DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION

Advisory Committee on 

Immunization Practices (ACIP)

Summary Report

February 24, 2016 

Atlanta, Georgia 

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 24, 2016

Table of Contents Page

Agenda 4-5 

Acronyms 6-8 

Wednesday: February 24, 2016

Welcome and Introductions 9-12

Agency Updates

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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)

12-17

Human Papillomavirus (HPV) Vaccines

Introduction

Background: 2-Dose Schedules 

9-Valent HPV Vaccine: 2- Versus 3-Dose Trail Data

Summary: 2-Dose Schedules, Bivalent and Quadrivalent

HPV Vaccines

Work Group Plans

17-36

Meningococcal Vaccine

Introduction

Men-B-FHbp Vaccine Update

Results of a Mass Immunization Campaign with MenB-4C in Quebec, Canada

Considerations for use of MenACWY Vaccines in HIV-Infected Persons

Meningococcal Disease Among Men Who Have Sex With Men (MSM) Unites States January 

2012-June 2015

Considerations for Use of Men ACWY Vaccines in MSM

36-65

Japanese Encephalitis (JE) Vaccines

Introduction

Duration of Protection Following Primary Series and Booster Dose in Adults

Duration of Protection and Need for Booster Dose in Children

JE Vaccine Work Group Summary and Plans

65-74

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Influenza

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Introduction

Influenza Surveillance Update

Quadrivalent Recominant Influenza Vaccine

Influenza Vaccine and Egg Allergy

Proposed Recommendations for 2016-2017

74-100

Update on CDC’s Response to Zika Virus 100-108

Cholera

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VaxchoraTM Clinical Data

Cholera Vaccine GRADE Evaluation and Work Group Plans

108-122

Vaccine Supply 122

Public Comment 123-127 

Certification 128 

Membership Roster 129-138 

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Acronyms

AAAAI American Academy of Allergy, Asthma, and Immunology 

AAFP American Academy of Family Physicians 

AAP American Academy of Pediatrics

ACAAI American College of Allergy, Asthma, and Immunology 

ACIP Advisory Committee on Immunization Practices

ACNM American College of Nurse Midwives 

ACP American College of Physicians 

ACS Advisory Committee Statement 

AS04 Adjuvant System 04 

AE Adverse Events

AEFI Adverse Events Following Immunization 

AIN Anal Intraepithelial Neoplasia 

AMA American Medical Association

ASPR Assistant Secretary for Preparedness and Response 

ASTHO Association of State and Territorial Health Officials 

BARDA Biomedical Advanced Research and Development Authority 

BCH Boston Children’s Hospital 

BLA Biologics License Application 

BMC Boston Medical Center 

CBRN Chemical, Biological, Radiological, and Nuclear Threats 

CDC Centers for Disease Control and Prevention

CEO Chief Executive Officer 

CFU Colony Forming Units 

cLIA Competitive Luminex Immunoassay 

CICP Countermeasures Injury Compensation Program 

CIQ Quebec Immunization Committee 

CISA Project Clinical Immunization Safety Assessment Project

CMS Center for Medicare and Medicaid

COI Conflict of Interest 

COID Committee on Infectious Disease, AAP 

CVD Center for Vaccine Development 

DEET N,N-diethyl-meta-toluamide 

DD Deputy Director

DHS Department of Homeland Security 

DMID Division of Microbiology and Infectious Diseases 

DNA Deoxyribonucleic Acid 

DoD Department of Defense

DPEI Division of Preparedness and Emerging Infections

DSMB Data Safety Monitoring Board 

DSTDP Division of STD Prevention 

DVA Department of Veterans Affairs

DVD Division of Viral Diseases 

EAACI European Academy of Allergy and Clinical Immunology 

ED Emergency Department 

EHR Electronic Health Record 

EID Emerging Infectious Diseases 

EIS Epidemic Intelligence Service 

EMA European Medicines Agency 

EMR Electronic Medical Record 

EPA Environmental Protection Agency

EOC Emergency Operation Center

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Epi-X Epidemic Information Exchange 

FDA Food and Drug Administration

fHbp Factor H-Binding Protein 

FLU VE Influenza Vaccine Effectiveness Network

GAVI Global Alliance for Vaccines and Immunization 

GBS Guillain-Barré Syndrome 

GMT Geometric Mean Titers 

GRADE Grading of Recommendation Assessment, Development and Evaluation 

GSK GlaxoSmithKline 

HCP Healthcare Personnel 

HCW Healthcare Workers 

HD-IIV High-Dose Inactivated Influenza Vaccine 

HHS (Department of) Health and Human Services

HI Hemagglutination Inhibition 

HIV Human Iimmunodeficiency Virus 

HOPS HIV Outpatient Study 

HPV Human Papillomavirus

HRSA Health Resources and Services Administration 

ICON International Consensus 

ICU Intensive Care Unit 

IDSA Infectious Disease Society of America 

IgA Immunoglobulin A

IgG Immunoglobulin G

IHS Indian Health Service 

IIS Immunization Information System 

IIV Inactivated Influenza Vaccine 

ILI Influenza-Like Illness

ILINet Influenza-Like Illness Surveillance Network

IM Intramuscularly 

IMD Invasive Meningococcal Disease 

ISD Immunization Services Division 

JE Japanese Encephalitis

LAIV Live Attenuated Influenza Vaccine 

MCM Medical Countermeasure 

MenACWY Quadrivalent Meningococcal Conjugate Vaccine

MenB Serogroup B Meningococcal Disease

MERS Middle East Respiratory Syndrome 

MFI Median Fluorescence Intensity 

MMWR Morbidity and Mortality Weekly Report

MSM Men Who Have Sex With Men 

MVPDB Meningitis and Vaccine Preventable Diseases Branch 

NACCHO National Association of County and City Health Officials 

NACI National Advisory Committee on Immunization 

NAIP National Adult Immunization Plan 

NCEZID National Center for Emerging and Zoonotic Infectious Diseases

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

NCHS National Center for Health Statistics 

NCIRD National Center for Immunization and Respiratory Diseases 

NFID National Foundation for Infectious Diseases 

NHBA Neisserial Heparin-Binding Antigen 

NHBS National HIV Behavioral Surveillance 

NIAID National Institute of Allergy and Infectious Diseases 

NIH National Institutes of Health

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NP Nasopharyngeal 

NVAC National Vaccine Advisory Committee 

NVP National Vaccine Plan 

NVPO National Vaccine Program Office 

NYC New York City 

PCR Polymerase Chain Reaction 

PEP Post-Exposure Prophylaxis 

PHEIC Public Health Emergency of International Concern 

PHEMCE Public Health Emergency Medical Countermeasure Enterprise 

PIDS Pediatric Infectious Diseases Society 

PMD para-menthane-diol 

PPB Prime-Prime-Boost 

RCT Randomized Controlled Trial

RIV4 Quadrivalent Recombinant Influenza Vaccine 

SAEs Serious Adverse Events 

sBLA Supplemental Biologics License Application 

SCR Seroconversion Rate 

SHEA Society for Healthcare Epidemiology of America 

SME Subject Matter Experts 

STI Sexually Transmitted Infection 

SVA Serum Vibriocidal Antibody

TBE Tick-Borne Encephalitis 

Tdap Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis

TIV Trivalent Influenza Vaccine

UK United Kingdom

US United States

USAID United States Agency for International Development 

USDA US Department of Agriculture 

VAERS Vaccine Adverse Event Reporting System

V. cholera Vibrio cholerae

VE Vaccine Effectiveness

VFC Vaccines for Children

VICP Vaccine Injury Compensation Program 

VIMM VistA Immunization Enhancements 

VLP Virus-Like Particle 

VRBPAC Vaccines and Related Biological Products Advisory Committee

VSD Vaccine Safety Datalink

VTEU Vaccine and Treatment Evaluation Units 

WAO World Allergy Organization 

WG Work Group

WHO World Health Organization

WOCBA Women of Child Bearing Age 

WRAIR Walter Reed Army Institute of Research 

YF Yellow Fever

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Welcome and Introductions

Nancy Bennett, MD, MS

ACIP Chair

Amanda Cohn, MD

Executive Secretary, ACIP / CDC

Dr. Bennett called the February 2016 Advisory Committee on Immunization Practices (ACIP) 

meeting to order and welcomed those present. She introduced Dr. Amanda Cohn, the New 

ACIP Executive Secretary. Dr. Cohn joins ACIP from the Immunization Services Division (ISD) 

where she was the Deputy Director. She obtained her medical degree from Emory University, 

completed her Residency in Pediatrics at Boston Children’s Hospital (BCH) and Boston Medical 

Center (BMC). She came to the Centers for Disease Control and Prevention (CDC) in 2004 as 

an Epidemic Intelligence Service (EIS) Officer, and joined the Meningitis and Vaccine 

Preventable Diseases Branch (MVPDB) in 2006. She focused on meningococcal disease, and 

served as the CDC Lead for the ACIP Meningococcal Vaccines Work Group (WG) from 2007 

through 2014. She is Board Certified in Pediatrics and is a Fellow of the American Academy of 

Pediatrics (AAP). She is also the mother of three daughters, as is Dr. Bennett, so they have 

more in common than just sitting in the front of the room. 

Dr. Cohn thanked everyone for welcoming her to the role of ACIP Executive Secretary. She 

reported that her older daughters have received all doses of Human Papillomavirus (HPV) 

vaccine, and that her youngest daughter is not yet old enough. She welcomed everyone to the 

February 2016 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: 

Stephanie Thomas, Natalie Greene, Chris Caraway, and Dr. Jean Claire Smith. She expressed 

appreciation for all of the work these individuals perform every meeting. She reported that 

because Dr. Rima Khabbaz was unable to attend, Dr. Nancy Messonnier was joining them in 

her place. Dr. Messonnier is the Deputy Director of the National Center for Immunization and 

Respiratory Diseases (NCIRD).

Dr. Cohn 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 press interested in conducting interviews with ACIP members were instructed to 

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

Welcome & Introductions 

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The next ACIP meeting will be convened at CDC on Wednesday and Thursday, June 22-23, 

2016. Registration for all meeting attendees is required. The registration deadline for Non-US 

citizens is May 18, 2016 and for US citizens registration closes June 6, 2016. Registration is 

not required for webcast viewing. As a reminder for non-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 then introduced and welcomed the following new Ex Officio members and Liaison 

Representatives: 

Ex Officio Members

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Dr. Narayan Nair replaces Dr. Melissa Houston for the Health Resources and Services 

Administration (HRSA)

Dr. Jane Kim replaces Dr. Linda Kinsinger for the Department of Veterans Affairs (DVA) 

Dr. Sergienko, Department of Defense (DoD), was unable to attend and was represented by 

Col. Margaret Yacovone who joined the meeting via teleconference

Liaison Representatives

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Dr. Sean O’Leary, Associate Professor of Pediatric Infectious Diseases and General 

Academic pediatrics at Children’s Hospital Colorado at the University of Colorado School of 

Medicine, replaces Dr. Mark Sawyer for the Pediatric Infectious Diseases Society (PIDS), 

who served as a voting member of ACIP from July 2008 through June 2013, following which 

he joined ACIP as a Liaison Representative

Dr. Kimberly Martin was in attendance representing the Association of State and Territorial 

Health Officials (ASTHO) 

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 may be provided prior to specific votes by 

ACIP to enable these comments to be considered before a vote. During this meeting, there was 

one public comment opportunity scheduled for 4:55 PM. 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 3 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 3 minutes. Participants unable to present comments during this 

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

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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 three ACIP publications since October 2015, which are 

reflected in the following table: 

Applications for ACIP membership are due no later than November 4, 2016 for the 4-year term 

beginning July 1, 2017. Detailed instructions for submission of names of potential candidates to 

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

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

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

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

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

Dr. Jean Clare Smith at jsmith2@cdc.gov

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. 

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Dr. Bennett announced that two individuals with long histories with ACIP, Dr. Larry Pickering 

and Carol Baker, will be honored in the next several months:

 

The National Foundation for Infectious Diseases (NFID) will present Dr. Larry Pickering, past 

ACIP Executive Secretary, with the John P. Utz Leadership Award. The Award is presented to 

individuals who exemplify and support National Foundation for Infectious Diseases (NFID) 

leadership goals through service to NFID and/or the field of infectious diseases. The second 

award is to Dr. Larry Pickering and Dr. Carol Baker, former ACIP Chair, who will both be 

honored with the 12th Annual Stanley A. Plotkin Lectureship in Vaccinology during the 2016 

Pediatric Academic Societies (PAS) meeting in May. This lectureship was established to honor 

Dr. Plotkin, PAS’s Founding Father. Dr. Baker will be presenting A Time to Save: The Vaccine 

Story and Dr. Pickering will be presenting Complexities of Vaccine Recommendations: Lessons 

Learned. Dr. Bennett invited everyone to join her in congratulating these two important 

members.

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

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

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Dr. Belongia receives research support from Medimmune and has a conflict for influenza.

The remainder of the ACIP members declared no conflicts.

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

Centers for Disease Control and Prevention (CDC)

Dr. Messonnier reported that it continues to be a very busy time at CDC. Apparently, the 

agency has set a new record because there are four simultaneous activations in the Emergency 

Operations Center (EOC) with Ebola, polio, the Michigan situation, and now Zika.

Agency Updates

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Regarding Ebola, the Sierra Leone vaccine trial has completed vaccination. Over 8,000 HCP 

and other frontline workers were vaccinated in 5 districts in Sierra Leone. Current ongoing work 

includes adverse event (AE) monitoring of participants, blood draws at 6 through 12 months 

post-vaccination, and follow-up of pregnancies. Trial results are expected by Fall 2016.

In terms of polio containment, a major part of the polio eradication effort is containment of 

laboratory samples. There is an extensive survey underway of laboratories throughout the 

country to determine whether anyone has polio-containing materials, and to ensure that those 

are handled appropriately.

Regarding upcoming meetings, the theme of the 2016 National Adult and Influenza 

Immunization Summit scheduled for May 10-12, 2016 in Atlanta is “Making Vaccination Happen 

in a Changing Environment.” The Division of Viral Diseases (DVD) is hosting a small meeting in 

May 2016 titled “RSV Disease in the United States: Identifying Gaps in Epidemiology Prior to 

the Advent of Vaccines.”

Centers for Medicare and Medicaid Services (CMS)

Dr. Hance announced that CMS conducted a survey of state Medicaid agencies to try to 

determine exactly what preventive services they are covering for adults, including 

immunizations. The survey also focused on cost sharing. CMS will soon release the report on 

this survey, which will be released through the website: www.Medicaid.gov 

Department of Defense (DoD)

No report.

 

Department of Veterans Affairs (DVA)

Dr. Jane Kim reported that the Veterans Information Systems and Technology Architecture 

(VistA), DVA’s nationwide immunization system, has a project known as VistA Immunization 

Enhancements (VIMM) that will be initiating data sharing to state and city immunization 

registries. Pilot testing will begin later in 2016. VA is also developing clinical reminder support 

tools for the electronic medical record (EMR) to prompt clinicians to offer tetanus; tetanus 

toxoid, reduced diphtheria toxoid, acellular pertussis (Tdap), and herpes zoster immunizations 

to patients who meet criteria. These tools will be disseminated nationwide throughout the VA 

system in March 2016.

Food and Drug Administration (FDA)

Dr. Sun reported that since the last ACIP meeting, FDA approved the first adjuvanted seasonal 

influenza vaccine, FLUADTM, for individuals 65 years of age and older. GARDASIL® 9 received 

supplemental approval for boys 9 through 16 years of age for the prevention of anal cancer, 

genital warts, and anal intraepithelial neoplasia (AIN). A supplement was also approved for the 

anthrax vaccine, BioThrax®, for post-exposure prophylaxis (PEP). This is noteworthy because it 

is the first animal rule approval for a vaccine indication. FDA convened a Vaccines and Related 

Biological Products Advisory Committee (VRBPAC) meeting on November 13, 2015 on the topic 

of maternal immunization. Topics discussed included:

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Use of serologic endpoints as markers for protection

Safety assessment of infants after maternal immunization

Duration of follow-up

Potential immunologic interference of maternal immunization with infant immunization

Use of observational studies for vaccines recommended by ACIP, such as Tdap and 

influenza, to evaluate the effectiveness of maternal immunization

Health Resources and Services Administration (HRSA)

Dr. Nair reported that the national Vaccine Immunization Compensation Program (VICP) has 

had a busy year processing claims. As of January 2016, over 375 claims have been filed for the 

current fiscal year. Thus far in this fiscal year, 127 claims have been adjudicated. Of those, 

125 were compensable and 2 were dismissed. Approximately $75 million in awards have been 

paid to petitioners, and $6 million have been paid to attorneys for fees and costs for 

compensated and dismissed claims. More data about the program can be obtained on the 

HRSA website. HRSA has completed development of proposed regulations to make changes 

to the Vaccine Injury Table. The Notice for Proposed Rulemaking was posted for public 

comments in July 2015, and was available for 180 days. A hearing to obtain comments from 

the public on the proposed changes took place on January 14, 2016. Comments received from 

the public are still being reviewed. To date in this fiscal year, the Countermeasures Injury 

Compensation Program (CICP) has compensated 2 claims totaling $125,000. Both programs 

are involved in outreach programs to inform providers and make the public aware of this safety 

net program.

Indian Health Services (IHS)

Ms. Groom announced that this year, IHS rolled out a mandatory influenza vaccination policy for 

its healthcare personnel (HCP). Because bargaining had not been completed with unions, IHS 

was able to implement the policy only partially. However, a 10% increase was observed among 

IHS’s HCP even with partial implementation. Bargaining was recently completed with the 

largest union, so hopefully there will be more complete implementation of the policy next year. 

In addition, IHS is rolling out two performance measures for the agency that pertain to 

immunizations. The first is a composite adult immunization measure that will assess the 

proportion of adults 19 years of age and older who have received all age-appropriate 

vaccinations with Tdap, herpes zoster, and pneumococcal vaccines. The second is a 

developmental measure to assess Tdap and influenza vaccination among pregnant women.

National Institutes of Health (NIH)

Dr. Gorman reported that Dr. Carole Heilman would retire as the Division Director of the Division 

of Microbiology and Infectious Diseases (DMID) on February 12, 2016 following an illustrious 

38-year career at NIH. Since her 1999 appointment as DMID director, Dr. Heilman has 

managed a highly complex global research program in infectious diseases, providing scientific 

direction and oversight for an extensive extramural research portfolio. Under her leadership, 

DMID has built a robust research infrastructure encompassing national and regional 

biocontainment laboratories, Centers of Excellence, and Vaccine and Treatment Evaluation 

Units (VTEU).

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Known for fostering a collaborative work environment and encouraging open scientific 

discourse, Dr. Heilman has received numerous awards for scientific management and 

leadership. Her honors include three Department of Health and Human Services (HHS) 

Secretary's Awards for Distinguished Service, recognizing her contributions to developing 

pertussis, biodefense, and AIDS vaccines. Dr. Irene Glowinski will serve as Acting Director of 

DMID while NIH conducts a national search for Dr. Heilman’s replacement. Dr. Gorman said 

that when he wonders whether one person can make a difference in a group as large as the 

federal government, he thinks of Dr. Heilman and realizes that it can be done.

In terms of research and publications, Dr. Gorman indicated that Dr. Gellin would provide a 

detailed presentation during the Zika Virus session. NIH is in the process of collecting serum, 

now on an impromptu and soon on a systematic basis, so that reagents and determinants of 

immune correlates of protection can be studied. NIH is also considering vaccine development 

and hopes to pivot rapidly from the experience with dengue and Chikungunya to the new virus 

that is vector-borne. The National Institute of Allergy and Infectious Diseases (NIAID) has 

initiated work on several fronts to address Zika virus including the development of animal 

models to better understand the impact of the virus on the body; in vitro assays to test 

therapeutics for activity against the virus; and improved diagnostics to rapidly identify the virus 

and distinguish it from its close relatives (e.g., dengue). Several NIAID-supported Zika vaccine 

efforts already are under way, including the use of the following vaccine approaches: 

Deoxyribonucleic acid (DNA) vaccines, live attenuated vaccines, and VSV-vectored vaccines 

[Fauci AS1, Morens DM. Zika Virus in the Americas - Yet Another Arbovirus Threat. N Engl J 

Med. 2016 Jan 13. [Epub ahead of print] http://www.nejm.org/doi/full/10.1056/NEJMp1600297]. 

NIAID recently issued a notice to highlight the NIH’s interest in supporting research and product 

development to combat Zika virus. Areas of high priority include: diagnostics, therapeutics, 

vaccines, and basic research to better understand infection; pathogenesis; biology of mosquito 

vectors, host-virus interaction and identification of relevant biomarkers [NIH Guide Notice:

http://grants.nih.gov/grants/guide/notice-files/NOT-AI-16-026.htm] 

NIAID is organizing a workshop to be convened March 28-29, 2016 to bring together 

researchers from around the world with HHS entities (CDC, FDA, ASPR/BARDA, and NIH) and 

industry partners. The discussion will include a review of the latest information on the virology, 

pathogenesis, and epidemiology (including the potential link to microcephaly) of Zika virus, as 

well as efforts toward the development of diagnostics, therapeutics, vaccines, and novel vector 

control strategies.

There has been a recent publication of NIH’s safety and immunogenicity study of sequential 

rotavirus vaccine schedules. NIAID-supported researchers studied the two rotavirus vaccines 

licensed for infants in the United States (US), RotaTeq® and Rotarix®, to determine whether 

switching from one vaccine product to another works as well as using the same vaccine for all of 

the doses. According to current recommendations and depending upon which vaccine is used, 

infants receive a series of two or three doses. In many cases, infants receive the same vaccine 

for all of their doses. However, in some situations HCPs may switch from one product to the 

other to complete the vaccine series. In this study, researchers determined that mixed rotavirus 

vaccine schedules are safe and non-inferior in immunogenicity when compared with each 

licensed rotavirus vaccine when administered alone [Libster R, McNeal M, Walter EB, Shane 

AL, Winokur P, Cress G, Berry AA, Kotloff KL, Sarpong K, Turley CB, Harrison CJ, Pahud BA, 

Marbin J, Dunn J, El-Khorazaty J, Barrett J, Edwards KM; Safety and Immunogenicity of 

Sequential Rotavirus Vaccine Schedules. VTEU Rotavirus Vaccine Study Work Group. 

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Pediatrics. 2016 Jan 28. pii: peds.2015-2603. [Epub ahead of print; 

https://www.clinicaltrials.gov/ct2/show/NCT01266850].

NIH has a new dengue vaccine entering a Phase 3 trial in Brazil. This is a large-scale clinical 

trial to evaluate whether a candidate vaccine can prevent the mosquito-borne illness dengue 

fever. The vaccine, TV003, was developed by scientists in the laboratory of Stephen 

Whitehead, PhD, at NIAID. The Butantan Institute, a non-profit producer of immunobiologic 

products for Brazil, licensed the NIAID dengue vaccine technology and is sponsoring the 

placebo-controlled, multi-center Phase 3 trial using test vaccine produced in Sao Paulo. The 

new trial plans to enroll almost 17,000 healthy people 2 through 59 years of age in 13 cities, 

beginning in Sao Paulo [https://clinicaltrials.gov/ct2/show/ NCT02406729].

An experimental vaccine to protect against the mosquito-borne illness Chikungunya is being 

tested in a Phase 2 trial sponsored by NIH. Results from an initial trial of the vaccine, which 

was developed by scientists at NIAID, were reported in 2014. In that study, all 25 vaccine 

recipients developed robust immune responses and no safety concerns were noted. The new 

trial is designed to enroll 400 healthy adult volunteers 18 through 60 years of age at six sites in 

the Caribbean. It will continue to collect data on the candidate vaccine’s safety and ability to 

elicit immune responses, including antibodies [https://www.clinicaltrials.gov/ct2/show/ 

NCT02562482?term=NCT02562482&rank=1].

There was a special issue of Vaccine: Advancing Maternal Immunization Programs through 

Research in Low and Medium Income Countries. This builds upon a long and storied history 

from ACIP in promoting maternal immunizations, and brings together a lot of the research in a 

single area. This work is ongoing [Volume 33, Issue 47, 25 November 2015, ISSN 0264-410X; 

Guest editors M. Nesin (NIH), J. Read (NIH), M. Koso-Thomas (NIH), M. Brewinski Isaacs (NIH) 

and A. Sobanjo-ter Meulen (B&M Gates Foundation)].

National Vaccine Advisory Committee (NVAC)

Dr. Orenstein reported that NVAC last met on February 2-3, 2016. A topic of significant focus 

has been drivers of vaccine innovation, potential ways to incentivize innovation, and possible 

barriers. They look forward to the June 2016 meeting when an initial landscape analysis will be 

done of what those barriers can be. They have heard from domestic and global groups, 

including Dr. Seth Berkley, who is the Chief Executive Officer (CEO) of the Global Alliance for 

Vaccines and Immunization (GAVI), and who is talking about creation of a vaccine development 

fund. During the June 2016 NVAC meeting, there will be a report of selected recommendations 

from NVAC’s Maternal Immunization WG, which is assessing overcoming barriers to developing 

vaccines and vaccine recommendations for existing vaccines for pregnant women. Another 

major focus is the National Vaccine Plan (NVP) 2010-2020, for which NVAC will be intimately 

involved with a midcourse review. NVAC is following adult immunization implementation issues, 

and has heard information about efforts pertaining to containment of polioviruses. Type 2 

poliovirus is now formally eradicated, so there is an extensive area to prevent reintroduction 

from laboratories.

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National Vaccine Program Office (NVPO)

Dr. Gellin noted that many had participated in the NVP midcourse review, the purpose of which 

is to determine whether the direction set in 2010 is the same direction that should be continued. 

The National Adult Immunization Plan (NAIP) has been launched. The NAIP has the following 

four broad goals:

Goal 1: Strengthen the adult immunization infrastructure 

Goal 2: Improve access to adult vaccines 

Goal 3: Increase community demand for adult immunizations

Goal 4: Foster innovation in adult vaccine development and vaccination-related technologies

In related work with CDC and the Immunization Action Coalition (IAC), NVPO is co-sponsoring 

the National Adult and Influenza Immunization Summit, which will be in Atlanta May 10-12, 

2016.

NVAC issued a vaccine confidence report last summer, which is now the “playbook” for moving 

forward. NVPO is sponsoring a funding opportunity of up to $250,000 to assess the outlines of 

the recommendations from NVAC. The announcement can be found on www.grants.gov 

Introduction

Allison Kempe, MD, MPH

Chair, ACIP HPV Vaccines WG 

Dr. Kempe reminded everyone that in February 2015, ACIP voted on the 9-valent HPV (9vHPV) 

vaccine recommendations. In June 2015, the WG reviewed the status of the 9vHPV vaccine 

introduction, reviewed a variety of data, and discussed the issue of potential additional 9vHPV

vaccination for those who received a different HPV vaccine. In October 2015, the WG reviewed 

the HPV vaccination program in terms of coverage and implementation, safety, and impact. 

To frame the discussion for this session, Dr. Kempe reminded everyone of some historical 

recent dates pertaining to 9vHPV vaccine. The vaccine was licensed by the FDA in December 

2014 and was recommended by ACIP in February 2015, with a Morbidity and Mortality Weekly 

Report (MMWR) Policy Note published in March 2015. 9vHPV vaccine was recommended as 1 

of 3 HPV vaccines that can be used for females and 1 of 2 for males in the currently

recommended age groups. 

Regarding the male age indications at the time of the first application to FDA, 9vHPV 

immunogenicity trials in males 16 through 26 years of age were not completed. In December 

2014, the vaccine was licensed for females 9 through 26 years of age and males 9 through 15 

years of age. On December 14, 2015, FDA extended the age indication to include males 16

through 26 years of age. Regarding manufacturer plans, Merck previously reported that they 

intended to maintain 4vHPV in the US market until 9vHPV was approved by the FDA for use in 

males 16 through 26 years of age. This has now occurred, so Merck plans to retire 4vHPV by 

the end of 2016 in the US. 

Human Papillomavirus (HPV) Vaccines

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Since the last ACIP meeting, the WG has been reviewing data on 2-dose schedules, including 

9-valent HPV vaccine 2- versus 3- dose immunogenicity data and 2-dose trials for other HPV 

vaccines, as well as modeling and cost-effectiveness data. The WG also has been discussing 

policy considerations related to 2-dose schedules, including what additional data may be 

needed for policy plans, the timeline, and decisions that would go along with those 

considerations.

During this session, presentations were given on the following topics:







Data on 2-dose HPV vaccination schedules 

Information and background needed for discussion and decisions about HPV vaccine policy 

options that ACIP will address over the next few meetings

WG’s future plans

Background: 2-Dose Schedules

Lauri Markowitz, MD

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Markowitz began with some brief background information for the HPV session, including 

general background and previous ACIP considerations of 2-dose schedules.

There are three licensed HPV vaccines. They are all virus-like particle (VLP) vaccines that are 

made from the L1 protein of the virus, which is the major capsid protein of the virus. They differ 

by the types targeted as listed here: 

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The bivalent vaccine has a different adjuvant, AS04, which has been shown to produce higher 

antibody titers than the adjuvant in the 4vHPV vaccines. The 4vHPV vaccine and the 9vHPV 

vaccine have the same adjuvant, but there is more adjuvant content in the 9vHPV vaccine. 

There is a higher antigen content for HPV 6, 16, 18 in the 9vHPV compared with 4vHPV. The 

dates of FDA licensure are shown, as well as the licensed age groups. All vaccines are 

licensed as a 3-dose schedule as either a 0, 1, 6 month or 0, 2, 6 month schedule. Although 

there were three licensed vaccines through 2014, almost all vaccine used in the US was 

4vHPV.

For licensure of the HPV vaccines, efficacy and immunogenicity data were obtained. These 

included efficacy data from trials in 15 through 26 year olds with trial endpoints of cervical precancer lesions as well as some other pre-cancers and genital warts, and data from bridging 

immunogenicity trials in 9 through 15 year olds. Licensure in this age group, and age in which 

efficacy trials are not feasible, was based on non-inferior antibody response compared with 

young adult women in the efficacy trials. This is important as it is obviously relevant for how the 

trials were conducted for the 2- versus 3-dose schedules.

In terms of some brief background about what is known about the immunogenicity of HPV 

vaccines, there is high seroconversion after vaccination at greater than 98%. In addition, 

vaccination induces higher antibody titers than natural infection. The main basis of protection is 

neutralizing antibody; however, the minimal protective antibody threshold is not known. Clinical 

trials used different serologic assays, and the results are difficult to compare across studies or 

HPV types. For the 4vHPV vaccine, Merck used a competitive Luminex immunoassay (cLIA)

that measures neutralizing antibody to 1 epitope. The GlaxoSmithKline (GSK) trials for 2vHPV 

vaccine used an enzyme-linked immunosorbent assay (ELISA), which measures neutralizing 

and non-neutralizing antibody. Of note in the pre-clinical trials, some 4vHPV vaccinees lost 

detectable HPV 18 antibody as measured by the cLIA, but no loss of protection was detected. 

Vaccination at younger ages results in higher antibody titers. This last point is illustrated in this 

graphic, which shows the geometric mean titers (GMTs) one month after the third dose of 

4vHPV vaccine by age at vaccination, with age shown on the x axis: 

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As shown, the GMTs decreased with increasing age at vaccination for all 4 types. [Giuliano, et 

al. JID 2007]. The same decrease in GMTs with increasing age at vaccination was seen in the 

2vHPV and 9vHPV trials 

There has been global interest in simplified schedules for HPV vaccine. Such schedules could 

facilitate implementation, reduce logistical challenges, and decrease resource needs. They also 

might increase acceptability for providers, parents, and vaccinees. Interest in evaluating 2-dose 

schedules in young adolescents was stimulated by data from clinical trials with 3 doses showing 

high efficacy, high serologic response to vaccination, and higher antibody titers in the younger 

age groups. 

The 3-dose schedules for which vaccines were originally tested and licensed (0 months, 1 to 2 

months, and 6 months) can be considered a “prime-prime-boost” (PPB), with the first 2 doses 

being the priming doses and the third being the boost. The 2-dose schedule that has been 

studied is a 0, 6 month schedule. This schedule can be considered a prime and boost with the 

second prime eliminated. Memory B cells require at least 4 to 6 months to mature and 

differentiate into high-affinity B cells. The approximate 6-month interval between the first and 

last dose allows the last dose to reactivate memory B cells efficiently [Siegrist. Chapter 2. 

Vaccine Immunology. In Vaccines 2013; Stanley et al. Expert Reviews 2014].

Based on some of the data that Dr. Markowitz reviewed later during this session, regulatory 

approvals have been obtained for 2-dose vaccination schedules for the 2vHPV and 4vHPV 

vaccines in other countries. Approval for 2-dose schedules has been based primarily on the 

immunobridging data, which showed non-inferior antibody response with 2 doses (0, 6 months) 

in adolescents compared with a 3-dose schedule in young adult women. In 2014, the European 

Medicines Agency (EMA) granted marketing authorization for a 2-dose schedule for those 9 

through 14 years of age for 2vHPV and 9 through 13 years of age for 4vHPV. Following 

regulatory approval by the EMA, in 2014 the World Health Organization (WHO) changed its

recommendation from a 3-dose to a 2-dose schedule for those starting the vaccination series 

before age 15 [Weekly Epidemiologic Record 2014; 89: 221-236]. Many countries changed 

from a 3- to 2-dose schedule for this age group, including European and Latin American 

countries and some provinces in Canada. 

During the June 2014 ACIP meeting, data on 2-dose schedules for 2vHPV and 4vHPV were 

reviewed by ACIP. At that time, there was no FDA indication for a 2-dose schedule for any HPV 

vaccine, and there were no plans by either manufacturer for submission of 2-dose data to FDA 

for 2vHPV or 4vHPV. Also at that time, data for the 9vHPV was being considered by ACIP and 

there were no data on 2-dose schedules in the initial Biologics License Application (BLA) under 

review by FDA at that time. However, a 2- versus 3-doses trial had been initiated by the 

manufacturer for the 9vHPV vaccine. In 2014, ACIP decided to continue to review 9vHPV as a 

3-dose schedule, and to consider 2-dose schedules after the data from the 2- versus 3-dose 

trial of 9vHPV vaccine and other data become available. 

