Dr. Collins and Dr. Kathy Hudson have published an article in the New England Journal of 

Medicine (NEJM) about the 21st Century Cures Act and the view from NIH. To summarize, they 

felt that the 21st Century Cures act would cut bureaucratic red tape related to paperwork and 

scientific conferences, enhance data sharing and privacy protection for volunteers, improve 

support for the next generation of researchers, and encourage NIH to extend its efforts to 

include diverse populations. Drs. Collins, Hudson, and Michael Lauer also published in the 

Journal of the American Medical Association (JAMA) in which they talked about a new era of 

trust and transparency in clinical trials and clinical trials reform. The authors described a multifaceted approach to improve the quality and efficiency of clinical trials. This effort focuses on a 

variety of key points along the lifespan of a clinical trial, and the initiatives will reengineer the 

process by which clinical investigators develop ideas for new trials, how NIH reviews and 

selects clinical trials for support and oversees the process, and how results and aggregate data 

are shared both broadly and rapidly. 

The first HIV vaccine efficacy study in seven years has begun. The experimental vaccine being 

tested is based on one investigated in the RV144 clinical trials in Thailand led by the US Military 

HIV Research Program and the Thailand Ministry of Health. The Thailand trial delivered 

landmark results in 2009 when it found for the first time that a vaccine could prevent HIV 

infection, although moderately. For the new HVTN 702 HIV Vaccine Study, the design, 

schedule, and components of the RV144 vaccine have been modified in an attempt to increase 

the magnitude and duration of the vaccine-elicited protective immune response. A new regimen 

has been adapted to the HIV subtype that predominates in South Africa.

In terms of antimicrobial resistance, there are two major efforts at NIH. The Antimicrobial 

Research Leadership Group and the Vaccine and Therapeutic Evaluation Units (VTEU) have 

been working on some projects. NIH recently launched a study that is hoping to enroll 400 

children in a clinical trial to determine whether shorter courses of antibiotics, 5 days instead of 

10, are effective in treating community-acquired pneumonia in children who show improvement 

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after the first few days of antibiotics. That study is being conducted at Duke, Cincinnati, 

Children’s Hospital of Philadelphia, and Children’s Hospital at Pittsburgh. NIH recently 

published the results of a different clinical trial that examined shortening the treatment for middle 

ear infection, which showed that 5 days of therapy is less effective than 10 days of therapy. Of 

the 229 participants, 77 or 35% in the 5-day treatment experienced clinical failure or worsening

of symptoms compared to only 39/238 or 16% in the 10-day treatment group. 

Dr. Bennett thanked Dr. Gorman for his service to ACIP, emphasizing that he would be missed 

very much.

National Vaccine Program Office (NVPO) / NVAC

Dr. Gellin reported on both NVPO and NVAC. He reported that NVAC met earlier in the month. 

The highlights are that they completed and approved the mid-course review of the National 

Vaccine Plan (NVP). Essentially, this review constitutes the reprioritization of the aspects of the 

plan going forward. The 21st Century Cures Act came up at NVAC as well. This is a 1000-page 

bill, approximately 20 pages of which focus on vaccines. There is a piece that asks the 

Secretary to develop a report on the state of vaccine innovation. NVAC is in the process of 

assembling the approach to that report, but among them is to reach out to stakeholders broadly. 

NVAC will be the convener of that stakeholder session and is working on the timing, which 

probably will be in conjunction with the June NVAC meeting. This is a way to ensure that 

stakeholders are at the NVAC table, and for others to contribute their views on vaccine 

innovations.

Turning to NVPO, the National Adult Immunization Plan: A Path to Implementation is now 

available. This is a companion piece to the National Adult Immunization Plan (NAIP). Along 

with partners in HHS, NVPO is now launching an awards program for people in non-federal 

organizations who are engaged in work to support the goals of the NVP. Nominations are due 

by April 26, 2017 and the non-monetary awards will be announced at the June 2017 NVAC 

meeting. Information regarding the criteria are on the website.

In terms of the transition, with Dr. Gellin’s departure, Dr. Jewel Mullin, who has been the 

Assistant Secretary for Health, will be the Acting Director of NVPO going forward as the 

department is now assembling a national search. He said it had been a treat to be involved with 

ACIP for many years. Dr. Bennett thanked Dr. Gellin for everything, noting that there are not 

enough words to sum up the incredible contributions Dr. Gellin has made to keeping America 

safe. She thanked him for his service, and emphasized that he also would be missed very 

much.

Tom Shimabukuro, MD, MPH, MBA

Immunization Safety Office

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Dr. Shimabukuro explained that the mission of the Immunization Safety Office (ISO) is to assess 

the safety of vaccines administered to children, adolescents, and adults. Post-licensure vaccine 

safety monitoring includes activities to rapidly identify new or rare AEs of clinical importance; 

Vaccination Errors

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monitor changes in patterns for known AEs; assess safety in special populations (e.g., pregnant 

women); and determine patient risk factors for particular AEs. 

ISO’s post-licensure vaccine safety monitoring infrastructures include: 1) Vaccine Adverse 

Event Reporting System (VAERS), a collaboration between CDC and FDA, which is a US 

frontline spontaneous (or passive) reporting system to detect potential vaccine safety problems; 

2) Vaccine Safety Datalink (VSD), a collaboration between CDC and healthcare plans, which is 

a large linked database system used for active surveillance and research; and 3) Clinical 

Immunization Safety Assessment (CISA) Project, a collaboration between CDC and academic 

medical centers, which conduct individual clinical vaccine safety assessments and clinical 

research. 

For the purpose of this review, a vaccination error is defined as a preventable event that might 

reflect incorrect use and/or potentially result in patient harm. It is important to understand that 

VAERS is a passive system. The reporting limitations of VAERS include reporting bias, 

inconsistent data quality and completeness, lack of an unvaccinated comparison group, and 

inconsistent pregnancy reporting. It is important to remember that it is generally not possible to 

assess whether a vaccine caused an AE from VAERS data alone.

The data Dr. Shimabukuro reported during this session were from a study published in 2015 by 

Hibbs et al in Vaccine titled Vaccination Errors Reported to the Vaccine Adverse Event 

Reporting System (VAERS). During this time period, there were just over 300,000 total reports 

to VAERS. Of these, just over 20,000 (7% of the total) were classified as vaccination error 

reports. Of the 20,000 just over 15,000 (75%) did not document an AE in the report and just 

over 5,000 (25%) did document an AE in the report. In the early 2000s, there were not many 

reports of errors in VAERS and the percentages were quite low. In the later years of this study 

period, there were increases in total reports, the number of error reports, and the percentage of 

error reports. This trend has persisted to the present, though there have been some slight 

differences in the actual types of errors reported to VAERS.

The vaccine error groups were created by investigators who assigned specific Medical 

Dictionary for Regulatory Activities (MedDRA) Preferred Terms to the error groups. Multiple 

MedDRA codes are assigned to error groups. The reports by error group in VAERS from 2000-

2013 are shown in the following table:

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Note that there are slightly more errors than there are reports. That is because reports may be 

assigned more than one MedDRA term (i.e., not mutually exclusive). Therefore, a report might 

be included in more than one vaccine error group. The top three rows are highlighted as they 

represent the top three error groups. Inappropriate scheduling accounts for 27% of the errors 

reported, storage and dispensing is 23%, and wrong vaccine is 15%. These comprise twothirds of all errors reported to VAERS during the time period.

Inappropriate schedule errors include wrong age and wrong timing between doses. Of these 

errors, 57% occur in children 0 through 18 years of age. Within this age group, 53% of these 

errors were reported in children less than 1 year of age. This probably is not unexpected, given 

that a lot of vaccine is administered during the first year of life in a fairly complicated schedule. 

The most common vaccines associated with wrong timing were quadrivalent human 

papillomavirus (HPV) vaccine and rotavirus vaccine. Within these two vaccines, commonly 

reported for quadrivalent HPV vaccine were delays between dose 1 and dose 2, based on a 5% 

random sample review of these reports. Technically, a delay between dose 1 and dose 2 is not 

an error. The reason these are categorized as errors is because there was documentation in 

the report that there was some type of delay in receiving the second dose. The median delay 

was 577 days with a range from 179 to over 2067 days. Also commonly reported for this 

vaccine was dose 3 being given too soon, prior to the 12-week minimum interval. For rotavirus 

vaccine, the common timing errors were the first dose given after 15 weeks and the last dose 

given after 32 weeks. It is not recommended to give the first dose after 15 weeks or the last 

dose after 32 weeks according to the prescribing information.

The second most common error, storage and dispensing errors, was 23% of the total. These 

basically broke down into two groups: expired vaccine administered (55%) and incorrect 

storage (44%). Within expired vaccine administered, commonly reported vaccines were 

seasonal LAIV; herpes zoster; and measles, mumps and rubella (MMR). Within incorrect 

storage of vaccine based on a 5% random sample of reports, vaccines kept outside of proper 

storage temperatures were reported 88% of the time, so that appears to be the most common 

type of error for incorrect storage of vaccine. In 55% of these reports, the vaccine was exposed 

to temperatures below recommended storage temperatures, so they were stored too cold.

The third most common type of error reported was wrong vaccine administered at 15% of the 

total errors reported. This appears to occur commonly among vaccines with similar names, 

acronyms, and antigens. The following table shows common wrong vaccine mix-ups:

Common Wrong Vaccine Mix-Ups in Either Combination

Varicella (VARIVAX®) with Herpes zoster (ZOSTAVAX®)

Diphtheria, tetanus and pertussis 

(DTaP)

with Tetanus, diphtheria and pertussis 

(Tdap)

One type of trivalent inactivated 

influenza vaccine (IIV3)

with Another type of IIV3 with a different age 

indication

Pneumococcal conjugate with Pneumococcal polysaccharide

Hepatitis A with Hepatitis B

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Adverse health events were reported in 25% of the errors. Of these, 92% were non-serious and 

8% were serious. These percentages are similar to non-error reports to VAERS. The most 

common adverse health events were injection site erythema (13%), injection site pain (11%),

and pyrexia (11%). This is similar to what is observed in non-error reports as well. The 

administration error group had the highest percentage of reports with a documented adverse 

health event (in 60% of administration error reports). The types of errors were wrong site, 

wrong technique, and incorrect route. 

A number of reports of error clusters were detected. A cluster is defined as the same error in 

multiple individuals at the same location or clinic. There were 936 error clusters involving at 

least 6141 patients. The cluster size ranged from 2 to 501 patients, with a median of 5. Of the 

clusters, 110 involved 10 or more patients. In 586 clusters, the specific number of patients 

affected was stated as “unknown” or “several.” They basically submitted a report saying there 

was a cluster error, but did not specify the number. That is why the total estimate is said to be 

“at least” 6141, because it is likely to be an underestimate. Storage errors were the most 

common type of error clusters at 72% of all cluster reports. Incorrect storage (582 clusters, 

1715 patients) and expired vaccine administered (96 clusters, 1340 patients) were the most 

commonly reported. LAIV was the most commonly reported expired vaccine administered (45 

clusters, 990 patients). 

Moving to case series reports of vaccination errors, the first case series involved a VAERS 

review of rotavirus vaccine error reports. For the purpose of this presentation, Dr. Shimabukuro

focused on the vaccine injection errors. In the following graphic, the two types of rotavirus 

vaccines licensed in the US are shown, RotaTeq® and Rotarix®. In the VAERS review, there 

were 39 total reports of rotavirus vaccine being injected. Of these, 33 were with the Rotarix®

product and 6 were with RotaTeq®. With the Rotarix®, there was one cluster of 6 that occurred 

on the same day with the same provider. Reasons documented in the report for this error 

included misinterpretation of instructions, inadequate training, not reading the package insert, 

confusing the oral applicator syringe with the syringe for injection, and confusing the vial with a 

vial for injectable vaccine. On the righthand side of the graphic, the Rotarix® vaccine is in the 

process of being reconstituted. The person is holding the syringe component, and then there is 

an adapter and a vial. The way this works is that the syringe is plunged to reconstitute the 

vaccine, withdraw, remove it from the adapter, and use the syringe the squirt into the infant’s 

mouth:

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To test the theory that the syringe is being used to inject, Ms. Beth Hibbs, the lead for this 

project, went into the field and tested as many needles as she could find. The conclusion is that 

a needle simply cannot be attached onto this syringe. Therefore, it is highly unlikely that this is 

occurring because there is a freestanding needle syringe unit that is being injected. There is 

some other mechanism by which these errors are taking place. There was not sufficient 

information in the reports to draw conclusions. The following is an example of the current 

Rotarix® package, which shows the universal sign for do not inject and then prominently 

displayed in red is “FOR ORAL USE ONLY” to make the provider aware that this is not an 

injectable vaccine:

Graphic Courtesy of GSK

The next case series is a VAERS review of meningococcal conjugate vaccination error reports 

involving the Menveo® product, which is supplied in two vials that must be combined before 

administration. The liquid component shown in the left side of the following graphic is used to 

reconstitute the lyophilized component shown on the right side

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Administration errors involved only one component of Menveo® being given to patients. A total 

of 390 reports were detected from the period 2010-2015. Of these, 66% of recipients received 

only the liquid component and 34% received only the lyophilized component. When there was 

information about how that actually occurred, some common diluents used were sterile water, 

saline, HepB vaccine, and Diphtheria and Tetanus Toxoid and Pertussis (DTaP) vaccine. That 

is, other vaccines were used to reconstitute the lyophilized component. There also were reports 

of errors occurring with another two-component vaccine. There is a combination DTaP/IPV/Hib 

vaccine that needs to be reconstituted, and similar reports were detected for that vaccine as 

well. The following graphic shows changes made to the Menveo® label after publication of this 

paper:

On the left side, the old label has pink and smaller font. On the right side is the new label with 

changes in the font size and color so that “NOT TO BE USED ALONE” stands out more clearly 

to the provider reading the labels.

Another interesting investigation was of unintentional administration of insulin instead of 

influenza vaccine. This involved an apparent mix-up in which a cluster of 5 adult patients 

unintentionally received insulin instead of influenza vaccine. These patients were teachers who 

received their injections at a school clinic. All 5 experienced symptoms of hypoglycemia and 

two required treatment in the emergency department (ED) for severe hypoglycemia. This 

investigation was conducted by the St. Louis County Department of Public Health with 

assistance from the state health department, CDC, FDA, and the vaccine manufacturer. The 

conclusion was that improper storage, including inadequate segregation of insulin and influenza 

vaccine products in clearly labeled containers or bins, lack of standardized procedures for 

confirming the contents of vials, and decreased vigilance in preparation and administration likely 

contributed to the incident [Clogston et al. Unintentional administration of insulin instead of 

influenza vaccine: a case study and review of reports to US vaccine and drug safety monitoring 

systems. Drugs & Therapy Perspectives. 2016;32:439-446]. 

In summary, vaccination error reports comprised 6% to 15% of all reports to VAERS during the 

period 2007-2013. The number and percentage of total VAERS reports of vaccination error 

reports have increased substantially from 2000-2013. Of the vaccination error reports to 

VAERS, 75% did not document an adverse health event. Of the 25% of vaccination error 

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reports to VAERS that did document an adverse health event, the adverse health events were 

generally similar to non-error reports. Based on reports to VAERS, vaccination errors usually 

do not appear to pose a substantial safety risk. However, errors do have an impact in terms of 

additional costs, possible effect on immunological protection, patient/parent inconvenience, and 

loss of confidence in the healthcare delivery system. Some errors do or have the potential to 

cause patient harm, such as the following:

 Unintentional administration of insulin instead of vaccine 

http://link.springer.com/article/10.1007/s40267-016-0333-2

 Reuse of syringes on multiple patients at a vaccination clinic 

https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6449a3.htm 

 Incorrect reconstitution of measles-rubella vaccine using atracurium instead of the 

approved diluent in Syria, which resulted in 15 deaths

http://www.who.int/mediacentre/news/statements/2014/interim-findings-idleb-syria/en/

Current strategies for reducing vaccination errors include: 1) Education and training on vaccine 

timing and spacing, especially for vaccines with complex schedules; 2) Training on proper 

administration technique, including general injection safety; 3) Improved monitoring of vaccine 

storage temperatures and expiration dates; 4) Improvements in differentiating vaccines and 

other products with similar sounding names and acronyms; and 5) Implementation and 

enforcement of procedures to properly screen for vaccine contraindications. A future strategy 

that has promise is passive engineered interventions that take human judgment and human 

behavior out of the process, which can prevent or substantially decrease the likelihood that an 

error will be made. One example that has been discussed is an indicator on the label of a 

vaccine that changes color when the vaccine has been out of temperature for too long; that is, a 

visual que to let the provider know that the vaccine needs to be discarded.

Following are some resources for reporting vaccination errors and strategies to prevent errors: 

 VAERS guidance on reporting vaccination errors https://vaers.hhs.gov/esub/index, 

https://vaers.hhs.gov/esub/eSubpopup.htm 

 Strategies to Prevent Administration Errors (in the Pink Book)

https://www.cdc.gov/vaccines/pubs/pinkbook/vac-admin.html

 CDC Vaccine Storage & Handling Tool Kit

http://www.cdc.gov/vaccines/recs/storage/toolkit

 One & Only Campaign https://www.cdc.gov/injectionsafety/1anonly.html

 Technically Speaking: Vaccine Administration Errors (CHOP) 

http://www.chop.edu/news/technically-speaking-vaccine-administration-errors

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Discussion Points

Dr. Szilagy asked Dr. Shimabukuro to describe how some of the interventions are woven into 

AFIX (Assessment, Feedback, Incentives, and eXchange) visits.