Later that year, 9vHPV vaccine was licensed as a 3-dose schedule and was recommended by 

ACIP in February 2015 as one of the HPV vaccines that could be used for the routine 

immunization schedule. The 9vHPV vaccine became available through the Vaccines For

Children (VFC) Program in April 2015. Approximately 7 million doses were distributed in the US

through December 2015. At this point, the 9vHPV 2- versus 3-dose trial data became available

and were to be reviewed by ACIP along with other data on 2-dose schedules. 

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Comparison of Immunogenicity of 2-Dose 

and 3-Dose Regimens of 9vHPV Vaccine

Alain Luxembourg, MD, PhD

Director, Clinical Research

Merck Research Laboratories

Dr. Luxembourg presented the latest data for Merck’s 2- versus 3-dose trial for 9vHPV vaccine. 

The 3-dose regimen of 9vHPV vaccine was licensed in December 2014 in the US; in 2015 in 

Canada, the European Union (EU), Australia, Chile, and Hong-Kong; and in 2016 in Ecuador, 

Korea, and New Zealand under the name GARDASIL® 9 to prevent the following: 







Cervical, vulvar, vaginal, and anal cancers caused by HPV 16/18/31/33/45/52/58

Cervical, vulvar, vaginal, and anal dysplasia caused by HPV 6/11/16/18/31/33/45/52/58

Genital warts caused by HPV 6/11

In February 2015, ACIP recommended GARDASIL® 9 for routine vaccination. Licensure of 

9vHPV vaccine is under review in other countries. 

Initial licensure of 9vHPV vaccine was for 3 doses for all age ranges. WHO changed its 

recommendation for HPV vaccines in terms of dose schedules in October 2014 to 2 doses for 

girls 9 through 14 years of age with the following caveats:







If dose 2 is administered <5 months after dose 1, a third dose should be given >6 

months after the first dose

No maximum recommended interval (≤12-15 months suggested to complete schedule 

promptly and prior to becoming sexually active)

3 doses in individuals ≥15 years of age and those known to be immunocompromised 

and/or HIV-infected

At this time, there is no current licensure or recommendation of a 2-dose regimen in the US. 

The 2-dose data for 4vHPV vaccine became available around the time when efficacy data 

became available for 9vHPV vaccine. Considering the imminent submission of the 9vHPV 

vaccine data to FDA, the results of the 2-dose immunogenicity study of GARDASIL® were not 

submitted to FDA. 9vHPV was developed as a 3-dose vaccine because the development 

began in 2007, a year after 4vHPV vaccine was approved. At that time, the standard regimen 

was 3 doses and 2-dose regimens were not discussed very much. For that reason, all of the 

trials were conducted with a 3-dose regimen.

Protocol 10 was begun in 2013 to assess a 2-dose regimen of 9vHPV vaccine. The results of

the primary immunogenicity analyses (4 weeks post-last dose) are expected to be reviewed by 

the FDA in 2016. The study will continue for 2 more years for assessment of antibody 

persistence and immune memory, and these results will be presented as soon as they become 

available. Merck is also planning a separate larger study known as Protocol 025 to assess

long-term immunogenicity and effectiveness. Protocol 025 is still in the planning stage. Merck 

will update the WG as planning progresses.

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Protocol 10 is an open-label study with males and females in which all subjects received 9vHPV 

vaccine. Cohort 1 is comprised of females 9 through 14 years of age who received 2 doses 

administered with a 6-month interval. Cohort 2 is comprised of males 9 through 14 years of age 

who received 2 doses administered with a 6-month interval. Cohort 3 is comprised of females 

and males 9 through 14 years of age who received 2 doses with a 12-month interval. Cohort 4 

is a control group comprised of young women 16 through 26 years of age who received 3 doses 

at 0, 2, and 6 months. Cohort 4 serves as the control because it uses the population and dose 

regimen that were used to establish vaccine efficacy. Since there is no immune correlate of 

protection threshold of protective antibody determined for HPV vaccines, the only 

immunogenicity comparison that has clinical significance is a comparison to a group where 

efficacy was established.

Cohort 5 is an exploratory cohort comprised of females 9 through 14 years of age who received 

3 doses to assess the dose effect in the same age range and same gender. It is exploratory 

because it is scientifically important and interesting, but is not necessarily a comparison for 

which a conclusion can be drawn regarding clinical significance. There was a 4-week window 

for all of the vaccination dates. The study will continue for two more years for assessment of 

immunogenicity, including assessment of immune memory at Month 36, with a challenge dose 

administered.

The duration of Protocol 10 is 37 months. The primary objectives are to:



























Demonstrate non-inferiority of GMTs at 1 month after the last dose in girls and boys who 

received a 2-dose regimen versus young women who received a 3-dose regimen

Same approach as that previously accepted for licensure of 3-dose regimen of 

GARDASIL®

Non-inferiority criterion: exclude 1.5-fold decrease (2- versus 3-dose)

Perform 3 non-inferiority tests: 

Girls (0, 6) vs. Women (0, 2, 6)

Boys (0, 6) vs. Women (0, 2, 6)

Girls/Boys (0, 12) vs. Women (0, 2, 6)

The objectives for the exploratory analyses are to:

Compare GMTs 1 month after the last dose in: 

Girls (0, 6) vs. Girls (0, 2, 6)

Girls (0, 12) vs. Girls (0, 2, 6)

Assess antibody persistence at months 24 and 36

Assess evidence of immune memory (additional dose at month 36)

No hypothesis testing for the exploratory analyses

In terms of the results for the primary objectives, at 1 month post-last dose in 2-dose (0, 6) girls 

versus 3-dose (0, 2, 6) women, the point estimates were higher for 2 doses for all HPV types. 

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The non-inferiority criterion was met for all 9 HPV types. The fold difference for girls/women 

was over 2 for most types. Types 45 and 52 were somewhat lower, but still, the non-inferiority 

criterion was met for all HPV types, with the lower bound of the 95% confidence interval greater 

than 0.67 (thereby excluding a 1.5-fold decrease). For boys receiving 2-doses (0, 6) versus

women receiving 3-dose (0, 2, 6), substantially higher immunogenicity was achieved among 

boys receiving 2 doses versus women receiving three doses. The non-inferiority criterion was 

met for all 9 HPV types. Types 45 and 52 were in the lower range, while types 16 and 33 were 

among the highest. For 2-doses (0, 12) for girls and boys versus 3-doses (0, 2, 6) for women, 

the non-inferiority criterion was met for all 9 HPV types. 

As part of the objectives, seroconversion rates were also assessed. It is very clear from the 

following table showing the 5 cohorts and 9 HPV types that all seroconversion rates for any type 

were greater than 97%, which very much aligns with what has been observed in 3-dose HPV 

trials:

For the exploratory analyses of 2 doses (0, 6) in girls 9 through 14 years of age versus 3 doses

(0, 2, 6) in girls 9 through 14 years of age, at first glance GMTs look very similar for all 9 HPV 

types. But looking at the fold difference, the point estimate of the GMT ratio is greater than 1 for 

Types 6, 11, 16, 33, and 58 and lower than 1 for Types 18, 31, 45, and 52. A fold difference of 

greater than 1 means that the GMT is higher with the 2-dose than the 3-dose regimen, while a 

fold difference of less than 1 means that the GMT is higher with the 3-dose than the 2-dose 

regimen. For Types 31, 45, and 52 the 95% confidence interval of the GMT ratio does not 

include 1, which indicates a significantly lower GMT for 2-dose than 3-dose.

The same comparison was conducted between girls receiving a 2-dose regimen at 12 months 

(0, 12) versus girls receiving a 3-dose regimen (0, 2, 6). The GMTs were generally higher with 

the 0, 12 regimen. The fold difference was greater than 1 for Types 6, 11, 16, 18, 31, 33, 52, 

and 58. The fold difference was less than 1 for Type 45, and the 95% confidence interval of the 

GMT ratio did not include 1. Thus, there was a significantly lower GMT for Type 45 and a 

similar or higher GMT for all other types.

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Given that GARDASIL® 9 is now a licensed product, a vaccination report card was not used and 

injection site and systemic adverse events (AE) were not systematically assessed. However, 

serious AE (SAE) and discontinuations due to an AE were assessed. During the study, a few 

SAEs were evenly distributed among the groups. Among these, there were no vaccine-related 

SAEs and no deaths. One (1) discontinuation due to urticaria was reported at 1 day post-dose 1

in Cohort 3 that resolved.

In summary, the primary study hypotheses were met. Non-inferiority was met for HPV 

6/11/16/18/31/33/45/52/58 GMTs at 1 month after last vaccination in girls and boys 9 through 14 

years of age who received 2 doses of 9vHPV vaccine versus women 16 through 26 years of 

age who received 3 doses. That supports extending the efficacy findings in women who 

received 3 doses to girls and boys who received 2 doses, using the same process that was 

used for 3 doses in boys and girls. The exploratory analyses showed that for some HPV types, 

GMTs were lower in girls who received 2 doses versus girls who received 3 doses. The clinical 

significance of this observation is unknown but may deserve further investigation, especially 

based on longer follow-up. With respect to safety, 9vHPV vaccine was generally well-tolerated 

in all vaccination groups. There were no vaccine-related SAEs, no deaths, and only 1 

discontinuation due to an AE. There were no new safety findings compared with previous 

clinical studies of the 9vHPV vaccine. 

There are a number of key points and potential limitations to be considered with these results. 

Regarding the time interval between dose 1 and dose 2, per WHO and EMA, if for any reason, 

the interval between doses 1 and 2 is less than 5 months, a third dose should be given 6 

months after dose 1. There is a single post-marketing effectiveness study of GARDASIL® using 

genital warts as an end point that indicates lower effectiveness if the time interval between 

doses 1 and 2 is less than 5 months [Blomberg et al Clin Infect Dis 2015; 61:676-682]. This 

suggests that there may be less flexibility with a 2-dose regimen than with a 3-dose regimen. 

Though little is known about a single dose, there are post-marketing effectiveness studies of 

4vHPV vaccine that indicate lower effectiveness of a single dose. Thus, ensuring series 

completion is essential. Duration of protection provided by 2 doses of 9vHPV vaccine has not 

been assessed, there is no efficacy assessment, and there are no long-term follow-up data. 

Data are forthcoming from the longer term follow-up study that is planned, but they are not 

available at this time. Immunogenicity assessment will continue through Month 37 in this study

and a separate, larger, long-term immunogenicity and effectiveness study is planned given the 

absence of an immune threshold of protection. 

In conclusion, administration of a 2-dose series of 9vHPV vaccine in girls and boys 9 through 14 

years of age, with the second dose given at 6 or 12 months following the first dose (± 4 week 

window) generates non-inferior GMTs for all 9 HPV types compared with the 3-dose regimen in 

young women 16 through 26 years of age. The efficacy of the 2-dose regimen, durability of 

responses, and long-term effectiveness remain to be evaluated in long-term follow-up clinical 

studies and post-licensure epidemiological studies. 

Discussion Points

Ms. Pellegrini requested clarification regarding whether Merck would be submitting these data to 

FDA, and whether an indication for a 2-dose schedule would be sought based on the data.

Dr. Luxembourg replied that Merck does not plan to submit the 2-dose data of GARDASIL® to 

FDA. GARDASIL® will likely exit the market in the United States at the end of the year.

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Dr. Bennett requested clarification of Ms. Pellegrini’s question regarding 9vHPV vaccine.

Dr. Luxembourg clarified that his first reply regarded the 4vHPV vaccine. FDA is currently 

reviewing the results of the 2-dose study for the 9vHPV vaccine.

Dr. Karron asked how GARDASIL® 9 is being used in the other countries where it has been 

approved.

Dr. Luxembourg responded that at this point, GARDASIL® 9 is commercially available in the US, 

Canada, and a few European countries only as a 3-dose schedule.

Dr. Belongia asked Dr. Luxembourg to comment further on the observation that the GMT ratio 

was higher for the 2-dose schedule at 0, 12 months versus the 2-dose schedule at 0, 6 months, 

and whether Merck would propose to utilize the longer interval in its application for a 2-dose 

schedule licensure.

Dr. Luxembourg explained that the study was designed to conduct a comparison with young 

women who received a 3-dose schedule. Both of those regimens testing 0, 6 and 0, 12 met the 

non-inferiority criterion, which means that both regimens are equivalent in that regard. There 

may be differences in GMT levels, but the differences in GMT levels in the HPV vaccine field do 

not have identifiable clinical significance aside from the comparison to an efficacy population. 

Merck’s intent with respect to assessing a 0, 6 regimen and a 0, 12 regimen was not only 

scientific, but also was for practical reasons. Merck recognizes that depending upon how the 

vaccine is administered (school program, office setting, et cetera), it is important to provide the 

public health community with more flexibility in terms of time interval between the 2 doses.

Dr. Reingold requested further information regarding when results are anticipated from the 

planned long-term effectiveness and post-licensure epidemiological studies. 

Dr. Luxembourg replied that Protocol 10 is ongoing, with two more years of follow-up planned. 

The analyses of antibody persistence and immune memory are anticipated to be completed by 

the end of 2017. The long-term effectiveness study is still in the planning stages and has not 

yet begun, given continued discussions with regulators. Merck anticipates that the study will 

begin in 2017 and will include at least 10 years of follow-up, and perhaps longer.

Dr. Kelly Moore asked whether there is a biological plausible mechanism by which starting at a 

higher or equivalent GMT with a 2-dose series could result in a more rapid degradation than in a 

3-dose series.

Dr. Luxembourg responded that this will be assessed with the antibody persistence analyses. 

Studies have been conducted with other HPV vaccines, but this does not seem to present a 

concern as there does not seem to be a dramatic decrease over time in GMT ratios between 

girls who received 2 doses versus women who received 3 doses. Certainly, this is one point 

that needs to be monitored thoroughly in antibody persistence analyses. 

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Summary: 2-Dose Schedules, Bivalent and Quadrivalent HPV Vaccines

Lauri Markowitz, MD

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

In this presentation, Dr. Markowitz provided an overview of data on 2-dose vaccination 

schedules for 2vHPV and 4vHPV vaccines. Data on 2-dose schedules for these vaccines are 

useful to review as ACIP considers data on 2 doses for 9vHPV vaccine for two reasons. 

Although there are some differences between the vaccines, trials of 2vHPV and 4vHPV 

vaccines can provide contributory data to consider related to the 9vHPV decision. Importantly, 

the 2- versus 3-dose trials of these vaccines have longer follow-up to date than the 9vHPV trial. 

Also, recommendations for 2-dose schedules might be considered for 2vHPV and 4vHPV 

vaccines, and there certainly would be questions regarding persons who received less than 3 

doses of 2vHPV or 4vHPV if 2 doses of the 9vHPV are recommended.

Data on 2-dose schedules of 2vHPV or 4vHPV vaccines include immunogenicity, efficacy, and 

post-licensure effectiveness data. Dr. Markowitz focused primarily on immunogenicity data in 

this presentation as a complement to the data presented by Dr. Luxembourg on 9vHPV vaccine,

but briefly mentioned the efficacy and post-licensure effectiveness data.

For the bivalent vaccine, Dr. Markowitz reviewed three trials designed to evaluate 2-dose 

schedules. The following table shows where each trial was conducted; age groups; number of 

doses; the schedule, with interval in months between doses; and the longest follow-up available

to date:

 

The first two are industry-sponsored studies used to obtain regulatory approval and the third is 

independent. As noted, all three trials provide a comparison of 2 doses in the younger age 

group with 3 doses in the young adult women, which was the primary comparison. The first and 

last studies also provided a direct comparison of 2 and 3 doses in the younger age group. The 

second trial compared two different 2-dose schedules in the younger age group: 0, 6 and 0,12 

months schedules—similar to the 9vHPV vaccine trial just presented. 

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The first study by Romanowski was considered a proof of concept study. It also included a 

dose ranging component and other groups as well, but Dr. Markowitz showed only the groups of 

interest for ACIP’s discussion during this session. A follow-up extension study evaluated groups 

that received the licensed formulation through 60 months. From this proof of concept study, 

there were many findings but the main ones of interest for this discussion were that the 2-dose 

schedule in girls 9 through 14 years of age was immunologically non-inferior to the 3-dose 

schedule in the young adult women. Within the same age group, GMTs were lower with 2-dose 

schedule given at 0 and 6 months compared with the 3-dose schedule. This was observed for 

both girls 9 through 14 years of age and women 15 through 25 years of age.

In terms of the longer follow-up of two groups of interest, those 9 through 14 years of age who 

received 2 doses and those 15 through 25 years of age who received 3 doses, all subjects 

remained seropositive for HPV 16 and 18 through month 60 after vaccination. The GMTs over 

time for HPV 16 are shown in the following figure: 

Romanowski, et al. Hum Vaccin 2016

The antibody kinetics are similar to those seen in all of the HPV vaccine trials, with a peak 

antibody titer after the first dose, a decline, and then a plateau reached at about 24 months. 

GMTs were non-inferior in the 2-dose group compared with 3-dose group through month 60. 

The lines are almost identical, so they are difficult to see. GMTs were substantially higher than 

after natural infection shown by the lower dotted line through Month 60 of follow-up.

The unpublished trial of the bivalent vaccine was a larger trial that was designed to confirm the 

findings in the proof of concept trial. Though the results are unpublished, data have been 

presented at meetings and are available online [Clinical Study Report HPV-070 (114700) at 

http://www.gsk-clinicalstudyregister.com Clinicaltrials.gov NCT01381575]. There were two 2-

dose groups of subjects 9 through 14 years of age (0,6 and 0,12 month schedules) and a single 

3-dose group 5 through 25 years of age (0, 1, 6 months—the standard schedule). Results for 

this study are presented here as GMT ratios:

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For the above and subsequent slides, Dr. Markowitz showed the GMT ratios as 2 doses over 3 

doses for consistency though they were presented differently in some of the publications. Noninferiority was defined as the lower 95% CI for the GMT ratio being >.5 in all studies. On the 

left, the 2-dose 0, 6 month schedule in 9 through 14 year olds is compared with the 3-dose 

schedule in young adult women. The non-inferiority criterion was met. On the right is the 

comparison of the 2-dose at 0, 12 month schedule in 9 through 14 olds with the 3-dose 

schedule in young adult women. GMT ratios are greater than 1 and again, the non-inferiority 

criterion was met. There was over 99% seroconversion in all groups. In summary, one month 

after the last dose, GMTs with both 0, 6 and 0,12 schedules in subjects 9 through 14 years of 

age were non-inferior to the 3-dose 0,1,6 schedule in subjects 15 through 15 years of age. 

Recently posted on the GSK website are the results for 36 months, which are very similar to 

these results.

The third bivalent vaccine trial by Lazcano-Ponce was an independent study conducted in 

Mexico. There were two groups 9 through 10 years of age (0, 6 months and 0, 1, 6—the 

standard schedule) and a group 18 through 24 years of age who received 3 doses in the 

standard schedule. The group providing data on 2 doses was on a 0-, 6-, 60-month schedule 

with a planned interim analysis at Month 21. Shown in this table are the data from this trial: 

HPV Type 2 dose 9–10 yrs/

3 dose 18–24 yrs

2 dose 9–10 yrs/

3 dose 9–10 yrs

 GMT Ratio (95% CI) GMT Ratio (95% CI)

HPV 16 1.4 (1.3, 1.4) 0.6 (0.6, 0.7)

HPV 18 1.4 (1.3, 1.7) 0.6 (0.5, 0.7)

All vaccinees were seropositive when tested at 7 and 21 months. For the comparison of 2 

doses in subjects 9 through 10 years of age with 3 doses in subjects 18 through 24 years of 

age, the antibody response was generally higher after 2 doses in subjects 9 through 10 years of 

age as noted by GMTs greater than 1. The non-inferiority criterion was met. In the comparison 

of 2 doses and 3 doses in subjects 9 through 10 years of age, GMTs were lower in the 2-dose 

schedule. The GMT ratios were less than 1, but the lower limit of the CI was greater than 0.5. 

The non-inferiority criterion for this study was considered to be met.

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Regarding the data available for 4vHPV vaccine, Dr. Markowitz reviewed the following three 

trials that were designed to evaluate the immunogenicity of 2 doses of 4vHPV vaccine:

Data from the Hernandez-Avila and Sankaranarayanan trails were not available when ACIP 

reviewed the data in 2014. The first two studies included a comparison of 2 doses at 0, 6 

months in the younger age group with 3 doses in young adult women, which was the main 

analysis for these studies. All studies allowed for a direct comparison of 2 and 3 doses within

the same age group, although the age ranges differed slightly in these studies. Follow-up was

through 36 months in Dobson, 21 months in Hernandez-Avila, and 48 months in 

Sankaranarayanan. 

The study conducted in Canada by Dobson has been reviewed with the ACIP previously. The 9

through 13 year olds were randomized to receive 2 or 3 doses. A third group of women 16

through 26 years of age received 3 doses. There were 36 months of follow-up. Although an 

independent study, data from this trial were submitted to regulatory authorities in other countries 

to obtain approval for a 2-dose schedule of 4vHPV vaccine. The following table shows the 36 

month results: 

The main analysis on the left was comparing the 2-dose girls with the 3-dose young adult 

women. Non-inferiority criteria were met for all types, and the titers were generally higher in the 

9 through 13 year olds shown by the GMT ratios being greater than 1. In the comparison of the 

2- and 3-dose schedules within subjects 9 through 13 years of age on the right, GMTs were

generally lower in the 2-dose group and non-inferiority was lost for HPV 6 and 18. At earlier 

time points in this study not shown on this table, GMTs were lower in the 2-dose group, but the 

non-inferiority criterion was still met for these comparisons. Non-inferiority was lost by 24 

months for HPV 18, and by 36 months for HPV 6.

HPV 

Type

2 dose 9–13 yrs/

3 dose 16–26 yrs

2 dose 9–13 yrs/

3 dose 9–13 yrs

 GMT Ratio (95% CI) GMT Ratio (95% CI)

HPV 6 1.36 (0.97, 1.90) 0.64 (0.46*, 0.90)

HPV 11 1.43 (1.03, 1.99) 0.73 (0.52, 1.02)

HPV 16 1.70 (1.16, 2.49) 0.81 (0.55, 1.20)

HPV 18 1.46 (0.88, 2.41) 0.43 (0.26*, 0.73)

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The following graphic shows more detail of the antibody kinetics through 36 months for the three 

groups:

 

The dashed line at the bottom of the above graphic is the serostatus cut off value of the assay. 

Of note, the antibody kinetics were similar in all groups, with the peak antibody titer 1 month 

after the last dose and then declined and a plateau at about 18 to 24 months. For HPV 18, 

GMTs for the 3-dose, 9 through 13 year old group were higher than the 2-dose girls. At later 

time points, the lines diverge and this is where GMTs lost non-inferiority. However, as shown 

here, the GMTs in this 2-dose group were not inferior to the GMTs in the 16 through 26 year 

olds who received 3 doses. 

The Hernandez-Avila 4vHPV vaccine was conducted in Mexico. There were also three groups 

in this trial: 2 groups at age 9 through 10 (a 2-dose and a 3-dose group), and a 3-dose group of 

subjects 18 through 24 years of age. In this trial, over 98% in all groups were seropositive for 

HPV 16. For HPV 18, seropositivity was lower in all groups compared with Month 7. HPV 18 

seropositivity was 56.6% in women 18 through 24 years of age who received 3 doses, 86% 

among the girls who received 3 doses, and 70% among girls who received 2 doses. The 56% 

seropositivity in women 18 through 24 years of age is consistent with findings in pre-licensure 

efficacy trials of 4vHPV; whereas, HPV 18 seropostivity measured by the cLIA declined over 

time but no loss of protection was detected in these trials. The following table shows GMTs at 

Month 21 after vaccination: 

HPV Type 2 dose 9–10 yrs/

3 dose 18–24 yrs

2 dose 9–10 yrs/

3 dose 9–10 yrs

 GMT Ratio (95% CI) GMT Ratio (95% CI)

HPV 6 1.29 (1.02 – 1.62) 1.21 (0.96 – 1.52)

HPV 11 1.52 (1.21 – 1.91) 0.87 (0.69 – 1.10)

HPV 16 1.49 (1.12 – 1.98) 1.16 (0.88 – 1.55)

HPV 18 1.27 (0.96 – 1.67) 0.74 (0.57– 0.98)

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In the analysis comparing the 2-dose schedule among girls 9 through 10 years of age with the 

3-dose schedule among women at 18 through 24 years of age, the non-inferiority criterion was 

met for all types. The antibody response was generally higher in girls 9 through 10 years of age 

who received 2 doses, with GMTs ratios greater than 1. In the comparison of the 2- and 3-dose 

schedules within girls 9 through 10 years of age, the GMT ratios were less than 1 for a few of 

the types, but again, the study’s non-inferiority criteria were still met. 

The Sankaranarayanan trial was designed as an immunogencity and efficacy trial of 2 versus 3 

doses of 4vHPV vaccine in India. Girls 10 through 18 years of age were enrolled. The design 

was a cluster randomized trial of 2 doses at 0, 6 months versus 3 doses in the standard 3-dose 

schedule. This was designed to be an efficacy trial assessing pre-cancer outcomes. However, 

recruitment and vaccination were suspended for reasons unrelated to this study. Because of 

this, vaccination did not occur as scheduled and the randomized design was lost. The study 

was analyzed as an observational cohort. Over 17,000 girls were enrolled and randomized to 

the two groups. However, vaccination occurred according to 4 different schedules:









1-Dose Group: Women who were randomized to the 2 dose or the 3 dose group, but 

only received one dose

2-Dose Group (0, 2 Months): Women who were randomized to the 3-dose arm, but did 

not receive the third dose

2-Dose Group (0, 6 Months)

3-Dose Group (0, 2, 6 Months) 

The following figure shows median fluorescence intensity (MFI) for HPV 16 antibodies, 

expressed as mean MFI: 

 

Time after first dose (months)

The number of girls with specimens tested was far less than the number who received vaccine 

in each group, ranging from about 300 to 500. The dashed line is the seropostivity threshold 

established by the investigators for this assay. For HPV16, the antibody kinetics of the 2-dose 

0, 6 month schedule was similar to antibody response of the 3-dose group. The mean MFI of 

the 2- dose group was non-inferior to the 3-dose group at all time points through 48 months. 

The antibody response after 2 doses administered at 0 and 2 months reached lower peak titer

and was inferior to the 3-dose group at 18 months and 36 months. For the 1-dose group, GMTs 

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were inferior to 3-dose group at 18 and 36 months. There were some differences, but a similar 

pattern was observed for HPV 18, 6, and 11.

In summary for the immunogenicity of 2-dose schedules of 2vHPV and 4vHPV vaccine, for the 

comparison of 2 doses (0,6 months or 0,12 months) in girls versus 3 doses in young adult 

women, antibody response was non-inferior in the 2-dose group and was generally higher for 

both vaccines. Antibody kinetics were similar, and these findings were consistent in all trials 

that evaluated the 2 doses (0, 6 months) versus 3 doses in girls the same age. In the 

comparison of 2 doses (0, 6 months) versus 3 doses (standard schedule) in girls of the same 

age for the 2vHPV vaccine, GMTs were generally lower in the 2-dose group, although formal 

hypothesis testing was not done in some of the studies. For 4vHPV vaccine, GMTs were lower 

for some types in 2 of the 3 studies.

There are some data on efficacy with 2-dose schedules. For the bivalent vaccine, there are 

data from a post-hoc analysis of efficacy against incident HPV 16/18 infection. This is an 

analysis of combined data from two randomized controlled efficacy trials in women 15 through 

25 years of age. In these 2 trials, participants were randomized to receive a 3-dose vaccine 

schedule or control. Most, but not all, women completed the 3-dose schedule and there was a 

post-hoc analysis of efficacy against incident infection by number of doses received. There was 

high efficacy in all groups and no significant difference by number of doses. There are 

limitations to these data including that in this post-hoc evaluation. Women who were 

randomized to receive 3 doses but received fewer doses could have been different from those 

who completed the series. However, these data suggest efficacy with less than 3 doses. It is 

important to note that the 2-dose schedule in these studies was not a 0, 6 months schedule, but 

instead was a 0, 1 month schedule because the study was designed to evaluate vaccine at 0, 1,

6 months [Kreimer, et al. Lancet Oncol 2015].

While the same type of data are not available for 4vHPV vaccine, there are some relevant data 

from the recently published trial in India in which girls 10 through 18 years of age were

randomized to receive 2 or 3 doses of HPV vaccine. As mentioned earlier, this trial was 

suspended and lost its randomized design and was analyzed as an observational cohort study. 

Girls were followed up for the immunogenicity evaluation just presented, and with cervical 

samples. The median time between first vaccination and cervical sample was 3.9 years. The 

incidence of infection was 0.6% in the 3-dose group and 1% in the 2-dose 0, 6 month group; 2% 

in the 2-dose 0, 2 month group; and 1.6% in the one dose group. While point estimates varied, 

there was no statistically significant difference between these groups and all groups were lower 

than what was expected from historical data. Further analyses are needed for this study, which 

hopefully will be forthcoming. Unvaccinated age and residence matched women are being 

enrolled into a cohort and will be followed to provide incidence data for comparison. Follow-up 

of women in this study is planned for 20 years [Sankaranarayanan, et al. Lancet Oncol 2016].

While Dr. Markowitz did not review post-licensure studies of vaccine effectiveness for 2 doses, 

but briefly mentioned the scope of these studies and noted that these data will be reviewed 

during a future ACIP meeting. There are at least 6 studies that have evaluated post-licensure 

effectiveness after introduction of HPV vaccination programs by number of doses (5 of 4vHPV 

and 1 of 2vHPV): 

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1

Gertig BMC Med 2013, 2Crowe BMJ 2014, 3Herwijer JAMA 2014, 4 Blomberg CID 2015, 5Dominiak-Felden PloS One 2015, 6Kavanagh BJC 2014

These studies have mainly been conducted in countries with good national health registries. 

Outcomes evaluated included cervical cytological or histological abnormalities, condyloma, or 

HPV prevalence. There are a variety of challenges and limitations pertaining to these types of 

studies. For example, there could have been differences between 2- and 3-dose recipients. 

Most 2-dose recipients did not receive a 0, 6 month 2-dose schedule as these analyses were 

conducted when a 3-dose schedule was recommended and the 2-dose recipients were those 

who did not complete the recommended 3-dose schedule. Moreover, there are a variety of 

methodologic challenges for these post-licensure studies. Most of these studies did show lower 

efficacy for those who received less than a 3-dose schedule. As noted, these data will be 

reviewed in more detail during a future ACIP meeting.

To summarize all of these data, the main analyses for immunogenicity and those used by 

regulatory agencies are comparisons of antibody response of 2 doses in young adolescents, 

with 3 doses in young adult women—the age during which efficacy has been demonstrated in 

clinical trials. This is because there is no established minimum antibody threshold for 

protection. Two doses (0, 6 months or 0, 12 months) in subjects 9 through 14 years of age 

were non-inferior compared with 3 doses in young adult women. Follow-up was through 36 

months for 2vHPV and 4vHPV vaccines. In some trials, antibody titers were lower for some 

types after 2 doses (0, 6 months) compared with 3 doses in the same age group. 

There are limited efficacy data. For 2vHPV vaccine, data are from a post-hoc analysis of 3-

dose RCTs in subjects 15 through 25 years of age. For 4vHPV vaccine, data are from the 

interrupted RCT of 2- versus 3-dose in vaccination among subjects 10 through18 years of age 

that was analyzed as an observational study. The studies suggest efficacy with less than 3 

doses, but also raise a variety of interesting questions. For 2vHPV vaccine in particular, the 

study evaluated an older age group than those who have been the focus of the 2-dose

immunobridging studies and provided data on a different dose interval, perhaps suggesting 

efficacy for a wider age range and for shorter intervals between doses. Also, while the criteria 

that have been used and will be used to evaluate reduced dose schedules are non-inferior 

antibody compared to a 3-dose schedule in the age groups in which efficacy was demonstrated 

in the clinical trials, some available data suggest that lower levels of antibody might be also be 

Vaccine Country Design / Study Population Outcome

4vHPV Australia1 Retrospective cohort study using 

linked registry data

Cytological and histological 

cervical abnormalities

 Australia2

 

Case-control study using linked 

registry data

Histological cervical lesions 

 Sweden3

 

Open cohort using nationwide 

health registers

Condyloma

 Denmark4

 

Cohort using nationwide health 

registries

Condyloma 

 Belgium5

 

Retrospective cohort using 

reimbursement database

Condyloma

2vHPV Scotland6

 

Women screened for cervical 

cancer 

HPV prevalence 

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protective. Post-licensure effectiveness, most of which found lower effectiveness with less than 

3 doses, will be reviewed with ACIP during the next meeting. 

In summary, data on 2-dose schedules for 2vHPV and 4vHPV vaccines can provide 

supplementary evidence for consideration of 2-dose schedules for 9vHPV vaccine; however, it 

is important to remember that there are some differences between vaccines. These data also 

could be used for consideration of 2-dose recommendations for 2vHPV and 4vHPV vaccines

themselves. The HPV Vaccines WG will further review and evaluate these and other data using 

GRADE, and findings will be presented and discussed at a future ACIP meeting.

Work Group Plans

Elissa Meites, MD, MPH

Medical Epidemiologist

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Meites summarized that information presented during this session provided background for 

considering 2-dose schedules for HPV vaccines. New data were presented from the 2-dose 

immunogenicity trial of 9vHPV vaccine in girls and boys, and an overview of current data on 2-

dose schedules for 2vHPV and 4vHPV vaccines. There are plans to present additional 2-dose 

data during a future ACIP meeting. There also will be a variety of issues for ACIP to consider: 











GRADE for 2-dose schedules

Review of post-licensure effectiveness data

Modeling data and cost-effectiveness

Programmatic considerations 

Additional follow-up data from the 9vHPV vaccine trial 

There are a number of issues for ACIP to consider. One issue pertains to whether a 2-dose 

schedule should be recommended. If so, the following would need to be addressed: 

 The target age or age range for a potential 2-dose recommendation 

 The recommended interval or range of intervals (there could be a minimum number of 

months-between-doses in a 2-dose schedule, or a specific interval, such as 0-6 or 0-12) 

 Wording of a potential recommendation to clarify whether exactly 2 doses are 

recommended versus allowing for 2 or 3 doses

 Whether special populations should be included in a potential 2-dose recommendation, 

or if three doses would continue to be recommended for some groups, such as 

immunocompromised persons or others 

 Which HPV vaccines would be included in a 2-dose recommendation 

Another issue to be aware of is FDA approval. All HPV vaccines currently available in the US 

are FDA-approved as a 3-dose series. For 9-valent vaccine, data from the 2-dose trial in a 

Supplemental Biologics License Application (sBLA) will be reviewed by the FDA. A 2-dose 

schedule for this vaccine would be off-label unless the label is changed at some point. For 

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4vHPV vaccine, there are no plans for the manufacturer to submit 2-dose data to FDA, so a 2-

dose schedule would be off-label. Similarly, there are no plans for the manufacturer to submit 

2-dose data to FDA for 2vHPV vaccine, so a 2-dose schedule would be off-label.

A further issue to consider is incomplete series, since currently about 20% of teens starting a 3-

dose series did not complete it. If a 2-dose recommendation is made, it could specify for each 

HPV vaccine whether and when a 2nd dose or a 3rd dose should be given. For 4vHPV vaccine, 

the manufacturer plans to retire this vaccine in the US at the end of 2016. However, if a 2-dose 

recommendation is made, it might still apply to people who began but did not complete a 3-dose 

series.

The workgroup plans to present the following data at the next ACIP meeting in June 2016:















GRADE for 2-dose schedules, including immunogenicity, efficacy, and post-licensure 

effectiveness data 

Modeling data for cost-effectiveness of 2-dose schedules 

Programmatic considerations 

Initial discussion of potential recommendations

Additional topics that will be presented to ACIP in the future include: 

Further follow-up data from the 9-valent vaccine trial, when available

Decisions from the FDA, if any, that might change the indicated number of doses of 

9vHPV vaccine

Proposed recommendations and vote on 2-dose schedules

Discussion Points

Dr. Reingold noted that according to a New York Times article a couple of days before this 

meeting [summarizing the 2016 research by Markowitz et al published in Pediatrics], current 

coverage seems to be having an even more impressive herd immunity effect than predicted. He 

wondered whether anything was known about the likely herd effect of a 2-dose schedule versus 

a 3-dose schedule, or whether the fact that the impressive herd effect might give ACIP even 

more impetus to make a 2-dose recommendation given the context of the epidemiologic 

situation. He also requested that Dr. Bennett comment on the implications of ACIP making an 

off-label recommendation.

Dr. Markowitz replied that in terms of impact, the data suggest that there is either some efficacy 

from less than a complete 3-dose schedule or herd immunity. It is not possible to say which it 

is. Certainly, the fact that greater impact is being observed than expected if a complete 3-dose 

schedule is needed for high efficacy suggests that one or both of those is operating. In terms of 

whether a similar herd immunity effect would be observed with a 2-dose schedule, if there is 

high efficacy from a 2-dose schedule, the same herd effect would be anticipated from a 2-dose 

as for a 3-dose schedule. It is known from other countries that there is a profound herd effect 

from vaccination programs. The most compelling data come from Australia where they have 

been able to demonstrate a very large impact on genital warts among males, even though they 

were targeting only females in the vaccination program. Australia had very high coverage. 

Therefore, it is known that herd protection can be achieved through high coverage.

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Regarding the implications of off-label recommendations, Dr. Bennett replied that it is clear that 

ACIP has and will continue to make off-label recommendations. With respect to how those are 

implemented, particularly in the environment of the new data, she did not believe the 

implications would be negative if ACIP chose to make an off-label recommendation.

Dr. Messonnier added that ACIP has made off-label recommendations in the past, but the 

context of those was quite different from this. There have been off-label recommendations for 

small subgroups or that have been seen as bridges to something that is not recommended. The 

programmatic complexities of an off-label recommendation in this setting would be much greater 

in terms of how to communicate that, how providers would implement that given the different 

messages they would be getting from different sources, et cetera. One of the reasons the 

workgroup outlined further discussion in June 2016 is to allow time to consider some of the 

programmatic considerations. From the CDC perspective, the hope is that FDA and Merck can 

do an efficient consideration of the BLA and that there will be a rapid response.

Dr. Sun (FDA) responded that the FDA is reviewing the submission pertaining to 2 doses, and a 

regulatory decision will be made in short order. Given that the review process is ongoing, he 

was not at liberty to say more than that at this point.

Dr. Karron expressed her hope that ACIP could take into consideration any deliberations and 

decisions that occur earlier than June 2016 in terms of timelines for bringing draft 

recommendations forward to ACIP for a vote. They may not want to wait until the October 2016 

meeting to be making decisions about 2 and 3 doses.

Carol Hayes (ACNM) reminded everyone that every vote ACIP has made regarding 

immunization and pregnancy has been off-label.

Introduction

Lorry Rubin, MD

Chair, Meningococcal Work Group

Advisory Committee on Immunization Practices

Dr. Rubin explained that this session would include two parts. The first part of the session 

would focus on an update pertaining to serogroup B meningococcal vaccines, including newly 

available data. No discussion of changes to current recommendations was planned. The 

second part of the session would focus on a discussion of meningococcal disease in HIVinfected persons and men who have sex with men (MSM). No vote was anticipated during this 

session.

Additional data for MenB vaccines reviewed by the WG since June 2015 has included safety 

and immunogenicity data from two Phase 3 studies for MenB-FHbp, including immunogenicity 

data on 10 secondary strains and 10 outbreak strains and the results of a mass immunization 

campaign with MenB-4C in Quebec, Canada. In addition, the WG reviewed reports to the 

Vaccine Adverse Events Reporting System (VAERS) to monitor MenB safety. No safety signals 

have been reported to date.

Meningococcal Vaccines

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An ad hoc WG comprised of ACIP Meningococcal WG members, ACIP members, state public 

health officials, college health professionals, and CDC reconvened on September 3, 2015 with 

biweekly meetings. The objectives of this ad hoc WG are to: 1) review available data on the 

recent epidemiology of meningococcal disease and outbreaks; 2) update and harmonize the 

current meningococcal outbreak guidelines for serogroups A, B, C, W, and Y. The 

Meningococcal Outbreak WG recommendations will be presented in an informational session 

during the June 2016 ACIP meeting. Harmonized outbreak guidelines will be published on 

CDC’s website.

Dr. Rubin indicated that the presentation topics for this session would include the following:











MenB-FHbp vaccine update

Results of a mass immunization campaign with MenB-4C in Quebec Canada 

Considerations for use of MenACWY vaccines in HIV-infected persons

Meningococcal disease among MSM, United States, January 2012-June 2015

Summary of Work Group Discussions on Meningococcal Disease in MSM

MenB-FHbp Vaccine Update

Dr. Laura York

Medical Development

Scientific and Clinical Affairs

Pfizer

Trumenba®, Pfizer’s MenB-FHbp vaccine, is based on a surface-exposed factor H 

binding protein (FHbp) expressed in over 97% of invasive meningococcal B (MenB) strains. 

The fHbp sequences segregate into two genetically and immunologically distinct subfamilies, A 

and B, as shown in the following phylogenetic tree:

 Subfamily B: 71%

 Subfamily A: 29%

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Pictorially, it is easy to see that this protein extends from the bacteria so that it is readily 

accessible to antibody. This protein functions as an important meningococcal virulence factor. 

It binds to factor H and down regulates the complement system and, therefore, limits the 

amount of complement-mediated lysis—the protective mechanisms against meningococci. The 

MenB-FHbp sequences segregate into two genetically and immunologically distinct subfamilies, 

A and B. Within the subfamilies, these proteins are very similar in their sequence identities, so 

MenB-FHbp contains two lipidated protein variants (A05 and B01), one from each subfamily to 

elicit antibodies that are going to recognize across those FHbps within each subfamily and 

thereby provide a broadly protective response [Madico et al. 2006; Schneider et al. 2006; 

Mascioni et al. 2009; Seib et al. 2009; Ala’Aldeen et al. 2010; McNeil et al. 2009; Jacobson, 

Moellig, Olcen 2009].

The following table delineates the Trumenba® clinical plan:

Boxed in green are the trials that supported the accelerated approval in the US. Part of the 

approval process was to provide ongoing studies to FDA when they are completed as postapproval commitments. As the data become available, Pfizer has been providing those data to 

the ACIP WG. During the considerations, data were provided to ACIP not only from the 7 

licensure trials, but also from the safety and immunogenicity studies of concomitant 

administration of Menactra® and Adacel®, the large-scale Phase 2 safety study, and antibody 

persistence studies from Stage 2 of an early immunogenicity study.

Dr. York indicated that during this session, she would provide an update on the two final studies 

within this clinical development plan for the adolescent indication: 1) a lot consistency, safety, 

and immunogenicity study in adolescents 10 through 18 years of age, and 2) a safety and 

immunogenicity study in young adults 18 through 25 years of age. She noted that she would 

review the immunogenicity data and compare that to data provided for licensure through two 

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trials, referred to as Studies 1 and 2, that provided pivotal immunogenicity, a safety and 

immunogenicity assessment with concomitant Gardasil® conducted in the US referred to as 

Study 3, and Study 4 conducted in Europe to assess 2- and 3-dose schedules. In total, there is 

now a large database from 11 clinical studies.

Study 1 (B1971009) is a Phase 3 immunogenicity, lot consistency, clinical safety and tolerability 

study of Trumenba® in healthy adolescents 10 through 19 years of age conducted in the US, 

Canada, and Europe. This study is comprised of approximately 3600 subjects of whom 2693 

received Trumenba® and 897 received HAV/saline. Study 2 (B1971016) is a Phase 3 

immunogenicity and safety / tolerability study of Trumenba® in healthy adults 18 through 26 

years of age conducted in the US and Europe. This study is comprised of approximately 3300 

subjects of whom 2471 received Trumenba® and 822 received saline. In both studies, 

immunizations were administered on a 0, 2, and 6 month schedule.

As post-approval commitment studies, Studies 1 and 2 provide the confirmatory human serum 

bactericidal assay (hSBA) data; that is, they are confirming the data generated in the licensure 

trials in Studies 3 and 4. These are confirmatory hSBA responses, which is the correlate used 

to predict protection against 4 MenB strains that are agreed to be representative of the 

prevalent strains in the US. The fHBP variants expressed by these strains are not homologous 

to the vaccine components. They are A22, A56, B24, and B44. This is shown on the 

phylogenetic tree below: 

These studies also provide supportive hSBA data, meaning that hSBA responses are shown 

against a panel of 10 additional strains, which are referred to as secondary strains. They 

express variants that are prevalent and are not homologous to the vaccine components. In 

total, with the 4 primary strains and the 10 additional strains, these account for about 80% of the 

meningococcal strains that are circulating.

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As a reminder, there were 5 co-primary endpoints for licensure, meaning that subjects had to 

achieve a 4-fold rise in hSBA titer 30 days post-dose 3 to each of the 4 representative strains 

(A22, A56, B24, and B44). The fifth primary endpoint was a composite response, looking at the 

subjects who achieved an hSBA titer of greater than or equal to 1:8 and 1:16 on the A22 strain 

for all 4 test strains. This shows the ability of the antibody within an individual to recognize 

across the diversity of the FHbp being expressed by these 4 representative strains, and inferring 

activity against the FHbp within the same subfamilies. A high proportion of individuals among 

adolescents and young adults who responded obtained an hSBA titer 4-fold rise against each of 

the 4 strains. Importantly, a high proportion of these individuals achieved an hSBA titer of 

greater than 1:8 for all 4 test strains.

In terms of comparison across the three studies, there is consistency across the responses with 

a high proportion of individuals who achieved the 4-fold rise in titers after receiving the third 

dose, and also comparable levels of individuals who have a composite response achieving an 

hSBA titer of greater than 1:8 for all 4 test strains. 1:8 is higher than the accepted correlate of 

protection of 1:4. This consistency of responses to vaccine is, in fact, observed across the 

Phase 1 and Phase 2 studies where this immunogenicity data is available. There are 

comparable responses across the studies regardless of the geographic area in which the 

studies were conducted. Therefore, the Phase 2 and 3 studies confirm the data that informed 

the licensure of Trumenba® and provide evidence that Trumenba® will provide a bactericidal 

response which will be active against the diverse MenB strains that are circulating and causing 

disease in the US.

This is supported by the data from the 10 additional strains A06, A07, A12, A15, A19, A29, B3, 

B9, B15, and B16. Again, a high percent of subjects attained an hSBA titer of greater than 1:8 

which is above the correlate of protection. The 10 strains are distributed well across the subfamilies and across adolescents and adults, there is a consistent high response and the ability 

of the antibody to recognize across these variants. These are prevalent variants in the diseasecausing MenB strains.

Pfizer was also asked to provide ACIP with data from an exploratory analysis performed on 

some diverse FHbp variants expressed by outbreak strains B24, A22, B03, B44, B228, and 

B153. These data are from 10 different isolates from 10 different outbreaks occurring in the US 

and France from 2011 through 2015. The hSBA titer of the correlate of protection was 1:4.

These 10 strains are diverse in the hSBA variants they express. They can be prevalent 

variants. In fact, 5 of these strains express B24. A22 and other prevalent variant B03 and B44 

are also prevalent variants. There are also unique variants like B228 and B153. These data 

were generated with a small number of serum samples with exploratory hSBA assays, which 

sometimes can have challenges in development of the assay. These data demonstrate that all 

of the strains are susceptible to killing, and that the level of responses observed overall and in 

general are similar to what has been observed in the clinical studies. In the totality of the 

immunogenicity data to date, these data would be expected to support that Trumenba® would 

be expected to elicit a broadly protective immune response.

In terms of evaluation of safety, the safety profile demonstrated by Trumenba® in Studies 1 and 

2 were consistent with the safety data that supported licensure, and in which the majority of 

local and systemic events were mild to moderate in severity and transient after each 

vaccination. The most common AEs were pain at the injection site, fatigue, headache, muscle 

pain, and chills. There was no clear pattern of potentiation with progressive dosing. The SAE 

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rates were comparable between Trumenba® recipients (1.7%) and controls (1.6%) in 4 

controlled trials. In both Study 1 and Study 2, Trumenba® was well-tolerated in adolescents and 

young adults. The reactogenicity profile was consistent with the prior studies, and there is a low 

SAE rate overall of 1.9% versus 2.4% in the vaccine and control groups, respectively in 

adolescents and 1.3% for both the vaccine and control groups in young adults.

In the total safety database comprised of data from 11 clinical trials, studies have been 

conducted in the US, several European Countries, Canada, Australia, and Chile. Approximately 

15,000 subjects who have received Trumenba® and approximately 5500 controls are included in 

the database. Approximately 3000 of these individuals are from the US. Trumenba® has 

demonstrated an acceptable safety profile. The most common local and systemic reactions 

were injection site pain, headache, fatigue, and muscle pain. Reactogenicity events were 

mostly mild and moderate and of short duration. The median duration was 2 to 3 days for local 

reactions and 1 to 2 days for systemic reactions, and there was no potentiation of reactions with 

subsequent doses. Trumenba® has demonstrated an acceptable safety profile when coadministered with other routinely administered adolescent vaccines like MCV4/Tdap, dTaP-IPV, 

or HPV4. Similar proportions of newly diagnosed chronic medical conditions, autoimmune 

diseases, and neuroinflammatory conditions were reported in Trumenba® recipients and 

controls. Rates of SAE are similar between Trumenba® recipients (1.6%) and controls (1.9%).

In summary, Trumenba® was designed to provide broad protection against MenB. The newly 

available hSBA data confirm that Trumenba® elicits bactericidal activity against diverse 

meningococcal serogroup B strains. Trumenba® demonstrates a favorable safety profile in 

adolescents and young adults. Spontaneous safety data collected post-approval supports the 

safety profile observed in clinical studies, with reactogenicity events being the most frequent 

events reported. Trumenba® was recently used in mass vaccination campaigns for outbreak 

control at two US colleges. One of the colleges with an opt-out policy and a student population 

of approximately 4500 had very good compliance. The other had an opt-in policy and probably 

less than 50% received the first dose in a target population of around 20,000. No new safety 

signals have been detected based on post-marketing surveillance. The data support 

administration with routinely recommended adolescent vaccines. In total, the data continue to 

support the expectation that immunization with Trumenba® will provide a broadly protective 

response against MenB disease when used both for outbreak control and prevention of endemic 

disease. The full public health potential of Trumenba® can be realized only with broad 

implementation in populations at risk of meningococcal disease.

Discussion Points

Regarding protection against outbreaks shown on Slide 9, Dr. Walter noted that two strains 

seemed to show lower protection than others and wondered whether there was something 

different about them.

Dr. York replied that these are small numbers. Strain-specific differences are observed, and 

some are more difficult to set up in the assays. In general, overall these data show that there is 

a possibility of killing. The trend would be toward having the kind of protection that has been 

observed in clinical trials.

Dr. Kempe asked whether there are any immunogenicity data on subsets who received 1 dose, 

or prime and booster and not the intermediate dose.

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Dr. York responded that with a single dose, there is greater than a 50% response to 3 of the 

strains and approximately 20% to 25% to 1 of the B strains. In general, there is a response to 

one dose. Certainly, there is an increase in the response after receiving additional doses. 

There are data from one of the pivotal licensure trials in Europe comparing the 2- versus 3-dose 

schedule (Slide 16), which show the 4-fold response after a 3-dose schedule at 0, 2, 6 and 0, 1, 

6 months and in increasing intervals of two doses at 0, 6; 0, 4; or 0, 2 months. The responses 

are substantial, but are not as high as if 3 doses had been received. Clearly, there is still a high 

level of protective response with a longer interval.

Dr. Reingold asked whether the vaccine has any effect on carriage. Dr. York responded that 

Pfizer is working on those data.

Noting that there had been 3 or more college outbreaks, Dr. Baker wondered whether Pfizer 

had done any testing with its assay against those strains.

Dr. York indicated that the 10 strains she showed include US strains as well as strains from 

France.

Dr. Cohn inquired about the magnitude of the response against the additional 10 strains 

compared to the primary 4 strains in terms of GMTs.

Dr. York responded that as might be expected, there are differences in the GMTs depending 

upon the strain. But, there is a comparable response within those. What is typically observed in 

B subfamily strains will be consistent through that, but it may be quite high as well. The GMTs 

are quite predictable. It is within the overall range and is not restricted to a particular subfamily.

Results of a Mass Immunization Campaign With 4CMenB 

Vaccine In the Saguenay-Lac-Saint-Jean Region, Quebec, Canada

Gaston De Serres, MD, PhD

Institut National De Sante Publique

Du Québec and Laval University

Dr. De Serres described the Canadian experience regarding a mass immunization campaign 

against MenB using the 4-component meningococcal B vaccine, produced by Novartis and 

purchased by GSK. He indicated that the information he was presenting was funded by the 

Ministry of Health.

Québec has a population of approximately 8 million, but the outbreak occurred within a subregion of the province known as Saguenay-Lac-Saint-Jean. Comparing the number of reported 

cases per year, Quebec has the largest number but is not the largest province. Ontario has 

nearly twice the population, but the number was much lower. Canada has an incidence of 

0.33/100 000 and Quebec had an incidence approximately twice that level at 0.76/100 000. The 

highest incidence was in infants, which rapidly declined in preschoolers, was pretty low between 

5 and 14 years of age, but increased in older teenagers and young adults.

In the early 2000’s, the ST-269 clone emerged. This was not just a cloncal complex. It was a 

specific clone that emerged and spread rapidly throughout the province. The Saguenay-LacSaint-Jean Region 2 is a small region of approximately 270,000 people with nearly 60,000 

children less than 20 years of age. The incidence among those under 20 years of age during 

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the period 2006 through 2013 was above 10 / 100,000. For the other regions, the incidence 

was much lower. Even for adults, the incidence was higher among adults in Saguenay-LacSaint-Jean than in the rest of the regions. The following table shows all of the invasive 

meningococcal disease (IMD) reported in the region since 1990, with serogroup B beginning to 

increase from 2004, with a fairly high incidence in this region:

In the Saguenay-Lac St-Jean Region, there was high incidence in infants and teenagers. In

terms of whether the strain matched the 4CMenB vaccine, nearly 90% of the isolates in that 

region were the ST-269 clone. None of the isolates antigens were the exact match with the 

MenB-4C components. Of the MenB ST-269 clonal complex, 96% were predicted to express 

two antigens similar to the vaccine components: factor H-binding protein (fHbp) peptide 15 

(variant 1) and Neisserial Heparin-Binding Antigen (NHBA) peptide 21.

The vaccine was licensed in December 2013 and in April 2014, the Quebec Immunization 

Committee (CIQ) recommended vaccinating approximately 60,000 children 2 months through 

20 years of age. The immunization schedule was 4 doses among children 2 through 5 months 

of age, 3 doses among children 6 through 11 months of age, and 2 doses for children 12 

months of age and older. The campaign began in May and June 2014, during which the first 

dose was administered with the idea of administering the second dose during the following 

school year during September and October 2014. The campaign ended December 31, 2014. 

The vaccine was offered in schools for primary and high school children, and in public health 

clinics for pre-schoolers.

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When the campaign was recommended, there were a lot of data regarding the reactogenicity of 

the vaccine. A passive VAERS is already in place that is fed by physicians. In this province, 

adverse events following immunization (AEFI) reporting is mandatory for all physicians. Active 

surveillance was added so that all vaccinees whose parents provided an email address on the 

consent form were sent a message one week after each dose with a link to a web-based 

questionnaire on a secure server. The outcomes included AEFI of sufficient severity to cause 

absenteeism or a medical consultation during the 7 days post-vaccination. In order to assess 

SAEs, another questionnaire was sent six months post-last dose. Telephone calls were made 

by nurses to validate the information on all hospitalizations, seizures, arthralgia, SAEs 

(hospitalizations, life-threatening sequelae, deaths), and other AEFIs considered severe. 

Coverage was good until 16 years of age, with overall coverage of 83% receiving 1 dose and 

76% receiving 2 doses as shown in the following table:

Of the vaccinees, 69% provided an email address. The participation rate was not large. For the 

first dose, there was a participation rate of 39% among those sent an email message and 27% 

among all vaccinees. For the second dose, participation was 32% among those sent an email 

message and 22% among all vaccinees. Six months post-last dose, participation was 23% 

among those sent an email message.

In terms of fever, that vaccine was associated in clinical trials with a high proportion of fever. 

For Doses 1, 2, 3, and 4 in infants, the onset was primarily the day of vaccination and the 

following day. By Day 3, fever was largely baseline. The percentage reporting an AEFI causing 

absenteeism or a medical consultation was consistently more frequent with the second dose 

than the first. Injection site reaction and general malaise were by far the most predominant 

reasons for absence or consultation. When the absentees attributable to fever, general 

malaise, or local reactions were calculated with onset on Day 1 or 2, it was 1.8% to 3.4% for 

those younger than 18 years of age. The province has a generous maternal leave policy, so in 

the first year of life, the mother is generally at home and there is no absence because of that. 

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However, 3.8% to just under 7% of those 6 through 16 years of age had an absenteeism due to 

those adverse events.

Seizures were less than what was expected based on the clinical trial, but there were 6 febrile 

convulsions as follows:













1 year old 6 hours post-dose 1 

2 year old 8 hours post-dose 2

4 year old 4 hours 30 minutes post-dose 2

5 year old 30 minutes post-dose 2

6 month old 28 hours post-dose 3

1 year old 48 hours post-dose 3 

No clustering was observed in terms of hospitalizations. The diagnoses of patients are show in 

the following table:

Age Day of Hospital admission Diagnosis

2 year old Day 2 post dose1 Bronchiolitis

2 month old Day 2 post dose 1 Fever and dehydration

1 year old Day 5 post dose 1 Bronchospasm

1 year old Day 6 post dose 1 URTI and bronchospasm

6 year old Day6 post dose 1 Viral mesenteric adenitis

9 year old <15 min. post dose 2 Anaphylaxis (4CMenB + Twinrix) 

Had similar problem with MMR

4 month old Day 1 post dose 2 Bronchiolitis

4 year old Day 1 post dose 2 2 episodes of febrile seizures

2 year old Day 2 post dose 2 Bronchospasm

1 year old Day 3 post dose 3 Febrile seizure

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The most frequent SAEs requiring hospitalization were respiratory problems and other types of 

infections, with all SAEs shown in the following table:

4 Months 

After Dose 1

6 months 

after dose 2

Total

Respiratory infections /problems 21 31 52

Infections (urinary, ocular, dental, etc.) 16 22 38

Surgery 11 4 15

Trauma 7 1 8

Fever /dehydration 3 2 5

Seizures 2 2 4

Renal lithiasis 0 4 4

Food allergy 2 1 3

Nephrotic syndrome 0 3 3

Anemia 0 3 3

Epilepsy 1 2 3

Crohn disease 2 1 3

Diabetes 1 1 2

Other 5 9 14

 

In the targeted cohort, 16 deaths occurred between May 1, 2014 and May 30, 2015. Of those, 5 

deaths occurred within 6 months of a dose of 4CMenB, 4 were due to motor vehicle accidents, 

and 1 occurred 5 months after a single dose of 4CMenB. The death that occurred 5 months 

following the single dose of 4CMenB was investigated by a coroner, who concluded that the 

vaccine was not involved.

There were 102 AEFIs reported between May 1, 2014 and August 28, 2015. The reported rates 

per 10,000 administered doses were as follows:

Overall 10.3

Fever 2.9

Local Reaction 2.3

Allergic-Like Event 2.7

Seizures 0.9

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There was 1 incident of Kawasaki Disease (KD) in a 4-year old child with onset 100 days postDose 2. In the month preceding KD, the child had received a dose of DapT-Polio (BoostrixPolio®) and Flumist®. 

In terms of the impact on disease, the upper panel in the following graphic presents the region 

and the green arrow shows the start of the campaign, with only two cases reported after the 

campaign that occurred in adults:

The lower panel in the above table shows the rest of the province, in which the incidence also 

decreased. In terms of the two cases that occurred in the Saguenay-Lac St-Jean Region in 

March 2015, one case was in an unvaccinated 44 year old who had stayed in an ice fishing 

shelter during the week prior to disease onset. The second was in an unvaccinated 13 year old 

living outside the Saguenay-Lac St Jean Region that was related to the first case in that the 

child was in the same ice fishing shelter as the first adult case during the week prior to disease 

onset. Symptom onset occurred two days after those of the first case. In April 2015, a case 

occurred in an unvaccinated 64 year old who lived in another village in the Saguenay-Lac StJean Region, which was determined to be unrelated to the other cases. With regard to vaccine 

effectiveness, no B-IMD cases were observed among the 47,115 vaccinated residents 2 months 

to 20 years of age. There were 2 cases among 230,444 unvaccinated residents. Crude 

vaccine effectiveness was 100%, though this was not statistically significant.

In summary, because 4CMenB was recently licensed and there was a limited number of 

participants in the clinical trials, an enhanced surveillance for safety was set-up. Active 

surveillance was already set up for pandemic influenza by the Canadian Immunization 

Research Network (CIRN). That surveillance has the advantage to timely inform public health if 

there is any problem. Participation was not huge, but the hope was that if that was a problem, 

people would be participating and that this may over-estimate the risk but would be unlikely to 

under-estimate it. The passive surveillance covers all people even if they do not want to 

participate in active surveillence, so there were two ways to assess that. The safety profile was 

similar to that reported in clinical trials. There was no signal of unexpected AEFIs and no 

cluster of SAEs. High fever and febrile convulsions were present, but were not more frequent 

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than expected. A few cases of KD were reported in the clinical trials, but there was no increase 

in KD. Only 1 case occurred during the campaign, which was distant from the second dose. 

Most surprising was the rate of absenteeism of 3% to 5.7% of children and adolescents, which 

is quite substantial and affects the societal cost of 4CMenB.

In conclusion, the results suggest direct protection during the 18 months following the 

administration of the first dose of 4CMenB. There is no evidence of indirect or herd protection in 

adults. A decrease in incidence also occurred in the rest of the province. During the mass 

campaign in the Saguenay-Lac St Jean Region, the safety profile of the 4CMenB vaccine was 

as expected. In terms of local reactions, vaccinees complained that this vaccine was more 

painful than other vaccines. On the short-term, the vaccine seems to be effective. Duration of 

protection remains unknown.

Discussion Points

Dr. Karron wondered whether there are any data on the prophylactic use of antipyretics or nonsteroidal anti-inflammatories on the safety profile and / or immunogenicity of the vaccine, given 

the information about absenteeism and pain.

Dr. De Serres replied that because he had just 15 minutes, he eliminated his sides about that. 

They recommended anti-pyretic use. Approximately 80% of children took antipyretics. Below 2 

years of age, it was 90% plus. The effect reported was with antipyretics. Immunogenicity was 

not assessed; however, a greater impact was observed with the first dose in terms of reducing 

fever. The reduction was about 44% with the first dose and was smaller with the second dose. 

An impact was observed among different age groups, but not above 11 years of age.

Dr. York added that because this was an older age group and fever is observed a very low 

percentage of the time, no studies were set up to assess whether there would be reductions in 

immune responses based on use of antipyretics. Reporting of whether antipyretics were used 

was assessed, but not to that extent. Prophylactic use would not be expected in the age group 

in the studies.

Dr. Stephens asked for Dr. De Serres’ for his thoughts about why the disease disappeared in

the rest of the province, particularly given that a herd immunity effect was not observed.

Dr. De Serres said that he thought meningococcal in general and MenB in particular have 

epidemic cycles with long waves. It is possible that this outbreak occurred on the declining side 

of the current surge. However, he said he had no good explanation for why this region was 

specifically affected compared to other regions. Everyone has asked this question, but it is not 

possible to provide a sound response at this time.

Dr. Moore noted that absenteeism is intriguing to follow, but this finding is not typically reported. 

She wondered whether Canada had experience with other vaccines for which absenteeism 

following immunization was assessed to which this could be compared.

Dr. Serres replied that they do not. Because of the outcome they selected to follow with active 

surveillance, and they acquired this information. However, there are no data about absenteeism 

in the overall vaccination program.

Dr. Bennett asked whether they have baseline rates of absenteeism.

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Dr. De Serres responded that they do not, but they assessed absenteeism occurring during 

Days 1 and 2 compared to what occurred during the rest of the week. That is an unusual way to 

set the baseline.

Dr. Rubin asked whether the denominators included just the people who responded from among 

those who provided their email address, or included the entire population.

Dr. De Serres indicated that the results he provided were for those who responded with their 

email address.

Regarding the data suggesting that there might be an increase of absenteeism or medical 

consultation post-vaccination after a subsequent dose, Dr. Rubin asked whether they were able 

to put some error bars around that and if that might have any implications for revaccination.

Dr. De Serres replied that they did not put the bars on this. Studies were conducted in younger 

children who received more than two doses, and for which there may be some answers. But it 

is not clear whether that would be the same in someone who received two doses as an 

adolescent and a booster dose 5 to 10 years later. He has not seen any data about that.

Ms. Pellegrini noted that coverage rates among children were extremely impressive. She 

wondered whether they were able to execute the school-based vaccination campaign with the 

existing infrastructure or if additional public health personnel or others were tasked for that 

campaign.

Dr. De Serres responded that the existing infrastructure was utilized. However, some people 

were engaged in other nursing work with the public health system who were rerouted for a few 

weeks to help out.

Considerations for Use of MenACWY Vaccines in HIV-Infected Persons

Jessica MacNeil, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

During this presentation, Ms. MacNeil reviewed the use of meningococcal conjugate vaccine in 

human immunodeficiency virus (HIV)-infected persons. She summarized the evidence of 

increased risk for meningococcal disease in HIV-infected persons, MenACWY vaccine response 

in HIV-infected adolescents, and other considerations.

In terms of background, HIV is an established risk factor for several bacterial infections. A 

growing body of evidence supports an increased risk of meningococcal disease among HIVinfected persons. ACIP does not currently include HIV-infected persons in the 

recommendations for routine vaccination of persons at increased risk of meningococcal 

disease. However, if an HIV-infected person aged 2 years of age or older is vaccinated, he / 

she should receive a 2-dose primary series.

Data on HIV and meningococcal disease has been limited historically. An analysis of 

surveillance data from 1988-1993 from the 8-county metropolitan area of Atlanta found that HIVinfected adults had a nearly 24-fold increased risk of meningococcal disease1

. More recently, 

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the Group for Enteric, Respiratory, and Meningeal disease Surveillance in South Africa’s 

(GERMS-SA)2 study reported that 45% of 308 meningococcal disease patients were HIVinfected, the age adjusted relative risk was 11.3 (95%CI 8.9-14.3), and that the case-fatality 

ratio among HIV-infected cases was 20% versus 11% among HIV-uninfected cases [1

Stephens 

DS, Hajjeh RA, Baughman WS, Harvey RC, Wenger JD, Farley MM. Sporadic meningococcal 

disease in adults: results of a 5-year population-based study. Ann Intern Med. 1995: 123:937-

40; 2

Cohen C, Singh E, Wu HM, Martin S, de Gouveia L, Klugman KP, et al; Group for Enteric 

Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA). Increased 

incidence of meningococcal disease in HIV-infected individuals associated with higher casefatality ratios in South Africa. AIDS. 2010; 24:1351-60].

Expanded chart reviews were completed for HIV-infected meningococcal disease cases 

reported through the Active Bacterial Core surveillance (ABCs) system from 2000-2008. 