Dr. Melinda Wharton (Director, ISD/NCIRD) replied that as part of quality assurance visits 

immunization programs make, generally to participating VFC providers, built into the visits are 

reviews of storage and handling procedures and vaccine management. That is the primary 

quality control the system schedules into the program.

Ms. Pellegrini asked whether there is a process for going to the settings where larger clusters 

are occurring to engage in some type of remedial action to ensure that it does not happen 

again.

Dr. Shimabukuro said he thought that was more of an institution and local health department 

issue. CDC primarily performs surveillance and investigations. He can report on the number 

and type of clusters and why they occur.

Dr. Melinda Wharton (Director, ISD/NCIRD) added that for single reports which come in 

routinely, there is not necessarily a high level of follow-up. Certainly, for some of the incidents 

where there are clusters, this is more concerning. For example, with syringe reuse or 

mishandling of vaccines in clinics, state or local public health would be involved in follow-up 

generally speaking. This is not something CDC would necessarily be involved in. In general, 

CDC learns about these incidents because a problem is identified and reported to state or local 

public health departments. They may be reported later to the VAERS system, but usually those 

types of incidents raise a sufficient level of concern that state or local health authorities are 

alerted.

Dr. Cohn observed that additional immunizations added specifically to the adolescent schedule

seemed to comprise a number of the errors described. She asked whether Dr. Shimabukuro 

could say anything about the number of doses that were given over that period of time in 

relation to the number of reports received.

Dr. Shimabukuro replied that in 2007, there was a large increase in reports and also an increase 

in the number of error reports and the percentage of error reports as a total. The short answer 

is that it is not exactly clear why this happened, but several reasons are suspected. About that 

time, a number of new products appeared on the market. Zostavax®, Gardasil®, and RotaTeq®

were licensed in 2006 and ACAM® started being used in 2007. It appears to be a combination 

of more new vaccines on the market, more vaccines being administered, and a period of getting 

used to the schedule. When a new vaccine comes on the market, there tends to be a spike in 

reports in VAERS which then decreases and levels off. Relatively speaking, a substantial 

number of reports in that spike are errors when the roll out is occurring and providers are getting 

used to the schedule. It also may be that there is just more awareness of errors and less 

reluctance to report errors, or a combination of all of those things.

Dr. Bennett observed that one of the problems with VAERS is the inability to calculate rates of 

AEs or errors. She wondered whether there was any potential going forward that EMRs would 

help to identify errors, or if errors do not make it into EMRs.

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Dr. Shimabukuro said he thought there were some ICD codes for medical errors. CDC could 

perhaps assess how frequently errors are reported. This work has not been done in VSD yet, 

but it is something they could look into.

Dr. Stephens asked whether there are any active, prospective studies that are examining error 

rates in settings.

Dr. Shimabukuro replied that he was not aware of any ongoing studies examining error rates for 

vaccines. There have been more studies assessing drug errors than vaccination errors. That 

may be because most vaccination errors do not cause patient harm.

Dr. Weinbaum (ISD/NCIRD) reported that there is a study looking at schedule errors, which is 

one of the top errors, using a centralized system of Immunization Information Systems (IIS) 

(microphone issues)

Dr. Bridges indicated that the National Adult Influenza Immunization Summit WG also 

recognized these problems with errors that may be more common in temporary or seasonal 

clinics, and developed a checklist that is available on the Summit website on which they would 

like feedback.

Dr. Moore commented that in the future, it would be helpful when discussing vaccine safety and 

VAERS reports to identify vaccines that are new to the market separated from those that have 

been on the market for a long time or errors that are reported based on multiple vaccines. This 

will make it easier to distinguish when an increase like this occurs that is associated with a 

number of vaccines coming onto the market how much of that is reports about these new 

vaccines that may be errors because of unfamiliarity with a new product as opposed to errors 

that are occurring with vaccines that have been on the schedule for a long time. She asked 

whether there was any change in the reporting, such as making it easier to report online, that 

also could have contributed to an increase in reports.

Dr. Shimabukuro replied that one possible reason was that in 2007, there was a switch from

COSTART (Coding Symbols for a Thesaurus of Adverse Reaction Terms) coding to MedDRA 

coding. MedDRA coding evolves and the codes tend to get more specific from more general. 

With the switch to MedDRA coding, there were more options for errors with more specific codes. 

There were still error codes in COSTART, so it could be argued that an increase in errors 

should still be observed because there were COSTART options to select for an error. However, 

the wider variety of error codes available in MedDRA may have changed some of the coding 

behaviors of the coders because they have more options to choose from and are more aware of 

error codes.

Ms. Hayes (ACNM) indicated that her concern with the number of vaccines that were given 

when they had previously been stored at an improper temperature range and may lose their 

efficacy. In the clinics she has worked in, they are required to take a daily temperature of the 

refrigerator. There are extensive materials on vaccine handling procedures on CDC’s website, 

but they have not been updated in a while, so she was curious as to whether there were any 

plans to work on improving the language around proper storage and handling.

Dr. Shimabukuro clarified that this is probably not administration of vaccine that was known to 

be out of temperature. These were realizations after the vaccine was administered.

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Dr. Melinda Wharton (Director, ISD, NCIRD) emphasized that issues pertaining to vaccine 

storage and handling have been a major focus of the ISD program state immunization programs 

and quality assurance visits for the past several years. An increase in the use of digital data 

loggers has made it easier to identify excursions and make appropriate interpretations of their 

significance. Often excursions might occur that are not of sufficient duration or magnitude that 

the vaccine potency is affected and, therefore, it is safe to use the vaccine. Assuring that 

offices have appropriate vaccine management practices in place, including recording and 

monitoring temperatures and taking appropriate actions when there are excursions is clearly an 

important priority for CDC. An extensive update was done over the summer of storage and 

handling materials, which are on the website.

Kelly L. Moore MD, MPH 

Director, Tennessee Immunization Program 

Chair, Mumps ACIP Work Group

Dr. Moore introduced the Mumps WG that has recently been constituted. She reported that 

numerous mumps outbreaks have been reported in the US since 2006, particularly among 

highly vaccinated college populations. The second largest number of reported cases since 

2006 occurred in 2016. Widespread distribution of these outbreaks across the US resulted in 

increased interest from state and local health departments and universities to implement third 

dose of MMR vaccination campaigns to control these outbreaks. However, data on the effect of 

a third MMR dose for outbreak control are limited. This map reflects the distribution of reported 

mumps cases and outbreaks across the US in 2016:

Mumps outbreaks are not required to be reported to CDC; however, state and local health 

departments and universities have voluntarily reported numerous outbreaks. In 2016, at least 

19 university-based outbreaks were reported. The stars in the map represent states that 

reported outbreaks last year. When these outbreaks occur, the disease itself has not been 

serious for most individual patients. However, the disruption for the universities and disruption 

Mumps

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and expense for local and state public health, including public health laboratories, has been 

significant.

Dr. Moore shared the list of the Mumps WG members and expressed appreciation for 

everyone’s expertise as they try to address new information available on this topic. Regarding 

the proposed terms of reference for the Mumps WG, the objective is strictly to evaluate and 

propose policy options to prevent or control mumps outbreaks in the US. The activities related 

to that in the coming months are to: 1) Review the epidemiology of mumps in the 2-dose 

vaccine era, including the international experience; 2) Review available evidence on duration of 

immunity for mumps after 2 doses of MMR and other risk factors for vaccine failure; 3) Review 

the available evidence on benefit provided by a third dose of MMR for mumps outbreak control; 

and 4) Evaluate programmatic implications and cost of various policy options for a third dose of 

MMR to prevent or control mumps outbreaks. 

Regarding the timeline, the goal of the February 2017 meeting is to inform ACIP of the new WG, 

members, terms of reference, and kick off with a presentation focused on an overview of current 

mumps recommendations and epidemiology in the US. The first WG conference call is 

scheduled for March 2017. During the October 2017 ACIP meeting, an update will be provided 

on the WG’s deliberations. During the February 2018 ACIP meeting, the WG anticipates 

presenting recommendations to ACIP. 

Mona Marin, MD

Division of Viral Diseases

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

In anticipation of the WG deliberations and presentations to ACIP, Dr. Marin reviewed mumps 

vaccination recommendations and epidemiology in the US. For this presentation, she provided 

an overview of mumps disease and transmission, described mumps vaccine and vaccination 

recommendations in the US, presented mumps epidemiology in the US with a focus on recent 

years, and discussed the main topics that the WG will address based on the proposed terms of 

reference.

Mumps is an acute viral illness that classically presents with parotitis in approximately 60% to 

70% of patients. Other presentations include other salivary gland swelling and non-specific 

respiratory symptoms or asymptomatic infection, which occur in approximately 30% of patients. 

In the pre-vaccine era, mumps complications were common with orchitis and mastitis being the 

most frequent. More serious complications such as aseptic meningitis leading to 

hospitalizations also occurred. In the vaccine era, complication rates and hospitalizations have 

been drastically reduced [McLean HQ et al. MMWR 2013; Data from US outbreak investigations 

2006-2015].

Mumps is transmitted person-to-person by direct contact with infected droplets or saliva or by 

inhalation of infectious respiratory droplets. It requires close contact for spread. The 

infectiousness is less than for measles and varicella1. The infectious period is from 2 days 

before to 5 days after parotitis onset, although virus was isolated outside this period. 

Importantly, transmission can occur from patients with non-specific respiratory symptoms and 

asymptomatic infection. Mumps has a long incubation period of an average 16 to 18 days.

Infectiousness before symptoms and transmission from persons with asymptomatic or nonspecific presentation contribute to prolongation of transmission and outbreaks [1Hope Simpson 

RE. The Lancet 1952].

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Mumps is preventable by vaccination. In the US, mumps vaccine was licensed as a single 

antigen vaccine in 1967. Currently, the vaccine is available as combination vaccines either as

MMR licensed in 1971 or MMR plus varicella (MMRV) licensed in 2005. These vaccines 

contain a live attenuated mumps strain, the Jeryl-Lynn strain, which belongs to genotype A. 

Effectiveness estimates for MMR for preventing clinical mumps are ~77% for one dose and

~88% for two doses 1,2 [1 Schaffzin JK et al. Pediatrics 2007, Marin M et al. Vaccine 2008; and 

Cohen C et al. Emerg Infect Dis 2007, Deeks SL et al. CMAJ. 2011, Dominguez A et al. Vaccine

2010, Sartorius B et al. Euro Surveill 2005, Harling R et al. Vaccine 2005].

Recommendations for mumps vaccine use have evolved since the vaccine was licensed in 

1967. It was not until 1977 that ACIP recommended 1 dose for all children at any age after 12 

months1. In 1989, a second dose of measles vaccine was recommended for improved measles 

control, and it was indicated that both doses of measles vaccine should be given as combined 

MMR, stating that mumps revaccination is particularly important2. Effectively, the 

recommendation for a second dose of measles vaccine delivered a second dose of mumps 

vaccine. In 2006, a formal recommendation for 2 doses of a mumps-containing vaccine was 

issued to cover school-aged children in grades K-12 and adults in high risk groups, including 

healthcare facility personnel, international travelers, and students at post-high school 

educational institutions3 [1ACIP. MMWR 1977; 26:393-4; 2ACIP. MMWR 1989; 38(S-9):1-18; 

3ACIP. MMWR 2006; 55(22):629-30].

Reports of mumps cases declined dramatically following MMR vaccine licensure and the 1-dose 

recommendation. The second dose of MMR vaccine recommended in 1989 subsequently 

improved mumps control as well. From 1993 through 2005, only a few hundred cases were 

reported annually and vaccination coverage was high. However, several large mumps 

outbreaks have been reported from 2006 through February 2017. It is important to note that 

despite these recent outbreaks, there has still been a 99% decline in mumps cases compared 

with the pre-vaccine era [Source: National Notifiable Diseases Surveillance System (cases, 

passive surveillance); National Immunization Survey (NIS) (1st dose coverage 19-35 year olds), 

National Health Interview Survey & NIS-Teen (2nd dose coverage); 2016 case data is 

preliminary (Feb 9, 2017) and subject to change].

The first large outbreak of the last decade occurred in 2006, with more than 6500 cases 

reported in 8 Midwestern states. This was the first multi-state outbreak attributable to 2-dose 

vaccine failure. Incidence was highest in young adults age 18 through 24 years, most of whom 

were college students. The 2-dose MMR coverage rate in affected colleges was 90% to 99%, 

with most students having received their second dose more than 10 years previously. 

Dormitory living, freshman class status, and time since the second dose were risk factors in 

college investigations. Standard control measures, including isolation and vaccine catch-up 

campaigns, were implemented to control this outbreak [Dayan GH et al. N Engl J Med 2008; 

Cortese MM et al. Clin Infect Dis 2008; Marin M et al. Vaccine 2008].

Then in 2009 -2010, two large outbreaks occurred among highly vaccinated populations and 

accounted for most of the mumps cases reported nationally during this period. In the

Northeastern US outbreak, 97% of the cases were among members of the Orthodox Jewish 

community. In this outbreak, adolescent males were the most affected group and 89% of them 

had 2 doses of MMR vaccine. This community has unique schools with high densities and 

partner-style learning, as well as large households. These characteristics resulted in prolonged, 

intense exposures that likely overcame the protection afforded by the vaccine1. The second 

outbreak occurred in Guam. In this outbreak, the highest attack rate was in school-aged 

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children 9 through 14 years of age, of whom 96% were vaccinated with 2 doses of MMR, as well 

as among ethnic minorities with higher household densities2. A third dose of MMR vaccine was 

used for outbreak control in these settings [1Barskey AE et al. N Engl J Med 2012; 2Nelson GE 

et al. Pediatr Infect Dis J 2013].

Moving on to the most recent 6 years, an increase in the number of mumps cases and

incidence and numerous outbreaks have been reported. In 2016 in particular, a high number of 

mumps cases and outbreaks were reported. For cases, even if the states with the 3 largest 

numbers of cases (Arkansas, Iowa, Oklahoma) are removed, the number of cases and 

incidence remain the highest of the past 6 years. Genotyping G virus has been the most 

commonly identified virus since 2006 when laboratory surveillance was established. Regarding 

outbreaks, during the second half of 2010 through 2015, 23 outbreaks with 20 or more cases 

have been reported in 18 states. Of these, 22 occurred in close contact settings, of which 18 

were universities. In these outbreaks, the highest incidence was in those 18 through 25 years 

of age. In half of university outbreaks more than 85% of case-patients had documented 2 MMR 

doses. The spread outside the affected community was minimal, in only 3 outbreaks. Also, size 

of the outbreaks was limited. About 56% had less than 50 cases [Source: National Notifiable 

Diseases Surveillance System (cases, passive surveillance); 2016 data is preliminary (Feb 9, 

2017) and subject to change; Clemmons N, CDC, personal communication Feb 2017 

(outbreaks)].

Several factors may contribute to the increasing number of mumps outbreaks. With a vaccine 

effectiveness of 77% for 1 dose and 88% for 2 doses, cases can still occur among vaccinated 

persons. Evidence also points to waning of vaccine-induced immunity, especially in the era of 

low disease incidence and absence of boosting from wild disease. Serologic studies have 

shown that seropositivity and neutralizing antibody titers decline over time1-5. However, there 

are no established correlates of protection3. Therefore, the implications of declining titer remain 

uncertain. Additionally, mumps vaccine also induces cell-mediated immunity. Although the 

contribution of the cell-mediated immunity to protection against mumps infection has not been 

clearly defined, evidence indicates that it declines over time less than seropositivity, if at all6. 

Epidemiologic studies also suggest waning of immunity with decreased vaccine effectiveness7

and increased odds of contacting disease with time since vaccination8-9, but evidence is still 

limited. However, waning of immunity itself does not explain the general geographical focal 

nature and that the oldest vaccinated cohorts are not always most affected [1Davidkin I et al. J 

Infect Dis 2008; 2LeBaron CW et al. J Infect Dis 2009; 3Rubin SA et al. J Infect Dis 2008;

4 Date 

AA et al. J Infect Dis 2008; 5Kontio, J Infect Dis 2012; 6Jokinen S et al. J Infect Dis 2007; 

7Cohen C et al. Emerg Infect Dis 2007; 8Cortese MM et al. Clin Infect Dis 2008; 9Vygen S et al. 

Euro Surveill 2016].

Intense exposure settings account for these features. Therefore, force of infection based on 

observations that outbreaks have occurred in settings with high population density and contact 

rates that facilitate transmission, such as college campuses or close-knit communities, is 

frequently postulated as a risk factor for current mumps outbreaks. Concern was raised that 

mumps vaccine-induced immunity may be less effective against other strains. There is no 

evidence to date. All sera collected from vaccinated children neutralized diverse mumps virus 

strains1,2. However, antigenic differences among strains led to lower antibody levels against 

non-vaccine strains1-3. These differences might become more important with increasing time 

since vaccination. Several examples that support these factors will be provided next. [

1Rubin 

SA et al. J Infect Dis 2008; 2Rubin SA et al. J Virol 2012; 3Orvell C et al. J Gen Virol 2002].