Incidence calculations from this analysis are limited to cases that met the CDC AIDS 

surveillance case definition, because name-based HIV reporting was not available in all of the 

states during the study years. In terms of the findings, 33 HIV-infected meningococcal disease 

cases were reported in ABCs during 2000-2008. Of those cases, 70% were caused by 

serogroup C, W, or Y. In the 7 years since this review has been completed, an additional 12 

cases of meningococcal disease have been reported in HIV-infected persons in ABCs during 

2009-2015. Of those cases, 83% were caused by serogroup C, W, or Y [Harris CM et al. 

Meningococcal Disease in Patients with HIV Infection-A Review of Cases Reported Through 

Active Surveillance in the United States, 2000-2008. Manuscript Under Preparation].

HIV-related clinical data were collected on meningococcal cases with HIV-infection as part of 

the expanded chart review. In general, patients presented with a wide range of CD4 counts and 

several met the CDC AIDS surveillance case definition. The majority were also currently taking 

antiretroviral therapies at the time of meningococcal disease presentation. Of the cases, 17 met 

the CDC AIDS surveillance case definition and were included in the incidence calculations. 

Meningococcal disease incidence among persons with AIDS was 3.5/100,000 compared to 0.3/ 

100,000 among persons not meeting the CDC AIDS case definition, resulting in a rate ratio of 

12.9. In this study, an increase in risk was observed for both HIV-infected men and women and 

the rate ratio among men was not significantly different than that among women [Harris CM et 

al. Meningococcal Disease in Patients with HIV Infection-A Review of Cases Reported Through 

Active Surveillance in the United States, 2000-2008. Manuscript Under Preparation].

In New York City, meningococcal surveillance data from 2000-2011 was matched to death and 

HIV registries. As part of this study, an age-matched case-control analysis was also performed 

among HIV-infected persons and included a subset of cases with CD4 count and viral load 

measurements near the time of meningococcal disease. A total of 40 HIV-infected cases were 

reported in New York City during 2000-2011. Of those cases, 87% were caused by serogroup 

C, W, or Y. The incidence of meningococcal disease among persons infected with HIV was 

calculated. Incidence was 3.4/100,000 in HIV-infected persons compared to 0.34/100,000 

among HIV-uninfected persons, for a risk ratio of 10. A higher case fatality ratio was observed 

among HIV-uninfected cases compared to HIV-infected cases. The risk of meningococcal 

disease decreased during the study period for both HIV-infected and HIV-uninfected persons in 

New York City. Meningococcal disease incidence among HIV-infected persons decreased from 

4.7/100,000 in 2000-2002 to 1.9/100,000 during 2009 through 2011. In the case-control 

analysis among persons infected with HIV, patients with meningococcal disease were 5.3 times 

as likely as age-matched controls to have low CD4 counts and 4.5 times more likely to have 

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high viral loads [Miller L, Arakaki L, Ramautar A, Bodach S, Braustein S, et al. Elevated Risk for 

Invasive Meningococcal Disease Among Persons with HIV. Ann Intern Med. 2014; 160:30-38].

The most recent study, which is from the United Kingdom (UK), assessed risk for 

meningococcal disease among HIV-infected children and adults during 2011-2013. Incidence of 

meningococcal disease was 6.6/100,000 in HIV-infected persons compared to 1.5/100,000 

among HIV-negative persons, for a risk ratio of 4.5 [Simmons RD. et al. Risk of invasive 

meningococcal disease in children and adults with HIV in England: a population-based cohort 

study. BMC Med. 2015; 13: 297].

All but one of the cases in HIV-infected persons occurred in adults 16 through 64 years of age, 

which meant that there was a 22.7-fold increased risk for HIV-infected adults compared with 

HIV-uninfected adults. During 2011-2013, 14 HIV-infected cases were reported in the UK. Of 

these, 71% were caused by serogroup C, W, or Y. Most of the HIV-infected cases were aware 

of their HIV status and were receiving antiretroviral treatment. The most common clinical 

presentation was septicemia. Although intensive care admission was common, none of the 

HIV-infected patients died [Simmons RD. et al. Risk of invasive meningococcal disease in 

children and adults with HIV in England: a population-based cohort study. BMC Med. 2015; 13: 

297].

To summarize the epidemiologic data, there is an increased risk for meningococcal disease in 

HIV-infected persons. Among HIV-infected persons, low CD4 count or high viral load increases 

risk. In some studies, a similar increase in risk was observed for both HIV-infected men and 

women. However, overall risk is declining along with meningococcal disease incidence in the 

US. In HIV-infected persons, meningococcal disease is primarily due to serogroups C, W, and 

Y. Data on the case-fatality ratio for HIV-infected meningococcal disease cases is mixed.

Regarding vaccine response for HIV-infected persons, the data on HIV-infected adolescents is 

based on approximately 300 adolescents included in this study. The proportion of HIV-infected 

adolescents with more than a 4-fold increased risk in rSBA titers at week 4 was 52% for 

serogroup C and 53% for serogroup Y. For HIV-infected adolescents who received a single 

dose of MenACWY-D, the response was significantly lower for those with either a low CD4 

count or a high viral load [Phase I/II, Open-Label Trial of Safety and Immunogenicity of 

Meningococcal (Groups A, C, Y, and W-135) Polysaccharide Diphtheria Toxoid Conjugate 

Vaccine in Human Immunodeficiency Virus-Infected Adolescents. Pediatric Infectious Disease 

Journal. 29(5):391-396, May 2010].

In terms of GMTs against serogroup C at 0, 4, 24, 28, and 72 weeks, despite a second dose of 

vaccine at 24 weeks, response rates remained low through 72 weeks for those with low CD4 

counts at study entry. For those with higher CD4 counts at study entry who received one dose 

of MenACWY-D, after an initial response at 4 weeks, GMTs waned rapidly. Persons with higher 

CD4 counts at study entry who received two doses of MenACWY-D, after an initial response at 

4 weeks, GMTs waned rapidly after both Dose 1 and Dose 2. Overall, the response to 

serogroup Y is higher than for serogroup C, but the same pattern of rapidly waning titers is 

observed. Regarding the percent of subjects who still had antibodies at week 72 or 

approximately 1.5 years after 1 or 2 doses of MenACWY-D, the primary study endpoint was the 

percent of subjects with rSBA titers ≥1:128. For serogroup C, titers waned to 21% to 35%. For 

serogroup Y, titers waned to 63% to 71%. The proportion of subjects with rSBA titers ≥1:8 are 

slightly higher than titers of ≥1:128 [Immunogenicity and Safety of 1 vs 2 Doses of Quadrivalent 

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Meningococcal Conjugate Vaccine in Youth Infected with Human Immunodeficiency Virus. The 

Journal of Pediatrics. 161(4):676-681. October 2012].

In summary, seroresponse to MenACWY-D conjugate vaccine in HIV-infected adolescents is 

suppressed compared to healthy adolescents. Low CD4 count or high viral load suppresses 

response further. In addition, the immune response to MenACWY-D wanes rapidly. Although a 

boost response is seen to a second dose, duration of protection will likely be an issue.

In addition to the evidence of increased risk for meningococcal disease in HIV-infected persons 

and meningococcal vaccine response, the WG also discussed other programmatic 

considerations for the use of meningococcal vaccines in HIV-infected persons. There are 

approximately 1.2 million persons 13 years of age or older living with HIV in the US1

. An 

additional 50,000 new HIV infections occur each year1

. Only about 50% of persons diagnosed 

with HIV receive regular HIV care2

. Of those retained in care, approximately 89% are 

prescribed antiretroviral therapy and 77% achieve viral suppression2

. For HIV-infected persons 

in care, HIV clinics may already be administering other vaccines recommended for HIV-infected 

persons. HIV-infected persons in care may be more likely to have CD4 counts and viral loads 

that are favorable for immunogenicity to the meningococcal vaccine [1 http://www.cdc.gov/hiv 

/statistics/overview/ataglance.html; 2 http://www.cdc.gov/hiv/prevention/programs/pwp/ 

linkage.html].

Although vaccine coverage data specifically for HIV-infected adults is sparse, coverage with 

influenza, hepatitis B, and hepatitis A vaccine has been estimated for HIV-infected persons in 

care through the HIV Outpatient Study (HOPS). Among active patients in HOPS clinics, annual 

influenza vaccination rates were between 26% and 51% during 1999-20131,2. Additionally, 32% 

of eligible patients were vaccinated with at least 1 dose of hepatitis B vaccine, and 23% of 

eligible patients were vaccinated with at least 1 dose of hepatitis A vaccine during 1992-20023 

[

1

Durham MD. Rates and correlates of influenza vaccination among HIV-infected adults in the 

HIV Outpatient Study (HOPS), USA, 1999–2008. Preventive Medicine 53 (2011) 89–94; 

2

Durham MD. Seasonal Influenza Vaccination Rates in the HIV Outpatient Study—United 

States, 1999–2013. CID 60 (2015) 976-7; 3

Tedaldi EM. Hepatitis A and B Vaccination Practices 

for Ambulatory Patients Infected with HIV. CID 38 (2004) 1483-9].

The current consideration is for use of MenACWY conjugate vaccine only. In HIV-infected 

persons, risk appears to be due primarily to serogroups C, W, and Y. No safety or 

immunogenicity data is available for use of serogroup B meningococcal vaccines in HIV-infected 

persons. The current consideration includes all HIV-infected persons 2 months of age and 

older. Because increased risk from HIV-infection is life long, regular booster doses would be 

recommended for HIV-infected persons similar to other groups at increased risk.

AAP currently recommends MenACWY vaccine for HIV-infected children 2 years of age and 

older. Here is the language from the 2015 Red Book addressing the use of MenACWY vaccine 

in HIV-infected children:

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Current AAP and ACIP recommendations are not harmonized for HIV-infected children 2 years

of age and older.

Regarding risk of meningococcal disease in MSM, of meningococcal disease cases among 

MSM for whom HIV status is known, the majority (59%) are HIV-infected. This makes 

disentangling the relative contribution of HIV and MSM status to the increase in risk challenging 

in MSM populations. However, vaccinating HIV-infected persons offers an opportunity also to 

potentially impact meningococcal disease risk among MSM.

In summary, a growing body of evidence supports an increased risk of meningococcal disease 

among HIV-infected persons. The incidence of meningococcal disease in HIV-infected persons 

is elevated and ranges from 3.4 to 6.6/ 100,000 persons. That translates to a relative risk of 4.5 

to 12.9 compared to HIV-uninfected persons. In HIV-infected persons, risk is primarily due to 

serogroups C, W, and Y. Suboptimal vaccine response and programmatic challenges may limit 

the impact of vaccination on disease burden in HIV-infected persons. However, HIV-infected 

persons represent a relatively small, defined population who are already recommended to 

receive specialized medical care.

There is strong support from the WG for including HIV-infected persons in the groups at 

increased risk of meningococcal disease. The primary considerations for the WG included the 

evidence of increased risk of meningococcal disease in HIV-infected persons, the potential 

benefits of vaccination in the targeted group, and the fact that HIV-infected persons represent a 

population who are already receiving specialized medical care. However, the WG also 

recognizes that there is suboptimal vaccine response and likely issues with duration of 

protection in HIV-infected persons, which may limit the impact of vaccination in this group.

Listed below are the current recommendations for use of MenACWY conjugate vaccine in 

persons at increased risk for meningococcal disease:

















Routine vaccination of persons aged ≥2 months at increased risk of meningococcal 

disease, including:

Persons with persistent complement component deficiencies1

 

Persons with anatomic or functional asplenia2

 

Microbiologists who are exposed routinely to isolates of Neisseria 

meningitidis

Persons at risk during a community outbreak attributable to a vaccine 

serogroup

Persons who travel to or reside in countries in which meningococcal disease 

is hyperendemic or epidemic

Unvaccinated or incompletely vaccinated first-year college students living in 

residence halls

Military recruits

[

1

Including inherited or chronic deficiencies in C3, C5-9, properdin, factor D, or factor H; 

2

Including sickle cell disease].

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The WG proposes adding persons with HIV infection to the list of groups recommended for 

routine vaccination with MenACWY vaccine. Guidance for use of MenACWY for HIV-Infected 

persons would be as follows:













Persons aged ≥2 years with HIV who have not been previously vaccinated should 

receive a two dose primary series of MenACWY (0, 2 months)

Multi-dose schedule for children aged <2 years

Persons with HIV who have been previously vaccinated should receive a booster dose 

at the earliest opportunity, and then continue to receive boosters at the appropriate 

interval

Current booster recommendations: 3 years if age <7 years at previous dose and 

5 years if age ≥7 years at previous dose

A cost-effectiveness analysis and a GRADE analysis for routine use of MenACWY in HIVinfected persons 2 months of age and older are currently in progress and will be shared with 

ACIP as they are completed.

ACIP members were asked to consider the following questions for discussion:

In addition to the cost-effectiveness analysis and GRADE, are there additional analyses 

that ACIP would like to see?

Is ACIP in agreement with the Meningococcal Vaccines Work Group proposal to 

consider routine use of MenACWY in HIV-infected persons ≥2 months of age?

Discussion Points

Based on such a dramatic decline in such a short period of time, Dr. Moore asked whether there 

was discussion in the WG about potentially reducing the interval for booster doses among HIVinfected adults to 3 years instead of 5 years, or if there are 5-year data on their antibody titers.

Ms. MacNeil replied that the WG did not discuss moving to a shorter interval, given that they 

were thinking about simplicity and harmonization with the current recommendations for other 

groups at increased risk. However, they could certainly discuss a shorter interval.

Dr. Messonnier asked whether there are any data on more than a single vaccination. Following 

the rationale Dr. Moore used, if the interval was shortened, what would be done after that. That 

is, are there any data on multiple doses of conjugate vaccines?

Ms. MacNeil responded that there are not. For HIV-infected adolescents, the two studies she 

presented are the only data they have for either vaccine.

Given the conversation, Dr. Baker (IDSA) suggested that when the cost-effectiveness study is 

done, boosting on a 3- or 5-year schedule should be considered. Medically, it makes more 

sense to have a 3-year interval. Programmatically, it is a nightmare. However, this might be 

informative.

Dr. Riley asked whether there are any data on co-administration with other vaccines, particularly 

in this population.

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Ms. MacNeil responded that while there are not for HIV-infected persons in particular, there are 

data for healthy adolescents.

Dr. Bennett emphasized that the rates of vaccination among HIV-infected individuals were 

incredibly low, especially since they are among people who are receiving care. She asked 

whether the WG had considered how this vaccine would be implemented among those groups, 

given the existing poor rates.

Ms. MacNeil indicated that one reason the WG was considering HIV-infected persons was 

because HIV care providers are already providing other vaccines and could provide this vaccine 

as well. Rates of vaccination in the general adult population are relatively similar.

Dr. Romero asked whether there are any data on the AEs associated with revaccination of 

younger children, and why there is a lower mortality rate in HIV-infected individuals.

Dr. Messonnier responded that there are some CDC data, but it is comparable to healthy 

individuals.

Ms. MacNeil responded that in the two US studies and the UK, the case fatality ratio is lower for 

HIV-infected persons. There is a variety of reasons. It could be that people get into care more 

quickly, they are being treated more aggressively perhaps because they are 

immunosuppressed, the disease process is not as severe, et cetera.

Meningococcal Disease Among MSM in the US: January 2012-June 2015

Temitope A. Folaranmi MBChB, MPH, MPP

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

For this presentation, Dr. Folaranmi discussed the results of an analysis of surveillance data on 

meningococcal disease among MSM in the US, including instances of community-based 

outbreaks or clusters of invasive meningococcal disease (IMD) among MSM. The first reported 

outbreak of IMD among this group occurred in Toronto in 2001. The first reported US outbreak 

occurred in Chicago in 2003. Subsequent clusters/outbreaks have occurred in New York City 

(2010-2013), Los Angeles County (2012-2013), Paris (2013), Belgium (2013), Berlin (2013), and 

Chicago (2015). All outbreaks were caused by serogroup C ST-11 clonal complex, a common 

invasive strain of Neisseria meningitidis and a frequent cause of outbreak cases. These 

clusters had between a 25% to 50% case fatality ratio. These ratios were high when compared 

to 10% to 15% case fatality ratio seen in the general US population. Similarly, 68% and 75% of 

the cases in New York City and the most recent Chicago outbreak were HIV-infected. These 

percentages were also high compared to an HIV prevalence of 19% observed in the general US 

MSM population.

These instances of community-based outbreaks and clusters have raised the question as to 

why MSM have an increased risk for IMD. Therefore, the study objectives were to:

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









Identify IMD cases reported among MSM within the observation period

Describe IMD epidemiology and case characteristics among MSM and non-MSM 

Assess rates of IMD and prevalence of known IMD risk factors among MSM

Estimate the relative risk of IMD among MSM compared to non-MSM

Estimate the relative risk of IMD among HIV infected MSM compared to HIV uninfected 

MSM

Regarding the methods used in the analyses, meningococcal disease surveillance data are 

reportable in the US. All US states and territories have passive reporting that includes all 

confirmed and probable cases. When a meningococcal case is reported, an intensive case 

investigation is conducted by the health department to identify close contacts who may require 

prophylaxis for the disease. Information on the sex of sex partners and HIV status may be 

captured in case notes, but is not usually reported through surveillance.

To address the first objective to identify IMD cases that occurred among MSM, CDC posted two 

Epi-X calls for cases posted in May 2013 and June 2015. State health departments, including 

Washington, DC and New York City, were asked to review all meningococcal disease cases 

among men 18 through 64 years of age occurring during the study period of January 2012 

through June 2015. If MSM cases were identified, case investigation and risk factor data were 

abstracted. If no MSM case was identified, zero report was requested. After data abstraction, 

all IMD cases were classified into five groups: 











MSM cases in New York City (MSM-NYC)

MSM cases in Los Angeles County (MSM-LAC)

MSM cases in Chicago, including those from the metro area (MSM-Chicago)

MSM sporadic cases and all other MSM cases (MSM-Others)

Men not known to be MSM (Non-MSM)

Cases within the three jurisdictions (New York City, Chicago, Los Angeles County) were 

grouped separately because they reported an outbreak or cluster during the observation period. 

Not all MSM cases that occurred within the three jurisdictions within the observation period were 

part of a cluster or outbreak. However, for analysis, all cases that occurred within each 

jurisdiction during the observation period were grouped together.

To address the other four objectives, the denominator was estimated for the disease rate 

calculation. MSM was defined as “sex with another man in the past five years.” Similarly, the 

MSM population per jurisdiction was defined as the “population of men aged 18 through 64 

years X MSM prevalence.” To estimate the population of men 18 through 64 years of age, the 

2012 population estimate data of the American Community Survey (ACS) was utilized. The 

ACS is a yearly survey conducted by the US Census Bureau. Using the survey data, the 

number of men 18 through 64 years of age in the US was estimated to be 96,618,006.

To estimate MSM prevalence per jurisdiction, data were used from a recent study conducted by 

subject matter experts (SMEs) from CDC’s Division of STD Prevention (DSTDP) and Emory 

University. The estimates were 6.8% for Los Angeles County, 7.3% for New York City, 6.6% for 

Chicago, and 3.3% for other US jurisdictions. The overall prevalence of MSM in the US was 

estimated to be 3.9% [Jeremy Grey, Kyle Bernstein et al, 2015. Estimating the population sizes 

of men who have sex with men (MSM) in the U.S. states and counties using data from the 

American Community Survey. Manuscripts under Review].

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Estimation of the HIV-infected MSM population in each jurisdiction was based on 2012 HIV 

surveillance data1,2,3,4. The HIV uninfected MSM population per jurisdiction was calculated 

using the formula: (Population of Men Aged 18-64 Years * MSM Prevalence) – Surveillance 

Estimate of HIV Infected MSM. MSM-Others’ Cases Estimate was calculated using the formula: 

Total U.S. Estimate – (LAC+ NYC + Chicago Estimate). HIV status data were not available 

among non-MSM cases[1

http://www.nyc.gov/html/doh/downloads/pdf/dires/surveillance-reportdec-2013.pdf; 

2

https://www.cityofchicago.org/content/dam/city/depts/cdph/HIV_STI/2014HIVSTISurveillanceRe

port.pdf; 3 http://publichealth.lacounty.gov/wwwfiles/ph/hae/hiv/2012AnnualHIVSurveillance 

Report.pdf; 4

http://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-reportvol-25.pdf].

Regarding the results, 527 meningococcal disease cases were identified overall among men 18 

through 64 years of age reported to CDC between January 2012 and June 2015. Of these 

cases, 74 (14%) were identified as MSM from 17 states and 453 (86%) cases were among nonMSM from 47 states and Washington, DC. Before analyzing the data by the jurisdictional 

classifications described earlier, the age group and MSM status was first assessed for all case 

patients to understand whether the case patient would have been eligible for vaccination 

through the vaccination platform. Case patients 18 through 24 years of age accounted for 31% 

of the non-MSM cases, case patients 26 through 35 years of age accounted for 43% of the 

MSM cases, case patients 36 through 45 years of age accounted for 19%, case patients 46 

through 55 years of age accounted for 16%, and case patients 56 through 64 years of age 

accounted for 1%. Overall, the median age for all MSM cases was 31 years and the median 

age for non-MSM cases was 34 years.

This graphic shows the frequency of meningococcal disease cases by month within the 

observation period:

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Subsequently, the data were analyzed by jurisdiction. Of the 74 MSM cases identified in this 

study, 23, 14, and 11 MSM cases occurred in New York City, Los Angeles County, and 

Chicago, respectively. Of the cases, 26 were classified as MSM-Other because they were 

sporadic cases in states and geographic areas outside of the three jurisdictions.

The majority of cases in the MSM and non-MSM categories were non-Hispanic. However, an 

equal proportion of Hispanic and non-Hispanic cases were observed in Los Angeles County. 

The majority of the MSM-Others, MSM-LAC, and Non-MSM categories were White. However, 

Blacks accounted for a greater proportion of the cases from New York City and Chicago.

Clinically, meningitis and bacteremia were the two most common presentations. The clinical 

presentations reported are not mutually exclusive. About 10% of all MSM cases had both 

meningitis and bacteremia, or either of them and another clinical presentation such as septic 

shock or pneumonia. Therefore, the percentages may exceed 100%. Among the MSM cases 

within MSM-Others, MSM-NYC, MSM-LAC, and MSM-Chicago case fatality ratios were 

observed of 39%, 26%, 36%, and 27% respectively. Among non-MSM cases, the case fatality 

ratio was 24%.

The serogroups included in MenACWY vaccines accounted for most of the MSM cases with 

known serogroup information. However, serogroup C was predominated among MSM cases. 

On the other hand, a wide distribution of serogroups is observed among the non-MSM cases. 

Serogroup information for about 16% of non-MSM cases was not available. Between 36% and 

65% of the MSM cases were HIV-infected. Overall, 59% of all MSM cases with known HIV 

status were HIV-infected. When the data were restricted to only serogroup C, W, and Y cases, 

the overall HIV prevalence among MSM was 58%. Across all case patients, serogroup C cases 

were 1.5 times more likely to have a fatal outcome. When comparing case fatality to MSM 

status, a significant association was not observed between them. However, outcome data was 

unknown in 15% of the cases of the non-MSM case patients. Similarly, a significant association 

was not observed between case fatality and HIV status among MSM. Similar findings were 

observed when data were restricted to only serogroups C, W, and Y cases.

Next, behaviors reported among the MSM cases were assessed. Of MSM case patients, 33% 

reported smoking; 49% reported use of recreational drugs, including marijuana; 47% reported 

multiple sexual partners or engaged in anonymous sex; 61% reported using dating apps or 

websites to meet partners; and 21% had a history of recent travel. There are variations in the 

number of cases assessed due to limited availability of data reporting these behaviors.

Regarding the risk of IMD among MSM and non-MSM, first the annualized incidence rates 

among MSM were estimated and compared those to the incidence among non-MSM within 

each jurisdiction. Overall, the incidence among MSM in the US was 0.59 cases/100,000. This 

is compared to 0.15 cases/100,000 among non-MSM. Thus, MSM have 4 times the incidence 

risk of IMD compared to non-MSM. MSM within the MSM-Others category have 1.8 times the 

incidence risk for IMD when compared to non-MSM cases. The three MSM cluster categories 

have a relative risk of IMD ranging from 14.6 to 23 when compared to non-MSM cases.

Next, incidence rates were compared between HIV-infected and HIV-uninfected MSM. Overall, 

it was observed that HIV-infected MSM had 10.1 times the risk of IMD compared to HIVuninfected MSM cases. It was observed that MSM cases within the MSM-Others category had 

a higher relative risk for IMD when compared to HIV-uninfected MSM cases. On the other 

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hand, the relative risk for IMD among HIV-infected MSM within the three cluster categories 

ranged from 4.1 to 6.8 compared to HIV-uninfected MSM.

IMD annualized incidence rates among HIV-infected MSM and other men were then compared 

within each jurisdiction. Other male cases is defined as “all non-MSM and HIV-uninfected MSM 

cases combined.” Overall, HIV-infected MSM have 16 times the risk of IMD compared to all 

Other Male cases. HIV-infected MSM within the MSM-Others category have 6.7 times the risk 

of IMD compared to other men cases; whereas, within the cluster categories, HIV-infected MSM 

have a relative risk ranging from 22.5 to 34 when compared to Other Male cases. In summary 

of relative risk when the data was restricted to only serogroups in MenACWY vaccines, an 

increase was observed in the overall relative risk of IMD among MSM from 4 to 7.3 when 

compared with non-MSM cases having serogroup C, W, and Y infections. The relative risk for 

IMD among MSM compared to non-MSM in the MSM-Others category was 3.3. The relative 

risk for IMD among the cluster cases ranged from 21.3 to 38.9 when compared to non-MSM 

cases. 

HIV-infected MSM with serogroup C, W, and Y infection had a relative risk of 9.2 when 

compared to the HIV-uninfected MSM overall. However, within the MSM-Others category, the 

relative risk for IMD increased to 10.3 when compared to HIV-uninfected MSM. A decline was 

noted in IMD risk among the cluster cases with a relative risk that ranged from 1.8 to 7.7 when 

compared to HIV-uninfected MSM cases. HIV-infected MSM had a relative risk of 25.7 and 6.7 

in the overall and MSM-Others category respectively. Among the cluster cases, the relative risk 

ranged from 12.9 to 48.4 when compared to Other Men cases. Additionally, HIV-uninfected

MSM were compared to non-MSM cases only. Overall, a relative risk of 3.0 was observed 

among HIV-uninfected MSM when compared to non-MSM cases. On the other hand, the 

relative risk in the MSM-Others category was 0.97 when compared to non-MSM cases. Among 

the cluster MSM cases, the relative risk for IMD among HIV-uninfected MSM ranged from 9.3 to 

22.8. Finally, it was observed that IMD risk diminished among MSM in non-outbreak settings 

when HIV infection is removed from the equation as shown by the decline in relative risk from 

3.3 to 0.97.

Regarding the salient issues from the analyses, MSM had a higher incidence in terms of IMD 

risk among MSM in both outbreak and non-outbreak settings compared to the general non-MSM 

male population. It was noted that serogroup C accounted for the majority of the MSM cases 

reported during the observation period. This is consistent with all previous outbreaks reported 

among MSM; however, the reason for this occurrence remains unclear.

Similarly, HIV prevalence among MSM with IMD was high at 59% when compared to the 

general HIV prevalence of 19% among MSM in the US.1 It is unclear why there is no significant 

association observed between HIV status and case fatality among the MSM cases in the 

analysis. This may be related to access to HIV care and the care-seeking behavior of the case 

patients. Unfortunately, there are no data on viral load or CD4 count status that would allow for 

a stratified analysis. Based on the analyses, it was observed that being MSM combined with 

HIV infection conferred a higher risk for meningococcal disease than being MSM alone. 

Similarly, HIV infection seems to be responsible for most of the increased risk observed among 

MSM-Others [1

Prevalence and Awareness of HIV Infection Among Men Who Have Sex With 

Men—21 Cities, United States, 2008. Morbidity and Mortality Weekly Report (MMWR). 

2010;59(37):1201-7].

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In terms of high risk behaviors among MSM with IMD, a high prevalence of recreational drug 

use among MSM with IMD of 48% was observed compared with a recreational drug use 

prevalence of 10%1 among US adults. A high prevalence of smoking was observed among 

MSM with IMD of 30% compared with an 18%2 prevalence among US individuals 12 years of 

age and older. The reasons for increased IMD risk in outbreak settings are unclear, but may 

include an increase in the number of contacts and/or higher-risk behaviors. MSM with these 

behaviors may also be at increased risk of being infected with HIV [1

Jamal A, Agaku I, O'Connor 

E, King B, Kenemer J, Neff L. Current Cigarette Smoking Among Adults — United States, 

2005–2013. (MMWR). 2014;63(47):1108-12; 2

Center for Behavioral Health Statistics and 

Quality. Behavioral health trends in the United States: Results from the 2014 National Survey on 

Drug Use and Health. 2015].

The analysis is not without limitations. Ascertainment of MSM and HIV status during case 

investigations is still a challenge. The estimates are conservative, and it is likely that 

misclassification of MSM status may underestimate the rate. Systematic collection of 

information on sexual behavior by health departments will help reduce misclassification in future 

analyses. Similarly, IMD incidence may vary depending upon the accuracy of denominator 

estimates. CDC recommended that all health departments routinely assess MSM and HIV 

status for cases that occur in men 16 years of age and older. It remains unclear how broadly 

and completely this recommendation has been implemented. Given the lack of a proper control 

population and missing/incomplete data, assessment of risk factors is difficult.

The key messages from this analysis are that MSM had increased incidence of IMD, but the 

overall incidence remains low in both outbreak and non-outbreak settings compared to the 

general population. Incidence increases with HIV infection and was higher among serogroups 

C, W, and Y infections in case patients. Also, most MSM case patients are in the older age 

groups and would not have been vaccinated as part of the current adolescent vaccination 

platform for MenACWY.

Considerations for Use of MenACWY Vaccines in MSM

Jessica MacNeil, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Ms. MacNeil presented a summary of the WG discussions on meningococcal disease among 

MSM. The ongoing clusters and outbreaks of meningococcal disease among MSM have 

increased awareness of meningococcal disease cases occurring in MSM. However, 

understanding the risk for meningococcal disease in MSM is challenging given the associations 

with HIV-infection and higher-risk behaviors and the limited data available to evaluate and tease 

apart these potential risk factors.

During the clusters and outbreaks among MSM in New York City, Los Angeles County, and 

Chicago, MenACWY vaccines were used as part of outbreak response, with local vaccination 

recommendations targeting either a subgroup of MSM1 or all MSM. In these jurisdictions, 

vaccination recommendations for MSM continue to remain in place. ACIP recommendations 

support the use of meningococcal vaccines in response to outbreaks. However, these reactive 

vaccination campaigns often require considerable resources and effort on the part of the 

affected health department. Despite these challenges, the initial vaccination response was 

demonstrated to be cost-effective in New York City2

 [1MSM, regardless of HIV status, who 

regularly have close or intimate sexual contact with men met through an online website, digital 

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application ("app"), or at a bar or party; 2Simons et. al. Cost-Effectiveness of Meningococcal 

Vaccination Among Men Who Have Sex With Men in New York City. J Acquir Immune Defic 

Syndr. 2016 Feb 1;71(2):146-54].

As the WG reviewed the available data on the epidemiology of meningococcal disease among 

MSM, the key discussion points were that outbreaks of meningococcal disease continue to 

occur among MSM; MSM had higher incidence rates than non-MSM in both outbreak and nonoutbreak settings; and in non-outbreak settings, HIV infection appears to be the main driver of 

increased risk for MSM. The reasons for outbreaks among MSM are unclear, but may include 

close social networks, an increased number of contacts, and/or higher risk behaviors. 

As presented earlier, it is estimated that approximately 3.9% of the US adult male population is 

MSM, which translates to a population size of approximately 3.8 million people. To evaluate the 

potential programmatic issues and challenges for vaccinating MSM with meningococcal 

vaccines, the WG looked at other vaccines currently recommended by ACIP for MSM or 

subgroups of MSM, including HPV, Hepatitis A, and Hepatitis B vaccines. These vaccines may 

be administered to MSM in a variety of settings and requires disclosure of MSM status to health 

care providers (e.g., primary care, STD clinics, et cetera).

The National HIV Behavioral Surveillance (NHBS) surveyed over 10,000 US adult MSM in 2014. 

Of these, 82.2% visited a health care provider in past year1

. Among HIV-infected MSM, 97% 

had used health care. Among other MSM, 80% had used health care. Approximately 80% 

disclosed MSM activity to a healthcare provider. The locations of usual care included doctor’s 

office or HMO (55.6%), clinic or health center (28.1%), hospital emergency room (13.5%), and 

other (2.4%) [1

Unpublished data, courtesy S. Oliver and E. Meites].

Many STD clinics providing health care to populations which include MSM offer vaccines, 

including meningococcal vaccine. In a survey from the National Coalition of STD Directors

(NCSD) of 78 STD clinics from 46 US states, three-quarters stocked at least one vaccine and 

nearly half stocked a meningococcal vaccine [Unpublished data, courtesy E. McGinnis and 

NCSD].

The NHBS survey also provides estimates of HPV vaccine coverage among MSM. In the 2011 

NHBS survey1

, only 5% of MSM 18 through 26 years of age reported receiving at least 1 dose 

of HPV vaccine, with 13% coverage among HIV-infected MSM. In late 2011, the ACIP 

recommendation for HPV vaccine for males and MSM was changed from permissive to routine. 

In the next NHBS cycle in MSM in 20142

, 17% of MSM 18 through 26 years of age reported 

receiving any HPV vaccine, with 37% coverage among HIV-infected MSM [1

Meites, E et al. HPV 

vaccine coverage among men who have sex with men – National HIV Behavioral Surveillance, 

United States 2011; Vaccine 2014; 2 Unpublished data, courtesy S. Oliver and E. Meites].

After reviewing the available data, no consensus was reached by the WG for including MSM or 

a particular sub-group of MSM in the groups at increased risk for meningococcal disease. The 

primary reasons include the low absolute risk for meningococcal disease currently in nonoutbreak settings and potential programmatic challenges for implementing a vaccination 

program in MSM. The WG feels that continued study is needed to better understand 

transmission and risk factors for this population. In terms of meningococcal disease cases, the 

prevalence of HIV is high, with nearly 60% of MSM meningococcal diseases cases co-infected 

with HIV. This is compared to an overall HIV prevalence in the general US MSM population of 

19%1

. Therefore, a recommendation for vaccination of HIV-infected persons could address an 

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important proportion of MSM meningococcal disease risk [1Prevalence and Awareness of HIV 

Infection Among Men Who Have Sex With Men—21 Cities, United States, 2008. Morbidity and 

Mortality Weekly Report (MMWR). 2010;59(37):1201-7].

MenACWY vaccines will continue to be used to vaccinate at risk populations if additional 

outbreaks of meningococcal disease among MSM occur. In addition, enhanced surveillance for 

cases of meningococcal disease in MSM and HIV-infected persons is ongoing. Updates will be 

shared with the WG and ACIP as additional data become available. 

Discussion Points

In terms of changing the recommendations, it seemed key to Dr. Kempe to understand how 

much of the MSM risk is due to HIV. Dr. Folaranmi’s slide 49, “Relative Risk of IMD among 

MSM with Serogroup C, W, and Y Infections” seemed to contain the most salient information. 

There are no 95% confidence intervals. The last line appeared to be the comparison between 

non-HIV MSM with non-MSM. She asked Dr. Folaranmi to expand on this.

Dr. Folaranmi explained that for the first line, the general MSM population was compared to the 

non-MSM population. The goal was to tease out the effect of HIV infection, which is why HIVinfected MSM were compared to non-MSM. The risk is almost 1, meaning that the majority of 

risk observed among MSM compared to non-MSM is likely due to HIV infection in the sporadic 

setting. That effect was not seen in the clusters. Most of the cases in the clusters were due to 

outbreaks.

Regarding why more is not known about risk factors for meningococcal disease in MSM and 

potential problems with not having proper controls, Dr. Reingold pointed out that many casecontrol studies have been conducted on MSM to assess numbers of partners, going to bath 

houses, and various other risk factors for HIV infection. He was curious as to whether or not 

having controls was a resource problem or if there was a plan to conduct case-control risk factor 

studies. In terms of this type of analysis, he suggested that it might be better to calculate 

population attributable risks instead of simply trying to compare relative risks in terms of trying to 

sort out how much of this is HIV and how much is MSM.

Dr. Folaranmi replied that the population attributable risk was not calculated, but it is something 

to consider for further analysis. With respect to the control group, the group referred to as nonMSM cannot be confidently said to be all non-MSM, which is why the term “Other men not 

known to be MSM” is used. They are not a perfect control group to use to analyze the data. He 

did not know of any studies that assessed risk factors between MSM and non-MSM. One study 

was conducted in New York City that attributed one possible risk factor, STDs in the past year 

before infection and HIV infection. Those two risk factors were identified in that particular casecontrol study. CDC’s population was very small, comparing approximately 50 MSM cases to 

about 50 controls.

Dr. Reingold clarified that he was talking about case-control studies comparing MSM who have 

meningococcal versus those who do not to assess risk factors among MSM (going to bath 

houses, number of sex partners, condom use, et cetera). Presumably, those studies could be 

conducted.

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Ms. Martin (SME) responded that CDC has discussed conducting a risk factor study. Part of the 

problem is that the number of cases is low, so it would have to be a national study. New York 

City conducted a study, but their comparison group is somewhat different from the case group 

and raises some questions pertaining to the validity of the findings.

Ms. Pellegrini said she was struggling most with the limitations of ACIP’s mandate. This is a 

very complex population with a lot of confounding risk factors. It is not clear whether vaccine is 

the right public health intervention to achieve this goal. Can IMD actually be reduced by 

reducing HIV infection, promoting condom use, et cetera? She wondered whether their CDC 

colleagues could discuss how these conversations occur within the agency, because she is very 

concerned about potentially sending a recommendation to Dr. Frieden and putting the agency in 

a position of deciding whether to support the recommendation and essentially divert public 

health resources to this less effective intervention simply because ACIP is not tasked with 

determining how to reduce meningitis.

To clarify any misunderstanding, Dr. Messonnier noted that the place the WG came to on this 

issue was not moving toward a vaccine recommendation. Given all of the complexities, they 

recognize that this is not what the current science says at this point. The larger issue is an 

interesting one. Before meningococcal vaccines were available, a number of studies evaluated 

smoking as a risk factor for meningococcal disease that found that active and passive smoking 

had an attributable risk of 25% to 30% of cases of meningococcal disease. However, no one 

was going to make passive smoking regulations based on this. Fortunately, there were many 

other drivers of that. This is a very specific, very small subgroup and it is difficult to determine 

whether that is going to drive the public health conversation. The team is working with those in 

the STD and HIV worlds’ and this is part of it. However, Dr. Reingold and Ms. Pellegrini raised 

another important issue as well: Given the many other issues in this population, even launching 

research studies focused on this or nesting the issue in other studies is difficult.

Something that troubled Dr. Bennett regarded where the estimates for the percentage of the 

population that engage in MSM come from and whether they are accurate. This population may 

or may not want to disclose, and the rates in that population are quite dependent upon the 

denominator. Therefore, it concerned her that the denominator may be underestimated.

With respect to the outbreak comments, Dr. Moore thought in addition to the denominator 

having a significant effect on conclusions, the outbreaks themselves skew the perspective as 

this demonstrates. There is the allusion on slide 3 of Ms. MacNeil’s second presentation to the 

fact that the outbreak response in New York City was demonstrated to be cost-effective. She 

requested that Dr. Zucker from New York City discussed what sort of cost-effectiveness they 

observed.

Dr. Zucker (NYC) said she would need to pull up the precise numbers to bring back to the 

group, but recalled that it was under $100,000 and was within or less than the costeffectiveness range used for the meningococcal recommendations. It was surprising to her 

from the New York City perspective that it was clear that HIV is an increased risk factor—the 

data supported that. They showed, at least in that setting, that it was cost-effective to conduct 

the vaccine campaign in the outbreak setting. Relative to what they just heard in terms of 

numbers and increased risk, having a recent vote with over $1 million to prevent one case of 

IMD-B, perhaps they should have GRADE numbers to show what a national campaign would 

look like in terms of the cost-effectiveness for vaccinating HIV-infected persons whether it is 

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MSM or a subgroup. She was surprised that there was not more discussion about moving 

toward a routine recommendation, at least for some of the subgroups.

Ms. MacNeil indicated that the cost-effectiveness analysis performed for GRADE would be 

presented in June 2016 for HIV-infected persons.

Dr. Duchin (NACCHO) said he wanted to further explore some of the incidence numbers in the 

various sub-strata presented. For the HIV-infected cohorts, particularly in the three cities, the 

incidence rates are much higher than they are for adolescents for whom meningococcal 

vaccination is routinely recommended. Even for some of the HIV-uninfected populations, they 

are comparable. He requested further information about what the WG thought about that issue, 

and whether it would be appropriate to consider vaccination where it has been established that 

the rate of disease is so much higher than it is for other populations for whom the vaccine is 

already recommended.

Ms. MacNeil responded that the three jurisdictions that had outbreaks or clusters recommended 

vaccination of MSM, and those recommendations remain in place for those jurisdictions.

Dr. Duchin (NACCHO) asked whether she was saying that there would be a different policy for 

jurisdictions in which outbreaks are occurring versus where they have not yet occurred.

Ms. MacNeil replied that the WG did not discuss this because the recommendations are already 

in place in response to the outbreaks.

Dr. Baker (IDSA) congratulated the presenters for summarizing information that took days for 

her to hear repeatedly. This is very complex and difficult to tease out. It would be great to 

conduct a case-control study, but it would cost a prohibitive amount. She thinks the HIV data 

are very clear and compelling. The AAP recommended MenACWY many years ago when the 

vaccine became available to drop down to two years with booster doses. HIV-infected people is 

a subgroup. They are a larger subgroup than children born with congenital complement 

deficiencies, which are on the list of high risk individuals. When attempting to add, tear apart, 

figure out, or analyze MSM, it is complicated. She thinks the HIV data are clear and that a 

policy group should not care about what proportion are being vaccinated. Does ACIP 

recommend influenza vaccine for everyone 6 months of age and older? Yes. Is it a good policy 

decision? Yes. Do we have some groups that are well below 50%? Yes. It is not bad policy. 

ACIP is not in charge of implementing. There is no reason not to add vaccine to public health 

measures to reduce risk. Influenza vaccine recommendations are added to hand-washing, 

cough etiquette, and other measures. It is not either / or.

Dr. Zucker (NYC) clarified that New York City is focused on HIV-positive persons. A person is 

MSM, but is high risk MSM high risk as defined from an outbreak cluster in terms of increased 

used of looking for partners on apps. It is not a routine MSM recommendation.

Public Comment

Lynn Bozof

National Meningitis Association, Inc. (NMA)

Thank you. Hi. I’m Lynn Bozof, President of the National Meningitis Association (NMA). Most 

of you are familiar with my story of losing my son, Evan, to meningococcal disease as a college 

junior. I did not originally plan to speak at this meeting because there were no mening votes 

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scheduled. But, I’m getting constant phone calls and emails from people with major difficulties 

finding serogroup B vaccines. So, I felt I needed to say something. Then with the recent 

outbreak at Santa Clara University and the MenB case at Yale, this is obviously an issue that 

we still need to think about. Thank goodness there were no fatalities from those cases. The 

Category B recommendations seemed like a really great place to start. We saw people that 

wanted to fully protect their children who would just talk to their health care provider and let 

them know this is important to them. Unfortunately, that is really not working out. We hear from 

parents that their child’s doctors aren’t aware of the MenB recommendations. Even fewer are 

carrying it, and they don’t know where to send people for it. The other day, we had a workshop 

and one of the moms whose son contracted serogroup B at Princeton had to make 12 phone 

calls to find the vaccine for her younger son. We had another college-age survivor that had to 

make 5 phone calls to find the vaccine. These are people that are motivated. These are people 

that want to be vaccinated. If it’s so difficult for them, what is the average person going to do? 

They are going to give up. So, when we have someone who wants to be vaccinated, yet can’t 

find the vaccine, it’s a bad situation. When health care providers don’t know how to deal with a 

vaccine request, that’s a bad situation. We really need to do better. Most people want to send 

their children off to college fully protected. We should make this easy. It should be a “nobrainer.” But, it’s really turning out to be a challenge to get vaccinated for serogroup B. So, I’m 

hoping that in the next ACIP meeting that this can be addressed again. Thank you.

Introduction

Lorry Rubin, MD

ACIP, Workgroup Chair 

Dr. Rubin reminded everyone that inactivated vero cell culture-derived Japanese encephalitis 

vaccine (JE-VC; IXIARO®) is the only JE vaccine available in the US. JE-VC is manufactured 

by Valneva, formerly Intercell. Inactivated mouse brain–derived JE vaccine (JE-MB; JE-VAX®) 

is no longer available in the US.

In terms of how ACIP recommendations for the use of JE-VC have evolved, in 2009 the FDA 

licensed JE-VC for use in adults and ACIP approved recommendations for a primary series in 

adults. In 2010, the MMWR Recommendations and Reports from 1993 were updated. In 2011, 

ACIP approved recommendations for use of a booster dose in adults based on new information 

and a Policy Note was published in the MMWR. In 2013, ACIP approved recommendations for 

use of a primary series in children and an additional Policy Note was published in the MMWR. 

The JE Vaccine WG’s objectives are to: 1) review newly available safety and immunogenicity 

data for JE-VC; 2) review epidemiology and risk of JE in travelers; 3) review ACIP 

recommendations for use of JE vaccine in consideration of updated safety, immunogenicity, and 

traveler risk data; and 4) update the MMWR Recommendations and Reports published in 2010. 

Presentations during this session focused on duration of protection following the primary series 

and a booster dose in adults, duration of protection and consideration of need for a booster 

dose in children, and the JE Vaccine WG’s summary and plans. 

Japanese Encephalitis Vaccine

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Duration of Protection Following Primary 

Series and Booster Dose of IXIARO® in Adults

Dr. Katrin Dubischar

Senior Scientist, Clinical Research

Valneva Austria GmbH

Dr. Dubischar reminded everyone that the IXIARO® primary series was approved by FDA in 

2009 for use in persons 17 years of age and older. Initial data on antibody persistence after a 

primary series of IXIARO®, the immunogenicity and safety of a booster dose, and duration of 

protection after the booster were added to the IXIARO® prescribing information in 2010. The 

data were presented to ACIP and a booster recommendation was issued in 20111

. In 2013, the 

IXIARO primary series indication was expanded to include children from 2 months of age, and 

ACIP issued a respective recommendation. Data on need for and timing of a booster in children 

were not available at the time. New clinical data are now available on duration of protection 

after primary series and after a booster dose, in both adults and children [1

MMWR, May 27, 

2011, Vol. 60, No. 20].

Three clinical trials in adults provide data relevant to persistence of antibodies. New clinical 

data for IXIARO® are available for both antibody persistence after primary series and after 

booster dose: 

Study

Follow-Up 

After Primary 

Series

(Reviewed by ACIP)

Follow-Up 

After Primary Series

(New Data)

Follow-Up 

After Booster

(Reviewed by ACIP)

Follow-Up 

After Booster

(New Data)

IC51-303 36 months 60 months Not Done

IC51-311 15 months 12 months 

(all subjects)

76 months 

(subgroup)

IC51-305 24 months 13 months

Trial IC51-303 was a long-term immunogenicity and safety study. The design was a single-arm 

Phase 3 follow-up study, with no treatment administered. The study population was comprised 

of 181 subjects 18 years of age and older for the first 24 months after the first dose, with 152 

subjects included in the analysis up to Month 60 after the first dose. Follow-up was at 2, 6,12, 

24, 36, 48, and 60 months after the first vaccination. There were 4 study sites in Austria, 

Germany, and Romania. The endpoints included:











Primary endpoint of SCR at Month 24 after first vaccination

Secondary endpoint of GMT at Month 24 after first vaccination

Immunogenicity (SCR and GMT) at Months 2, 6,12, 36, 48, and 60

Rate of subjects with SAEs and medically attended AEs up to Month 6

SAEs

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The seroprotection rate was defined as the rate of subjects with a protective titer (PRNT50

≥1:10). There was a decrease in seroprotection from 99% down to about 80% within the first 12 

months. Seroprotection then remained stable at approximately 80% for up to 5 years after the 

first dose. The GMT decreased markedly in the first year, then remained stable at 

approximately 40 for up to 5 years. The study was conducted in an area where tick-borne 

encephalitis (TBE) vaccine is relatively common. It was observed in the pivotal studies that a 

response to a first dose of JE vaccine is enhanced in people who have had a prior TBE

vaccination. For that reason, a post-hoc analysis was performed to assess the impact of TBE 

vaccination on the seroprotection rate. Subjects were grouped by their TBE virus vaccination 

status at each study visit as follows:







No TBE vaccination up to the specific time point before the JE series

TBE vaccination prior to the first dose of IXIARO®, but no TBE vaccination during the study

TBE vaccination during the study after IXIARO® vaccination

Among the subjects without any TBE vaccination before or during the study, the seroprotection 

rate decreased to approximately 60% at the end of 5 years follow-up; whereas, people with prior 

or concomitant TBE vaccination tended to show higher seroprotection rates over time [Schuller 

et al 2008, Dubischar-Kastner et al. Abstract LB-2357, American Society of Tropical Hygiene 

2011].

Trial IC51-311 was the main booster dose trial for XIARO® to assess the effect of a booster 

dose on long-term immunity. This was a single-arm, open-label follow-up study conducted in 

198 subjects 18 years of age and older. The treatment group received a 0.5 mL booster of 

IXIARO® intramuscularly at Month 15 after primary immunization. Follow-up occurred at 1, 6, 

and 12 months after the booster. There were 3 study sites in Austria and Germany. The 

endpoints were:





A primary endpoint of SCR at Month 12 after the booster vaccination

Main secondary endpoints of SCR at Day 28 and Month 6 after the booster vaccination; 

GMTs at Day 28, Month 6, and Month 12; and solicited and unsolicited AEs up to Month 12

In this trial, the seroprotection rate dropped from 97% to 69% by 15 Months after the start of the 

primary series. GMT after primary immunization declined from about 170 to 23 [Eder et al, Long 

term immunity following a booster dose of the inactivated Japanese Encephalitis vaccine 

IXIARO®, IC51. Vaccine 2011,29;2607–2612].

Trial IC51-305 was an open-label, Phase 3 supportive booster / long-term immunogenicity 

follow-up study. The objectives of the trial were to determine long-term immunogenicity, and 

response to a booster dose in subjects without measurable antibody titers. The study 

population consisted of 356 subjects 18 years of age and older who received one of three 

different doses / schedules of IXIARO® in a preceding trial. Dr. Dubischar showed only data for 

the standard schedule group during this session. A 0.5 mL booster of IXIARO® was 

administered to seronegative subjects only. Subjects who were seronegative at Month 6 were 

boosted at Month 11. Subjects who were seronegative at Month 12 were boosted at Month 23. 

Follow-up was at 2 years after the primary series and up to 12 months after the booster. There 

were 2 study sites in Germany and Northern Ireland where TBE vaccination is not practiced at 

all. The primary endpoint was seropositivity at Month 24. Seronegative subjects received a 

booster, but remained classified as seronegative for subsequent time points in this analysis. 

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The main secondary endpoints included seroprotection at Month 6, 12, and 24; GMTs at Month 

6, 12, 24; and SAEs and medically attended AEs and local and systemic tolerability of the 

booster. In this trial, the seroprotection rate dropped from 97% to 58% by Month 12 after start of 

the primary series. By Month 24 after the primary series, only 48% of the subjects retained 

protective titer levels. A stronger decline was observed in the GMTs from 219 to 16 by Month 

24 [Dubischar-Kastner et al Vaccine 2010].

For Trial IC51-311, the main booster dose trial, neutralizing antibodies also were assessed at 1, 

6, and 12 months after booster. The seroprotection rate increased from about 70% at the prebooster time point to 100% within 1 month of the booster dose, and remained at 99% for at least 

12 months after the booster dose. There was about a 40-fold increase in GMTs with the 

booster dose. Up to about Month 12 after the booster dose, GMTs were retained at higher 

levels than observed after the primary series.

A study was conducted as an extension of the IXIARO® main booster trial that assessed 

neutralizing antibodies 6 years after the booster dose in a subset of the original study population

at 2 of the 3 original study centers. For this study, the investigators were able to call back 67 of 

the original 198 subjects from main booster trial for serological sampling on average 76 months 

from their booster dose. Among these subjets, the seroprotection rate remained at 96% 

approximately 6 years after the booster dose and the GMTs were about 150. The data from 

that study also were used for mathematical modeling of the antibody decline. A PRNT50 titer of 

1:10 was defined as the limit for protection. Duration of protection depends upon the titer level 

after the booster dose. The modeling estimated that about 75% of subjects will be protected for 

a minimum of 10 years. The average duration of protection is projected to be 14 years, with a 

range 2 to 25 years. The authors concluded that a second booster dose should be scheduled 

after 10 years for this vaccine [Paulke-Korinek et al, Persistence of Antibodies Six Years after 

Booster Vaccination with Inactivated Vaccine against Japanese Encephalitis. Vaccine 2015].

To summarize the data on boosting in adults, based on waning neutralizing antibody titers and a 

seroprotection rate range of 83% to 58% in the clinical trials, a booster of IXIARO® should be 

considered or recommended at 12 months after the primary series. Clinical data demonstrate

that a booster dose of IXIARO® will elicit a memory response at least until 23 months after the 

primary series. After an IXIARO® booster dose, clinical data demonstrate high levels of 

seroprotection for 6 years. Mathematical modelling suggests seroprotection may persist for at

least 10 years after the booster dose of IXIARO® in 75% of vaccinees. Safety data for a booster 

dose of IXIARO® were presented to ACIP for the booster recommendation vote in 2011. No 

safety concerns were identified, and the AE profile was in-line with the primary series. 

In conclusion of the discussion regarding an adult booster dose, Dr. Dubischar presented 

information about the regulatory status and outlook for an IXIARO®

 booster dose

recommendation in adults.

In Europe, the Summary of Product Characteristics gives clear guidance for HCP for the first 

booster dose:

“A booster dose (third dose) should be given within the second year (i.e., 12 - 24 months) after 

primary immunization, prior to potential re-exposure to JEV. Persons at continuous risk for 

acquiring Japanese encephalitis (laboratory personnel or persons residing in endemic areas) 

should receive a booster dose at month 12 after primary immunization.”

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A recommendation for a second booster dose after 10 years is currently under review by the 

EMA.

In the US, both the Prescribing Information and the ACIP recommendations use less 

prescriptive language than Europe for first booster dose:

“Individuals 17 years of age and older: If the primary series of two doses was completed 

more than 1 year previously, a booster dose may be given if ongoing exposure or reexposure to JEV is expected.”

FDA indicated that without actual safety and immunogenicity data instead of mathematical 

modeling, no recommendation for a second booster would be granted in the label. Therefore, 

Valneva has no current plans to submit additional antibody persistence data for IXIARO® to 

FDA. 

Duration of Protection and the Need for

A Booster Dose of IXIARO® in Children

Dr. Katrin Dubischar

Senior Scientist, Clinical Research

Valneva Austria GmbH

Dr. Dubischar next presented an overview of clinical data pertaining to duration of protection 

after a primary series and booster dose of IXIARO® in children. Two clinical trials in children 

provide data relevant to persistence of antibodies, and one clinical trial provides data on 

antibody persistence following a booster dose. This presentation provided a comprehensive 

summary of the following available clinical data on primary series and booster: 

Tria

l 

IC5

1-

322 

/ 

IC5

1-

324

wa

s a 

saf

ety and immunogenicity study of IXIARO® in a JE vaccine naïve, pediatric travelers population

comprised of children and adolescents 2 months or older through less than 18 years of age. 

This was an open-label, single-arm trial with an extension study and 100 children were

evaluated for safety and 64 children were evaluated for immunogenicity. There were 23 children 

enrolled in the extension study IC51-324. The treatment group was comprised of 12 children 

less than 3 years of age who were given a 0.25 mL dose of IXIARO®, and 88 children 3 years of 

age to 18 years of age who were given a 0.5 mL dose of IXIARO®. Follow-up was at Day 56 

and Month 7 in the parent study and at Months 12, 24, and 36 in the extension trial. There were 

15 study sites in Australia, Germany, USA, Denmark, and Sweden. The parent study primary 

Study Region

Duration of 

Follow-Up 

Initial Study*

Duration of 

Follow-Up 

Extension Study*

Follow-Up 

After Booster

IC51-322 / 

IC51-324

JE NonEndemic 7 months 36 months 

(subgroup)

None 

administered

IC51-323 / 

IC51-325 JE Endemic 7 months 36 months 

(subgroup)

24 months 

(subgroup), 

booster given at 

month 12

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enpoint was rate of SAEs and medically-attended AEs until Day 56. The secondary endpoint

was immunogenicity (SCR/ GMT) up to Month 36. 

Long-term data are limited in traveling children due to recruitment issues. In children aged 3 

years of age or less at primary immunization, the seroprotection rate decreased in the first 6 

months, then remained stable at approximately 90% for up to 3 years. One child less than 3 

years of age was enrolled in the extension study, and retained a protective titer. The GMTs 

declined in the first 7 months, and then remained fairly stable over time [Dubischar-Kastner et 

al., Abstract P 2.7, 5th Northern European Conference on Travel Medicine, June 5-8 2014 

Bergen, Norway; and Dubischar-Kastner et al., Abstract FC2.04, Presented at the 14th 

Conference of the International Society of Travel Medicine, May 25-28 2015, Quebec, Canada].

Trial IC51-325 was an antibody persistence / booster study in Philippine children to assess longterm persistence of immunity and the safety and immunogenicity of an IXIARO® booster dose in 

children from JE endemic regions. The study population was comprised of 300 children and 

adolescents 2 months through 17 years of age who were vaccinated in a preceding trial.. This 

was an open-label, randomized, Phase 3 study. Subjects were randomized 1:1 into a booster 

group (12 months after first vaccination) and non-booster group of 150 subjects each. Followup occurred at Month 13 after the first immunization (4 weeks after booster dose) and Month 24 

for safety and immunogenicity. There were 3 study sites in the Philippines. The primary 

endpoint was seroconversion rate at 1 month after the booster dose. The secondary endpoints

included GMTs at 1 month after the booster dose and SAEs and medically attended AEs 1 

month after the booster dose.

Of the children in this study, 149 were followed for a maximum of 3 years with a mean age of 

4.6 years at the time of primary vaccination. The seroprotection rate decreased in the first 6 

months, then remained stable at approximately 90% for up to 3 years based on combined data 

for all ages / doses. Though marginal, there was a constant increase in GMTs. Looking at the 

individual titers of the subjects, titer increases that were suggestive of natural boosting were 

observed in 24 of 150 children during follow-up. Children 1 to less than 3 years of age and 3 to 

less than 12 years of age showed a stronger decline in seroprotection rate down to 

approximately 80% at Month 7, although the numbers are limited in some of the age cohorts. A 

booster dose was received by 148 children 12 months after the primary series, with a mean age 

of 5.6 years at the time of the booster. The booster increased the seroprotection rate to 100%

and this level was sustained for 2 years. As in adults, GMTs increased about 40-fold after the

booster, and remained higher compared with GMTs 2 months after the primary series. 

In terms of safety, the booster dose in children was very well-tolerated. Most AEs were mild or 

moderate, and the AE rate with the booster was lower than with the primary series. The most 

common AEs were local reactions, fever, loss of appetite, and headache. All of these were 

reported in less than 10% of children. Two SAEs occurred within 4 weeks after booster, 

including an abscess of the right flank and dengue fever) [Dubischar-Kastner et al., Abstract P 

2.8, 5th Northern European Conference on Travel Medicine, June 5-8 2014 Bergen, Norway; 

Dubischar-Kastner et al., Abstract FC2.04, Presented at the 14th Conference of the 

International Society of Travel Medicine, May 25-28 2015, Quebec, Canada].

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In summary, in a small, mainly adolescent pediatric cohort from JEV non-endemic regions, 

antibody titers declined considerably up to Month 36 after vaccination with IXIARO®, but the 

seroprotection rate was still high at 89.5% in 17/19 subjects. In a larger pediatric cohort from a 

JEV-endemic country, antibody titers also declined considerably up to Month 36. 

Seroprotection rates remained greater than 80% in all age groups. Natural boosting through 

JEV virus exposure may have contributed to persistence of antibodies in this trial. Together, 

data suggest that booster dose administration may not be absolutely necessary in any pediatric 

age group for a minimum of 3 years after the primary series. However, titers in children 

declined substantially within the first year after the primary series, and the long-term 

seroprotection rate was enhanced by a booster dose, which was well-tolerated. Valneva 

considers administration of a booster dose in children 12 months after primary series justified for 

programmatic reasons in terms of uniformity of medical use for adults / children and optimization 

of long-term protection. 

In Europe, a first booster recommendation for IXIARO® in children is currently under regulatory 

review. There is indication that the adult booster recommendation will be extended for children: 

“A booster dose (third dose) should be given within the second year (i.e., 12 - 24 

months) after primary immunization, prior to potential re-exposure to JEV ...”

 

In the US, the FDA is currently reviewing the pediatric booster data on IXIARO®, which were 

submitted as part of the post-marketing commitment. Valneva plans to file a supplemental BLA 

with the FDA in 2016 with proposed edits to the prescribing information for a first booster dose 

of IXIARO® in children. The proposed wording for a pediatric booster dose of IXIARO could 

resemble the adult language in the prescribing information:

“If the primary series of two doses was completed more than 1 year previously, a 

booster dose may be given if ongoing exposure or re-exposure to JEV is expected.”

 

In Europe and the US, there will not be a recommendation for a second booster dose of 

IXIARO® in children.

JE Vaccine WG Summary and Plans

Dr. Susan Hills

Medical Epidemiologist

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Dr. Hills presented on behalf of the JE Vaccine WG a summary of the new safety, 

immunogenicity, and other data presented during this session. She also discussed plans and 

the timeline for presentation and discussion of additional data and topics.

As a reminder, when the JE Vaccine WG was reformed in March 2015, its objectives were to: 

1) review newly available safety and immunogenicity data for JE-VC; 2) review updated data on 

the epidemiology and risk of JE in travelers; 3) review ACIP recommendations for use of JE 

vaccine in consideration of updated safety, immunogenicity, and traveler risk data; and 4) 

prepare a revised MMWR Recommendations and Reports to update the document that was 

published in 2010. 

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As a reminder, ACIP approved the JE-VC booster dose recommendation in 2011 which states:

“If the primary series of JE-VC was administered >1 year previously, a booster dose may 

be given before potential JE virus exposure.”

 

Data supporting the booster dose recommendation came from three clinical trials that provided 

data on persistence of protective neutralizing antibodies after a primary 2-dose JE-VC series. 

At 12 through 15 months after the 2-dose primary series, 58% to 83% of subjects were 

seroprotected based on these 3 studies. At 24 months after the 2-dose primary series, 48% to 

82% of subjects were seroprotected in the 2 studies with data. Thus, the results of the 

percentage of subjects with protective JE titers were quite variable. In the study that had an 

82% seroprotection rate at 24 months, subjects were followed up for 60 months. At 5 years, 

82% (124/152) of subjects were seroprotected. The neutralizing antibody GMT was 43. In 

addition, a post-hoc analysis was done for this study that stratified subjects by TBE vaccination 

status. Seroprotection rates and GMTs were higher if TBE vaccine was administered after 

commencement of JE-VC vaccination. The seroprotection rate at 24 through 60 months was 

90% to 100% in the TBE vaccine group and 64% to 72% in the vaccine group who did not 

receive TBE vaccine. GMTs in the TBE vaccine group were significantly higher than GMTs in 

the non-TBE vaccine group at 24, 36, and 48 months. 

The WG reviewed and assessed these data. The WG’s assessment and summary of the 

duration of protection following a JE-VC primary series in adults are that after a 2-dose primary 

series, long-term seroprotection rates and GMTs are lower in those not administered TBE 

vaccine compared with those administered TBE vaccine. TBE vaccine is not available in the US 

and other flavivirus vaccines, such as YF vaccine, are not routinely administered with JE-VC. 

Therefore, JE seroprotection rates and GMTs for US travelers are likely to be most similar to the 

lower rates and GMTs in the study group not administered TBE vaccine. Following the WG’s 

review, two options were considered. The first was to make no change to the current booster 

dose recommendations. The second was to strengthen the existing permissive ACIP 

recommendation from 2011. The WG concluded that the data were sufficient to consider a 

strengthened booster dose recommendation. The suggested recommendation would be as 

follows:

“If the primary series of JE-VC was administered >1 year previously, a booster dose should 

be given before potential JE virus exposure.”

The WG would be interested in feedback on this suggested change. Depending upon feedback, 

the WG would consider putting the recommendation up for a vote during the next ACIP meeting.

The second topic presented by Dr. Dubischar regarded new data on duration of protection 

following a booster dose in adults. In summary, in observational study, at approximately 6 years 

after booster dose, 96% (64/67) of subjects were seroprotected and the neutralizing antibody 

GMT was 148. This study was conducted in areas where TBE vaccine is not routinely 

administered. In one modeling study, and estimated 75% of subjects would be seroprotected at 

10 years or later.

The WG reviewed and discussed these data and its assessment was that after a 2-dose primary 

series and a booster dose, seroprotection rates were high for at least 6 years. In addition, FDA

has indicated that there will be no recommendation for a second booster dose as there are no 

immunogenicity and safety data to support such a recommendation. Following the WG’s 

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review, two options were considered. The first was to make an off-label recommendation for a 

second booster dose. The second was no off-label recommendation, but incorporation of the 

data into an updated MMWR Recommendations and Report document to make information 

available for vaccine providers. The WG concluded that the data were not sufficient to support 

an off-label recommendation for a second booster dose. The plan is to incorporate the data into

an updated MMWR Recommendations and Reports document.

The final topic presented by Dr. Dubischar pertained to duration of protection following a 2-dose 

primary series in children. One study was conducted among pediatric travelers from nonendemic countries. The long-term study cohort included only 23 children, including 1 child in

the 2 month to 2 year age group who received two 0.25mL doses of vaccine, 3 children in the 3 

to 11 year age group who were administered two 0.5mL doses of vaccine, and 19 children in 12

to 17 year age group who received two 0.5mL doses of vaccine. At 36 months, 89% (17/19) 

children were seroprotected and the GMTs were 58. Although seroprotection rates and GMTs

decreased between 1 and 6 months following the primary series, seroprotection rates and 

GMTs were then maintained at similar levels from Months 6 through Month 36. In the long-term 

duration of protection studies, seroprotection rates at 36 months were higher in the pediatric 

study compared with the adult study. At 36 months, 89% (17/19) were children seroprotected

compared with 72% (41/57) of adults in the non-TBE vaccine group in the adult study.

Data on duration of protection in children were also available from one study conducted among 

children in the Philippines, which is a JE-endemic country. At 36 months after a 2-dose primary 

series, 90% (128/142) of children were seroprotected and the GMT was 59. While 

seroprotection rates were variable by age group, in all age groups at least 81% of children were 

seroprotected. At 24 months after a booster dose, 100% (143/143) of children were 

seroprotected and the GMT was 350. 

The WG discussed these data from the pediatric studies. The WG’s assessment and summary 

of the need for a booster dose in children was as follows. There are limited safety and 

immunogenicity data on the need for a booster dose in children. The available data suggest 

high seroprotection rates at 3 years following a 2-dose primary series. The data have been 

submitted to FDA and are under review. Following the WG’s review, two options were 

considered. The first was an off-label recommendation for a booster dose while awaiting FDA 

review of data. The second was no off-label recommendation, but incorporation of the data into

an updated MMWR Recommendations and Reports document while awaiting FDA review of 

data. The WG concluded that no off-label recommendation would be requested. The plan is to 

incorporate the data into an updated MMWR Recommendations and Reports document to make

the information available for providers, and to await FDA review of the data.