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This graph shows the results of a study that documented decreasing vaccine effectiveness with 

time since vaccination: 

Vaccine effectiveness was calculated during a mumps outbreak in UK in 2004-2005 with more 

than 56,000 cases primarily among under-vaccinated persons. The yellow line represents the 

first dose vaccine effectiveness which overall was 88%, while the aqua line represents the 

second dose vaccine effectiveness which overall was 95%. However, as seen from the graph, 

for the first dose, effectiveness declined from 96% in 2 year olds to 66% in 11 through 12 year 

olds. For the second dose, effectiveness declined from 99% in 5 through 6 year olds to 86% in 

11 through 12 year olds. Assuming that age serves as a proxy for time since vaccination, these 

findings support waning immunity [1Cohen C et al. Emerg Infect Dis 2007; 2Anderson RM, May 

RM. Nature 1985].

For serologic evidence of waning of vaccine-induced immunity, the following table presents data 

from a study that assessed mumps neutralizing antibodies against the Jeryl Lynn strain, which 

is the vaccine strain (shaded line), and a genotype G strain identified during the 2006 outbreak 

in IA (second row in the table): 

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Neutralizing antibody is considered to contribute to protection, but the level required for 

protection has not been established. In this study, testing was performed on specimens 

collected days before receipt of the second dose of MMR (second column titled 2-5 years after 

MMR1), 1 month after the second dose MMR (third column) and 10 years after MMR2 (last 

column). This study found that antibody induced by vaccination effectively neutralized the 

genotype G virus for all study subjects at each time point tested, including 10 years after 

vaccination. However, the geometric mean titers (GMTs) against the genotype G strain were 

lower than the titers measured against the Jeryl Lynn strain, reflecting variability in antibody 

responses between strains. Titers to both viruses decreased over time since vaccination. As 

previously mentioned, in the absence of a correlate of protection, the clinical significance of 

these findings cannot be conclusively ascertained [Rubin SA et al. J Infect Dis 2008].

The hypothesis that waning immunity is a cause for mumps outbreaks led to interest in the use 

of a third dose of MMR vaccine for outbreak control. As mentioned earlier, third dose 

intervention campaigns were conducted in New York/Orange County where 81% of eligible 

students were vaccinated with a third dose1 and in Guam where 33% of eligible students 

received a third dose2. As indicated by the two epicurves shown below, attack rates declined 

after a third MMR dose was administered in both school-based studies:

 New York/Orange County Guam

However, in Guam, statistical significance could not be established due to the small number of 

cases recorded and in both studies, because of the late timing of the third dose campaigns 

during the course of the outbreaks, the possibility of the declines being unrelated to the 

intervention could not be excluded [1 Ogbuanu IU et al. Pediatrics 2012; 2 Nelson GE et al. 

Pediatr Infect Dis J 2013].

These data were presented to ACIP in 2012. At that time, ACIP determined that the data were 

insufficient to recommend for or against the use of a third dose of MMR vaccine for mumps 

outbreak control. Subsequently, CDC issued guidance for consideration for use of a third dose 

in specifically identified target populations along with criteria for public health departments to 

consider for decision-making. That includes settings with high 2-dose coverage, intense 

exposure, and ongoing transmission.

Data on laboratory evidence of the impact of a third MMR dose became available more recently. 

A study of neutralizing antibody titers in young adults 18 through 28 years of age found that very 

few subjects had titers that were negative (0.8%) or low (5.8%) before the third dose. 

Compared with pre-third dose considered baseline, GMTs were modestly but significantly higher 

at both 1 month and 1 year after the third MMR dose. However, as seen in the graph, the 

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distribution curves show only minimal shifts in mumps titers from baseline (the continuous line) 

to 1 month (the dotted line) and 1 year (the dashed line in the middle)1: 

 

These findings raise the question of short- versus long-term benefit of a third dose and 

implications for routine use versus outbreak policy recommendations. The qualitative aspects of 

the mumps immune response (e.g., antibody avidity, B-cell memory, or cell-mediated immune 

responses) have not been assessed [1Fiebelkorn AP et al. Open Forum Infect Dis 2014].

To conclude, use of the mumps vaccine reduced disease levels by approximately 99% since 

vaccine introduction in the US. Since 2006, mumps outbreaks have occurred in highly 2-dose 

vaccinated populations. The current 2-dose schedule is sufficient for mumps control in the 

general population, but outbreaks can occur in well-vaccinated populations in specific settings. 

Intense exposure settings and waning immunity appear to be risk factors for secondary vaccine 

failure. The benefit of a third MMR dose still needs to be assessed. 

Dr. Marin ended with a summary of the main topics for WG discussion. The WG will review the 

available evidence for risk factors for mumps among 2-dose MMR vaccine recipients, including 

whether mumps vaccine protects against currently circulating mumps virus genotypes in the US. 

The WG also will review available evidence on benefit provided by the third MMR dose, whether 

there is an additional benefit and, if so, whether it is a short- or long-term benefit. More 

epidemiologic and laboratory evidence is forthcoming for the WG to review, including vaccine 

effectiveness in Iowa during the 2015 outbreak and Arkansas during the 2016-2017 outbreak, 

and antibody kinetics more than 5 years after the third MMR dose. Finally, the WG will 

examine the programmatic implications and conduct a cost analysis of various policy options for 

a potential third dose MMR recommendation to prevent or control mumps outbreaks.

Discussion Points

Dr. Reingold inquired as to whether more natural boosting at an earlier time period when the 

virus was circulating might explain why a reduction in vaccine effectiveness does not seem to 

be as true in older individuals.

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Dr. Marin clarified that when she referred to the older cohort, she meant within college 

investigations and the age span was narrow from 18 through 24 years of age. Higher rates of 

disease were seen in students 18 through 20 years of age, but not in those 21 and older. Given 

their year of birth, they were unlikely to be exposed to natural disease. The population over 30 

to 40 years of age may have had exposure to natural disease.

Dr. Reingold noted that the pace seemed leisurely for the WG to report back to ACIP on 

forthcoming data. If these are important policy questions for health departments, he wondered 

whether the pace could be accelerated somewhat.

Dr. Marin replied that the Iowa investigation is almost complete. The analysis is largely finished, 

so those data will be available in a few months.

Dr. Messonnier agreed about the timeframe, but emphasized that the WG had not had their first 

meeting yet. One of the questions regards whether ACIP will be comfortable making a new 

recommendation based on the clinical efficacy data from existing investigations, or if they would 

like to see additional information, including some of the questions related to strain changes that 

will require more serological studies and will take longer. The WG certainly would welcome 

moving faster if they can.

Dr. Bennett noted that while Dr. Marin reported on the immunization rates overall at the 

institutions where there were outbreaks, but not on the rates comparatively between cases and 

non-cases. She wondered whether there has been any attempt to assess that and, if so, 

whether ACIP would see those data. In addition, she asked whether additional risk factor

analyses could be performed. These seem like good opportunities potentially for case-control 

studies.

Dr. Marin indicated that the college investigations examined the coverage rate among cases

versus non-cases in 2006, 2009, and 2010 but not so much in the past year. Most students in 

college now came from a time when 2-dose coverage was pretty high among children 4 through 

6 years of age. There is a large portion of the population for which immunization status is not 

known. It is more difficult to get coverage information, but 2-dose coverage is high for college 

populations.

Dr. Moore assured Dr. Reingold that the WG would not be any more leisurely than absolutely 

necessary. Given that two universities reported cases to her in the previous three weeks, she 

personally feels the urgency to have the evidence to make an appropriate evidence-based 

decision. As soon as the WG feels that they have sufficient evidence presented to them to 

make an evidence-based recommendation, they will bring it to ACIP post-haste. 

Dr. Schaffner (NFID/IDSA) asked whether there are epidemiologic or molecular data suggesting 

the source of these mumps virus outbreaks that are occurring, particularly in universities in 

terms of whether they are domestic or international mumps viruses.

Dr. Marin responded that the virus tested in 2006 was similar to the virus that cause the UK 

outbreak in 2005-2006. The index case in the outbreak in the Orthodox Jewish community was 

a 11-year old 2-dose vaccinated child who returned from the UK and two weeks later developed 

mumps. The genotype circulating is similar to the genotype circulating in Western Europe.

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Dr. Pallansch emphasized that unlike measles and rubella, mumps has not been eliminated 

from indigenous circulation in the US. It is just that currently genotype G is the most 

predominant, but is not exclusive. Importations are recognized, but genotype G being widely

distributed globally makes it very difficult to say specifically in most situations. For some of the 

college outbreaks, it is not going to be possible to answer that question definitively.

Dr. Schaffner (NFID/IDSA) pointed out that while wild mumps is often an asymptomatic 

infection, not a lot of studies have been done about asymptomatic infections in the context of 

these outbreaks to his knowledge. He wondered whether this opportunity could be taken to 

study how frequently asymptomatic infection occurs among people who have been vaccinated, 

because they may be subtle transmitters.

Dr. Marin responded that this was an important point in 2006 when they went to Iowa. In the 

two colleges that were investigated, only 16% of students with mumps reported contact with a 

known mumps case. That suggested that there was a lot of asymptomatic disease that 

contributed to transmission.

Dr. Thompson (NVAC) pointed out that there is now an MMRV vaccine. She thinks that the 

timing of MMRV introduction and its increased use in 2006 is completely coincidental with the 

outbreaks. It is important for ACIP to examine this in its review and present the evidence. In 

the context of a third dose recommendation, she also thinks ACIP will need to say something 

about MMR versus MMRV, or if it is just MMR-containing vaccines.

Dr. Marin indicated that MMRV is licensed through 12 years of age. She agreed that it was 

coincidence, because MMRV was licensed in the US in 2005 and was not available during 

2008-2009 due to a shortage. Also, after the ACIP MMRV Safety WG made recommendations 

for MMRV use, not many providers are using it for the first dose.

Dr. Even (ACHA) thought it was striking that none of the recent outbreaks have been reported in 

the military, which is comprised of the same age group and close quarters. She wondered 

whether DoD was doing something different.

Dr. Marin replied that the experience of the military has often been mentioned in support of a 

third dose. The military implemented vaccination of recruits regardless of their vaccination 

status in 1991, so those entering the military probably received a third dose. They made some 

changes based on serology, but the protocol is primarily giving a dose to everybody regardless 

of their status.

Margaret Yacovone (DoD) indicated that for all recruits entering the military, if there is no 

evidence of 2 doses of MMR, their antibodies are checked. If they are negative on any, they 

receive 2 doses of MMR. As a result, the military has very high immunity such that even if there 

is an isolated case, there is not transmission. Not all services in all recruit sites check for 

mumps. The DoD is trying to change this so that it will be unified across the services, especially 

with the outbreaks of mumps that have occurred throughout the US.

Dr. Romero indicated that in Arkansas, children under 10 years of age comprise most of the 

outbreak population.

Dr. Marin indicated that based on the age distribution of cases in Arkansas through the previous 

week, it was true that there have been a lot of cases in the younger age group. However, there 

are cases in the older age groups as well, 57% of case patients in Arkansas have been 5 

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through 17 years of age. A potential explanation for the age distribution is case finding. Cases 

are reported primarily by schools. There is not good reporting from workplaces or other 

settings.

Dr. Riley asked whether there are good data to suggest for the college outbreaks that even for 

international students, the vaccination rates are just as high as for US-born students.

Dr. Marin said she did not think they specifically assessed international students, but national 

serologic surveys, examined mumps immunity by place of birth. People born outside the US 

have somewhat higher levels. One explanation might be that about 38% of the countries do not 

vaccinate against mumps. The mumps epidemiology is such that by 14 to 15 years of age, 90% 

of people have antibodies. College students coming from abroad from countries with no 

vaccination probably are immune.

Dr. Whitley Williams (NMA) asked whether Margaret Yacovone from DoD knew what percent of 

the recruits tested have negative mumps serology.

Margaret Yacovone (DoD) responded that she did not have that information, but they were 

finding higher antibody titers in some of their populations who were born abroad. They can 

share these data if it would help with ACIP’s decision-making. The DoD has examined this a 

few times over the past several years.

Dr. Marin replied that this would be useful.

Dr. Maldonado said she understood that the patients from Arkansas may differ in other ways. 

For example, many of them are Marshallese students and tend to be younger and their 

symptoms are distinct as well. They have recurrent parotitis, which is generally not seen in a 

normal mumps outbreak situation.

Dr. Marin pointed out that it is difficult to confirm recurrent disease, especially in a situation like 

mumps where parotitis can be determined by other agents. Confirmation would be needed of 

both episodes, and she did not know how often that happened in Arkansas. There is evidence 

in the literature of symptomatic mumps after a previous infection occurred. Those were 

documented by laboratory confirmation and the profile of the immune response which supported 

reinfection.

Dr. Romero added that interesting about the Arkansas outbreak is that they are not seeing the 

secondary complications. For example, they would expect to see many more cases of aseptic 

meningitis, encephalitis, hearing loss, and orchitis. However, they are not seeing that. They do 

see some cases of orchitis, but not the central nervous system (CNS) disease that is anticipated 

with mumps. He would interpret that to mean that there is some protection from the vaccine.

Dr. Duchin (NACCHO) reported that Washington State is also experiencing an outbreak, 

primarily in King County. On an encouraging note, when they had to exclude students from a 

school district with about 15,000 total students who are unimmunized or did not have up-to-date 

MMR vaccination, over half were immunized and returned to school rather than staying out the 

entire exclusion period that would have been required. This is encouraging to see, and it 

suggests that there is not a true objection to vaccination and may just be other barriers. A 

certain percentage refuses to be vaccinated and are staying out of school for a prolonged 

period.

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Ms. Pellegrini noted the disproportionate share of Native Hawaiian and other Pacific Islanders 

with mumps in 2016. That is because about half of US cases in 2016 were reported from 

Arkansas that had a large outbreak affecting primarily the Marshallese community.

Introduction

Emmanuel (Chip) Walter, MD, MPH

Chair, Flavivirus Vaccines Work Group 

Advisory Committee on Immunization Practices

Dr. Walter reminded everyone that this WG was renamed the “Flavivirus Vaccines Work Group” 

to encompass work on Japanese encephalitis (JE), Yellow Fever (YF), dengue, and Zika 

vaccines. During the last few months, the WG began a review of dengue epidemiology, 

immunology, and diagnostics to prepare for submission of a dengue vaccine BLA. During the 

past few months, the WG also has monitored the YF vaccine supply and worked with the 

manufacturer on contingency plans to address shortages. 

In terms of the dengue vaccine tentative timeline, Sanofi Pasteur is expected to submit a BLA 

during 2017. In June 2017, Sanofi Pasteur will present dengue vaccine data to ACIP. In 

October 2017, the WG will present modeling and cost-effectiveness data to ACIP. In February 

2018, the WG will present the GRADE evaluation and proposed recommendations to ACIP. 

Dengue Virus Vaccines

Steve Waterman, MD, MPH

Chief, Dengue Branch 

Centers for Disease Control and Prevention 

San Juan, Puerto Rico

Dr. Waterman discussed the need for a dengue virus (DENV) vaccine in terms of the clinical 

disease burden and lack of primary prevention tools, vaccines constructs and candidates, 

epidemiologic challenges to vaccine evaluation, and results of the lead-candidate vaccine trial

from Sanofi Pasteur. As a reminder, dengue viruses belong to Flavivirus genus of the 

Flaviviridae family. There are four antigenically distinct serotypes: DENV-1, DENV-2, DENV-2, 

DENV-4. These are enveloped single-stranded viruses with 3 structural proteins, the envelope, 

capsid, and membrane proteins. This phylogeny dendrogram based on the complete amino 

acid sequence of the polyproteins of important flaviviruses pathogens show that dengue, Zika, 

and YF viruses all share primate hosts and Aedes mosquito vectors. Dengue is relatively 

closely related to Zika virus:

Dengue Virus Vaccine

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Lazear and Diamond 2016, Journal of Virology

DENV is primarily transmitted through a man-mosquito-man transmission cycle, with incubation 

periods in humans and mosquitos of roughly a week in each species. Dengue is arguably the 

most important arbovirus in terms of morbidity and mortality. It is an emerging disease, which is 

both epidemic and endemic in tropical and sub-tropical regions with an expanding distribution. 

The estimated global burden based on literature review and modeling is that there are an 

estimated 390 million infections annually with 96 million clinically apparent infections, 2 million 

severe dengue cases, and 20,000 deaths worldwide.

Severe illness has a distinct pathology involving shock, hemorrhage, and severe organ 

involvement. Shock involves systemic vascular permeability leading to vascular hypovolemia 

and Dengue Shock Syndrome (DSS). Hemorrhage involves bleeding manifestations, which are 

commonly due to the combined effects of thrombocytopenia and deranged hemostasis. Severe 

organ impairment such as encephalitis and hepatitis can occur. Risk factors for severe dengue 

have been studied extensively. One of the major risk factors is secondary infection with a 

second dengue serotype, although not all severe dengue is as a result of a secondary infection. 

Virus strain, host genetics, co-morbidities (especially in older adults), young age, and being 

female also have been identified as risk factors for severe disease.

The pathogenesis of severe disease seems to be related to viral burden, which often has been

linked to heterologous non-neutralizing antibody enhancing infection. The immune response

triggers inflammatory mediators, cytokines and chemokines which are thought to promote

capillary permeability syndrome, although the exact mechanism is unclear. Coagulopathy is 

probably a result of the loss of essential coagulation proteins, but this is not completely 

understood in terms of the pathogenesis.