To complete the ACIP JE Vaccine WG objectives, the following topics will be addressed during 

future ACIP meetings: 









A presentation of updated post-licensure safety data

A review of the epidemiology and risk of JE in travelers

A review of the ACIP recommendations for use of JE vaccine in consideration of the 

updated safety, immunogenicity, and traveler data presented to ACIP during this and 

previous ACIP meetings

A presentation of a draft of the updated MMWR Recommendations and Reports document

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In conclusion, Dr. Hills noted that a new WG member and Chair will be identified to replace Dr. 

Lorry Rubin. She thanked Dr. Rubin for his substantial input to the ACIP JE and YF Vaccines 

WG.

Introduction

Ruth Karron, MD

Chair, Influenza Work Group

Dr. Karron reported that since the October 2015 ACIP meeting, the Influenza WG has 

considered recent data pertaining to duration of protection following vaccination, and discussion 

of recommendations regarding timing of vaccination; data pertaining to egg allergy and 

influenza vaccination, particularly use of live attenuated influenza vaccine (LAIV) for egg-allergic 

persons; and clinical data for quadrivalent recombinant influenza vaccine (RIV4). She indicated 

that the topics for this session would focus on an influenza surveillance update, RIV4, influenza 

vaccination and egg allergy, and proposed recommendations for 2016-2017.

Influenza Surveillance Update

Lynnette Brammer, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Ms. Brammer presented an influenza surveillance update and interim estimates of 2015–2016 

seasonal influenza VE against medically-attended influenza from the US Flu VE Network. In 

terms of the number and percent of specimens testing positive for influenza at approximately 

250 clinical laboratories across the country that report to CDC each week, the most recent week 

was Week 6 that ended on February 13, 2016. At that time, 12% of specimens tested were 

positive for influenza. The previous week, it was about 2.5%. To put that into perspective, 

activity is still very low. At the peak of influenza activity last year, 27% of clinical laboratory 

specimens tested positive for influenza. To date for this season, 75% of the influenza tests at 

public health laboratories were influenza A viruses and 25% were influenza B viruses. Among 

the influenza A viruses tested, 71.5% were A (H1N1)pdm09 viruses. The remainder of the As 

were A (H3N2) viruses. Among the influenza B viruses, 75% of those tested for lineage were in 

the B/Yamagata-lineage and the remaining 25% were in the B/Victoria-lineage.

The public health laboratories sent a subset of the viruses they tested to CDC for further 

characterization. Among those viruses, all 181 influenza A (H1N1)pdm09 viruses were 

antigenically characterized as A/California/7/2009-like contained in the current vaccine. All 228 

H3N2 viruses genetically sequenced belonged to genetic groups for which a majority of the 

viruses antigenically characterized were similar to the cell-propagated A/Switzerland/ 

9715293/2013 contained in the current vaccine. A subset of 107 H3N2 viruses were also 

antigenically characterized, and 100 (93.5%) were A/Switzerland/9715293/2013-like by HI 

testing or neutralization testing. All 88 B/Yamagata-lineage viruses antigenically characterized 

were B/Phuket/3073/2013-like, which is included as an influenza B component of the 2015-2016 

Northern Hemisphere trivalent and quadrivalent influenza vaccines. All 35 B/Victoria-lineage 

Influenza

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viruses antigenically characterized were B/Brisbane/60/2008-like, which is included as an 

influenza B component of the 2015-2016 Northern Hemisphere quadrivalent influenza vaccines.

CDC receives reports of outpatient illness from approximately 2000 primary care sites across 

the country. During Week 6, 3.1% of those visits were for influenza-like illness (ILI). This year 

has been later with less activity than the previous two seasons, but not as mild as the 2011-

2012 influenza season. Hospitalization data reported through FluServ-NET reflect a similar 

picture. The current rate of hospitalizations is 4.1/100,000, which is much lower than observed 

during the previous three seasons and just slightly higher than the 2011-2012 influenza season. 

As would be expected given the low rate of hospitalizations and illness, influenza-associated 

pneumonia and influenza mortality reported to the National Center for Health Statistics (NCHS) 

has also been relatively low. The percentage of deaths that had pneumonia or influenza listed 

anywhere on the death certificate that occurred as of the week ending January 30th was 6.5%, 

which is well below the epidemic threshold of 7.6%. Influenza-associated deaths in children 

less than 18 years of age is a nationally notifiable condition. Thus far this year, 13 influenzaassociated pediatric deaths have been reported to CDC.

The following map shows the geographic distribution of influenza within states and territories, 

which is reported to CDC by state and territorial epidemiologists or their designees:

The map shows that influenza activity across the US has not been simultaneous this year. 

There has been more widespread activity in the Southwest and Northeast, and less activity in 

the center of the country thus far. However, that is expected to progress in the coming weeks. 

Regarding next season, the WHO Consultation on the Composition on Influenza Virus Vaccines 

for the Northern Hemisphere 2016-2017 is being held February 22-24, 2016. Announcement of 

their decision will be made on February 25, 2016. FDA’s VRBPAC will meet on March 4, 2016 

to make recommendations on the selection of vaccine virus strains for the US vaccines.

In summary, influenza activity to date is low compared to the previous three seasons. The rate 

of influenza associated hospitalizations is low, and pneumonia and influenza mortality have not 

exceeded threshold levels. Influenza A (H1N1) viruses have predominated, but A (H3N2) and B 

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viruses of both lineages have co-circulated. The majority of circulating viruses are similar to the 

vaccine strains. 

Interim estimates of influenza vaccine effectiveness for this season were presented to ACIP, but 

have not been published. These interim estimates included patients enrolled from November 2,

2015 through February 12, 2016. The methods are similar to previous years and have been 

described previously. Methods used to produce these interim estimates were the same as 

those used for interim estimates in previous seasons. Briefly, outpatients 6 months of age and 

older with acute respiratory illness and cough of 7 or fewer days duration were enrolled at five 

US Flu VE Network sites from November 2, 2015 through February 12, 2016. A test-negative 

design was used to estimate vaccine effectiveness by comparing vaccination odds among 

influenza RT-PCR positive cases and RT-PCR negative controls. Vaccination status was 

defined as “receipt of at least one dose of any 2015-16 seasonal influenza vaccine according to 

medical records, immunization registries, and/or self-report.” Vaccine effectiveness is estimated 

as one minus the adjusted odds ratio times 100. Variables included in the models for 

adjustment are study site, age, self-rated general health status, race/Hispanic ethnicity, interval 

(days) from onset to enrollment, and calendar time.

From November 2, 2015 through February 12, 2016, a total of 3,333 outpatients were enrolled 

at the five network sites. Of those, 92% (3,081) were RT-PCR negative for influenza and 8% 

(252) of enrolled patients were influenza-positive. The contribution of each of the viruses 

detected in this study is shown in this pie chart:

Both influenza A and B viruses circulated, with a majority of influenza A viruses being 

H1N1pdm09 and a majority of B viruses belonging to the Yamagata lineage.

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The following epi curve shows the number of enrolled participants with RT-PCR-confirmed 

influenza A or B by epidemiologic week of enrollment and the percent positivity for any influenza 

type by week. Note that laboratory testing is incomplete for patients enrolled during the most 

recent week, but the percent positivity continues to increase. Very few positive cases were 

enrolled before the first week of January, with a low percentage of those enrolled testing 

positive for influenza A or B during most weeks:

Interim adjusted estimates of VE against medically-attended influenza for all patients aged 6 

months and older was 59% with a 95% confidence interval from 44% to 70%. Interim adjusted 

VE against H1N1pdm09 for all ages combined was 51%, with a 95% confidence interval from 

25% to 69%. Adjusted estimates of VE against influenza B for all ages combined was 76%,

with a confidence interval from 59% to 86% and was similar against B/Yamagata lineage 

viruses with an adjusted VE of 79%. 

In summary, interim results from the US Flu VE Network for the 2015-2016 season through 

February 12, 2016 indicate that VE was 59% against medically-attended influenza. The interim 

estimate for this season is similar to previous seasons when vaccine was well-matched to 

circulating influenza viruses. Significant protection against circulating influenza H1N1pdm09 

and B viruses was observed for all ages combined, while VE was not estimated against H3N2 

viruses due to the small number of cases. The enrollment in VE studies for this year continues. 

Interim estimates may be less precise due to low numbers of flu cases enrolled, and the end-ofseason VE estimates may differ from interim estimates. 

Discussion Points

Dr. Reingold asked whether there was any suggestion so far regarding whether the LAIV 

vaccine is performing any better this season.

Ms. Brammer replied that there are not enough data at this point to know.

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Quadrivalent Recombinant Influenza Vaccine

Wayne Hachey DO, MPH

Protein Sciences

Dr. Hachey reported on a recent study that demonstrated the improved efficacy of a 

recombinant influenza vaccine versus an inactivated vaccine during the influenza season 

marked by a vaccine mismatch. The study was designed to demonstrate the clinical efficacy 

and safety of Flublok®

 Quadrivalent (RIV4) versus an inactivated quadrivalent vaccine (IIV4 

Fluarix® Quadrivalent). 

Flublok® is the first licensed recombinant hemagglutinin protein influenza vaccine. Because it 

does not require passage in eggs and therefore does not require an egg-adapted strain, the HA

for recombinant influenza vaccines matches the wild type of the FDA-specified strain. The 

2014-2015 influenza season was particularly unpleasant for adults 65 years of age and older. 

This was primarily due to widespread circulation of an H3N2 strain that was not antigenically 

matched to the vaccine, with over 80% of the identified H3N2 strains representing this 

mismatch. This mismatch lead to low vaccine effectiveness estimated at less than 20% overall, 

as well as high rates of laboratory-confirmed hospitalizations for pneumonia and influenza.

During this good season, Protein Sciences conducted a double-blind RCT that compared 

Flublok® Quadrivalent (RIV4) versus a licensed quadrivalent inactivated vaccine (Fluarix® 

Quadrivalent).

Flublok® quadrivalent attack rates were significantly lower than the IIV comparator at 2.2% 

versus 3.3%. These lower attack rates persisted throughout the season. Although viral cultures 

did not yield sufficient titers to test for antigenic similarity, the improved efficacy in the face of a 

mismatch is inferred from the fact that more than 80% of the circulating H3N2 viruses in that 

season were antigenically mismatched to the vaccines. In regard to safety, AEs were similar for 

both vaccines, with the exception of a lower incidence of local reactions, specifically pain and 

tenderness at the injection site in the Flublok® Quadrivalent group. 

The study hypothesis was that the relative vaccine efficacy for Flublok® Quadrivalent would be 

non-inferior to that of IIV4 in adults 50 years of age and older. Non-inferiority was specified by 

the lower bound of the 95% confidence interval for relative VE to be greater than -20%. 

Superiority determined in pre-specified exploratory analysis was determined by the threshold of 

the lower bound of the 95% confidence interval for relative VE at greater than 9%. Sample size 

was powered for the primary endpoint as well as pre-specified secondary analysis of subgroups. 

Between October 22 and December 23, 2014 9003 subjects were vaccinated. They were 

subsequently followed through May 22, 2015. ILI symptomatic subjects had nasopharyngeal 

(NP) swabs for both PCR and culture. The protocol-defined ILI required at least one respiratory 

symptom and at least one systemic symptom (temperature >99, chills, fatigue, headache or 

myalgia) occurring at least 14 days after vaccination. The protocol definition was identical to

that used for the High Dose IIV3 study in adults 65 years of age and older. HAI serology was 

tested in 613 subjects, reactogenicity was monitored for 7 days post-vaccination, and safety 

monitoring continued for 6 months post-vaccination. 

The antigenic composition of Flublok® Quadrivalent was 45 mcg per antigen of H1N1: 

A/California/07/2009, H3N2: A/Texas/50/2012, B/Massachusetts/2/2012 (B/Yamagata-lineage), 

and B/Brisbane/60/2008 (B/Victoria-lineage). The antigenic composition of IIV4 was 15 mcg 

per antigen of H1N1: A/ Christchurch/16/2010 (an A/California/7/2009-like virus), H3N2: 

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A/Texas/50/2012, B/Massachusetts/2/2012, and B/Brisbane/60/2008. Both vaccines contained

the HAs representing the strains selected by the WHO and VRBPAC for the 2014-2015 season. 

However, the Flublok® Quadrivalent contained a strain that was matched to the reference strain 

wild type.

This map depicts the geographic distribution of enrollment and shows the wide distribution 

across the US:

A total of 9003 participants were enrolled. After exclusions, the RIV4 group was comprised of 

4303 (96.2%) in the efficacy population, 314 (7%) in the immunogenicity population, 4328 

(96.7%) in the safety population, and 4228 (94.5%) completing the study. The IIV4 group began 

with 4489. Of those, 4301 (95.8%) were in the efficacy population, 300 (6.7%) were in the 

immunogenicity population, 4344 (96.8%) were in the safety population, and 4236 (94.4%) 

completed the study. Withdrawals were relatively rare and were evenly distributed between the 

two study populations.

In terms of demographics, the study included adults 50 years of age or older. Subjects were 

stratified to age categories of 50 through 64, 65 through 74, and 75 and older prior to being 

randomly assigned in a 1:1 ratio to receive a single dose of either vaccine. Distribution was 

even in terms of gender race and ethnicity.

Post-vaccination HAI antibody GMTs at Day 0 and Day 8 for A/H1 and B/ Massachusetts and 

B/Bisbane were comparable between the two vaccine groups, with the B/Brisbane titers being 

quite low for both vaccine groups. HAI antibody GMTs were significantly higher for the H3 

component after vaccination with Flublok® RIV4 than with IIV4.

For efficacy against rtPCR-confirmed protocol-defined ILI, 234 participants met the primary 

endpoint representing 96 or 2.2% of the RIV4 subjects and 138 or 3.2% of the IIV4 recipients. 

Specifically, those positive for H3N2 were a total of 187 with 73 in the RIV4 group and 114 in 

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IIV4. B strains represented rather small number of individuals at 23 and 24 subjects, 

respectively. Of the 102 individuals with culture-confirmed ILI, 38 were in the RIV4 group and 

64 were in the IIV4.

The efficacy of RIV4 relative to the traditional IIV4 for the primary endpoint was 31% with a 

lower bound of the two-sided 95% confidence interval for relative vaccine efficacy of 10%, which 

satisfied the non-inferiority and superiority criteria. As the predominant circulating strain was 

H3N2, a post-hoc analysis of VE against influenza A and B was conducted. Relative VE of 

RIV4 versus IIV4 was 37% for type A and 17% for type B. Efficacy against cell cultureconfirmed influenza was important to evaluate since this was a more rigorous assessment of the

true cause of ILI. Relative VE of RIV4 versus IIV4 was more pronounced at 43%. Of note is the 

wide confidence intervals for the B stains due to the relatively small number of individuals. 

This Kaplan-Meier curve presents the cumulative incidence of RT-PRC confirmed influenza over 

the season and displays the relative efficacy of the two study vaccines for influenza types A and 

B, with the protective effect of RIV4 in comparison to IIV4 apparent throughout the influenza 

season:

In a review of the primary and secondary endpoint analyses for PCR-confirmed protocol-defined 

ILI for all types of influenza, relative VE was about 31%. For those 50 through 64 years of age, 

VE was 41%. For those 65 years of age and older, VE was 0.17. However, the more rigorous 

culture-confirmed protocol-defined ILI for those over 65 was 0.43 and remained significant. Of 

note is the enhanced protective effect in individuals who have not received a prior influenza

vaccine, although this cannot be explained thus far.

Moving to safety, individuals were followed for 6 months post-immunization. Medically-attended 

ILI included 19 individuals, 6 in the RIV4 group and 13 in the IIV4 group. Hospitalizations were 

rare with a total of 4, 1 in the RIV4 group and 3 in the IIV4 group. No SAEs or AEs were 

vaccine-related for either vaccine group. The most common AEs were comparable in each 

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vaccine group and included cough, ILI, oropharyngeal pain, headache, upper respiratory tract 

infection, fatigue, myalgia, and productive cough. 

In terms of reactogenicity, the study participants were particularly compliant with reporting 

whether they experienced specifically solicited reactions to the vaccine. Memory aids that 

included both local and systemic reactions were returned by more than 96% of subjects in both 

treatment groups. The only difference between the two vaccine groups were with respect to 

local injection site pain and tenderness that were reported significantly more frequently by the 

IIV4 recipients, and injection site erythema was more commonly reported by RIV4 recipients.

In conclusion, Flublok® Quadrivalent met criterion for non-inferior efficacy against PCRconfirmed ILI, as well as the pre-specified criterion for superior efficacy over IIV4. Superiority 

possibly was driven by the efficacy against largely antigenically drifted influenza A. This is 

inferred because more than 80% of the circulating H3N2 viruses in 2014-2015 were 

antigenically mismatched to the vaccines. Efficacy against influenza B was similar to IIV4, 

which was observed with the trivalent vaccine. HAI antibody responses after Flublok® were 

especially high for A/H3, which is also consistent with previous trivalent vaccine data. Both 

vaccines had similar safety profiles. Injection site pain and tenderness were significantly less 

with Flublok® Quadrivalent group. There were no vaccine-related SAEs or medically-attended 

AEs. 

Discussion Points

Dr. Moore noted that in the study, vaccination occurred during the influenza season and the 

relatively early arriving influenza season. She wondered if Dr. Hachey could address how the 

study design prevented any confounding due to prior influenza infection among those who were 

enrolled, or particularly geographic differences in influenza disease activity during the period of 

vaccination with IIV4 or RIV4.

Dr. Hachey explained that the individuals were medically screened before entering the study, so 

anyone with any febrile or any illness at that time was excluded from enrollment. If 

asymptomatic at the time of enrollment, it is possible that someone could have had influenza 

already prior to enrolling in the study.

Dr. Belongia noted that there is not a clear understanding of the relative importance of egginduced mutations and how that might impact clinical effectiveness. There was a unique 

opportunity in a season with a mismatch and a vaccine not based on an egg-adapted virus. 

There was some suggestion that even in a mismatch, virus circulating relative to the vaccine 

strain that egg-induced mutations perhaps might make an additional contribution. He thought 

they had a gold mine of data in terms of evaluating the viruses from the H3N2 cases in the RIV4 

and IIV4 groups. He thought it would be interesting to sequence those viruses to assess the HA 

and specifically evaluate the people who received RIV4 versus IIV 4 to see if there are different 

clades, and also to look at the people who received the prior vaccine and those who did not to 

look for any differences that could help to better understand what is occurring.

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Dr. Ornstein (NVAC) said striking to him was the improved immunogenicity against the H3N2 

component with RIV4 versus IIV4. He wondered whether they had been able to study any of 

the drifted strains and done any serology to determine whether there are differences in 

immunogenicity against the actual drifted strains that occurred during that season.

Dr. Hachey responded that while they did not characterize the viruses, they do know that at 

least 80% of them were drifted. In previous studies with trivalent vaccine, also during 

mismatched years, particularly with H3 strains, vaccines tended to do much better. This was

approximately 5 years ago.

Dr. Orenstein (NVAC) said he thought it would be helpful to run HAI titers on those drifted 

strains to determine whether there were large differences there as well.

Dr. Bresee (SME) asked whether a similar study was planned for next year and in future years 

to have more than a single year of data. He agreed that characterizing these strains 

antigenically would be important to better understanding the data.

Dr. Hachey replied that they would be willing to conduct more studies if they were funded to do 

so. This study was part of the requirement imposed by FDA as part of the licensure process for 

individuals 50 years of age and above. It just happened to occur during a mismatch year.

Dr. Gemmill (NACI) asked whether it might be possible to expect or hope for a vaccine that 

offers broader coverage generally for more strains, or if they were just looking at a vaccine that 

helped to avoid eggs and offers more antigen in each dose. He thought the ideal vaccine would 

be one that lasts a long time and has coverage of all of the strains that might be circulating.

Dr. Hachey responded that everybody hopes for a universal vaccine. Unfortunately, that has 

eluded everyone thus far. One nice thing with recombinant technology is that a vaccine can be 

developed quickly in a matter of weeks that would represent a drifted strain. At this point, they 

are limited to about 6 million doses of vaccine. That is clearly not enough for the US population. 

For example, that particular year, they could have easily produced vaccine for the drifted strain. 

However, it would have been in limited amounts.

Dr. Decker (Sanofi Pasteur) referred to a slide showing HAI immune response Days 0 and 28 

GMTs. He did not understand why for three of the four strains included in the vaccine, the 

Flublok® antibody response was actually lower than the IIV response—not significantly, but 

numerically lower. It was materially higher for H3N2, but not for any of the other strains. He 

wondered if Dr. Hachey had any idea why that might be.

Dr. Hachey responded that historically, Flublok® has been statistically comparable, but not any 

better, than the inactivated vaccine for B strains. In prior studies, the serologies for the H1 

strains were better than the reference strains. However, it is important to keep in mind that with 

this particular season, essentially all of the A strains were H3N2. There were 6 non-typeable A 

strains. Other than that, the H1N1 was grossly under-represented. It may be a question of the 

number of samples.

Dr. Decker (Sanofi Pasteur) noted that Flublok® was superior to IIV4 for those 50 through 64 

years of age, but not for those 65 years of age and older. He wondered whether Dr. Hachey 

had any thoughts on that.

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Dr. Hachey responded that this was true for PCR-defined. The culture-confirmed is a much 

more stringent test and showed a relative efficacy of 43%. In an assessment of a subgroup of 

subjects 75 years of age or older, efficacy continues even with the PCR-confirmed.

Dr. Decker (Sanofi Pasteur) noted that for all four strains, Flublok® includes 45 mcg of protein 

and Dr. Hachey referred to that as a high-dose vaccine.

Dr. Hachey clarified that he called it a “higher than the standard dose vaccine.”

Dr. Decker (Sanofi Pasteur) said he was not sure how dose was measured, but looking at 

immunogenicity, standard IIV egg-based has 15 mcg. He wondered why it takes three times as 

much of the synthetic protein to get more or less the same response as with the egg-based 

protein.

Dr. Hachey responded that the RIV4 does get a better response than the egg-based. In the 

initial clinical trials with the trivalent vaccine, there were statistically superior responses to the 

H1 and H3 strains. Particularly in the 65 years of age and older group, when Fluzone® standard 

dose is compared with Flublok®, the improvement in serology, particularly in the elderly 

population, is almost identical to the high-dose Fluzone® vaccine. The two results are 

essentially the same.

Dr. Decker (Sanofi Pasteur) said that he did not have those results in front of him and was 

looking at the results just presented.

Influenza Vaccination and Egg Allergy 

John M. Kelso, MD

Division of Allergy, Asthma and Immunology

Scripps Clinic, San Diego and

Clinical Professor of Pediatrics and Internal Medicine 

University of California San Diego School of Medicine

Dr. Kelso presented information on the use of influenza vaccines in egg-allergic recipients, 

emphasizing that he has a particular interest in adverse reactions to vaccines. During this 

session, he discussed the risk of withholding influenza vaccine and the safety of IIV in eggallergic recipients, current guidelines regarding IIV and LAIV in egg-allergic recipients, new 

studies on administration of LAIV to egg-allergic recipients, and his personal recommendations.

Regarding the risk of withholding vaccine, an average of 294,128 persons are hospitalized each 

year in the US because of influenza, including an average of 21,156 hospitalizations in children 

less than 5 years of age. An average of 23,607 deaths occur each year in the US as a result of 

influenza, including an average of 124 children. Egg allergy is believed to affect 1.3 % of 

children and 0.2 % of adults1

. There are 73.7 million children in the US 2, meaning that there 

are approximately 1 million egg-allergic children [1

The Center for Food Safety and Applied 

Nutrition Food and Drug Administration US Department of Health and Human Services; 

2

www.childstats.gov/americaschildren].

Most influenza vaccines are still grown in eggs, literally, and contain measurable quantities of 

egg protein, typically measured as ovalbumin—the particularly allergenic egg protein that is in 

the vaccine. There is clearly a theoretical risk of giving something that contains egg protein to 

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someone who is allergic to egg protein. In terms of whether giving influenza vaccine causes 

systemic reactions when injected into egg-allergic patients, 27 studies have now been published 

on this that have collectively involved over 4100 egg-allergic subjects receiving influenza 

vaccine without any serious reactions, including respiratory distress or hypotension. There has 

been a very low rate of minor reactions (hives, mild wheezing), but this was exactly the same as 

in non-egg-allergic recipients [Des Roches A, et al. Egg-allergic patients can be safely 

vaccinated against influenza. J Allergy Clin Immunol 2012;130:1213-1216].

Thus, the occasional child who receives an influenza vaccine may have a couple of hives or 

may wheeze a little, but whether they are egg-allergic does not determine the rate of those 

reactions.

Regarding the subset of children who have particularly severe egg allergy, most studies have 

specifically included patients with histories of severe anaphylaxis (n = 513) with egg ingestion, 

and these patients also tolerate the vaccine. So, it appears that even severely egg-allergic 

patients can safely receive IIV. 

In terms of why no serious reactions are being reported, manufacturers of injectable IIV report 

that the maximum amount of ovalbumin is less than 1 μg per 0.5 mL dose. The measured 

amounts in independent laboratories are usually much lower than the claimed amounts. Thus, 

the vaccine does not appear to contain enough ovalbumin to cause a reaction.

In terms of the current state of US allergy guidelines, allergy guidelines are typically published 

by the Joint Task Force on Practice Parameters. The current US guidelines state the following 

[Annals of Allergy, Asthma & Immunology 2013; 111:301-2]:

“All patients with egg allergy of any severity, including anaphylaxis, should receive IIV 

annually, using any age-approved brand of IIV in an age-appropriate dose.”

“Special precautions regarding medical setting and waiting periods after administration 

of IIV to egg-allergic recipients beyond those recommended for any vaccine are not 

warranted.”

“Language that describes egg-allergic recipients as being at increased risk compared 

with non-egg-allergic recipients or requiring special precautions should be removed from 

guidelines and product labeling."

Dr. Kelso shared a draft document, the International Consensus (ICON) on Allergic Reactions to 

Vaccines, for which he had been given permission to share excerpts from current international 

allergy guidelines on allergic reactions to vaccines that includes the following allergy 

organizations: World Allergy Organization (WAO); European Academy of Allergy and Clinical 

Immunology (EAACI); American Academy of Allergy, Asthma, and Immunology (AAAAI); and 

American College of Allergy, Asthma, and Immunology (ACAAI). This document will state the 

following: 

“Egg allergy does not impart increased risk of anaphylactic reaction to immunization with 

either inactivated or live attenuated influenza vaccines”

“Although cases of immediate hypersensitivity reactions such as urticaria may occur, 

they are no more common in egg-allergic than non-egg-allergic vaccine recipients.” 

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In terms of vaccine guidelines, the current National Advisory Committee on Immunization 

(NACI) guideline states the following:

“Regarding administration of influenza vaccine to egg allergic persons, after careful 

review, NACI has concluded that egg allergic individuals may be vaccinated against 

influenza using TIV without prior influenza vaccine skin test and with the full dose, 

irrespective of a past severe reaction to egg and without any particular consideration, 

including immunization setting.”

These guidelines have been in place in Canada since 2014, and they have not observed any 

uptick in adverse reactions or safety signals in monitoring since putting these recommendations 

in place where they removed any precautions regarding administration of influenza vaccine to 

egg-allergic patients.

The current ACIP guidelines include this algorithm:

This algorithm basically says that if someone can eat eggs and nothing happens, they are not 

allergic and can get an influenza vaccine. If someone eats eggs and just gets hives, they can 

get an influenza vaccine, but it has to be administered in a physician’s office and they have to 

be monitored for 30 minutes following vaccine. Alternatively, such patients can receive the 

recombinant vaccine that does not contain egg protein. The algorithm goes on to say that those 

who have had a more severe reaction to the ingestion of eggs, should go to an allergist’s office 

to receive the vaccine and be monitored for 30 minutes.

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The ACIP guidelines go on to pay particular attention to LAIV to state that, “ACIP will continue to 

review safety data for use of LAIV in the setting of egg allergy.” There are several studies 

pertaining to this issue. The first of these included 68 children 2 through 16 years of age with 

egg allergy defined as a history of having not only an allergic reaction to the ingestion of eggs, 

but also the presence of IgE allergic antibody to eggs. Importantly, 40% of children were 

laboratory and clinically allergic to egg and had a history of anaphylactic reaction to egg. In 

addition, 55 children without egg allergy were included in this study. Participants were 

administered LAIV FluMist® in the usual manner, which contains less than 0.24 μg of ovalbumin 

per dose, and were observed for 1 hour. No patients developed an allergic sign or symptom 

during the hour of observation. These authors concluded that, “LAIV is a safe alternative to TIV 

in children with known egg allergy. It was not surprising that there were no immediate IgEmediated reactions after vaccination of the children with egg allergy because the quantity of 

ovalbumin in LAIV is comparable with that of TIV, which has previously been shown to be safe 

in patients with egg allergy” [Safe vaccination of patients with egg allergy by using live 

attenuated influenza vaccine; Des Roches A, Samaan K, Graham F, Lacombe-Barrios J, 

Paradis J, Paradis L, et al. J Allergy Clin Immunol Pract 2015; 3:138-9].

The next study included a larger number of chilren—this time 282 children 2 through 17 years of 

age with egg allergy. The reason that most of these studies include children is because egg 

allergy is much more common in children. Egg allergy in this study is defined either as: 1) 

positive food challenge result to egg within the last 12 months under medical supervision; 2) 

previous convincing clinical reaction within 12 months and current sensitization (skin test or 

specific IgE); or 3) current sensitization with a greater than 95% likelihood of clinical reaction 

even if they had never eaten egg. Of the participants, 115/282 (41%) had prior anaphylaxis. 

Participants were administered LAIV FluMist® containing less than 0.24 μg of ovalbumin per 

dose in the usual manner, and were observed for 1 hour. In this case, 151/282 received a 

second dose 4 weeks later for a total of 433 doses given. No anaphylaxis occurred. Possible 

allergic reactions occurred in 8/282 (2.8%) within one hour of vaccine receipt. These included 6 

rhinitis, 1 localized urticaria, and 1 gastrointestinal discomfort. All of these reactions were mild 

and self-limiting. The authors concluded that, “These data have demonstrated a safety profile in 

terms of systemic allergic reactions to LAIV in children with egg allergy, including those with a 

prior history of anaphylaxis, similar to that previously reported for children without egg allergy” 

[Safety of live attenuated influenza vaccine in atopic children with egg allergy; Turner PJ, 

Southern J, Andrews NJ, Miller E, Erlewyn-Lajeunesse M, Doyle C, et al; J Allergy Clin 

Immunol; 2015; 136:376-81].

Finally, the largest of these studies included 779 children 2 through 18 years of age with a 

current doctor diagnosis of egg allergy. Of these children, 270 (34.7%) had a history of 

anaphylaxis to egg. Participants were administered LAIV in the usual manner and were 

observed for 30 minutes. No systemic allergic reactions occurred. Possible allergic reactions 

occurred in 9/779 (1.2%) within 30 minutes. These included 4 rhinitis, 4 localized/contact 

urticaria, and 1 oropharyngeal itch. Again, all were mild and self-limiting. The authors 

concluded that, “Children with an egg allergy can be safely vaccinated with LAIV in any setting” 

[Turner PJ, Southern J, Andrews NJ, Miller E, Erlewyn-Lajeunesse M. ; BMJ 2015;351:h6291; 

BMJ 2015;351:h6291].

Collectively, of the three studies just covered, published reports now describe 1129 children with 

confirmed egg allergy, including 412 with a history of anaphylaxis to egg ingestion, who have 

been given LAIV without any immediate systemic reactions. As with the data on the IIV, the 

injectable vaccine, this is likely due to the very low amount of egg protein in the vaccine.

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To put this in perspective, in the allergy world where the ingestion of allergenic foods and the 

likelihood of causing a reaction are contemplated, the lowest observed-adverse effect level 

(LOAEL) is taken into consideration. The LOAEL is the lowest amount of the offending food that 

would elicit mild, objective symptoms (e.g., mild urticaria, erythema, and oral angioedema) in 

the most sensitive individuals. It has been determined that 0.35% of patients allergic to egg 

may react to 130 μg of egg-white proteins. This is more than 100-fold more than the amount in 

influenza vaccine. Injecting and ingesting vaccine are different, but to put this in to perspective, 

it would take a lot more ovalbumin by ingestion to provoke symptoms, even in the most 

exquisitely allergic patients [Taylor SL, et al. Factors affecting the determination of threshold 

doses for allergenic foods: how much is too much? J Allergy Clin Immunol 2002;109:24-30].

On the other end of the spectrum is allergic reactions after egg-free recombinant influenza 

vaccine reported to VAERS. A report was published last year of 12 patients who described 

signs and symptoms that were consistent with acute hypersensitivity reactions after 

administration of RIV3, which cannot possibly contain any ovalbumin. The cases were all 

considered to be possible anaphylaxis. Just like all other vaccines, about 1 per million cases of 

anaphylaxis occur after influenza vaccine regardless of whether the recipient is egg-allergic or 

whether the vaccine contains egg. A patient with a history of a prior allergic reaction to 

influenza vaccination, not egg, should be evaluated prior to subsequent vaccinations [Allergic 

reactions after egg-free recombinant influenza vaccine: reports to the US Vaccine Adverse 

Event Reporting System; Woo EJ; Clin Infect Dis 2015;60:777-780].

In terms of what precautions are advised to mitigate the risk of anaphylaxis with any vaccine, 

ACIP’s General Recommendations currently state as they always have that:

“Although anaphylactic reactions are rare after vaccination, their immediate onset and 

life-threatening nature require that all personnel and facilities providing vaccinations 

have procedures in place for anaphylaxis management. All vaccination providers should 

be familiar with the office emergency plan and be currently certified in cardiopulmonary 

resuscitation. Epinephrine and equipment for maintaining an airway should be available 

for immediate use.”

These recommendations are not peculiar to influenza vaccines or egg allergies. These are 

recommendations that have always been made for any vaccine.

Turning to his more personal thoughts, Dr. Kelso said that he wondered whether the algorithm is 

needed. It implies that egg allergy increases the risk for an anaphylactic reaction after influenza 

immunization, but an extensive body of data says this is not the case. It implies that children 

with severe reactions to egg ingestion are at increased risk for reactions, but hundreds of such 

children have been vaccinated uneventfully. It implies that RIV is safer than IIV or LAIV for eggallergic recipients, but all vaccines rarely cause anaphylaxis. It is inconsistent with US and 

international allergy guidelines. It is inconsistent with Canadian vaccine guidelines. It is an 

unnecessary barrier to immunization. Egg-allergic children and some adults are going 

unimmunized because practitioners do not want to take the risk. Many hospitalizations and 

some deaths occur among the unimmunized. With that in mind, Dr. Kelso indicated that his 

personal recommendations would be as follows:

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1. No restriction on the use of the LAIV in egg-allergic recipients (i.e., treat LAIV like IIV);

2. No special precautions for the administration of any influenza vaccine (IIV or LAIV) to 

any egg-allergic recipient (i.e., no special medical setting or waiting period beyond those 

recommended for any vaccine recipient); and

3. No algorithm. 

Discussion Points

Dr. Karron clarified what is done with a child who has a history of anaphylaxis to egg. The 

guidance does not recommend sending that child to an allergist. Instead, it says that such a 

child should be vaccinated by someone who is comfortable dealing with anaphylaxis. The 

argument can be made that anyone who offers vaccines anywhere, anytime should be prepared 

to deal with anaphylaxis. She said she thought that if the algorithm set up a barrier at all, it set 

up a barrier for those highly allergic children who have had an anaphylactic event. She would 

hope that those children are under an allergist’s care. Whether they need to receive their 

vaccines under that supervision is a different issue. For the average child who has had a mild 

event, the guidance is to go ahead and vaccinate.

Dr. Kelso agreed that the guidance states that a physician with experience in treating severe 

allergic reactions, which he thought most people would translate to mean allergist. If in fact it 

does not mean anything beyond the expertise that any vaccine provider can offer, he would 

argue that it can be covered by the General Recommendations rather than a special box.

Dr. Kempe asked how many of these studies assessed younger children, and how much 

experience there is in Canada with repetitive immunization in children with anaphylaxis.

Dr. Kelso responded that most of these studies went down to age 2. Some of the 27 studies on 

injectable vaccines included infants. Because many of the studies included children, they also 

included children who needed a booster dose a month later. So, in many of the injectable 

vaccine studies and at least one of the LAIV studies, the investigators specifically assessed 

booster doses given at least a month later and did not observe a risk with that.

Proposed Recommendations for 2016-2017

Lisa Grohskopf, MD

Influenza Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Grohskopf reiterated the core influenza recommendation, with no changes proposed by the 

WG:

Annual influenza vaccination is recommended for all persons of persons 6 months of 

age and older.





A licensed, age-appropriate influenza vaccine should be used

Recommendations for different vaccine types and specific populations discussed 

in the ACIP statement

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In the past four months, the WG has discussed timing of vaccination and decided that the 

available data did not indicate that the language should be changed substantially. The previous 

language in 2015-2016 read: 

Optimally, vaccination should occur before onset of influenza activity in the community. 

Healthcare providers should offer vaccination by October, if possible. Vaccination should 

continue to be offered as long as influenza viruses are circulating. Children aged 6 

months through 8 years who require 2 doses (see "Vaccine Dose Considerations for 

Children Aged 6 Months through 8 Years") should receive their first dose as soon as 

possible after vaccine becomes available, and the second dose ≥4 weeks later. 

The statement that “Healthcare providers should offer vaccination by October, if possible. 

Vaccination should continue to be offered as long as influenza viruses are circulating” was 

clarified in the proposed 2016-2017 language as follows:

Optimally, vaccination should occur before onset of influenza activity in the community. 

Healthcare providers should offer vaccination by the end of October, if possible. Children 

aged 6 months through 8 years who require 2 doses (see "Vaccine Dose Considerations 

for Children Aged 6 Months through 8 Years") should receive their first dose as soon as 

possible after vaccine becomes available, and the second dose ≥4 weeks later. 

Vaccination should continue to be offered as long as influenza viruses are circulating 

and unexpired vaccine is available.

Some WG members were concerned that people would interpret “by October” to mean August 

or September while the spirit of the recommendation was October. The other change shown in 

red is a minor modification to the duration of the time during which vaccination should be 

offered.

With regard to egg allergies, the 2015-2016 recommendations takes a stratified approach based 

on symptoms following egg exposure as follows [MMWR 2015; 64(30):818-825]: 











Hives only to eggs = mild allergy 

Any other symptoms = severe allergy

LAIV is not recommended for egg allergy

Until recently, there have been limited specific data on LAIV in this population

A 30-minute post-vaccination period has been recommended since 2012 to 

observe for signs of allergic reaction, based largely on other allergy literature 

rather than post-vaccination AEs

In terms of the discussion within the WG over the course of several calls to explain the 

proposed language and the published data, including data discussed by Dr. Kelso earlier in the 

session, and potential language discussed in the Influenza WG and with investigators of the 

Clinical Immunization Safety Assessment (CISA) project. Major considerations included the 

overall rarity of anaphylaxis following vaccination in general, and because it is a rarity, events 

may be missed in small studies. For example, a paper by McNeil (2015) which describes VSD 

results noted 33 anaphylaxis cases after 25,173,965 doses of all vaccines combined for a rate 

of about 1.31 (95% CI 0.90-1.84) per million doses. In this paper, 10 anaphylaxis cases 

occurred after IIV3 was administered alone. With over 7,434,628 doses, the rate was 1.83 

(95% CI 0.22-6.63) per million doses. That speaks to the relative rarity of these events in 

general. The 30-minute post-vaccination observation period was also discussed by the WG. 

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Some members thought it resulted in a false sense of security as severe reactions can occur 

after 30 minutes. In the same study by McNeil, the onset of symptoms was within 30 minutes in 

only 8 of 33 cases [McNeil MM et al, J Allergy Clin Immunol 2015]. Also discussed was the fact 

that since the recommendations were changed for the 2011-2012 season, there continue to be 

occasional VAERS reports of anaphylaxis following influenza vaccination of egg-allergic 

individuals. In not all cases is it known that this was due to egg, and it is probably not always 

possible to know that for certain. A stepwise approach such as has been taken in the past 

permits assessment of additional reports over seasons subsequent to change in 

recommendations. Similar to last time the WG discussed changing the recommendations, the 

discussion for those who are most severely allergic, the understanding was that these events 

are very rare and are probably not terribly likely. However, in the event that something 

happens, the feeling was that those with more severe allergy perhaps should be in a medical 

setting. This is the reason for the proposed recommendations.

In terms of the proposed recommendations for 2016-2017, the WG agreed that LAIV appears to 

be a low risk similar to that of inactivated vaccine and based on the data probably should not be 

treated differently from other vaccines. The proposed changes and algorithm follow:

A number of WG members wanted to call attention to the fact that the 15-minute waiting period 

recommended for all persons still applies, particularly adolescents, in case syncope occurs. 

This is pointed out in the current draft of the egg allergy language and would be pointed out in 

the general section about general precautions for vaccination.

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In terms of the language that would accompany the algorithm, the first two points would not 

change from the previous recommendations

1. Regardless of a recipient’s allergy history, all vaccines should be administered in 

settings in which personnel and equipment for rapid recognition and treatment of 

anaphylaxis are available.

2. A previous severe allergic reaction to influenza vaccine, regardless of the component 

suspected of being responsible for the reaction, is a contraindication to future receipt of 

the vaccine.

3. Persons with a history of egg allergy who have experienced only hives after exposure to 

egg should receive influenza vaccine. Any licensed influenza vaccine (i.e., any form of 

IIV, LAIV, or RIV) that is otherwise appropriate for the recipient’s age and health status 

may be used.

4. Persons who report having had reactions to egg involving symptoms other than hives, 

such as angioedema, respiratory distress, lightheadedness, or recurrent emesis; or who 

required epinephrine or another emergency medical intervention, may similarly receive 

any licensed influenza vaccine (i.e., any form of IIV, LAIV, or RIV) that is otherwise 

appropriate for age and medical conditions. The selected vaccine should be 

administered in a medical setting in which a healthcare provider with experience in the 

recognition and management of severe allergic conditions is immediately available. 

5. A 30 minute post-vaccination observation period, previously recommended following 

vaccination of egg-allergic recipients, is no longer recommended. However, regardless 

of allergy history, vaccine providers should consider observing all patients, particularly 

adolescents, with patients seated or lying down for 15 minutes after vaccination to 

decrease the risk for injury should syncope occur (24).

6. For persons with no known history of exposure to egg, but who are suspected of being 

egg-allergic on the basis of previously performed allergy testing, the recommendations in 

3) immediately above may be followed. 

Items 3, 4, and 5 reflect the changed language in the algorithm. With regard to retention of the 

algorithm, it has been found in the past that generally people seem to want one. It is possible to 

represent these recommendations wholly in text, but the reaction that tends to occur when 

discussing not having an algorithm for this and the 1- versus 2-dose question for young children 

has typically been that people like to have the algorithm to place in the ED or wherever else a 

quick visual reference is required.

Discussion Points

Dr. Moore said she was struggling with the idea of what the endpoint would be at which one 

would determine that an algorithm is no longer necessary. A number of studies have been 

presented with evidence of absence of an issue. VAERS is great for hypothesis generation, but 

does not suggest anything causal as is well-known from all sorts of things that can be reported 

to VAERS. She wondered at what point they decide there is enough evidence of absence of a 

problem specific to egg, at which point ACIP would be comfortable eliminating the algorithm. 

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Programmatically, the algorithm results in many people not getting vaccinated either because 

they are afraid of getting vaccinated because they have an egg allergy and they have heard that 

it is dangerous to get the influenza vaccine, or mass clinics, pharmacies, and school-located 

clinics have to spend a tremendous amount of time evaluating for this and then determining 

what to do. Many of them simply do not do that and decide that if there is an egg allergy 

question, they will skip it. This becomes quite a barrier to access for those folks.

Dr. Grohskopf replied that if a recommendation treated everyone the same way, an algorithm is 

probably not needed. In terms of getting to that step, the issue is that while there are data, the 

studies are relatively small and this is already known to be a rare event. While VAERS has 

obvious limitations, there has been a small number of cases in several seasons since the 

recommendations were originally changed in 2011-2012. Not enough to consider changing the 

recommendations back, but some of those cases have been discussed and it could never be 

determined with certainty whether those cases had more of a likelihood to do with egg than not. 

The general philosophy of the approach since 2011-2012 has been a season of data is 

reviewed, and perhaps a change is made. These particular recommendations, at least as they 

are presented at this point, there is no longer a waiting period which is an important barrier in a 

lot of clinical settings. Also, it still means that everybody can be vaccinated and not even an 

allergy-experienced person would be required to be there.

Dr. Kempe pointed out that this is basically a power issue and the confidence intervals are 

needed around the estimates. To her knowledge, nobody has assembled these data in a 

systematic review. That is why she was asking about the Canadian experience and whether 

there is anything where this has been done routinely that could help ACIP with larger numbers.

Dr. Gemmill (NACI) indicated that the work was done primarily in the province of Quebec, by Dr. 

De Serres who presented earlier on meningococcal B, in conjunction with the Quebec 

Association of Allergists. He said they feel very confident that they made the right decision so 

far. While the trickle down has not happened completely yet because it takes a while for 

practice to change once a recommendation has been made, there have been absolutely no 

signals. They have been in touch with their safety representatives to confirm that point. 

Perhaps more details can be provided in writing at a later time.

Dr. Byington (AAP) noted that the language regarding physician versus other providers may be 

very limiting in some cases if nurse practitioners, physicians assistants, et cetera are 

administering the vaccine. She wondered if provider could be substituted or physician was 

required.

Dr. Grohskopf responded that the WG discussed this at length and the final thinking was to 

include the word physician. 

Dr. Karron added that there was a diversity of opinions among the WG members.

Regarding the power issue raised by Dr. Kempe, Ms. Pellegrini said that if they are looking for 

reactions that are literally 1 in a million, it seemed to her that there is simply no way to conduct a 

study that is going to turn those up in a methodical way. Furthermore, there is no way to write 

an algorithm that is going to effectively screen for a 1 in a million event. Therefore, it was not 

clear whether they should bother with an algorithm.

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Dr. Kempe said she did not think they were looking for 1 in a million. If they had the numbers 

from Canada, an assessment could be done over a reasonable period what the point estimate 

could be with that number of people, and then make a more rational decision.

Dr. Grohskopf noted that something raised in the past when recommendations are changed, 

prior to changing there may be less use of something because it was not recommended to use 

it. This was brought up when it was recommended to start using the inactivated vaccine. Might 

more cases be seen in VAERS once it is recommended that it is okay to give the vaccine. One 

point that was raised was that LAIV is currently not recommended, so there may be more use 

and more reports in VAERS as a result.

It sounded to Dr. Messonnier that there may be more data that might be helpful to the ACIP 

members in thinking this through. The WG seemed to be suggesting a stepwise approach, 

gather additional data, and then reassess. There are other data that could be assembled, such 

as missed opportunities, to give the members some kind of confidence intervals. Because the 

data were not available during this meeting, the group could opt to table the recommendation 

until the next meeting when those data could be provided. Alternatively, they could take the 

incremental steps at some level that the WG was recommending, and hear further data at the 

next meeting or the meeting after that. Or, they could go all the way during this meeting.

Dr. Karron said that if they kept some type of algorithm, she would suggest removing the 

language “if a vaccine other than RIV is used” for two reasons: 1) RIV is not used in children, 

and 2) anaphylaxis can occur with RIV.

Dr. Kimberlin (AAP) said he was reading Item 4 on slide 9 as meaning that people with 

reactions to egg involving angioedema and so forth may receive the vaccine, and he would 

consider someone needing epinephrine or another emergency medical intervention to be pretty 

severe. Item 2 states “A previous severe allergic reaction to influenza vaccine, regardless of the 

component suspected” which might mean egg allergy or egg protein is a contraindication to 

receive the vaccine in the future. This seemed like a discrepancy to him.

Dr. Grohskopf clarified that Item 4 reflects symptoms following exposure to egg, while Item 2 

reflects symptoms following exposure to vaccine. Regardless of allergy history, having a 

previous severe reaction to a vaccine is a contraindication for further receipt of that vaccine. 

This point does not refer specifically to egg, but has been in the recommendations since 2011-

2012 because it was felt important to remind people of that. There was a specific request to 

insert that. Contextually, since most of the section talks about egg allergy, it probably does not 

fit as well.

Due to a time constraint pertaining to the Zika Virus session, Dr. Bennett suspended the 

conversation until later in the day. 

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Upon returning to the influenza discussion, Dr. Bennett reported that in speaking with the WG, 

putting the vote off until June would not be suitable due to the MMWR publication timeline. 

Moreover, it is unlikely that any additional information would be available by June. As a result, 

she asked whether anyone had a motion regarding the 2016-2017 recommendations.

Dr. Karron indicated that during the break, she caucused among the other ACIP Influenza WG 

members and the WG wished to propose the following changes based upon the earlier 

discussion:

1) Remove the algorithm figure entirely

2) Retain Items 1, 2, and 3 because they are just making general statements that are not 

controversial and merely reiterate what ACIP has said often

3) Retain Item 4, but strike the phrase “if a vaccine other than RIV is used,” state “The 

selected vaccine should be administered in a medical setting in which a healthcare 

provider with experience in the recognition and management of severe allergic 

conditions is immediately available,” and change physician to healthcare practitioner 

4) Eliminate Item 5 in its entirety, because observation of people following influenza 

vaccine should not differ from the General Recommendations and is redundant here

5) Eliminate Item 6 because this was added due to one famous case in the CISA literature 

in a child who was not suspected of being egg-allergic; that child had anaphylaxis and 

then was discovered upon skin testing to be egg-allergic and it was hypothesized that 

the vaccination sensitized the child, so that child would not have been discovered 

following this recommendation

Dr. Baker said that as a pediatrician, but not representing the AAP, she thought the suggested 

changes were perfect and that it should be kept simple. While it would be nice to have more 

data in the future, the data presented during this session were enough at this point.

Dr. Weber (SHEA) noted that if RIV is allowed, it could be given by anyone. If there is a 

requirement that a trained physician must be present to deal with anaphylaxis, that may mean 

someone who is approved to intubate a patient, which means it is going to be limited to ED and 

the intensive care unit (ICU) physicians. It would eliminate all family practice physicians, 

nurses, and clinics in his facility who are not licensed for intubation.

Dr. Bennett clarified that the recommendation was to change physician to healthcare provider. 

Dr. Moore thought the changes were wonderful and would make implementation much easier 

programmatically. In terms of the statement regarding administration in a setting where people 

can handle anaphylaxis, in general anyone who gives an immunization should be capable of 

responding and reacting to someone who has signs of anaphylaxis because any vaccine can 

cause that. She wondered whether something specific should be called out here, similar to Item 

6 which is already in the General Recommendations making it redundant to say it again here. 

Perhaps it would not be necessary to restate the provision here, because any vaccine can 

cause anaphylaxis.

Dr. Karron pointed out that this would be a major change to the existing language, and this 

would provide a way to do it in a stepwise manner. It may be that over time, there are no 

specific recommendations around this. That would be a radical change for now.

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Dr. Moore clarified that, for example, a pharmacy that is equipped to respond to someone who 

has anaphylaxis after administration of a drug should not be administering to this person. She 

was concerned about how to translate that to people who want to know where someone should 

go.

It was noted that the intent of the discussion in the WG was that it be in a healthcare setting 

where there is someone who can manage it, not in a local drug store.

In particularly, Dr. Karron noted that the WG talked about the fact that they did not necessarily 

want children with a previous history of anaphylactic responses to be vaccinated in the school 

setting.

Dr. Ezeanolue suggested saying “go to a healthcare setting.” This was not clear to him based 

on the language.

Dr. Moore suggested clarifying the language by stating “inpatient or outpatient medical setting.”

Dr. Harriman thought Item 1 addressed emergency management and that it did not need to be 

in both places.

It was noted that perhaps some language could be borrowed from the General 

Recommendations to be put in that area.

Dr. Grohskopf replied that they plan to add the list from the General Recommendations once 

that is further along.

Dr. Kempe thought it would be hard for doctors to understand this change without any 

explanation. She wondered if they should state “based on more recent data” to set the ground 

work for a change that is based on something.

Dr. Bennett thought that was a good suggestion, but pointed out that the group did not have to 

vote on that specifically. It could be part of the narrative.

Dr. Grohskopf noted that that is a substantial part of the narrative before these bullets. 

Dr. Savoy (AADP) asked if they were suggesting that the local CVS that has an office where 

there is a nurse practitioner who potentially has the equipment needed could or could not give a 

vaccine to an egg-allergic child. It sounded like some people were saying “yes” and the WG 

was saying “no.”

Dr. Foster (APhA) assumed “equipment” was referring to epinephrine, which is what most 

guidelines require. Perhaps the wording would be better if the word drugs was used rather than 

equipment. Most places do not have equipment, but pharmacists are trained to handle these 

types of reactions as part of the pharmacist training program. He did not think that would 

exclude people from getting vaccines in pharmacies.

Dr. Riley noted that the WG did not ask the question about whether it was okay or not okay.

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Dr. Karron clarified that the intent of the WG was that for those children who had a previous 

episode of anaphylaxis, that perhaps more of a medical environment would be appropriate. She 

wondered whether they were struggling over a problem that was truly a problem in the sense 

that a child who has had an anaphylactic response is not a child that is likely to be vaccinated in 

a pharmacy or a school setting. They would be more likely to be vaccinated in a healthcare 

setting.

Dr. Belongia wondered whether it would help to say clinical practice setting instead of medical 

setting to be clearer.

Dr. Savoy (AAFP) did not understand why a patient would think that a pharmacy-based or 

school-based clinic is not a healthcare, medical care, or provider-based setting. Aside from it 

not being inpatient, which is fairly obvious, it was not apparent how any of the words being 

suggested would clarify that.

Dr. Kempe thought this was a scope of practice issue. A well-equipped pharmacy clinic with a 

nurse practitioner who has handled anaphylaxis, that is probably within her scope of practice. 

She was not sure they could be more specific about the scope of practice for a provider in a 

given setting.

Dr. Bennett asked whether there was language in the General Recommendations that they 

could duplicate and place into this recommendation, or if they could refer back to the General 

Recommendations.

Dr. Messonnier thought that the problem was that this language was very similar to Item 1. It 

seemed that they were trying to say that additional precautions should be taken with these 

children with a history of anaphylaxis. One way to fix that might be instead of putting it here, to 

put the language with Item 1. The issue is not specific to this. Item 1 says everyone should get 

a vaccine in a place where they could have recognition and treatment of anaphylaxis. A 

sentence could be added there to say, “Patients with a history of anaphylaxis should take 

special care to make sure that this is available.” That would be a more general statement than 

trying to attach it to an influenza vaccine.

An inquiry was posed regarding whether that would also remove the stratification. Dr. 

Messonnier clarified that she was not suggesting removing the stratification. She was just 

noting that there were two sentences, both of which recommended the setting in which vaccine 

should be given. It might make more sense to combine them, because they were trying to make 

the contrast between Item 1 and Item 4 in which they were trying to say that this should be a 

more stepped up setting.

Dr. Rubin asked for clarification regarding whether Dr. Messonnier was suggesting that they 

move the language in Item 4 and make it part of Item 1.

Dr. Messonnier said she felt that the WG was trying to contrast that in general, everybody 

should get a vaccine in a certain setting but that patients with a history of anaphylaxis to egg 

should have more precautions. She thought the language would work better if it was included in 

Item 1.

Dr. Karron amended her motion to move the language under Item 4 to become paragraph 2 in 

Item 1. Then there would only be 3 points: 1, 2, and 3.

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Dr. Bennett clarified that there would still be 4 bullets, as only part of Item 4 would be moved.

Dr. Messonnier thought they were trying to achieve parallelism between a setting for everybody 

and setting for people with a history of egg allergies.

Dr. Belongia thought there appeared to be a contradiction. The last part of Item 4 seemed to 

imply that that was the situation for people who have reported having had bad reactions to eggs 

in the past. They can get any vaccine, but those people should receive vaccines in that setting. 

However, Item 1 says that everybody should receive a vaccine in that setting. That was 

discordant.

Dr. Bennett thought that if they could craft it in Item 1 it might be easier than trying to have it in 

two different places and be slightly different.

To clarify, Dr. Cohn suggested moving the paragraph in Item 4 that read, “The selected vaccine 

should be administered in a medical setting in which a healthcare provider with experience in 

the recognition and management of severe allergic conditions is immediately available” and 

move it to Item 1, but tailor/finalize the language slightly to reflect that same message in Item 1 

after the vote and send it around to everyone for approval before it is published.

Dr. Grohskopf said she was somewhat confused, because if they moved the last sentence from 

Item 4 and placed it in Item 1, there would be no difference specified between the two classes of 

individuals. Basically, 3 and 4 would be the same after that.

Dr. Karron agreed, noting that there were some general statements in the bullets that apply to 

everybody. Everybody should receive vaccines in settings where appropriate expertise is 

available. Anyone who has a reaction to influenza vaccine should not get it again. Then there 

are two categories of people: A, people who have had mild reactions (Item 3) and Category B, 

people who have had more severe reactions (Item 4). She thought to move information from 

Item 4 would not follow that logical flow.

Dr. Messonnier thought where people were getting stuck was understanding the categories, but 

not understanding what they were trying to convey would be different about people in Item 4. 

Pharmacists might say that now there are clinics where there are providers with experience in 

recognition and management of severe allergic reactions. Therefore, if someone has had a 

severe allergy, she wondered what they were suggesting they do.

Dr. Karron clarified that Item 1 said “in a setting where” and Item 4 said “medical setting,” which 

was the WG’s attempt to say that this should be a clinical setting.

Dr. Bennett asked whether it would be possible in Item 1 to delineate these specific groups just 

outlined clearly and directly.

Dr. Karron did not think it flowed from Item 1.

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Dr. Rubin pulled up a document from the AAP from Pediatrics 2007 titled “Preparations for 

Emergencies in the Offices of Pediatricians and Primary Care Providers.” In part, the paper 

stratifies how close an office is to a hospital (within 10 minutes, longer than 10 minutes). That 

stratification results in the type of equipment / expertise that is appropriate for the office, 

including airway management. He thought they were talking about the same thing. Airway 

management equipment was not as likely to be available in a pharmacy. That might change 

with more data.

Dr. Kempe thought they were getting two things confused. Item 1 pertained to generally being 

ready for anaphylaxis. This is about a belief on many people’s part in the past, which was 

probably false, that egg allergies specifically cause anaphylaxis with influenza vaccine. This is 

about people who have already had a severe allergic reaction. If they were known to have a 

reaction to influenza vaccine, it wouldn’t be given to them again. They were trying to uncouple 

the egg allergy issue from the influenza issue, and she thought it needed to be more explicit. 

Item 4 was not the same as Item 1.

Dr. Rubin was not clear that they were ready to make that step. If they were, the document 

would become a lot simpler.

Dr. Fryhofer (AMA/ACP) indicated that she was part of the WG and this was a long discussion 

during the WG meeting. Part of the reason they left physician was because that changed the 

context of the type of medical setting. The way the conversation was going, they might as well 

for Item 3 say “children with an egg allergy of any severity can get any of the vaccines.” 

However, she did not think that was the WG’s intent.

Dr. Riley’s understanding was exactly what Dr. Rubin said, which was that they were not ready 

to jump all the way to “don’t worry about it.” However, she thought she was hearing that the 

concern was that someone might still have anaphylaxis, so what they really wanted was 

availability of airway management. Why not just put that in? She would not try to lump that 

together with Item 1, because it would be confusing. The progression was general, mild allergy, 

then severe allergy.

Dr. Belongia thought that would address the ambiguity to a great degree if that term was used 

specifically.

Dr. Netoskie (AHIP) agreed with Dr. Riley. It seemed to him that under the topic of egg allergy, 

the most important message to begin with is that “you may administer vaccine to people who 

have had egg allergy issues.” He thought that should be first, followed by the conditions where 

there may be various levels of concern. From the physician education perspective, that is the 

key message that should come across first.

Dr. Schaffner (NFID) expressed concern that they were drifting into the ultimate management of 

anaphylaxis. From his point of view, the place where vaccines are administered need two 

pieces of equipment: an epi pen and a cell phone.

Dr. Rubin pointed out that the critical difference in Items 3 and 4 was that in 3 the vaccine 

should be administered and in 4 the vaccine may be administered.

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Dr. Moore emphasized that the data from allergists suggest that there is not even a biological 

plausibility to this causing anaphylaxis because of the minutia. She said she understood the 

difference in injection versus ingestion, but that that is difficult to make a case for. Perhaps they 

could state “Out of an abundance of caution” and then say that there is no evidence at this point 

that there are a lot of people who are having anaphylactic reactions to influenza vaccines who 

have a history of egg allergy.

Dr. Grohskopf responded that that is discussed in the background section that precedes this 

recommendation, in addition to the literature, including all of the literature discussed by Dr. 

Kelso. Going back the last several years, one of the concerns has been that there is a 

recommendation from the allergy community as well as the ACIP recommendation, which is for 

everybody. One thing that has been voiced consistently over the last three or four years has 

been the venues and settings in which vaccination is occurring have expanded and are much 

more diverse. There was overall some concern that there may be some settings that, even 

though it is repeatedly recommended that certain equipment should be available, it might not 

be. Perhaps including some particular language would help.

Dr. Bennett said she thought they needed to go to vote, but that they needed to clarify what they 

would be voting on since they had gone back and forth. Her proposal was to vote on what they 

had at the moment, and then if there was a wording change the WG felt should be made, they 

trust them to make the changes and review them after the fact. She did not think that continuing 

the discussion was going to get them anywhere, as they seemed to be going around in circles. 

She said if anyone adamantly objected, she would be happy to listen, but she thought they 

needed to move forward.

Ms. Pellegrini emphasized that they wanted to get this right. It is important and is a big change 

that would take a long time for physicians, patients, and families to get used to. She did not 

understand exactly what they had to do during this meeting, and whether they were under 

pressure for something to be published.

Dr. Bennett responded that they must approve these recommendations so that the MMWR

could be published in a timely manner. What they did not have to do was approve the exact 

wording. They merely had to approve it in spirit.

Dr. Fryhofer (AMA/ACP) noted that she is a practitioner who sees patients. When she saw the 

word “equipment” it meant to her that she needs to have an anesthesiologist there to intubate 

the patient. She thought this was creating a barrier that was an unintended consequence. 

Adding the airway management will make people think they have to be ready to intubate a 

patient. That is not a reality.

Dr. Bennett clarified that she was proposing that they vote without that, as it was added after the 

original language. She proposed they vote on the amended motion. She emphasized that 

there was no way this would be perfect by the end of the day, and that they should move 

forward with the sense that there would be an opportunity to see the specific wording and make 

comments on it after the WG has a chance to incorporate the comments. She said she had 

total trust in them that they understood the subtleties of what was said during the discussion.

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Vote: Influenza Vaccine Recommendations for 2016-2017

Dr. Karron made a motion to approve the 2016-2017 Influenza Vaccine Recommendations for 

2016-2017 with the changes as proposed. Dr. Walter seconded the motion. The motion carried 

with 11 affirmative votes, 0 negative votes, and 3 abstentions. The disposition of the vote was 

as follows:

11 Favored: Bennett, Harriman, Karron, Kempe, Moore, Pellegrini, Romero, Reingold, Riley, 

Rubin, Walter

 0 Opposed: N/A

 3 Abstained: Belongia, Ezeanolue, Stephens

Update on CDC’s Response to Zika Virus

Toby L. Merlin, MD

Director, Division of Preparedness and Emerging Infections

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Dr. Merlin provided an update on CDC’s response to Zika Virus. He summarized the current 

situation, CDC’s response activities, and the challenges and opportunities for vaccine 

development.

The Zika virus outbreak has grown in size and reach and is attracting interest from public and 

the media abroad, as well as in the US. In response to this emerging public health threat, CDC 

activated its Emergency Operations Center (EOC) on January 22, 2016 to help coordinate the 

public health response. On February 1, 2016, the WHO declared a Public Health Emergency of 

International Concern (PHEIC) because of clusters of microcephaly and other neurological 

disorders in some areas affected by Zika.

On February 8, 2016, CDC elevated its EOC activation to a Level 1, the highest level. President 

Obama also announced a request for $1.8 billion in emergency funds for several agencies to 

accelerate research into a vaccine and educate populations at risk for disease 

[https://www.whitehouse.gov/the-press-office/ 2016/02/08/fact-sheet-preparing-and-respondingzika-virus-home-and-abroad].

The goals of the CDC Zika virus response are as follows: 







Characterize the effects of Zika Virus infection (Zika) in the current outbreak

Effects of Zika in pregnant women, including the risk of fetal loss and congenital 

malformations, including microcephaly

Determine the risk of GBS associated with Zika

Zika Virus

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































Promote and evaluate interventions to prevent Zika, particularly in at-risk populations 

(pregnant women)

Personal protective measures (insect repellant, contraception)

Vector control 

Prevention of transmission via blood and transplantation

Travel advisories

Enable detection of Zika by development and distribution of Zika laboratory diagnostics

Current CDC investigations and collaborations include the following:

Brazil

Retrospective case-control study for risk of fetal Zika infections, potential co-factors, 

and microcephaly

Retrospective case-control study for risk of GBS

Columbia (protocols pending approval)

Prospective pregnancy cohort study to define spectrum of fetal outcomes associated 

with Zika infection

Virus persistence in semen, urine

Domestic (particularly Puerto Rico) 

Pregnancy registry and follow-up of cases

Other studies 

Histopathologic examination of tissues from affected pregnancies

Prior to 2015, Zika outbreaks occurred in Africa, Southeast Asia, and the Pacific Islands. In 

May 2015, the first locally-acquired cases in the Americas were reported in Brazil. Currently, 

outbreaks are occurring in many countries in the Americas and US territories, including Puerto 

Rico, American Samoa, and the US Virgin Islands. Thus far, local mosquito-borne transmission 

of Zika has not been reported in the continental US. Since 2011, there have been laboratoryconfirmed Zika virus disease cases identified in travelers returning to the US from areas with 

local transmission. With current outbreaks in the Americas, cases among US travelers will most 

likely increase. The following map depicts Zika cases in the US as of February 17, 2016:

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€

Imported cases may result in virus introduction and local spread in some areas of the US where 

Aedes mosquitos are present. CDC is not able to predict how much Zika virus will spread in the 

continental US. However, recent chikungunya and dengue outbreaks in the continental US 

suggest that Zika outbreaks may be limited to small, geographic clusters.

The following maps depict the approximate distribution of Aedes aegypti and Aedes albopictus

mosquitoes in the US:

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Aedes aegypti mosquitoes have been identified across the southern half of the US from 

California to Florida, while Aedes albopictus has been identified throughout much of the 

Southern and Eastern US. Imported cases may result in virus introduction and local spread in 

some areas of the US where Aedes mosquitos are present.

CDC is not able to predict how much Zika virus would spread in the continental US. The spread 

of Zika is most likely due to the movement of people, not the movement of mosquito 

populations. For Zika to cause an outbreak in the continental US people infected with the virus 

need to enter the US. An Aedes mosquito must bite the infected person during the relatively 

short time that the virus can be found in the person’s blood. The infected mosquito must live 

long enough for the virus to multiply and for the mosquito to bite another person.