Regarding dengue vaccine status, one vaccine has been registered by Sanofi Pasteur in

several countries including Mexico, Brazil, and the Philippines. There are multiple other vaccine 

candidates and many clinical trials underway. The vaccines would be indicated in pediatric and 

adult populations. The diagnostics necessary for clinical management and for assessing 

dengue vaccine trials are very good for acute disease, but antibody assays need to be 

improved. The recent co-circulation of Zika and DENV in many countries, which cannot be 

distinguished reliably by current available IgM tests, underscores this situation.

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Large disease and economic burdens associated with hospitalizations and clinical care during 

outbreaks drive the rationale for a dengue vaccine. The primary prevention of vector control, 

has not been effective in the last 50 years as evidenced by the expanding number of cases and 

distribution of the disease. An effective primary prevention tool is needed for dengue. 

Secondary prevention currently involves medical management of severe dengue, which can be 

quite effective in reducing mortality with severe dengue to less than 1%, but again the 

healthcare burden could be ameliorated significantly by having a primary prevention tool such 

as a vaccine.

A publication by Bhatt et al in Nature recently reviewed the evidence and modeled the likely 

burden of disease. As shown on the following map, DENVs circulate throughout the tropics and 

subtropics in the major continents: 

The largest burden of disease is in Asia, followed by the Americas in terms of documented 

disease, with Africa likely having a similar disease burden, but not very well-documented. 

Puerto Rico, the most affected US territory, experiences two or three large epidemics each 

decade with thousands of hospitalizations and dozens of deaths. Roughly 80% of the 

population of Puerto Rico is infected with dengue by the second decade of life.

This WHO Dengue Prevention Framework highlights the potential importance of vaccines for 

primary prevention, with key roles for surveillance and diagnostics in assessing vaccine efficacy

[Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control. New Edition. WHO, 

2009; Global Strategy for Dengue Prevention and Control 2012-2020. WHO, 2012].

The conventional correlate of protection for dengue is neutralizing antibodies by the plaque 

reduction neutralization titer (PRNT50-70) test and cell culture using cells that are not actually the 

primary targets of infection in vivo, which are Fc receptors (FcR)-bearing cells. Homotypic 

antibodies against the infecting serotype are protective for many years, if not for life. 

Heterotypic antibodies develop after infection to non-infecting serotypes and provide crossprotection against dengue infection for a limited time interval of 6 months (Sabin, 1952) or 

perhaps longer.

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As mentioned, secondary dengue infections have been shown to be a risk factor for severe 

dengue. In vitro studies demonstrate enhanced infection in cell culture in the presence of

heterotypic (non-neutralizing) antibodies, a phenomenon known as antibody dependent 

enhancement (ADE). Animal and mouse models have demonstrated similar results. The most 

convincing evidence for heterotypic antibody playing a role in pathogenesis for dengue is in 

infants where primary dengue infection in the presence of passively acquired maternal antibody

has been shown to lead to dengue hemorrhagic fever (DHF). Cohort studies of school children 

also have documented secondary infection being a risk factor. As a result of such studies, the 

ideal product profile has been viewed for some time as a tetravalent vaccine for all four 

serotypes. The ideal characteristic, as for other vaccines, would be logistically easy to deliver 

vaccines with high efficacy and without the need for booster doses.

A number of dengue vaccines are in development. The commercial vaccines furthest along are 

live-attenuated cell culture-adapted infectious cloned chimeric virus vaccines as well as a 

vaccine combining chimera with attenuated by site directed mutagenesis, recombinant subunits 

of DENV envelope proteins, and inactivated dengue viruses. Next generation in development

include viral vectored subunits, virus-like particles (VLPs), peptide chimeras, and DNA. The 

specific dengue vaccine candidates are shown in the table below:

Chimeric flavivirus vaccine technology involves using either YF 17D backbone or dengue 

genome cloned as complementary DNA (cDNA). The prM and E protein genes are then 

inserted into the structural backbone, chimeric cDNA is transcribed to RNA, transfected into cell 

culture and grown, which results in the chimeric vaccines with the envelope proteins having 

heterologous viruses as illustrated below:

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Good animal models are lacking for vaccine evaluation. A Macaque model does not produce 

disease and does not predict immunogenicity in humans. An AG 129 interferon deficient mouse 

model does produce DHF. A human challenge model is rarely used, although such human 

challenge is under consideration by NIH. Human clinical trials are the gold standard that are 

going to be required to determine the performance of dengue vaccine candidates.

Dengue epidemiology is a challenge to vaccine evaluation. Dengue is an acute febrile illness

(AFI) syndrome, which can only be defined by diagnostic testing. Many look-alike AFIs in 

dengue endemic areas include: malaria, influenza, leptospirosis, meliodosis, hepatitis A, et 

cetera. Other challenges are the cyclical and seasonal transmission in endemic areas with 

multiple serotypes, varying age-specific incidence in various parts of the world, and a spectrum 

of illness with a large percentage of asymptomatic infections and a small proportion of severe 

disease. These epidemiologic characteristics dictate a large population base for phase III trials 

because of the focal nature of dengue. Febrile illness surveillance needs to be set up to identify 

dengue fever (DF) syndromes, gather data on age-specific disease incidence, determine 

variation in incidence over several seasons, and have molecular and immuno–diagnostic testing

capability. Molecular testing is good for the first few days, and then after that serologic 

capability is needed [ Guidelines for Clinical Evaluation of Dengue Vaccine in Dengue Endemic 

Areas. Vaccine 2008;26:4113-4119].

This graphic illustrates the period of viremia during which an rRT-PCR or NS1 antigen detection 

can be diagnosed in the first few days of illness and post-fever onset. After about 5 days, IgM is 

present for a couple of months:

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In terms of some of the preparatory studies that have been conducted, a prospective cohort 

study was conducted in Ratchaburi, Thailand during 2006-2009. This study illustrates some of 

the complexities. This study included approximately 3000 children 3 through 13 years of age. 

Active surveillance was conducted for absences and febrile episodes in schools and home 

visits. Fever was defined as 37.5°C oral irrespective of duration. In this study, 0.53 febrile 

episodes were found per child per year. In terms of clinic visits by day post-fever onset, the 

investigators were able to examine 53% of the children within 1 to 2 days after fever onset, 30% 

after 3 to 4 days, and 14% after 5 to 6 days. Clinic evaluation included an initial and follow-up 

blood draw, with diagnostic testing by PCR and IgM anti-DENV. In this study, dengue incidence 

varied considerably year-by-year, ranging from 1.7% to 5.7%. The serotype incidence also 

varied markedly by year, ranging from 43% overall for DENV-1 to 8% overall DENV-4 over this 

3-year time period. The majority of the infections were mild illness or undifferentiated fever 

(UF). All of the DHF cases, 84% of classic DF cases, and 15% of the UF cases were 

hospitalized. Of the infections, 86% were secondary in these children in this highly endemic 

area [From Sabchareon, A et al. PLoS NTD 2012; 6: e1732].

The Sanofi Dengue Vaccine Efficacy Trials (CYD) were randomized, blinded, placebo-controlled

trials among children 2 through 16 years of age. The children were given 3 doses of tetravalent, 

live, attenuated vaccine at 0, 6, and 12 months. The control groups were given a normal saline 

vaccine diluent placebo. The endpoint was symptomatic, confirmed DF requiring clinical acute 

febrile illness and PCR-detected viremia. The follow-up period was 25 months total, including 

13 months after the last dose. Longer-term follow-up of 48 months is being conducted.

This table shows the characteristics of three published trials with large sample sizes in which 

pre-existing DENV antibody was present in approximately 70% to 80% of the children: 

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Site(s) Design N Ages (yrs)

Pre-Existing 

DENV 

Antibody (%)

Ratchaburi, Thailand Phase 2B 4002 4-11 69.5

Asia – Indonesia, Malaysia, 

Philippines, Thailand, 

Vietnam 

Phase 3 10,275 2-14 67.5

Latin America Colombia, 

Brazil, Mexico, Puerto Rico, 

Honduras 

Phase 3 20,869 9-16 79.4

In terms of the results of these trials, overall VE was about 61%. However, VE varied 

considerably by serotype. The lowest efficacy with this vaccine was for DENV-2 at 42% with 

higher VE for DENV-1 at 50%, DENV-3 at 74% and DENV-4 at 78%. In terms of clinical 

outcomes of dengue, there were no differences between the vaccine and placebo groups in 

clinical features or severity of dengue, including: duration of clinical syndrome, fever, 

hospitalization, bleeding, plasma leakage, thrombocytopenia, shock, or organ impairment. 

Regarding other outcomes, no safety signals were observed in the short-term. Long-term, 

blinded follow-up is ongoing. Immunogenicity and protection in children without previous DENV 

infection is poor.

 

In conclusion, tetravalent, DENV – chimeric yellow fever-dengue vaccine (CYD) has been 

shown, and is reflected in some recent recommendations from WHO’s Strategic Advisory Group 

of Experts on Immunization (SAGE), to be safe when administered to children living in a dengue 

endemic area and with a high background of previous DENV infection. A caveat is that in the 

Asian study, a higher rate of DHF was seen in the vaccine group in Year 3. Only partial 

protection has been shown against dengue, with lowest protection against DENV-2, followed by 

DENV-1, and highest protection against DENV-3 and 4 [From: Sabchareon, A et al. Lancet 

2012; 380:1559-1567; Capeding MR, et al Lancet 2014; 834: 1358-1365; Villar L, et al. NEJM 

2015: 372 113-123].

Sanofi Pasteur will be invited to present to the Flavivirus WG in the coming months, and would 

like to invite them to present during the next ACIP meeting to provide more details and answer 

questions.

Discussion Points

Dr. Belongia asked whether the type with which children were previously infected was known 

and if that was associated with the lower efficacy for DENV-1 and DENV-2.

Dr. Waterman indicated that there were pre-antibody samples in a limited number of children, 

and it is difficult to tell what the prior infecting serotypes were. There are additional studies, 

some of which are just coming out. A study was published recently in JID about the antibody 

response. This remains a complicated question with no definitive answers.

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Dr. Stephens asked whether there were estimates of efficacy for the individuals with poor 

immunogenicity who had a prior dengue infection. 

Dr. Waterman replied that it was approximately 40%, and that more detailed data will be 

presented from the studies.

Marc Fischer, MD, MPH

Arboviral Diseases Branch

Division of Vector-Borne Diseases 

National Center for Emerging and Zoonotic Infectious Diseases 

Centers for Disease Control and Prevention

Dr. Fischer reminded everyone that Zika virus was first isolated from a sentinel rhesus macaque 

monkey in Uganda in 1947. Prior to 2007, only sporadic human disease cases were reported 

from Africa and Southeast Asia. In 2007, the first Zika outbreak was reported on Yap Island, 

Federated States of Micronesia. In 2013–2015, more than 30,000 suspected cases were 

reported from outbreaks in French Polynesia and other Pacific islands. Prior to 2014, less than 

10 countries reported any type of mosquito-borne Zika virus activity. In 2015, with the spread to 

the Americas, there was a substantial increase over 2015 and 2016. The greatest increase was 

in the Pan American Health Organization (PAHO) regions of the Americas, but there were 

increases in other countries as well. As of mid-January 2017, 76 countries or territories around 

the world had reported Zika virus transmission at some point. In May 2015, the first locally 

acquired cases in the Americas were reported in Brazil. There likely had been transmission for 

a number of months prior to that. As of January 2017, local transmission has been reported in 

50 countries or territories in the Americas. The only countries in the Americas without reported 

local transmission are Bermuda, Canada, Chile, and Uruguay. 

The map below on the left shows the time of first reported cases, with lighter countries being 

earlier. The move into darker colors shows the spread and increase in transmission. The table 

on the right below reflects the number of locally transmitted Zika virus disease cases reported to 

PAHO by countries and territories in the Americas: 

Zika Virus Update

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As of mid-January 2017, almost 740,000 total suspect or confirmed cases had been reported. 

Brazil and Colombia accounted for approximately 60% of the total reported. About a quarter of 

the cases were laboratory-confirmed, while the remaining three-quarters of the cases were 

clinical cases that met the suspected case definition and could have included some other 

diseases or viruses, such as dengue. Most suspected and confirmed locally transmitted cases 

reported to PAHO, as of January 2017, were reported from South America (70%), followed by 

the Caribbean (20%), Central America (8%), and North America (2%).

From 2007–2014, only 14 Zika virus disease cases were identified in US travelers who traveled 

to the Pacific Islands or Asia. With recent outbreaks in the Americas, recent cases among US 

travelers increased substantially. Limited local mosquito-borne transmission has been identified 

in two states: Southern Florida and Southern Texas. There have been widespread outbreaks 

in three US territories: Puerto Rico, US Virgin Islands, and American Samoa. 

A total of 4710 travel-associated cases were reported to ArboNET from US states from January 

1, 2015 through January 25, 2017. It is important to note that travel-associated cases include 

cases in travelers and their contacts with presumed sexual or in-utero transmission, and one 

case with unknown route of person-to-person transmission. One laboratory-acquired case was 

reported in a researcher. A total of 35,644 locally acquired cases were reported in the territories. 

In the states, 219 locally-acquired cases were reported.

 

The following map shows these cases broken down by state, with darker shading having more 

cases. The cross-hatching shows Puerto Rico, American Samoa, the US Virgin Islands, and 

small regions in Southern Florida and Texas having local transmission. These numbers are 

updated weekly on the CDC webpage. In terms of the state of residence for these laboratoryconfirmed Zika virus disease cases, the highest reporting travel-associated cases were in New 

York (1001; 21%) and Florida (840; 18%), followed by California (411; 9%) and Texas (294, 

6%). The majority of locally-acquired cases were reported from Florida (213; 91%), followed by 

Texas (6; 3%):

Beginning in July 2016, sporadic locally-acquired cases were identified in multiple counties in 

South Florida. Active ongoing transmission was identified in three small areas of Miami-Dade 

County. That prompted recommendations for pregnant women to avoid travel to those areas, 

and for pregnant residents to be tested and followed for their pregnancy outcomes. There was 

an intensive public health response, including unprecedented aerial adulticide and larvicide 

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applications, which appeared to help control the outbreaks. At this time, there is no evidence of 

ongoing, sustained local transmission [Florida Health Newsroom].

This map shows where that transmission occurred. The main map is Miami-Dade County and 

then there are three insets that show how small the areas are where active, local transmission 

occurred. These areas are generally about 1- to 2-miles square, with the area in Miami Beach 

in the lower right being slightly larger: 

In November 2016, the first case of local mosquito-borne Zika virus infection was reported in 

Brownsville, Texas. This area borders Mexico and there are frequent border crossings in both 

directions, including people who go across the border daily. Active Zika virus transmission was 

reported in Mexico near the US-Mexico border. That continues to this day. In December, CDC 

designated Brownsville a Zika cautionary area, shown in yellow on the map. This means that 

there are recommendations for pregnant women to avoid travel to those areas and pregnant 

residents to be tested and followed. As of January 25, six cases of local mosquito-borne 

transmission had been identified and reported from the Brownsville area. This map tries to put 

into context the size of the area. The inset shows the county and area at the very tip of the 

bottom of Texas bordering the Gulf of Mexico and Mexico:

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The vast majority of reported Zika virus disease cases in the US territories for the time period

2015 through January 2017 were locally-acquired (N=33,712), with 97% (N=32,848) being 

reported from Puerto Rico, 2% (N=807) from the US Virgin Islands, and 1% (N=5) from 

American Samoa. This is a map of Puerto Rico showing cases by municipalities, with the 

darker shades being larger numbers of cases. The primary point is that all municipalities in 

Puerto Rico have reported local Zika virus transmission, so the outbreak on the island was 

widespread. The darker shadings are around the major metropolitan areas where the most 

cases were seen in the Northeast in the San Juan metropolitan area and Southwest in the 

Ponce metropolitan area:

This figure shows the age group distribution for reported Zika virus disease cases in the US 

states and territories as of January 25, 2017. The age distribution was similar for laboratoryconfirmed reported cases of Zika virus disease cases in the states, with a slightly higher 

proportion of cases among children and young adults in the territories. The higher numbers of 

cases in the 20-39 year age group and the 40-59 year age group may reflect, in part, the 

additional testing occurring in pregnant women as well as exposure among travelers in these 

age groups.

This is the epi curve showing month of illness onset for Zika virus disease cases reported in US 

states and territories, with the peak of the outbreak occurring in late summer, with a steep 

decline occurring in the fall and winter.

Returning to Zika virus transmission and clinical manifestations, Zika virus is an RNA flavivirus 

related to dengue, YF, JE, and West Nile viruses. Transmission to humans is primarily by 

Aedes (Stegomyia) species mosquitoes. In the Americas, that includes Aedes aegypti and 

Aedes albopictus. Infection is typically asymptomatic or causes mild dengue-like illness. 

However, recent outbreaks in the Americas and Pacific Islands have identified new modes of 

transmission and clinical manifestations.

In terms of clinical course, most infections are asymptomatic. The clinical illness is usually mild

and is characterized by fever, rash, arthralgia, or conjunctivitis. These symptoms usually last for 

several days to a week. Severe disease requiring hospitalization is uncommon and fatalities

have been rare. 

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Clinical manifestations newly identified in the last couple of years include fetal loss, 

microcephaly and other congenital anomalies, Guillain-Barré Syndrome (GBS) and other 

neurologic syndromes, and thrombocytopenia. 

Non-mosquito-borne modes of transmission that have been documented include intrauterine

transmission resulting in congenital infection, intrapartum from a viremic mother to a newborn, 

sexual transmission, laboratory exposure, and blood transfusion. Possible modes of 

transmission include organ or tissue transplantation, breast milk, and other body fluids. 

Regarding the risk of adverse outcomes of pregnancy, the incidence and clinical spectrum of 

congenital Zika virus infection remains unknown. The risk of fetal loss and congenital 

anomalies appear to be greater with infections early in pregnancy. The risk of congenital 

microcephaly following Zika virus infection during the first trimester of pregnancy is estimated to 

be 1% to 13%. It is probably on the lower end of that for microcephaly, but possibly in that 

range for all other anomalies as reported. 

This table shows microcephaly or other CNS malformations possibly associated with Zika virus 

infection reported to WHO by country or territory as of January 20, 2017. This includes cases 

that may not have laboratory confirmation, and can include cases that were acquired in 

residents in one country who then traveled to another country to deliver:

Country/Territory (N=29) (N=2,635)

Brazil 2,366 (90%)

Colombia 78 (3%)

United States 41 (2%)

Dominican Republic 22 (1%)

Martinique 18 (1%)

French Guiana 16 (1%)

Guatemala 15 (1%)

22 other countries/territories 79 (3%)

*Includes cases acquired in other countries

As mentioned, the clinical findings in infants with congenital Zika virus infection clearly extend 

beyond microcephaly, although that is one of the most severe manifestations and the first to be 

recognized. It now includes other brain anomalies including subcortical calcifications that 

appear to be a particular distribution, ventriculomegaly, abnormal gyral patterns, corpus 

callosum agenesis, and cerebellar hypoplasia. There also have been a number of ocular 

anomalies including microphthalmia, cataracts, chorioretinal atrophy, and optic nerve 

hypoplasia. Other neurologic sequelae related primarily to the brain anomalies include 

hypertonia or hypotonia, irritability, tremors, swallowing dysfunction, hearing loss, and visual 

impairment. Congenital contractures due to lack of movement of the fetus can include clubfoot

and arthrogryposis. 

Two cases of Zika virus perinatal transmission have been reported in the literature from French 

Polynesia from the 2015 outbreak. Both women developed mild rash illness within 3 days of 

delivery. One infant developed a transient rash and mild thrombocytopenia at 3 days of life. 

The second infant remained asymptomatic. Both mothers and infants had evidence of Zika 

virus RNA in serum. The newborns otherwise had unremarkable clinical courses.

Sexual transmission was first identified in sexual partners with discordant travel histories. The 

first report in 2011 was in a returning traveler from Colorado who went to Senegal. Little 

attention was given to this until 2016 when sexually transmitted cases were reported from 12 

countries, including 38 cases in the US all among travelers with discordant travel histories. 

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Most reported cases have been from men with symptomatic illness transmitting to their female 

or male partner. One report of transmission was from a woman to a man, and two reports of 

transmission were from asymptomatic men to their partners.

Zika viral RNA has been detected in semen up to 6 months after illness onset and in vaginal 

fluid up to 2 weeks after illness onset. Zika virus has been cultured from semen up to 70 days

after illness onset. However, most of the sexual transmission that has been reported has 

occurred within the first month to 40 days after illness onset in the transmitting partner. The 

data thus far are primarily from case reports, which may not reflect true incidence or risk of 

transmission. The full length of duration of RNA or live virus in semen or vaginal fluids and the 

level of risk remains unknown. There are ongoing studies to better determine that.

The incidence, duration, and risk factors for sexual transmission are unknown. One modeling 

study from Brazil suggested that the apparent increased incidence of disease in women

compared to men could possibly be due to sexual transmission. Obviously, there are many 

other factors like increased awareness and testing because of the concerns about congenital 

infection. Another model determined that sexual transmission is likely not a significant factor in 

driving an outbreak, that it really is mosquito-borne transmission that drives the outbreak, 

although sexual transmission certainly contributes to cases. Two prospective cohort studies in 

the US are ongoing to better evaluate the frequency and duration of Zika virus RNA and live 

virus in semen. One of these is being performed in Puerto Rico, and preliminary data have 

been published on that. The second is among men in the Continental US (CONUS). 

Pertaining to transfusion-transmitted Zika virus infections, Zika virus RNA was identified in 42 

(3%) of 1505 blood donors in French Polynesia in 2013–2014. None of those products were 

transfused, so there were no transfusion-related events. In 2016, at least 3 cases of 

transfusion-transmitted Zika virus infections were reported from Brazil. In February 2016, the 

FDA issued recommendations to reduce the risk of transfusion-transmitted Zika virus in the US. 

From April through December 2016, routine screening identified Zika virus RNA in 360 (0.6%) of 

54,588 blood donations screened in Puerto Rico. In August 2016, the FDA recommended 

routine Zika virus screening of all blood donations in the US, which is currently ongoing under 

an IND process.

From 1964 through 1980, there were 4 to 6 reports of probable Zika virus infections due to 

laboratory exposure. Based on the range and probability from some of the publications, it is 

unclear if they overlap with other publications because there are not enough details. In addition, 

there was at least one case in which a person worked in the laboratory and was conducting field 

work in the Zika forest. It was unclear whether that person was actually infected and whether it 

was due to mosquitos or work in the laboratory. In 2016, there was one report of confirmed Zika 

virus infection following a needle stick injury in a US researcher. That person developed a mild 

symptomatic illness without further complications. 

Zika virus transmission through breast milk has not been documented thus far. However, Zika 

virus RNA was detected in breast milk collected several days after onset of illness in the two 

women who had perinatal transmission documented in French Polynesia. In those cases, 

culture of the breast milk was negative for live virus. However, since that time both RT-PCR for 

RNA and culture have identified Zika virus in breast milk in one case that was collected 4 days 

after onset of illness in a woman in New Caledonia. There has since been a subsequent report 

of positive breast milk for both RNA and culture. The infant in the New Caledonia case 

remained asymptomatic and had no laboratory evidence of infection, and there has otherwise 

not been evidence of transmission thus far. Therefore, to date WHO and CDC believe that the 

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benefits of breastfeeding outweigh the theoretical risk of transmission to an infant through 

breast feeding.

As far as other body fluids, Zika virus RNA has been detected in saliva and tears. One case of 

possible person-to-person transmission was reported from Utah. The index patient developed 

fatal septic shock and had a level of viremia approximately 100,000 times higher than average. 

It is unclear why the patient had that high a level of viremia. Zika virus infection was diagnosed 

in a family member who had close contact (i.e., kissing and touching) with the index case 

outside and inside the hospital in the days leading up to his death. An extensive investigation 

was performed by the Utah Department of Health with CDC. No specific source or mode of 

transmission was identified. In addition, there was an extensive investigation of other family 

members who had contact with the patients, hospital and morgue workers, and the community. 

Among those hundreds of people, no additional infections were identified among people who 

had contact with the patient.

GBS following Zika virus infection was first described in French Polynesia during the 2013‒2014 

outbreak. An additional 19 countries have now reported at least one GBS case with laboratory 

evidence of Zika virus infection. There have been 13 GBS cases reported from US states and 

50 from Puerto Rico. Overall, there are an estimated 1.6 cases of GBS per 10,000 Zika virus 

infections. Outcomes and increased risk in older adults appear to be similar to GBS due to 

other causes. 

In terms of neurologic disease with non-congenital Zika virus infections, there have been rare 

published reports of encephalopathy, meningoencephalitis, myelitis, and uveitis. In addition, 

there have been reports of peripheral paresthesias, with or without GBS. The frequency is still 

to be defined.

An estimated 1% of symptomatic Zika virus disease cases may have mild thrombocytopenia

defined as a platelet count <100,000. That is based on work done in Puerto Rico. But, there 

have been rare reports of severe thrombocytopenia with hemorrhage or septic shock, including 

at least two fatal cases. One of these was the case described in Utah and one in Puerto Rico, 

and similar cases have been reported from other countries.

With respect to Zika virus treatment and prevention, the primary prevention mode is to reduce 

mosquito exposure through vector control and personal protective measures (e.g., insect 

repellent, door screens, window screens, and air conditioning). As recommended by CDC and 

many other countries, pregnant women are advised not to travel to areas with local transmission 

and to take steps to protect themselves against possible sexual transmission. Currently, there 

is no vaccine or medication to prevent or treat infection or disease. Numerous candidate

vaccines are being evaluated. There is a coordinated US government effort to facilitate 

development that includes Office of the Assistant Secretary for Preparedness and Response

(ASPR), Biomedical Advanced Research and Development Authority (BARDA), NIH, CDC, and

Department of Defense (DoD). As far as how these vaccines will be used, the targeted use 

likely will depend on the ongoing incidence and locations of disease, further information on the 

complications related to the disease, and the vaccine characteristics (e.g., safety, efficacy, and 

duration of protection). 

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Zika Vaccines in Development

Gerald R. Kovacs, PhD

Biomedical Advanced Research and Development Authority

Office of the Assistant Secretary for Preparedness and Response

US Department of Health and Human Services

Dr. Kovacs presented a brief update on what BARDA has done so far on the development of 

Zika vaccines. This is one of the most challenging, dangerous, and potentially insidious viruses 

the government is working on currently. While currently there is no licensed Zika vaccine 

available, vaccines for other flaviviruses have been developed and used for over 70 years. 

Active development programs for dengue and West Nile vaccines have been ongoing for over 

30 years; however, knowledge of Zika virus was limited at the outset of the epidemic. Past 

experience is being leveraged for Zika vaccine development. Zika research and development 

(R&D) efforts have been accelerated greatly by NIAID, Walter Reed Army Institute of Research 

(WRAIR), and BARDA. A coordinated, interagency portfolio management team was established 

to oversee and accelerate vaccine development. A multidisciplinary approach is taken to 

accelerate the types of countermeasures needed at any given time.

Regarding the product development pipeline and how the government works together, each 

agency has particular roles and responsibilities. In the case of Zika, NIH and DoD took on a 

very important role early in developing and testing candidates. ASPR/BARDA takes the handoff 

from NIH in this respect and is involved in advanced product development, which in essence 

means taking products through clinical development to manufacturing and scale-up. This is 

done primarily by partnering primarily with manufacturers. Suffice it to say that some 

manufacturers come to ASPR/BARDA for funding and some do not. A number of companies 

are currently developing Zika vaccines, diagnostics, other countermeasures, and therapeutics 

that do not have government funding. Importantly, the FDA works with all companies. In the 

traditional sense, the FDA usually works with companies after a certain amount of information is 

gathered pre-clinically, clinically, and toxicologically. In the case in which countermeasures are 

being developed in response to an epidemic such as Zika, the FDA takes on a different role and 

works with ASPR/BARDA daily to help develop vaccines in such a way that as much important 

information as possible can be gained in the shortest amount of time.

As of February 2016, there were only two US government-funded Zika vaccine projects 

ongoing, one with the NIH and the Institute Butantan and the other at the DNA-Vaccine 

Research Center (DNA-VRC) with a DNA plasmid approach. Little was being done in terms of 

preclinical development. These products were in the early phases of discovery, and there was 

nothing in Phase 1 yet. An interagency consortium of experts on vaccine development was 

formed and developed three aims towards the goal of developing a safe and efficacious Zika 

vaccine to prevent congenital Zika syndrome: 1) 2016-2018, evaluate available vaccine 

candidates to assess safety, efficacy, and immunogenicity and identify protective immune 

correlates during the time of highest disease incidence; 2) By 2018, deploy an available vaccine 

under an appropriate regulatory mechanism to US populations at high risk of exposure; and 3) 

By 2020, work with industry partners to commercialize vaccine(s) for broad distribution. 

Aim #1 involves evaluating as many vaccine candidates as possible, assessing a myriad of 

platforms, developing animal models, developing reagents, and developing enough data to 

perhaps apply a correlate of protection that would be useful for clinical developers. Aim #1 is 

currently being fulfilled with a vast number of candidates. Aim #2 is relatively aggressive. This 

involves vaccines at the pre-licensure stage that would be made available under an EUA or 

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Expanded Access IND. These vaccines would be used in CONUS, or Puerto Rico and other 

territories when there are outbreaks. The government is engaged in partnerships with a number 

of large and medium pharmaceutical companies, with the hope that by 2020 one or more of 

those manufacturers will have submitted a BLA to the FDA.

Before launching into supporting any type of vaccine candidate platform, all platforms available 

at the time were assessed. Some of these platforms, such as whole virus inactivated and live 

attenuated vaccine platform had been used in the past and placed in the market such as 

Japanese encephalitis, tickborne encephalitis (TBE), and yellow fever vaccines. The only issue 

with those platforms is that they take a significant amount of time to develop using Good 

Manufacturing Practices (GMP). Also available were a couple of nucleic acid platforms, DNA 

and mRNA. These platforms are more easily manufactured using GMP and can be quickly 

placed in the clinic setting as long as the correct antigen needed to vaccinate with is known. 

This was done with DNA and mRNA backbones. In earlier stages of development were viralvectored and recombinant/subunit candidates. The pros and cons for each candidate are 

compared in the table below:

Relative to the three aims, a number of candidates are in development. The NIH Vaccine 

Research Center (VRC) is developing a candidate DNA vaccine. In addition, an mRNA 

candidate vaccine was developed by Moderna, a commercial company based in Bostin, in 

coordination with NIH and BARDA. These vaccines are currently in phase 1 clinical trials. 

Inovio, another commercial company, is developing another DNA vaccine without US 

government support and started their Phase 1 trial about a month before the VRC. The hope is 

that some of these vaccines make it to Aim #2, the deployment stage for one or more of these 

candidates. Based on safety and efficacy data that will accrue over the next year or two, 

potentially the DNA and/or mRNA platforms may fulfill that goal.

 

The candidates envisioned to fulfill Aim #3 include products such as the two inactivated 

candidates being developed by Sanofi Pasteur and Takeda, and potentially the mRNA 

candidate being developed by BARDA and Moderna. That would be the first marketed mRNA 

vaccine. A fourth vaccine, which is being developed by the Laboratory of Infectious Diseases, is 

a live attenuated Zika-chimera. In addition to all of these, a number of earlier products are in 

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R&D including a VSV vectored vaccine (NIAID, Harvard), chimera and VLP (CDC), mRNA 

(VRC, GSK), and PIV (BARDA, Butantan).

The VRC has conducted a Phase 1 trial on the initial construct and is currently conducting 

another Phase 1 trial on a modified construct. These constructs primarily encode the prM and E 

genes in Zika virus and use the PharmaJet® injector. The initial results from the first trial are 

being analyzed currently. The second trial is ongoing and should be completed in a couple of 

months in anticipation of conducting the Phase 2/2b clinical trial. This trial will be conducted in 

the US in areas where Zika is observed, as well as in Central and South America. In this trial, 2 

doses of DNA plasmid vaccine will be administered using the needless PharmaJet® injector in 

either 4 mg or 8 mg 3 times in the phase 2a study. Those data will be analyzed and the best 

regimen and dose will be taken into a phase 2b trial, which is basically a 1:1 randomization of 

placebo to test vaccine in approximately 2400 people in 30+ sites in the US, Caribbean, Central 

and South America. These data may provide sufficient efficacy information to allow its access 

to be expanded in an IND and/or through an EUA. That would fulfil Aim #2 of the strategy.

The second nucleic acid candidate is being developed by BARDA in partnership with Moderna 

Therapeutics. This is a novel technology whereby synthetic mRNAs are used to deliver virtually 

any gene. It is very useful for the US government to have a platform such as this, because it is 

basically a “plug and play” technology. There is relatively little difference between different 

vaccines that are made using this platform. The key to developing this platform for vaccine 

purposes was an ingenious discovery made that nucleotides that are incorporated into the 

mRNA synthetically not only have to be native, but also they have to include pseudouridine. 

Doing so evades a lot of the innate immune responses intracellularly like toll-like receptor

responses. Once inside the cell, it acts like a native mRNA to express a foreign gene. This has 

produced a robust, protective immunological responses in animal models. Delivery is relatively 

simple with a needle and syringe. This technology is currently in a clinical Phase 1 trial in the 

US.

There are a number of purified whole virus inactivated vaccine candidates in development by 

two major pharmaceutical companies that have in the past or are currently developing flavivirus 

vaccines, Sanofi Pasteur and Takeda. They are using a formalin-inactivated Zika virus that is 

alum-adjuvanted. The proof-of-concept for this technology was done by WRAIR and NIAID last 

year. The vaccine is currently in Phase 1 clinical trials across the US. It has been published 

this vaccine is fully protective in non-human primates (NHP) and rodent models. NIAID and 

WRAIR are conducting Phase 1 clinical trials to evaluate safety, immunogenicity, regimen, 

dose-sparing, and prior flavivirus immunity in subjects who have received yellow fever vaccine. 

WRAIR is transferring the technology to one of its major pharmaceutical partners, Sanofi 

Pasteur, for accelerating development. Takeda is developing their technology on a different 

platform on their own.

Another candidate is the live attenuated dengue/recombinant Zika vaccine, which is being 

developed by NIAID’s Laboratory of Infectious Diseases (LID). The dengue quadrivalent 

vaccine described by Dr. Waterman earlier is basically a recombinant dengue 2 with the Zika 

prM and E genes inserted in place of the dengue 2 prM and E genes. This vaccine is being 

developed in combination with Butantan. The dengue component is currently in Phase 3 trials. 

The Zika component is currently in development, with a plan to begin Phase 1 with a 

monovalent Zika component probably in the end of 2017. This could be envisioned as not only 

a monovalent, but also a pentavalent Zika/dengue vaccine.

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These tables compare the vaccine landscape in February 2016 to January 2017:

 

There has been a significant amount of activity, with an influx of funding from the US 

government that helped to build this pipeline. Currently, there are 7 ongoing Phase 1 clinical 

trials with 4 different candidates. Of those, 3 are being fully supported by the US government. 

A number of candidates are in R&D and pre-clinical phases. The landscape looks much better 

than this year than it did last year at this time.

The following graphic was provided to show ACIP where hypothetically clinical trials might be in 

the future:

In dark blue are the ongoing, ready to begin Phase 1 trials with Zika vaccines. In red are the 

putative clinical trials that would be conducted based on the clinical development plans of the 

different manufacturers and the US government for the individual vaccine candidates. By 2019-

2020, at least one of those candidates will have completed Phase 3 studies.

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In conclusion, a number of key regulatory/clinical and manufacturing challenges and questions 

remain:

Regulatory/Clinical

 Will future disease incidence support evaluation of vaccine efficacy? In order to develop a 

vaccine based on prevention of clinical symptomatic disease, studies must be conducted in 

areas where there is a significant attack rate. Based on modeling exercises, this will 

become more difficult as time passes. Efforts are being made to develop animal models 

that will allow for the development of correlates of protection that potentially could be used 

as surrogates for different regulatory mechanisms. 

 Which regulatory path will be most feasible? The regulatory paths include the traditional 

path currently being taken assessing clinical endpoints in field trials. There also is an 

accelerated approval pathway that potentially could be used if a surrogate becomes 

available. The last one used in the past for biodefense purposes was the Animal Rule, 

which is presently being put on the “back burner.”

 Will human challenge and/or accelerated approval (correlate of protection) 

facilitate/accelerate evaluation? This was discussed in an NIH consultation a couple of 

months ago. The findings of that committee are now published and show that there is not 

sufficient information on Zika relative to its pathology and how it is transmitted from humans 

to humans to support a human clinical study at this time. As more information is accrued 

about the disease, the potential for this type of study will be revisited.

 Will an animal model(s) provide sufficient data to support efficacy determinations in 

humans?

 Will pre-immunity to other flaviviruses affect Zika vaccine take, and/or vice versa? This is a 

concern primarily based on antibody-dependent enhancement that has been observed with 

another flavivirus, dengue in particular. It is important to ensure that Zika vaccines “do no 

harm.” It also is important to determine, by virtue of so much cross-immunity being 

observed with different flaviviruses, if there is any effect on the actual take of a Zika vaccine 

in individuals who are flavi-positive already.

Manufacturing

 Will manufacturers be able to develop a vaccine fast enough to impact the epidemic?

 Will previous flavivirus vaccine platforms work well enough to prevent congenital infections?

 Will the market sustain more than one vaccine?

While as many vaccines as possible can be developed, it will be necessary for manufactures to 

stay in for the long-haul. With cuts in funding and decreasing enthusiasm about Zika, it 

becomes challenging for the US government to continue to engage with manufacturers on these 

types of products. The hope is that all of the partners will continue their endeavors with the US 

government, but this cannot be guaranteed.

One thing that is incredibly challenging about developing Zika vaccines versus other vaccines is 

that it may be necessary to develop a vaccine that is extremely potent—one that not only 

prevents symptomatic disease in the primary infection, but also one that prevents the 

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transmission of virus from mothers to children. Animal models are being developed in 

conjunction with the NIAID that will help to elucidate those pathways.

Discussion Points

Dr. Reingold inquired about safety, particularly with respect to GBS. He also wondered whether 

there are any trials for younger ages, noting that the trial mentioned was conducted in those 15 

to 35 years of age, which seems like an unusual age in any country.

Dr. Kovacs replied that the trial in 15 to 35 year olds is being conducted to support use in men 

and women of childbearing age, though there are exceptions to that range. The incidence rate 

of GBS is very low and it will not be possible to see any events in these clinical trials. The 

greatest concern with GBS is with Zika vaccination with the live attenuated vaccines.

Dr. Messonnier clarified that in thinking through vaccine development, consideration also must 

be given to delivery methodology in terms of other routine vaccinations. The 15-25 year old 

group is not an age range for which there is a platform for vaccination.

Dr. Hunter asked for clarification regarding whether the mRNA is being placed inside the 

vaccinee and the vaccinees themselves are making the antigen, and how long the mRNA 

persists in the person’s body.

Dr. Kovacs replied that the mRNA delivers only the gene and the body makes the vaccines. 

The active pharmaceutical ingredient is the mRNA nanoparticle. Studies conducted in small 

animals shows that the vaccine is disseminated throughout the body and expression can be 

seen for weeks. This technology is being developed not only for vaccine purposes, but also for 

the delivery of therapeutics such as monoclonal antibodies.

Dr. Romero requested further information about mRNA and 5-prime and 3-prime untranslated 

region (UTR). 

Dr. Kovacs explained that there is a robust expression level in vivo that can be taken advantage 

of for both purposes. The mRNA is transcribed in vitro off of a plasmid vector using T7 RNA 

polymerase. It does not have any fancy 5-prime or 3-prime UTRs. It looks just like a native 

mRNA. The insert in this case is prM and E. The polyadenosine (poly-A) tail is encoded on the 

plasmid, so it is transcribed with a poly-A tail.

Dr. Bennett wondered whether it is possible that what is being observed with the recent decline 

in Zika actually is the end of the epidemic, or if it is more likely due to seasonality.

Dr. Fischer replied that it is likely a combination of both. It is early in the Americas to determine 

the seasonality. From other locations where Zika virus is seen, there is likely seasonality that is 

similar to dengue. This means that in some areas, there is seasonal progression that is related 

either to temperature, rainfall, and humidity. In other areas, there may be low levels of endemic 

transmission that continues. With chikungunya, another arbovirus introduced into the Americas 

in 2014, the first season was quite large, the second season was smaller, and there were 

decreases in subsequent years. That probably offers a better idea with what might be observed 

with Zika virus.

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Dr. Gorman (NIH) requested further information on present or future plans to assess infants 

through 2 years of age, a period of time during which the brain continues to grow fairly rapidly.

Dr. Fischer reported that there are follow-up studies of the infants who were congenitally 

infected. In addition, there are plans for either case-control or a cohort study to follow-up young 

children who are infected postnatally through mosquito-borne infection. Based on surveillance 

data, thus far there has been no evidence of severe disease in young children or evidence of 

post-effects. There are other congenital infections for which that pattern would seem to be 

similar, where there are severe effects when transmission occurs in utero but not when it is 

seen postnatally. Those questions remain to be answered.

Introduction

Laura Riley, MD

Work Group Chair

Dr. Riley provided an overview of the Adult Immunization WG activities over the last year. The 

2017 Adult Immunization Schedule was published in the Annals of Internal Medicine on 

February 7th and in an MMWR announcement on February 9th. There was an error pertaining to 

meningococcal vaccination, so an erratum is due to be published in the MMWR on March 3rd. 

There has been wide promotion of the 2017 Adult Immunization Schedule by partner 

organizations, and the schedule has been evaluated for usefulness and usability. 

Implementation of Standards for Adult Immunization Practice

David Kim, MD

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Kim emphasized that low adult immunization coverage has been an ongoing challenge for 

CDC and its partners for a number of years. It is known that recommendations by HCPs is a 

key predictor for adult vaccination. Standards for adult immunization practice were published to 

improve awareness among HCPs and uptake of ACIP-recommended vaccines for adults. 

Regarding the most recent adult vaccination coverage rates based on the National Health 

Interview Survey (NHIS) and the Behavioral Risk Factor Surveillance System (BRFSS), a brief 

update was published on the CDC website on the same day that the 2017 schedule went live on 

February 7, 2017. The full article containing the adult vaccination coverage rates for 2015 is 

pending publication in the MMWR. The key findings include:

 A 3% increase in pneumococcal vaccination for adults 19 through 64 years of age who are 

at high risk from 20% in 2014 to 23% in 2015

 A 3% increase in Tdap vaccination to 23% for those 19 years of age and older, and a 10% 

increase to 42% for adults living with infants less than 1 year of age who are too young to

receive pertussis vaccination

Adult Immunization

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 A 2.7% increase in shingles vaccination to 30.6% for adults 60 years of age and older.

 Influenza vaccination of 41.7% for adults 18 years of age and older, similar to 2014 

estimates

 Pneumococcal vaccination of 63.6% for adult 65 years of age and older, similar to 2014 

estimates

 Hepatitis B vaccination of 24.4% for adults 19 through 59 years of age with diabetes, similar 

to 2014 estimates

 Persistent racial and ethnic disparities with lower coverage among Blacks and Hispanics, 

similar to 2014 estimates

Standards for Adult Immunization Practice were developed originally in 1990 by the National 

Coalition for Adult Immunization (NCAI) to improve vaccine delivery to adults, and were updated 

in 2014 by the National Vaccine Advisory Committee (NVAC). The standards state that all 

HCPs, including those who do not provide vaccine services, have a role in ensuring that their 

patients are current on vaccines. 

The standards include a call to action for HCP for adults to:

 ASSESS the vaccination status of all patients at every clinical encounter

 Strongly RECOMMEND vaccines that patients need

 ADMINISTER needed vaccines or REFER patients to a vaccine service provider

 DOCUMENT vaccines received by patients in state vaccine registries

The Standards are promoted widely through the National Adult and Influenza Immunization 

Summit (NAIIS) among other venues. The summit is a large collaborative of public and private 

organizations dedicated to improving the use of ACIP-recommended vaccines by working to 

improve access to immunization, educate providers, identify gaps, develop performance 

measures, and engage in other activities.

To assess the status of the implementation of the Standards, CDC conducted two surveys. One 

was administered to the general adult population to evaluate the extent to which they received 

care that reflects the Standards during their most recent visit to their HCP or pharmacist in the 

previous 12 months. The other survey was administered to HCPs and pharmacists to evaluate 

the extent to which they implemented the Standards during patient visits. These Internet panel 

surveys were conducted on outpatient visits from February through March 2016. The surveys 

were probability-based and were weighted to be nationally representative using established 

references, such as the US Bureau of Labor Statistics (BLS). The general adult survey 

included a sample of adults 19 years of age or older and asked about their visits to their HCP or 

pharmacist. The HCP survey included a sample of physicians, nurse practitioners, physician 

assistants, pharmacists, internal medicine, family medicine, OB/GYN, and specialty care. Black 

and Hispanic HCPs and pharmacists were over-sampled to have sufficient data for analyses.

In terms of the results for the general adult population, of the 3473 panelists invited to 

participate, 2004 (57.7%) accessed the survey and 1905 (95.1%) completed the survey. Based 

on the data analyzed for the 1905 completed surveys, 1476 (77.5%) had outpatient visits with 

HCP providers or pharmacists in the past 12 months, 459 (68.3%) self-reported as non-Hispanic 

white, 50% were female, the median age was 55 years (range 19–92 years), 1399 (94.7%) were 

insured, and 1203 (59.7%) had at least a college education. 

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Email invitations were sent to 74,067 HCPs. Of these, 1907 started the survey, 1684 (88.3%)

completed the survey, and data analysis was performed on 1641 eligible participants. Among 

the responding practices, there were 32.3% family medicine, 27.5% internal medicine, 21.3% 

OB/GYN, and 18.8% other specialties. Among these, 45.8% were private practices and 37.5% 

were healthcare system-owned practices. There were 65.9% non-Hispanic white participants. 

Email invitations were sent to 9310 pharmacists of whom 320 started the survey and 277 

(86.6%) completed the survey. Data analysis was performed on 277 eligible participants. Of 

the respondents, 44.2% were chain drug store pharmacists, 31.9% were retail or grocery store 

pharmacists, 17.7% were independent, 87.2% were employees, 7.2% contractors, 5.6% were 

owners, and 70% were non-Hispanic white. 

Of the 1476 adult respondents; 46% were assessed for vaccination; 23% received 

recommendations for vaccination; 19% received a recommendation for influenza; 9% received a 

recommendation for a non-influenza vaccination; and 18% received an offer for vaccination; 4% 

received referrals. Overall; 11% reporting having received an assessment, recommendation, 

offer, and referral primarily related to influenza vaccination; and 8% received vaccination. By 

provider specialty, adult patients reported having received the highest percentage for 

vaccination assessment, recommendation, and offers during their internal medicine and family 

medicine visits, followed by visits to OB/GYN and other specialty practices. Reported 

vaccination assessments by pharmacists lagged compared to clinical providers.

In terms of the responses by HCPs and pharmacists, each specialty reported a much higher 

percentage of vaccination assessment, recommendation, and administration compared to what 

the adult patients reported. Within each specialty, reported use of an IIS was low at 47% for 

family medicine and internal medicine, 39% for OB/GYN, 22% for other specialties, and 42% for 

pharmacies. High levels of assessment, recommendation, and administration or referral were 

reported by physicians, nurse practitioners, physician assistants, and pharmacists. Again, the 

reported use of IIS was low. Although the two surveys were administered in different 

populations, the results of what the adult patients and HCPs/pharmacists reported were 

compared. The following table shows the results of a comparison of the first component of the 

standards; that is, vaccination assessment by practice specialty:

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Clearly, there is a major difference between what HCPs/pharmacists and the general adult 

population report.

In summary, adult patients reported low levels of receipt of care that reflected the standards. In 

contrast, HCPs and pharmacists reported high levels of implementation of the standards, except 

for the use of vaccine registries.

 

Limitations to these surveys might explain some of the differences. For the adult patient survey, 

adult patients may not have been aware that some vaccination assessments done “behind the 

scene,” such as the staff checking patient records in the vaccine registry or reviewing patient 

medical records without necessarily talking with the patients. For the HCP survey, healthcare 

respondents may have generalized their immunization practices for some patients to all patients

or some vaccines to other vaccines. There are also study design limitation that include 

sampling and recall bias. There is a potential for sampling bias, given that these were selfselected internet panels of respondents and there could be differences between respondents 

and non-respondents. Recall bias is also of concern on self-report surveys and is not verified. 

The survey response rate cannot be calculated because opt-in recruitment sampling does not 

permit enumeration of the denominator. 

Dr. Kim stressed that this presentation should not have been a surprise to anyone. CDC simply 

quantified what most had suspected. The key messages are that the standards should be 

incorporated into routine clinical practice for every patient and at every visit. Adult patients need 

to hear from their HCPs and pharmacists about vaccines. The large discrepancy between what 

HCPs and pharmacists believe they are doing and what adult patients perceive regarding 

vaccination assessment could be improved this way. As mentioned earlier, an HCP 

recommendation is a key predictor for adults to get vaccination. Although the data were not 

presented during this session, the adult patient survey found a statistically significant 

association between providers giving a strong recommendation and patients actually getting 

vaccinated. Consistent implementation of the standards is needed to improve adult 

immunization coverage in the US. The NAIIS and state and local immunization program 

partners are hard at work to get the word out.

Discussion Points

Dr. Bennett asked whether providers were asked about standing orders and/or engagement of 

other members of their teams to implement immunizations.

Dr. Kim replied that the survey asked about standing orders; documentation; types of 

recordkeeping systems; and knowledge, attitudes, and issues that might play into implementing 

the standards. There are some analyses on this, for which the information will be coming out 

soon.

Dr. Kempe acknowledged the need to have more effective provider recommendations, et 

cetera. However, she thought it was somewhat of a false dichotomy to compare patients 

presenting for a visit who have been seen in the last 12 months who may or may not be eligible

for anything other than influenza vaccine and who generally are not aware that people are 

looking at their immunization records. She emphasized that while provider recommendation is 

extremely important, all of the systems that support provider recommendations are what really 

gets this done. Incorporation into adult practice of the systems that have been shown to be 

effective in pediatrics, where all of the action is in immunization, would be highly beneficial.

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Dr. Szilagyi pointed out that in the survey of patients, the percentage of patients who said they 

received an influenza vaccination was unbelievably low; whereas, it is known that 40% of adults 

receive an influenza vaccination. Something is off with the data. In the interest of not always 

flogging adult providers who are just inundated with chronic disease and managing patients with 

very serious adult problems, it would be great to hear presentations parallel to some pediatric 

presentations about what types of interventions have been found to work and how those could 

be implemented in healthcare systems and practices.

Dr. Belongia encouraged Dr. Kim not to compare the physician survey to the patient survey 

when publishing, because the limitations are great. That does not discount the message, which 

is important. However, that direct comparison is not really valid. He asked whether 

consideration had been given to systematically assessing the system and institutional barriers to 

doing a better job that providers face in their practices.

Dr. Kim replied that some questions have been asked related to barriers, such as questions 

about the obstacles providers face in terms of delivering vaccines to their patients. Some of this 

information is already known based on other surveys, information contained in the Community 

Guide, and elsewhere. The barriers can be combined into three major categories: 1) Financing 

(payments, billing coding, et cetera), which is perhaps the most important barrier from the 

provider perspective; 2) Systems (standing orders, EMR) to promote notification for the provider 

to begin the vaccination discussion and for patients to receive notification, perhaps before their 

appointment, so that the patient arrives prepared; and 3) Education and training for patients and 

providers. Of course, there are many competing priorities for providers. Vaccination may not 

be at the top or even near the top of their daily activities. Making it easier and perhaps taking it 

out of the hands of the busy HCP who has many things to address during a 10-minute visit by 

automating the process would be beneficial.

Dr. Foster (APhA) thought the data would be beneficial to share with the APhA members to 

illustrate the realistic perspective. He pointed out that pharmacists do consider themselves to 

be HCPs, so separating them out is going to result in a lot of feedback.

Regarding standing orders, Dr. Tan (IAC, NAIIS) reported that there is an IAC project called 

Take a Stand!TM. This initiative began in 2016 to help healthcare practices and provider 

systems implement standing orders to boost adult immunization rates. He expressed gratitude 

to the ACIP for all of their comments about implementation. Thanks to CDC’s leadership and 

support from the NVPO, the summit has been trying to address the implementation question. 

The summit website has a nice collection of a lot of the resources NAIIS has been assembling 

to address the various comments regarding provider implementation of adult vaccines. During 

the NAIIS in-person meeting scheduled for May 9-11, 2017 at the Hyatt Regency Atlanta in 

Atlanta, NAIIS will organize a meeting of healthcare systems to work with them to understand 

best practices to improve adult immunization rates. He acknowledged Dr. Kempe for her 

phenomenal success with her adolescent standing orders immunization project at Denver 

Health.

Dr. Bridges (SME) added that quality measures are known to drive a lot of action in healthcare 

systems, but there is a paucity of measures for adult immunization. A lot of work is being done 

at NVPO and through the NAIIS on developing additional quality measures for adult 

immunization. The VA and IHS have participated.

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Dr. Hayes (ACNM) applauded the study, recognizing that it created a new level for conversation 

on this topic. She inquired as to how the public was recruited for the survey, and if Dr. Kim had 

a breakdown of the types of nurse practitioners (adult, women’s health, nurse midwives, 

geriatric, et cetera) who answered the survey.

Dr. Kim replied that the public was recruited through an established internet panel through a list 

of commercially available names and demographic information, and it is an opt-in process. In 

terms of the breakdown of nurse practitioners, nurse midwives were not specifically identified as 

a recruitment variable. Recruitment was through a list of providers for physicians, nurse 

practitioners, and physician assistants. But, they could be practicing in a particular medical 

specialty. He does have this information and it will be included in any publications that may be 

forthcoming.

Dr. Moore pointed out that it was not clear just how much could be said about a survey with just 

over a 2% response rate among HCPs, which means that there could be a tremendous amount 

of self-selection bias among optimistic practitioners. It is important to remember that the 

immunization registries represent a very important tool that is very under-utilized for adult 

immunization. That is where all information about vaccines should be entered in these 

registries. Clinical decision support is available in registries that can help prompt HCPs so that 

they do not have to remember what an adult is supposed to have.

Dr. Savoy (AAFP) has found that as they expand to use a patient care team in her practice, 

patients may say they were not offered something if she did not specifically offer it herself, even 

if her MA or behavioral health nurse did offer. This suggests that the questions may need to be 

asked differently. For example, “When you were in the office, did anyone ask you X?”

Dr. Kim indicated that this was done on the survey. Respondents were asked who asked the 

question, during what time of the visit, and where (front desk, nurse triage, examination room, 

check-out).

Introduction

Emmanuel (Chip) Walter, MD, MPH

Chair, Flavivirus Vaccines Work Group 

Advisory Committee on Immunization Practices

Dr. Walter reminded everyone that intermittent production issues resulted in temporary supply 

shortages of yellow fever (YF) vaccine, YF-VAX®, in the US. Since November 2015, ordering 

restrictions have been in place for YF-VAX® due to supply shortages. In October 2016, the WG

briefed ACIP about YF-VAX® production and contingency plans to address any supply 

shortages. During this meeting, Dr. David Greenberg of Sanofi Pasteur will provide an update 

on yellow fever vaccine supply. 

Yellow Fever Vaccine

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Update on YF Vaccine Supply

David Greenberg, MD

Associate Vice President and Regional Medical Head, North America

Sanofi Pasteur

Dr. David Greenberg reported that in the past several years, intermittent production issues have 

resulted in temporary supply shortages. To improve supply, Sanofi Pasteur invested in and is

transitioning manufacturing to a new state-of-the-art facility planned for mid-2018. This 

transition was intended to be seamless and without impact on supply. In the first quarter of 

2016, a manufacturing issue resulted in the loss of a large number of doses being produced to 

bridge supply until the new facility was online. Sanofi Pasteur immediately instituted ordering 

restrictions to extend supply to HCPs. 

Given yellow fever outbreaks in other countries and global supply issues, stakeholder 

discussions were initiated in the Spring of 2016. Key participants have included CDC, FDA, and 

DoD. Sanofi Pasteur’s focus has been to assure a continuous YF vaccine supply for travelers, 

US government employees, military, and other response groups. Sanofi Pasteur has pursued 

multiple paths to ensure continuous supply of yellow fever vaccine, including product ordering 

restrictions; additional production of YF-VAX® vaccine in the existing facility; and importation of 

Stamaril® via an Expanded Access Investigational New Drug (IND) Program Expedited Access 

Pathway (EAP). 

In terms of product ordering restrictions, HCPs are required to verify that vaccine recipients are 

travelling within 30 days to a YF-endemic country or a country that requires proof of vaccination 

for entry. Account order limits have been activated to avoid account over-ordering. Regarding 

production of YF-VAX® vaccine, additional product was produced in the existing facility. Further 

manufacturing issues limited new production; thus, not enough product could be made to fully 

bridge to the new facility. Restrictions will enable continued use of YF-VAX® vaccine through 

mid-2017. With respect to importation of Stamaril® vaccine, Sanofi Pasteur worked closely with 

the FDA to rapidly develop and submit an EAP. The FDA rapidly reviewed the application and 

granted approval in October 2016. The EAP protocol allows the product to be used at 

authorized facilities in a restricted format. By mid-2017, Sanofi Pasteur will supply Stamaril®

vaccine under an EAP to fulfill US YF immunization demand. 

Stamaril® vaccine is the YF vaccine manufactured by Sanofi Pasteur in France. It is a live 

attenuated vaccine that contains the YF virus 17D-204 strain. This is the same strain as in YFVAX® vaccine. Stamaril® vaccine is used globally in more than 100 countries. It has been 

licensed for more than 30 years, and more than 430 million doses have been distributed. The 

safety and efficacy for Stamaril® vaccine are comparable to YF-VAX® vaccine. Stamaril®

vaccine is supplied as a vial of lyophilized powder and a syringe prefilled with diluent. 

As an investigational product, there are protocol and tracking requirements for the sites that 

administer Stamaril® vaccine. Sanofi Pasteur plans to enroll approximately 150 to 170 highvolume centers that can dedicate resources and train personnel to counsel, administer, and 

monitor safety. Outreach will begin in March 2017 in order for sites to review and accept the 

protocol and obtain approval from local Institutional Review Boards (IRBs) as needed. Sites are 

anticipated to be ready by the end of May 2017, including completion of training. YF providers 

and travelers will be notified in the May to June timeframe of Stamaril® vaccine sites. 

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Sanofi Pasteur is working closely with CDC programs, including the Division of Global Migration 

and Quarantine (DGMQ) and the Division of Vector-Borne Diseases (DVBD). In addition, they 

will share information and are developing support for communications materials and plans, 

product and logistics information, the Stamaril® vaccine site selection process, Stamaril®

vaccine site location information, and access to state health departments. 

In summary, Sanofi Pasteur will provide Stamaril® vaccine under an EAP by mid-2017. Site 

enrollment and training will begin in March to ensure readiness. Patients will be directed to 

designated clinics to receive Stamaril® vaccine. HCPs will be notified to send their patients to 

these sites. Stamaril® vaccine will be supplied to sites until the new production facility is online 

mid-2018. Sanofi Pasteur will continue to work diligently to make YF vaccine continuously 

available throughout this transition. 

Discussion Points

Dr. Hunter asked whether supplies are being diverted to the US that would otherwise go to 

Africa or South America.

Dr. Greenberg replied that the supply of Stamaril® vaccine in the Sanofi Pasteur manufacturing 

facility in France is very robust. The millions of doses that will be going to other international 

sites are not affected in any way by the relatively small number of doses that will be coming to 

the US.

Dr. Reingold pointed out that there seemed to be lingering misinformation that people need a 

YF vaccine every 10 years, and he wondered whether travel physicians will be counseled to 

determine whether their patients have ever had YF vaccine.

Dr. Greenberg responded that they leave that to the HCP. It is not Sanofi Pasteur’s place to 

comment on ACIP and WHO recommendations. The company is bound by the product 

information that is provided with the vaccine. At the end of the day, they will have to trust that 

providers will act in good faith based on good information. Sanofi Pasteur has done their best to 

supply the information.

Dr. Gershman (SME) added that the information about the booster dose is well-publicized, and 

that it is going to providers who should be aware of that and a smaller subset who will be 

receiving and administering the Stamaril® vaccine. That was passed by an ACIP vote in 2015 

and published in the MMWR, and the CDC Yellow Book in hard print and on-line, and CDC’s 

Traveler’s Heath website. There is fairly wide awareness about the change in the 10-year 

booster policy.

Dr. Fryhofer (ACP) noted that many doctors keep records only for 10 years. She has 

experienced some instances recently in which a person has lost the yellow book with the stamp, 

and the travel clinic has destroyed the records. Because she keeps her records for more than 

10 years, she has been having to retrieve records and send them to the travel clinics so they 

can give patients another YF stamp. She asked whether there is a special registry for YF 

vaccination that could incorporate a lifelong record, or if any thought has been given to this. 

She also wondered if a YF is documented in a state IIS it would be accepted as proof of 

vaccination.

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Dr. Gershman (SME) replied that there is no registry for individual patients; however, there is a 

registry of clinics that CDC maintains with the help of state health departments. It is up to 

individual practices to maintain good records. Every state has its own practices.

Dr. Moore added that registries do exist in all states except New Hampshire, which is working 

on theirs. A state immunization registry can accept YF vaccine documentation. If an 

immunizing provider reported administration of that to the state immunization registry along with 

other vaccines, that could be used as evidence that the person has had a YF vaccine in order to 

reissue a yellow card. However, she was not certain about International Health Regulations

(IHR).

Even though she does not administer YF vaccine herself, Dr. Fryhofer wondered if she could 

enter a YF vaccine into the state system even though she does not have the stamp.

Dr. Moore responded that ideally, the person who administers the vaccine should enter it. That 

is the best possible record. However, to her knowledge, if Dr. Fryhofer had a patient’s yellow 

card and was reviewing, she could report in the registry that an immunization was given.

No public comments were offered in-person during this session. However, Dr. Bennett noted 

that the following three letters were submitted for inclusion in the record:

Gilberto F. Chavez, M.D., M.P.H.

State Epidemiologist

California Department of Public Health

January 27, 2017

Nancy Bennett, M.D., M.S., Chair

Amanda Cohn MD, Executive Secretary

Advisory Committee on Immunization Practices

1600 Clifton Road, N.E., Mailstop A27

Atlanta, GA 30329

Dear Dr. Bennett, 

The California Department of Public Health (CDPH) commends the Advisory Committee on 

Immunization Practices’ (ACIP) ongoing work to protect the nation’s health by setting and 

adjusting national immunization policies based on available evidence. 

Despite high coverage rates of immunization with tetanus toxoid, reduced diphtheria toxoid and 

acellular pertussis vaccine (Tdap), pertussis disease in adolescents continues to be reported 

frequently in California. CDPH respectfully requests that ACIP reappraise its routine 

recommendation since 2006 for a single dose of Tdap vaccine for adolescents and adults in 

light of subsequent data (including references 1-16) on the limited duration of protection from 

acellular pertussis vaccines: 

• Are the current recommendations still appropriate, or are any changes warranted?

• What are the estimated benefits from the Tdap recommendations to individuals and communities in:

Day 2: Public Comment

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o Preventing or reducing the severity of pertussis, tetanus and diphtheria?

o Increasing coverage rates of other immunizations recommended for preteens?

 

Systematic review of the current data, and any adjustments in the recommendations that might 

follow, will help to sustain confidence in immunization, ACIP, and the policies, such as state 

school immunization requirements, that typically are based upon its recommendations.

Thank you for your consideration of this request.

Sincerely

Gilberto F. Chavez, M.D., M.P.H.

State Epidemiologist

California Department of Public Health 

References

1. Witt MA, Katz PH, Witt DJ. Unexpectedly limited durability of immunity following acellular pertussis vaccination in 

preadolescents in a North American outbreak. Clin Infect Dis. 2012;54:1730-5. 

2. Klein NP, Bartlett J, Rowhani-Rahbar A, Fireman B, Baxter R. Waning protection after fifth dose of acellular 

pertussis vaccine in children. N Engl J Med. 2012;367:1012–1019

3. Misegades LK, Winter K, Harriman K, et al. Association of childhood pertussis with receipt of 5 doses of 

pertussis vaccine by time since last vaccine dose, California, 2010. JAMA. 2012;308:2126–2132.

4. Tartof SY, Lewis M, Kenyon C, et al. Waning immunity to pertussis following 5 doses of DTaP. Pediatrics. 

2013;131:e1407. 

5. Quinn HE, Snelling TL, Macartney KK, McIntyre PB. Duration of protection after first dose of acellular pertussis 

vaccine in infants. Pediatrics. 2014;133:e513. 

6. Sheridan SL, McCall BJ, Davis CA, et al. Acellular pertussis vaccine effectiveness for children during the 2009–

2010 pertussis epidemic in Queensland. Med J Aust. 2014;200:334–338.7

7. Liko J, Robison SG, Cieslak PR. Pertussis vaccine performance in an epidemic year-Oregon, 2012. Clin Infect 

Dis. 2014;59:261-3. 

8. Sheridan SL, Ware RS, Grimwood K, Lambert SB. Number and order of whole-cell pertussis vaccines in infancy 

and disease protection. JAMA. 2012;308:454–456.

9. Liko J, Robison SG, Cieslak PR. Priming with whole-cell versus acellular pertussis vaccine. N Engl J Med. 

2013;368:581–582.

10. Witt MA, Arias L, Katz PH, Truong ET, Witt DJ. Reduced risk of pertussis among persons ever vaccinated with 

whole-cell pertussis vaccine compared to recipients of acellular pertussis vaccines in a large US cohort. Clin 

Infect Dis. 2013 56:1248-54. 

11. Klein NP, Bartlett J, Fireman B, Rowhani-Rahbar A, Baxter R. Comparative effectiveness of acellular versus 

whole-cell pertussis vaccines in teenagers. Pediatrics. 2013;131: e1716–e1722. 

12. Sheridan SL, Ware RS, Grimwood K, Lambert SB. Reduced risk of pertussis in whole-cell compared to acellular 

vaccine recipients is not confounded by age or receipt of booster-doses. Vaccine. 2015;33:5027-30.

13. Koepke R, Eickhoff JC, Ayele RA, et al. Estimating the effectiveness of tetanus-diphtheria-acellular pertussis 

vaccine (Tdap) for preventing pertussis: evidence of rapidly waning immunity and difference in effectiveness by 

Tdap brand. J Infect Dis. 2014;210:942-53. Acosta AM, DeBolt C, Tasslimi A, Lewis M, Stewart LK, Misegades 

LK, Messonnier NE, Clark TA, Martin SW, Patel M. Tdap vaccine effectiveness in adolescents during the 2012 

Washington State pertussis epidemic. Pediatrics. 2015;135:981-9. 

14. Klein NP, Bartlett J, Fireman B, Baxter R. Waning Tdap effectiveness in adolescents. Pediatrics. 2016;137:1-9. 

doi: 10.1542/peds.2015-3326. 

15. Terranella A, Rea V, Griffith M, et al. Vaccine effectiveness of tetanus toxoid, reduced diphtheria toxoid, and 

acellular pertussis vaccine during a pertussis outbreak in Maine. Vaccine. 2016;34:2496-500.

16. Skloff TH, Martin SW. Impact of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccinations on 

reported pertussis cases among those 11 to 18 years of age in an era of waning pertussis immunity: A follow-up 

analysis. JAMA Pediatr. 2016;170:453-8.

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February 07, 2017 6:09 PM

To: Advisory Committee on Immunization Practices (CDC) <acip@cdc.gov> 

Subject: Upcoming February ACIP Meeting

 

Hello:

 

Would you please add to your agenda for the February meeting consideration of adding 

Parkinson's disease (PD) to the chronic medical conditions listing for pneumococcal 

vaccines. Aspiration pneumonia is the number one cause of death in this chronic progressive 

disease and many people under the age of 65 are being denied these vaccines, yet 15% of PD 

patients are less than 50 years of age. If there are medical or scientific reasons for this 

exclusion, please let the PD community know.

 

Thank You Very Much,

 

Richard P. Hoffmann, PharmD

Parkinson's Disease Foundation Research Advocate Consumer Representative for the FDA 

Advisory Committee on PCNS Drugs

Pam Rockwell

Concord Massachusetts

No Affiliations

Written Comments for February 22, 2017 ACIP Meeting -Pam Rockwell, 1810 Main St., 

Concord MA, 01742, no affiliation, pam@tiac.net The ACIP should change the recommendation 

for flu vaccine so that women who are in their first trimester of pregnancy or are trying to get 

pregnant should not receive flu vaccine.

In 2015 I wrote to the ACIP: 

Pregnant women should not receive influenza vaccine in their first trimester. Fever 

and/or influenza infection during pregnancy has been linked to miscarriage and autism. 

There is growing evidence that autism is an autoimmune disorder caused by maternal 

antibodies that attack the fetal brain. In animal models of maternal antibody induced 

autism, female fetuses are reabsorbed, so that only males are born. ACIP discussed 

data in June that influenza vaccine in the first trimester increases the likelihood of 

miscarriage, but no data has ever been published about whether children exposed to 

prenatal vaccines develop normally, since studies are limited to one year. ACIP should 

stop recommending vaccination of women during their first trimester of pregnancy until 

follow-up studies on maternal vaccination can be done to determine if prenatal exposure 

to vaccines cause autism. Women naturally have reduced immune response during 

pregnancy. Such an evolutionary disadvantage must have an explanation. Perhaps 

making antibodies during pregnancy is bad for the future development or immunocompetence of the offspring.

Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2017

Richard Hoffmann

Parkinson's Disease Foundation Research Advocate Consumer Representative for the 

FDA Advisory Committee on PCNS Drugs

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In November 2016, the very first study published that evaluated whether there was a link 

between autism and maternal vaccination did indeed show a link between influenza vaccination 

in the first trimester and an increased autism risk of 4 cases in 1000 live births (a 20% increased 

risk): 

Zerbo O, et al Association Between Influenza Infection and Vaccination During 

Pregnancy and Risk of Autism Spectrum Disorder. JAMA Pediatr. Published online 

November 28, 2016. doi:10.1001/jamapediatrics.2016.3609 

https://www.ncbi.nlm.nih.gov/pubmed/27893896

“We found that influenza vaccination in the first trimester was associated, in an initial 

analysis unadjusted for multiple comparisons, with a slightly increased ASD risk after 

controlling for maternal allergy, asthma, autoimmune conditions, gestational diabetes, 

hypertension, age, education, race/ethnicity, child conception year, conception season, 

sex, and gestational age. However, adjusting for the multiplicity of hypotheses tested 

suggests that the results could be due to chance. If influenza vaccination during the 

first trimester of pregnancy causes ASD, our results suggest that it would amount 

to 4 additional ASD cases for every 1000 women vaccinated. Our finding of a 

possible association between maternal influenza vaccination in the first trimester 

and increased ASD risk parallels previous studies reporting an association 

between maternal viral infection or fever and increased ASD risk in the first 

trimester.”

The maternal autoantibody theory of autism explains the gender bias in autism by supposing 

that female fetuses are more susceptible to these antibodies and are more likely to be 

reabsorbed (in mice) or spontaneously abort (in primates), and this is supported by animal data. 

The Zerbo study only evaluated full term pregnancies, so it would not have noticed if female 

fetuses were at increased risk of spontaneous abortion. But at your June 2015 meeting, ACIP 

discussed a Vaccine Safety Datalink study led by Dr. Jim Donahue, et al. at the Marshfield 

Clinic titled, “Evaluating the risk of spontaneous abortion following administration of influenza 

vaccines containing H1N1pdm09 and H3N2 viral antigens,” which did show correlation between 

first trimester flu vaccine and miscarriages. (You discounted this data because you felt that 

women who do not receive flu shots are less likely to seek medical attention for a miscarriage, 

even though there is no evidence to support this excuse to ignore the data.) The combination of 

increased numbers of males with autism in the Zerbo study and the increased miscarriages in 

the VSD study mirrors the animal models of the maternal autoantibody theory of autism.

One of the confounding factors that is discussed in the Zerbo paper is autoimmunity. 

Autoimmune disorders are much more common in relatives, particularly female relatives, of 

children with autism. Because it is a known link, Dr. Zerbo checked for prior autoimmune 

diagnoses in the women in the study. But the study did not check to see if autoimmune 

disorders were diagnosed in the women after their influenza illness and/or vaccination. If flu 

infection or vaccination triggers a previously undetected autoimmune disorder, then perhaps 

that affects the fetus, either triggering a miscarriage or developmental disorder, as might be 

expected during a flare of an autoimmune disorder during pregnancy. 

My 17-year-old son is autistic, although I was not vaccinated or obviously sick during my 

pregnancy. One of the medical interventions that has made a big difference in my son’s 

progress is the drug amantadine, which was prescribed to him by a neurologist because it is a 

glutamate receptor antagonist, like the Alzheimer’s drug memantine, which is also used to treat 

autism. But amantadine also neutralizes influenza M2 proton pumps. I think this is not a 

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coincidence – that influenza M2 proton pumps mimic human glutamate receptors to avoid a 

strong immune response. That could mean that the autism and miscarriages described by 

Zerbo and Donahue are due to a specific antigen in the vaccine, and not necessarily a general 

response to any vaccine. 

But whatever the mechanism, right now you have evidence in front of you that flu vaccinations 

in the first trimester of pregnancy could trigger autism or miscarriage, and there are some 

animal models of autism and miscarriage that show that antibodies could be the cause. The 

ACIP should change their recommendation to advise women who are trying to get pregnant or 

are in their first trimester not to get vaccinated until you can collect some data that actually 

shows that the vaccines are safe. 

Thank you, 

Pam Rockwell

Some papers about maternal autoantibodies or infection and autism:

Wang L, Zhou D, Lee J, Niu H, Faust TW, Frattini S, Kowal C, Huerta PT, Volpe BT, Diamond 

B. Female mouse fetal loss mediated by maternal autoantibody. J Exp Med. 2012 Jun 

4;209(6):1083-9. doi: 10.1084/jem.20111986. Epub 2012 May 7. 

http://www.ncbi.nlm.nih.gov/pubmed/22565825 

Ross G, Sammaritano L, Nass R, Lockshin M. Effects of mothers' autoimmune disease during 

pregnancy on learning disabilities and hand preference in their children. Arch Pediatr Adolesc 

Med. 2003 Apr;157(4):397-402. http://www.ncbi.nlm.nih.gov/pubmed/12695238 

Betty Diamond Antibodies and the Brain: Lessons from Lupus J Immunol. 2010 September 1; 

185(5): 2637–2640. doi: 10.4049/jimmunol.1090080 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955457/ 

Kowal C, Diamond B. Aspects of CNS lupus: mouse models of anti-NMDA receptor antibody 

mediated reactivity. Methods Mol Biol. 2012;900:181-206. doi: 10.1007/978-1-60761-720-4_9. 

http://www.ncbi.nlm.nih.gov/pubmed/22933070 Pardo CA, 

Vargas DL, Zimmerman AW. Immunity, neuroglia and neuroinflammation in autism. Int Rev 

Psychiatry. 2005 Dec;17(6):485-95. http://www.ncbi.nlm.nih.gov/pubmed/16401547 

Braunschweig D, Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen LA, Pessah IN, 

Van de Water J. Autism: maternally derived antibodies specific for fetal brain proteins 

Neurotoxicology. 2008 Mar;29(2):226-31. Epub 2007 Nov 6. 

http://www.ncbi.nlm.nih.gov/pubmed/18078998 

W. Nordahl, M. Bauman, D. Braunschweig, A. M. Iosif, P. Ashwood, J. Van de Water and D. G. 

Amaral The Presence of Specific Maternal IgG Antibodies Is Associated with Abnormal Brain 

Enlargement in ASD and in Nonhuman Primate Model of ASD INSAR – the International 

Society for Autism, May 19, 2012: 12:00 PM 

https://imfar.confex.com/imfar/2012/webprogram/Paper11097.html 

Martin LA, Ashwood P, Braunschweig D, Cabanlit M, Van de Water J, Amaral DG. Stereotypies 

and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain 

Behav Immun. 2008 Aug;22(6):806- 16. Epub 2008 Feb 8. 

http://www.ncbi.nlm.nih.gov/pubmed/18262386 

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Morris CM, Zimmerman AW, Singer HS Childhood serum anti-fetal brain antibodies do not 

predict autism. Pediatr Neurol. 2009 Oct;41(4):288-90. 

http://www.ncbi.nlm.nih.gov/pubmed/19748049 

Zerbo O, Iosif AM, Walker C, Ozonoff S, Hansen RL, Hertz-Picciotto I. Is Maternal Influenza or 

Fever During Pregnancy Associated with Autism or Developmental Delays? Results from the 

CHARGE (CHildhood Autism Risks from Genetics and Environment) Study J Autism Dev Disord 

DOI 10.1007/s10803-012-1540-x http://www.ncbi.nlm.nih.gov/pubmed/22562209 

Atladóttir HO, Henriksen TB, Schendel DE, Parner ET. Autism After Infection, Febrile Episodes, 

and Antibiotic Use During Pregnancy: An Exploratory Study. Pediatrics. 2012 Nov 12. [Epub 

ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/23147969?dopt=Abstract 

Zerbo O, Iosif AM, Delwiche L, Walker C, Hertz-Picciotto I. Month of Conception and Risk of 

Autism. Epidemiology, 2011 Jul:22(4):469-75. Doi: 10.1097/EDE.0b013e31821d0b53. 

http://www.ncbi.nlm.nih.gov/pubmed/21543984 

Braunschweig D, Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen LA, Pessah IN, 

Van de Water J. Autism: maternally derived antibodies specific for fetal brain proteins 

Neurotoxicology. 2008 Mar;29(2):226-31. Epub 2007 Nov 6. 

http://www.ncbi.nlm.nih.gov/pubmed/18078998 

Christina M. Morris, Mikhail Pletnikov, Andrew W. Zimmerman Maternal Antibodies and the 

Placental-Fetal IgG Transfer Theory. (Chapter 14) In: Autism Current Theories and Exidence 

2nd Edition. Andrew W. Zimmerman, editor, Humana Press, 2008, pp. 309-328. ISBN: 978-1-

60327-489-0 

Brimberg L, Sadiq A, Gregersen PK, Diamond B. Brain-reactive IgG correlates with 

autoimmunity in mothers of a child with an autism spectrum disorder. Mol Psychiatry. 2013 

Nov;18(11):1171-7. doi: 10.1038/mp.2013.101. Epub 2013 Aug 20. 

https://www.ncbi.nlm.nih.gov/pubmed/23958959

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Upon reviewing the foregoing version of the February 22-23, 2017 ACIP meeting minutes, Dr. 

Nancy Bennett, ACIP Chair, certified that to the best of her knowledge, they are accurate and 

complete. Her original, signed certification is on file with the Management Analysis and 

Services Office (MASO) of CDC.

Certification

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September 26, 2016

Department of Health and Human Services 

Centers for Disease Control and Prevention

Advisory Committee on Immunization Practices

July 1, 2016 through June 30, 2017

CHAIR

BENNETT, Nancy, MD, MS

Professor of Medicine and Public Health Sciences

Director, Center for Community Health

Co-director, Clinical and Translational Science Institute

University of Rochester School of Medicine and Dentistry

Rochester, NY 

Term: 07/01/2015-06/30/2018

EXECUTIVE SECRETARY

COHN, Amanda, MD

Senior Advisor for Vaccines 

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Atlanta, GA

MEMBERS

ATMAR, Robert L., MD 

John S. Dunn Clinical Research Professor in Infectious Diseases 

Interim Chief, Section of Infectious Diseases 

Departments of Medicine and Molecular Virology & Microbiology

Baylor College of Medicine 

Chief, Infectious Diseases Service 

Ben Taub General Hospital, Harris Health System

Houston, TX

Term: 7/1/2016 – 6/30/2020

BELONGIA, Edward, MD

Director 

Center for Clinical Epidemiology & Population Health 

Marshfield Clinic Research Foundation

Marshfield, WI

Term: 07/01/2014-06/30/2018

EZEANOLUE, Echezona, MD, MPH 

Professor of Pediatrics and Public Health

Department of Epidemiology and Biostatistics

Director, Global Health and Implementation Research Initiatives

University of Nevada

Las Vegas, NV

Term: 07/01/2015-06/30/2019

ACIP Membership Roster

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HUNTER, Paul, MD

Associate Professor of Family Medicine and Community Health

University of Wisconsin School of Medicine and Public Health

Associate Medical Director 

City of Milwaukee Health Department 

Milwaukee, WI

Term: 7/1/2016 – 6/30/2020

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

LEE, Grace M., MD, MPH 

Associate Professor of Population Medicine & Pediatrics

Director, Center for Healthcare Research in Pediatrics (CHeRP) 

Harvard Pilgrim Health Care Institute & Harvard Medical School 

Associate Medical Director of Infection Control, Boston Children's Hospital 

Boston, MA 

Term: 7/1/2016 – 6/30/2020

MOORE, Kelly, MD, MPH,

Director, Tennessee Immunization Program 

Tennessee Department of Health 

Assistant Clinical Professor, Department of Health Policy 

Vanderbilt University School of Medicine 

Nashville, TN

Term: 07/01/2015-06/30/2019

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

STEPHENS, David, MD 

Professor of Medicine, Division of Infectious Diseases 

Chair, Department of Medicine 

Emory University School of Medicine 

Emory University 

Atlanta, GA 

Term: 07/01/2015-06/30/2019

SZILAGYI, Peter MD, MPH

Professor of Pediatrics

Executive Vice-Chair and Vice-Chair for Research 

Department of Pediatrics

University of California, Los Angeles (UCLA) Los

Angeles, California 

Term: 7/1/2016 – 6/30-2020

WALTER, Emmanuel (Chip), Jr., MD, MPH

Professor of Pediatrics

Duke University School of Medicine

Durham, NC

Term: 07/01/2015-06/30/2019

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)

Department of Defense (DoD) DEUSSING, ERIC, MD, MPH

Commander, Medical Corps, United States Navy 

Department of Defense Liaison

Centers for Disease Control and Prevention 

Atlanta, GA

Department of Veterans Affairs (DVA)

KIM, Jane A., MD, MPH

Deputy 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)

NAIR, Narayan, MD

CAPT, USPHS

Acting Division Director/Chief Medical Officer

Division of Injury Compensation Programs

Healthcare Systems Bureau

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)

SAVOY, Margot, MD, MPH 

Medical Director, Department of Family & Community Medicine

Christiana Care Health System

Wilmington, DE

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 Nurse Midwives (ACNM)

HAYES, Carol E., CNM, MN, MPH

Atlanta Perinatal Associates

Atlanta, GA

American College of Nurse Midwives (ACNM) (alternate)

MEHARRY, Pamela M., PHD, CNM

Midwifery Educator, Human Resources for Health

In partnership with University of Rwanda and University of Illinois, Chicago

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American College of Obstetricians and Gynecologists (ACOG)

AULT, Kevin A., MD, FACOG

Professor and Division Director

Department of Obstetrics and Gynecology

University of Kansas Medical Center 

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

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

Market Medical Executive, CIGNA 

Houston, TX

American Medical Association (AMA)

FRYHOFER, Sandra Adamson., MD

Adjunct Associate Professor of Medicine

Emory University School of Medicine

Atlanta, GA

American Nurses Association (ANA)

RITTLE, Charles (Chad), DNP, MPH, RN

Assistant Professor, Nursing Faculty

Chatham University, School of Health Sciences

Pittsburgh, PA

American Osteopathic Association (AOA)

GROGG, Stanley E., DO

Associate Dean/Professor of Pediatrics

Oklahoma State University-Center for Health Sciences

Tulsa, OK

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https://www.cdc.gov/vaccines/acip/meetings/downloads/min-archive/min-2017-02.pdf 
Advisory Committee on Immunization Practices (ACIP) Summary Report February 22-23, 2017

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American Pharmacists Association (APhA)

FOSTER, Stephan L., PharmD

Professor and Vice Chair, Department of Clinical Pharmacy

University of Tennessee Health Sciences Center, College of Pharmacy

Memphis, TN

Association of Immunization Managers (AIM)

FINLEY, Christine, RN, MPH 

Immunization Program Manager 

Vermont Department of Health

Burlington, VT

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

State Health Officer

North Dakota Department of Health

Bismarck, ND

Biotechnology Industry Organization (BIO)

ARTHUR, Phyllis A., MBA

Senior Director, Vaccines, Immunotherapeutics and Diagnostics Policy

Washington, DC 

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

Medical Officer of Health 

Kingston, Frontenac and Lennox & Addington Public Health 

Kingston, Ontario, Canada

Infectious Diseases Society of America (IDSA)

NEUZIL, Kathleen M., MD, MPH

Professor of Medicine

Director, Center for Vaccine Development

University of Maryland School of Medicine

Baltimore, MD

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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 County and City Health Officials (NACCHO) (alternate)

DUCHIN, Jeffrey, MD

Health Officer and Chief, Communicable Disease Epidemiology and Immunization Section 

Public Health - Seattle and King County

Professor in Medicine 

Division of Allergy and Infectious Diseases

University of Washington School of Medicine and School of Public Health

Seattle, WA

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, MD

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

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National Vaccine Advisory Committee (NVAC)

THOMPSON, Kimberly, ScD 

Chair, NVAC 

Professor of Preventive Medicine and Global Health

University of Central Florida, College of Medicine Orlando, FL 

Pediatric Infectious Diseases Society (PIDS)

O’LEARY, Sean, MD, MPH

Associate Professor of Pediatrics

Pediatric Infectious Diseases

General Academic Pediatrics

Children’s Hospital Colorado

University of Colorado School of Medicine

Pediatric Infectious Diseases Society (PIDS) (alternate)

SAWYER, Mark H, MD

Professor of Clinical Pediatrics

University of California, San Diego School of Medicine

San Diego, CA

Pharmaceutical Research and Manufacturers of America (PhRMA)

JOHNSON, David R, MD, MPH 

Associate Vice President, Global Medical Affairs, 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

This document has been archived for historical purposes. (3/1/2017) 

https://www.cdc.gov/vaccines/acip/meetings/downloads/min-archive/min-2017-02.pdf