The best way to prevent diseases spread by mosquitoes is to protect against mosquito bites 

through the following efforts: 







Wear long-sleeved shirts and long pants

Stay in places with air conditioning or that use window and door screens to keep mosquitoes 

outside

Use Environmental Protection Agency (EPA)-registered insect repellents: 







When used as directed, these insect repellents are proven safe and effective even 

for pregnant and breastfeeding women

Insect repellents should not be used in babies younger than 2 months of age 

Products containing higher than 30% N,N-diethyl-meta-toluamide (DEET) should not 

be used in children, and products containing para-menthane-diol (PMD) should not 

be used in children younger than 3 years of age







Use mosquito netting to cover babies younger than 2 months of age in carriers, strollers, or 

cribs to protect them from mosquito bites

Do not use oil of lemon eucalyptus in children younger than 3 years of age

Sleep under a mosquito bed net if air conditioned or screened rooms are not available or if 

sleeping outdoors

Recent chikungunya and dengue outbreaks in the continental US suggest that Zika outbreaks in 

the US mainland may be limited to small, geographic clusters. Better housing construction, less 

crowding, regular use of air conditioning, use of window screens and door screens, and state 

and local mosquito-control efforts have helped to limit transmission of these mosquito-borne 

viruses.

Currently, there is no vaccine or medication to prevent infection or disease. Developing safe 

and effective vaccines for the prevention of emerging infectious diseases, such as Zika, is a 

priority for the US government. Preliminary evidence indicates that a vaccine could be effective 

in preventing Zika virus infection. Natural infection elicits neutralizing antibodies, and the virus 

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appears to show minimal antigenic and genetic variation across strains. Moreover, there are 

limited data revealing neutralization across viral strains.

Plans are under development to leverage existing infrastructure to provide a coordinated and 

collaborative framework to support the accelerated development of Zika vaccines. Ongoing 

partnerships between National Institutes of Health / National Institute of Allergy and Infectious 

Diseases (NIH / NIAID), the Biomedical Advanced Research and Development Authority 

(BARDA), CDC, FDA, and the DoD’s Walter Reed Army Institute of Research (WRAIR), and 

industry partners will provide a coordinated and collaborative framework to support the 

accelerated development of Zika vaccines. There are many approaches and technologies 

being put forth, including recombinant, live-attenuated, live-chimeric with other flavivirus 

components, nucleic acid, whole-inactivated virions, and other virus-vectored platforms. These 

vaccine candidates are all in exploratory stages of development.

The President’s emergency funding request includes support for vaccine research and 

diagnostic development and procurement. The request includes funding for research, rapid 

advanced development, and commercialization of new vaccines and diagnostic tests for Zika 

virus. There is also some funding for the US Agency for International Development (USAID) to 

create new incentives for the development of vaccines and diagnostics.

 

Vaccine Development Update

Bruce Gellin, MD, MPH

Director, National Vaccine Program Office

Department of HHS, Public Health and Science

Dr. Gellin further described the vaccine development process and development pertaining to 

Zika virus. He first explained that the Public Health Emergency Medical Countermeasure 

Enterprise (PHEMCE) coordinates federal efforts to enhance chemical, biological, radiological, 

and nuclear threats (CBRN) and emerging infectious diseases (EID) preparedness from a 

medical countermeasure (MCM) perspective. He explained that he wanted to put Zika virus 

vaccine development in the context of the PHEMCE, given that it is “all hands on deck” 

regarding who has equities they can provide.

The PHEMCE is led by the HHS Office of the Assistant Secretary for Preparedness and 

Response (ASPR) and includes three primary HHS internal agency partners: CDC, FDA, and 

NIH. Also included are several interagency partners: DoD, VA, the Department of Homeland 

Security (DHS), and the US Department of Agriculture (USDA). PHEMCE Agency Lead roles 

are depicted in Figure 2 below:

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The PHEMCE strategic goals are to:

























Identify, create, develop, manufacture, and procure critical MCM

Establish and communicate clear regulatory pathways to facilitate MCM development and 

use

Develop logistics and operational plans for optimized use of MCM at all levels of response

Address MCM gaps for all sectors of the American civilian population

The HHS priorities on MCM for Zika virus include the following:

Detect Zika Infection

 Support advanced development of rapid serological diagnostics, including point of 

care, for the detection of antibodies in persons previously infected with Zika virus

Prevent Zika Infection

NIH/DOD/BARDA collaboration for USG-developed, manufactured, and evaluated 

Zika virus vaccine

NIH and BARDA to support private sector development of vaccine through federal 

funding opportunities

HHS to support international collaborations, including vaccine production at the 

Butantan Institute in Brazil 

Secure and Protect Blood Supply

Support advanced development of high throughput molecular diagnostics for 

screening blood supply 

Support late stage pathogen reduction systems

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The current Zika virus vaccine development landscape as of February 16, 2016 is depicted in 

the following graphic showing the various platforms and stages of clinical development:

It is important to understand that the vaccine and drug development pipeline is expensive, risky, 

and lengthy. This is illustrated by the following graphic that highlights the progress with Zika 

virus vaccine development relative to Ebola and Middle East Respiratory Syndrome (MERS) 

vaccine development:

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It is clear that there is a significant amount of interest in Zika virus vaccine development, and 

there are numerous technologies that could be utilized. There are a number of key questions 

and concerns related to Zika virus vaccine research and development, including the following:



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Safety Concerns

Pre-existing immunity to Zika, YF, dengue, and vaccine platforms

Is there a potential for antibody dependent enhancement?

Intended Usage

General usage (GUP) and post-exposure (PEP) prophylaxis

Special populations: pregnant women, women of child bearing age (WOCBA), 

infants, children

Vaccine Properties

Vaccine components (e.g., E protein, whole virus, adjuvants, other viruses)

Level and type of elicited immunity

Kinetics of vaccine immunity

Duration of immunity (Heterologous Prime/Boost Approach)

Routes of administration

Platform technology maturity

Manufacturing process maturity (potency assays, vaccine stability)

Zika Virus Natural and Adaptive Immunity in Animals and Humans

Correlates of protective immunity

Immunogenicity and protection study design

Assays and reagents 

There have been several workshops since early February 2016, and there are additional 

upcoming workshops of interest:

March 1-2, 2016 in Washington, DC

PAHO Meeting on the Zika virus research agenda and its public health implications in the 

Americas

March 28-29, 2016 in Washington, DC

HHS Stakeholders meeting on Zika virus and Medical Countermeasures

Contact information of interest pertaining to Zika virus vaccine development includes the 

following:

Request a Tech Watch Meeting Through www.medicalcountermeasures.gov

 Contact Jonathan Seals, Director Strategic Science and Technology Division, 

jonathan.seals@hhs.gov

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BARDA Broad Agency Announcement

BAA-16-100-SOL-00003 will support innovation through development of platform 

technologies that enhance capabilities for development and manufacturing of MCMs.

Technical Point of Contact: Mark Craven: mark.craven@hhs.gov

NIH Federal Funding Opportunity

NOT-AI-16-026 will support high-priority Zika virus research areas detailed in the 

solicitation

Introduction

Arthur Reingold, MD

University of California, Berkeley

Chair, ACIP Cholera Vaccine Work Group

Dr. Reingold reminded everyone that the Cholera Vaccine WG was formed in August 2015. 

During the October 2015 ACIP meeting, the WG presented an overview of cholera background 

and epidemiology. PaxVax filed a BLA with the FDA in October 2015 with a request for priority 

review for the use of its vaccine CVD 103-HgR. The vaccine is currently undergoing a fast-track 

review, which the FDA is anticipated to complete by June 2016. The plan is to call for an ACIP 

vote on recommendations for use of CVD 103-HgR in June 2016 for use in adults.

Since October 2015, the ACIP Cholera Vaccine WG has drafted policy questions, identified 

important and critical outcomes for review, conducted a systematic literature review, completed 

an initial GRADE evaluation of the evidence, and discussed considerations for 

recommendations for use. This is a somewhat unusual vaccine in that some of the studies are 

actually challenge studies in which the organism is intentionally introduced. 

Dr. Reingold indicated that during this session, Dr. Danzig from PaxVax would present clinical 

data on CVD 103-HgR, Dr. Wong from CDC would summarize the GRADE evaluation and WG 

plans, and that presentations would include the information and background needed for 

discussion about cholera vaccine to inform ACIP decisions during upcoming meetings. 

VaxchoraTM Clinical Data

Lisa Danzig, MD

VP Clinical Development and Medical Affairs

PaxVax

Dr. Danzig presented pivotal data that have been filed in support of the BLA for PaxVax CVD103-HgR vaccine called VaxchoraTM. She briefly reviewed the background on CVD-103-HgR 

and the clinical re-development program that included human challenge studies in which 

efficacy, lot consistency, immunogenicity, and bridging to older adults were determined.

Cholera Vaccine

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PaxVax is a privately held global specialty vaccines company with a mission to develop, 

manufacture, and commercialize innovative vaccines against infectious diseases in a socially 

responsible manner. PaxVax has approximately 180 dedicated employees who work across 

locations in the US and Europe. The PaxVax headquarters is in Redwood City, California. Its 

research and development site is in San Diego, California. The Thörishaus, Switzerland site 

includes multiple manufacturing, office, and laboratory spaces for Vivotif® production, quality 

testing, product release, and supply chain. 

PaxVax is initially focused on delivering vaccines for the travelers’ markets, with the following 

products: Vivotif®, which is a typhoid vaccine live oral Ty21a; VaxchoraTM, which is the oral 

cholera vaccine that is under FDA review; an Ad4 vector program that has included programs in 

HIV, influenza, anthrax, and Ad4/7; and new research and development that focuses on travel 

and specialties, including Zika virus vaccine.

Vibrio cholerae (V. cholera) O1 biotypes are the most common (Classical, El Tor). Each biotype 

has two distinct serotypes. The transmission route is via contaminated water and food. It 

causes a toxin-mediated secretory diarrhea, which if severe can be rapidly fatal if untreated. 

This is known as cholera gravis. It is endemic in over 50 countries and is found primarily in Asia

and Africa. In addition, there has recently been extensive disease burden in the Caribbean. 

Approximately 3 to 5 million cases are estimated to occur per year, with more than 100,000 

deaths. It is estimated that the majority (80%) of mild to moderate diarrhea cases do not come 

to medical attention, and therefore go unreported. Everyone is susceptible, but there is an even 

greater risk with blood group O and probably hypochlorhydria, but the reasons are unknown [Ali 

M, Nelson AR, Lopez AL, Sack DA. Updated global burden of cholera in endemic countries. 

PLoS Negl Trop Dis 2015;9(6):e0003832]. 

There is no licensed cholera vaccine in the US. Because cholera causes explosive diarrhea, 

infection can be rapidly fatal. If untreated, in its severest form cholera makes headlines. CVD 

103-HgR is not a new vaccine. It is a live, attenuated V. cholerae serogroup 01, serotype Inaba, 

classical biotype strain in which the toxigenic A1 ADP-ribosylating subunit of cholera toxin was 

deleted and only the non-toxic immunogenic B binding subunit of cholera toxin is synthesized. 

The first lots were tested in volunteers in 1988. It was available in 1994 through Berna 

commercially as Orochol®, Mutacol®, and Orochol® E (the higher dose). It was licensed in 

Switzerland, Canada, Argentina, Australia, and New Zealand in the 1990s. In 1997, Berna 

submitted a BLA to the FDA. There was a VRBPAC in 1998 that included a discussion of the 

design of the challenge studies that would be needed to support licensure in the US. The 

endpoints were discussed at that time, and a challenge study was redesigned that would be 

able to support the demonstration of an efficacy claim in a non-endemic population such as US 

travelers.

For unrelated business reasons in 2004, the production at Berna ceased. Subsequently, when 

Crucell bought Dukoral® in 2006, they returned the rights of the cholera vaccine to the Center 

for Vaccine Development (CVD) from which PaxVax acquired the right to re-develop CVD-103-

HgR in 2010. The PaxVax BLA for an adult indication was submitted on October 16, 2015 and 

was accepted for filing on December 15, 2015 with a review classification of “Priority.” The 

review goal date June 15, 2016 and this is on track. Proposed labeling feedback is anticipated

by mid-May 2016. No Advisory Committee is planned. 

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The commercial experience is more than 500,000 doses distributed over 10 years. The vaccine 

was well-tolerated, with an excellent safety profile. There have been more than 35 scientific 

publications between 1988 and 2010, which have been provided to the WG. Summarized 

briefly, efficacy in non-endemic populations was demonstrated in healthy volunteer cholera 

challenge studies with a number of cholera strains. The challenges ranged from 8 days to 6 

months following vaccination1

. There were field efficacy studies in endemic populations2. 

Safety, immunogenicity, and dose-finding studies were conducted in developed and developing 

countries3

. Orochol E is a 1 log higher dose, which is not included in the current vaccine 

formulation or application. Special populations include pediatric and HIV4

, and concomitant 

yellow fever (YF), malaria prophylaxis, and oral polio vaccination (OPV)

5 were also studied. 

Safety and immunogenicity of re-immunization at 2.5 and 3.5 years6 following vaccination were 

also studied and published. Interestingly, since there are no data on persistence, the 

seroconversion by serum vibriocidal antibody (SVA) following primary immunization was 81%. 

Following re-immunization, SVA was 57% at 2.5 years and 65% at 3.5 years. Fecal antibodies 

also decreased at 2.5 versus 3.5 years. This suggests that primary immunization elicited longterm local immunologic memory [1 Orochol Historical Studies: Table 1. North America Challenge 

Studies – (El Tor Inaba, El Tor Ogawa, Classical Inaba strains tested); 2 Orochol Historical 

Studies: Table 5. Studies in Cholera Endemic Areas; 3 Orochol Historical Studies: Table 2. RCT 

N. America or European Adults, Table 6: Non-pivotal Safety/Immunogenicity Studies; 4 Orochol 

Historical Studies: Table 3: Pediatric Studies, Table 4: Special Populations; 5 Orochol Historical 

Studies: Table 6: Non-Pivotal Safety/Immunogenicity Studies and Other Studies of Relevance; 

and 6

Kollaritsch et. al. Vaccine 18 (2000) 3031-3039; Levine BMC Biology 2010, 8:129]. 

The following table offers an overview of the current clinical program:

 

Study Objective(s) Design & Type of 

Control

Test Product; Route of 

Administration

Phase 1

Safety

002

Safety and 

immunogenicity

Randomized, 

double-blind, 

placebo-controlled

4 x 108 CFU/dose; 

oral

Phase 3

Challenge

003

Demonstrate 

protection from live 

cholera challenge

Randomized, 

double-blind, 

placebo-controlled

5 x 108 CFU/dose; oral

Phase 3

Lot Consistency 

004

Demonstrate clinical 

lot consistency

Randomized, 

double-blind, 

placebo-controlled

1 x 109 CFU/dose; oral

Phase 3

Older Adult 

005

Demonstrate 

equivalence in immune 

response of older and 

younger adults

Randomized, 

double-blind, 

placebo-controlled

1 x 109 CFU/dose; oral

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The Phase 1 study has been published. It confirmed the safety and immunogenicity of the 

earlier formulation. There was limited shedding and there was no transmission to household 

contacts. The household contacts of the study recipients received fecal swab stool culture and 

antibody tests to determine whether they were exposed to the organism when the vacinee 

brought it home [Clinical and Vaccine Immunology; p. 66 –73; January 2014; Volume 21; 

Number 1].

That supported moving forward with the PXVX-VC-200-003 challenge study to demonstrate 

efficacy at two time points. This pivotal efficacy challenge study used a closely monitored 

human infection model involving the ingestion of virulent V. cholerae O1 El Tor Inaba strain 

N16961 strain at 1 x105 colony forming units (CFU). The primary objective was to determine 

whether a single dose of PXVX0200 provides significant protection against a challenge with 

virulent cholera. The challenge was given at 10 days and 3 months after vaccination. The 

primary endpoint was the development of moderate to severe diarrhea or moderate to severe 

cholera, which was equal to or greater than 3.0 liter purge for the illness. “Severe” was defined 

as a 5.0 liter purge, and “moderate” was defined as 3.0 liter purge. Without rehydration therapy, 

this endpoint would be potentially life-threatening because the plasma volume for an average 

person is 2.5 liters. The success criterion was that the lower two-sided 95% confidence bound 

on protective efficacy must be greater than or equal to 30%. The secondary objectives were to: 

1) evaluate the impact of vaccination on disease severity, total stool volume by weight, 

incidence of diarrhea of any severity, incidence of fever, incidence of fecal shedding of wild type 

V. cholerae, peak concentration V. cholerae detected in stool; and 2) evaluate the tolerability of 

the vaccine. 

In terms of the data, the attack rate for moderate cholera for 3.0 liter liquid stool was 6% in the 

vaccine group challenged after 10 days. Relative to the placebo group at 59%, that is a 

significant reduction. Vaccine efficacy was 90%, with a lower bound of 63%. At the 3-month 

challenge, the attack rate was 12%. Vaccine efficacy was 80%. This study met the primary 

endpoints, with the lower bound over 30%. The subgroup analyses on the primary endpoints 

did not show major differences between blood groups O or non-O, males or females, or black or 

white. Not everyone was selected to be challenged, so there was a group who was followed for 

safety.

Protection was demonstrated for secondary endpoints including diarrhea of any severity 

(defined as >4 loose stools within a 24 hour period), volume of diarrhea, number of loose stools, 

number of days passing loose stools, and a 99% reduction in shedding of the challenge strain in

the vaccine versus placebo groups during the 11 days following challenge. 

Vibriocidal antibodies are a measure of immunity and have been inversely correlated with 

infection with cholera1

. In terms of the SVA against classical Inaba prior to challenge for the 

placebo and challenge groups, peak titers reached about 100-fold greater than baseline at 10 

days after study. While they subsequently declined, there is persistence of the antibody level 

above the placebo or the baseline level [1

M. Pasetti and M. Levine, Clinical and Vaccine 

Immunology, 19(2012) N11 p.1707–1711]. Here are these data following the 10-day postvaccination titers:

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These are the peak antibody titers, this time expressed as the fold increase from baseline on 

the x-axis against cumulative diarrhea by volume on the y-axis. Each subject is marked with a 

P in blue or a V in red, which represents the challenged subjects who received a placebo or 

vaccine. The vaccine recipients had high fold increases on the right and low stool volumes, in 

contrast to placebo recipients whose fold increases did not exceed 4-fold and who had high 

stool volumes.

The serum vibriocidal fold-increase measured on Day 11 was a predictor of protection against 

development of moderate to severe cholera following challenge in Study 003. As expected, 

since the vibriocidal response is thought to be mediated by the LPS, similar results were 

attained when vibriocidal assays were performed with strains representing the other major 

biotypes and serotypes. The GMT percent 4-fold rise for vaccinees and placebos were similar 

to those with the Classical Inaba strain as shown in the following table:

Vibriocidal GMT

Day 11 (95% CI)

Percent With 4-fold Vibriocidal Rise at 

Day 11

Cholera Strain 

used in Serum 

Vibriocidal 

Assay

PXVX0200

N = 94

Placebo

N=102

PXVX0200

N = 94

Placebo

N=102

Classical Inaba 4313* 65 89%* 2%

El Tor Inaba 6898* 63 90%* 4%

Classical 

Ogawa 2324* 94 86%* 3%

El Tor Ogawa 2239* 72 88%* 5%

112 

Challenge Study 003 Post-immunization 

Vibriocidal GMT and Percent 4-Fold Rise

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Equivalence was demonstrated in lot consistency for three lots with approximately 900 subjects 

per group, given that the geometric mean ratios for each pair of lots was 0.78-1.20 which was 

within the pre-specified interval of 0.67-1.5. Safety was also assessed in this 3000 subject 

study (004 Safety Profile). The single dose of cholera vaccine was well-tolerated in this study. 

Reactogenicity signs and symptoms after vaccine administration were reported by 51.90% of 

vaccine and 43.15% of placebo recipients (p=0.0024). There was slightly more reactogenicity in 

the vaccine group, but there were no meaningful differences in reactogenicity across lots. 

There were no significant differences between vaccine and placebo recipients with exception of: 

1) headache reported in 28.93% (791 of 2734) vaccine recipients and 23.62% of (81 of 343) 

placebo recipients (p=0.0419); most were mild (516 vaccine, 50 placebo) or moderate (261 

vaccine, 30 placebo); and 2) diarrhea, which although rare in both vaccine and placebo groups 

was reported 3 times more frequently in vaccine (3.88%) versus placebo (1.17%) (p=0.0079)

recipients.

Most diarrhea was mild or moderate (defined as ≥4 or ≥5 loose stools/24h respectively); severe 

diarrhea was defined as ≥ 6 loose stools/24h and was reported in 0.8% (22 of 2789) vaccine 

recipients and 0.0% (0 of 350) placebo recipients. The median duration of diarrhea was 1 day 

and resolved in all subjects within 2 days of onset. The median day of onset was 2 days after 

vaccination (range 1-7 days). There was one death during the study, which was a suicide that 

was considered to be unrelated, and 20 subjects reported at least one SAE (17 Vaccine, 3 

Placebo) which were all considered to be unrelated to the study.

Since a 4-fold rise in serum vibriocidal titer was correlated with protection, this was used to 

bridge the immune response from an older population to a younger population in which efficacy 

was demonstrated in study PXVX-VC-200-005. This study met the primary endpoints by 

demonstrating with 95% confidence that the seroconversion rate in older adults was within 10% 

of the rate in younger adults, and that the seroconversion rate in older adults was at least 70%, 

which was the pre-specified endpoint.

In terms of the overall reactogencity across all of the Phase 3 studies combined, 3325 vaccine 

and 563 placebo recipients participated in one of the Phase 3 studies. “Any” reactogenicity was 

reported in 50% of vaccinees and 46% of placebo subjects (p=0.06). Most reactogenicty was 

mild or moderate. The breakdown of the solicited post-immunization reactions within 7 days in 

the combined analysis for Studies 003, 004, 005 is shown in the following table:

Symptom

Vaxchora

n=3325

Placebo

n=562 p-value

Malaise 30.0% 29.4% 0.8

Headache 27.8% 26.0% 0.4

Abdominal Pain 18.3% 17.0% 0.5

Nausea 17.4% 15.6% 0.3

Anorexia 15.6% 16.8% 0.4

Diarrhea (≥4 

loose stools/24h) 3.8% 1.6% 0.008

Fever 0.7% 1.1% 0.3

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The vaccine was well-tolerated and there were no significant differences between groups, with

the exception of an approximately 2% increase in diarrhea more frequently in the vaccine group. 

However, that was mostly mild or moderate and was presented because a contributing element 

of that was from the consistency trial.

Adverse events were collected through Day 29 for most studies, with a follow-up period of up to 

181 days in subsets of all of the studies. The most common AEs described are show in the 

following table, and are listed by decreasing order of frequency in the vaccine group:

No meaningful differences were observed between the rates of vaccine and placebo recipients 

reporting unsolicited AEs during study. No SAEs were considered to be related to vaccine. 

The efficacy demonstrated in the human challenge correlates with the vibriocidal immune 

response at 11 days following vaccination. Vibriocidal titers were plotted for the subset of 

subjects from whom blood was taken at Days 29, 91, and 181. At all time points, titers 

remained well above the placebo and respective baseline.

Primed antigen-specific B cells also become memory B cells, which differentiate into antigen 

antibody secreting cells upon antigen re-exposure. Immunoglobulin G (IgG) and 

Immunoglobulin A (IgA) memory B cells from LPB toxin b-subunit (CTb) and toxin co-regulated 

pilus subunit (TcpA) have previously been found in cholera-infected patients for up to a year 

following disease [Harris, J. Infection and Immunity 2009]. The percent of anti-LPS IgA memory 

B cells measured in peripheral blood pre-challenge correlated with protection in the vaccinated 

subjects who were immunized over a challenge on Day 91. For comparison, there were some 

unchallenged vaccinees also in whom memory B cells appear to be induced. For reference, in 

the placebo group who was followed for safety and was not challenged at 170 days postchallenge, there was also a strong induction of memory B cells. So anti-LPS memory B cells 

increase and remain elevated at Day 181, which likely demonstrates an anamnestic response at 

6 months.

In summary, PaxVax redeveloped CVD 103-HgR (PXVX0200, Vaxchora®). It was welltolerated, with no related SAEs; a slight (~2%) increase in diarrhea, most of which was mild to 

moderate; and a similar profile to Orochol®. Protective efficacy against challenge was 90% at 

10 days following vaccination and 80% at 3 months following vaccination. The vaccine was 

found to be immunogenic in healthy adults 18 through 45 years of age and 46 through 65 years. 

There was 90% to 94% seroconversion by SVA to Classical Inaba. Seroconversion also was

demonstrated by SVA with other biotypes and serotypes (Classical Ogawa, El Tor Inaba, El Tor 

Symptom Vaxchora

n=3235

Placebo

n=562

Headache 2.5% 2.7%

Fatigue 2.2% 3.2%

URI 2.1% 2.1%

Back pain 1.4% 1.1%

Flatulence 1.1% 1.8%

Abdominal pain 1.1% 0.9%

Diarrhea (≥4 loose 

stools/24h hr) 0.5% 1.1%

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Ogawa). Vibriocidal serocoversion correlates with efficacy. Vibriocidal Ab levels remained well 

above baseline at Day 181. Anti-LPS memory B cells increase and remain elevated at Day 181. 

Discussion Points

Dr. Stephens asked whether Dr. Danzig could comment further on shedding in terms of other 

family members.

Dr. Danzig replied that in the Phase 1 studied, two subsets were measured every other day for 

the first week and shedding was demonstrated in the vacinees. All household contacts were 

measured with blood draws and fecal swabs or stool cultures, and no transmission of the 

shedding was demonstrated.

Cholera Vaccine GRADE Evaluation and Work Group Plans

Karen K. Wong, MD, MPH

Medical Officer

Division of Foodborne, Waterborne, and Environmental Diseases

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Dr. Wong presented the results of the cholera vaccine GRADE evaluation. She reiterated that 

no cholera vaccine is currently available in the US. Vaccines are available outside the US, but 

these require two doses. CVD 103-HgR, a live-attenuated, single dose oral cholera vaccine 

was previously licensed in other industrialized countries and marketed as Orochol® or Mutacol®, 

before manufacture ceased for business reasons. The company PaxVax acquired the license 

to re-develop this vaccine as VaxchoraTM, which Dr. Wong referred to in this presentation as the 

newer formulation of the vaccine. As noted earlier, a BLA was filed in October 2015 for adults 

18 years of age or older, with an FDA action date expected in mid-June 2016.

The WG examined the following policy question for the GRADE evaluation:

“Should live attenuated oral cholera vaccine CVD 103-HgR be recommended for use in 

adults 18 years of age or older who are at risk of travel-related exposure to toxigenic 

Vibrio cholerae O1?” 

The population includes adults who live in the US and are traveling to cholera-affected areas.

The intervention is CVD 103-HgR administered as a single oral dose. The current option is that 

no oral cholera vaccine is currently recommended or available to adults in the US.

Prior to reviewing the evidence, the WG selected outcome measures to be included in the 

evidence profile. Preventing cholera death, life-threatening cholera diarrhea, and severe 

cholera diarrhea were classified as critical outcomes. Preventing cholera diarrhea of any 

severity and inducing a vibriocidal antibody response were considered to be important 

outcomes. Serious and systemic adverse events and decrease in the effectiveness of coadministered vaccines or medications were considered to be critical outcomes.

The WG conducted a systematic review of PubMed and Embase papers in any language 

published between 1988, when the vaccine was first developed, and January 2016. Efforts 

were made to obtain available unpublished literature. The references of relevant papers were 

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reviewed for additional studies of interest. Articles were included if they presented data on CVD 

103-HgR and involved human subjects, reported primary data, included data relevant to the 

outcome measures being assessed, and included data for a relevant dose. 

In the initial review, 77 studies were identified. Of these, 49 were excluded (41 that either did 

not include CVD 103-HgR data or any primary data, 8 pediatric studies, and 1 cost-benefit 

analysis). This left 28 studies in the GRADE evaluation. Of the 28 studies, there were 3 studies 

of the newer formulation, all of which were RCTs. There were 25 studies of the older 

formulation, including 18 RCTs and 7 observational studies. Of the 28 studies, 5 were cholera 

challenge studies, including 3 RCTs (1 of which used the new formulation) and 2 observational 

studies. The following table summarizes the number of studies, by type, that were available to 

examine the outcomes of interest:

Outcomes for which limited data were available included preventing cholera death, preventing 

life-threatening cholera diarrhea, and decreasing the effectiveness of co-administered vaccines 

or medications. 

The GRADE evidence scoring method begins with an initial evidence type of 1 for RCTs and 3 

for observational studies. Criteria for moving the evidence type down by 1 or 2 points include:

risk of bias, inconsistency, indirectness, imprecision, and publication bias. Criteria for moving 

up by 1 or 2 points include: strength of association, dose response gradient, and opposing 

plausible residual confounding. This leads to a final evidence type for each outcome of 1 

through 4:









1 corresponds to evidence from RCTs or overwhelming evidence from observational 

studies

2 corresponds to RCTs with important limitations, or exceptionally strong evidence from 

observational studies

3 corresponds to observational studies, or RCTs with notable limitations

4 corresponds to clinical experience and observations, observational studies with 

important limitations, or RCTs with several major limitations

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The WG attempted to assess prevention of cholera death as an outcome of vaccination. 

However, cholera challenge studies are not designed to assess this outcome. There was one 

large field study that showed no difference in deaths from diarrhea of any etiology between 

vaccinated and comparison populations. Cause of death was assessed by verbal autopsy in an 

Indonesian population monitored over 4 years. The following table summarizes the challenge 

and field studies, with no differences in deaths detected:

The WG felt that there was insufficient evidence to assess prevention of cholera death by the 

vaccine. There was insufficient evidence to assess prevention of cholera death. Most criteria 

were unable to be assessed.

One RCT addressed the outcome of prevention of life-threatening cholera diarrhea [Chen, 

Cohen et al, 2014]. This study was with the new formulation of the vaccine. Challenge with 

toxigenic V. cholerae O1 in vaccinated and comparison groups was performed at 10 days or 3 

months after vaccination. The risk ratio was less than 1, which suggests a protective effect of 

the vaccine. There was strong evidence from 1 RCT with the newer formulation of vaccine that 

CVD 103-HgR prevents life-threatening cholera diarrhea. The overall evidence type was 1.

There were 3 RCTs that addressed prevention of severe cholera diarrhea [Chen, Cohen et al, 

2014; Tacket et al, 1999; and Richie et al, 2000]. There were 2 challenge RCTs, one of which 

assessed the outcome at multiple time points, that showed a strong consistent reduction in 

severe cholera diarrhea among vaccinated versus comparison individuals. There was one field 

RCT that found no significant difference in severe cholera diarrhea in vaccinated versus

unvaccinated individuals. This study was conducted in Indonesia among children and adults. In 

this study, individuals rather than clusters were randomized. Cholera outcomes were assessed 

by sentinel surveillance over 4 years. Incidence of cholera was low during the study period, 

making detection of an effect difficult. The evidence type for prevention of severe cholera 

diarrhea was downgraded for inconsistency, given that the 1 large field trial showed no effect. 

However, there was strong evidence from other studies with old and new vaccine formulations 

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that the vaccine prevents severe cholera diarrhea. The overall evidence type was determined 

to be 1.

There were 4 RCTs [Chen, Cohen et al, 2014; Richie et al, 2000; Tacket et al, 1999; and Levine 

et al, 1988] and 3 observational studies [Calain et al, 2004; Losonksy et al, 1993; and Tacket et 

al, 1992] that addressed prevention of cholera diarrhea of any severity. There were 5 challenge 

studies, some of which included multiple time points. Of these, 4 showed a statistically 

significant reduction in the proportion of vaccinated versus comparison groups developing 

cholera diarrhea, corresponding to VE ranging from 51% to approaching 100%. In these 

studies, challenge occurred from 8 days to up to 6 months post-vaccination. There was 1 field 

RCT [Richie et al, 2000] that found no difference between vaccinated and comparison 

populations in cholera diarrhea detected by sentinel surveillance over 4 years. Another study 

describing a mass vaccination campaign [Calain et al, 2004] during a cholera outbreak found 

that incidence of cholera diarrhea was lower in vaccinated versus comparison populations. The 

evidence type for prevention of cholera diarrhea of any severity was downgraded for 

inconsistency, as 1 large field trial showed no effect. There was strong evidence from other 

studies with old and new vaccine formulations that CVD 103-HgR prevents cholera diarrhea of 

any severity. The overall evidence type was 1.

Vibriocidal antibodies are the best available marker for protection against cholera. They 

correlate with serogroup-specific (O1 or O139) protection, but protect against both biotypes (El 

Tor, Classical) and both serotypes (Inaba, Ogawa). There were 19 RCTs and 3 observational 

studies that assessed immunogenicity. This figure shows the proportion demonstrating a 

vibriocidal antibody response in vaccinated persons, shown in red, versus comparison persons, 

shown in blue: 

Each row in the above graph represents a study population. Some studies assessed the 

outcome in more than one group or at multiple time points. Some studies did not report 

serology results in an unvaccinated comparison group. There is a horizontal separation 

between results from the vaccinated and comparison groups. This indicates a consistent

vibriocidal antibody response seen in studies with both the older and newer formulations of the 

vaccine. The vaccine efficacy for induction of vibriocidal antibody response from studies with 

the new formulation of the vaccine is 98% or higher. Observational studies with the older 

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vaccine formulation were downgraded for indirectness. However, there was strong evidence 

from studies with old and new formulations that the vaccine induces a vibriocidal antibody 

response. The overall evidence type was 1.

There were 20 RCTs, 4 observational studies, and post-marketing surveillance data that 

examined AEs from the vaccine. For SAEs, there was 1 field RCT that found no difference in 

overall mortality in the vaccinated versus comparison population over 4 years. Overall, there 

were no differences detected between vaccinated and comparison populations for any SAEs. 

For systemic adverse events, there was 1 unpublished RCT with the new vaccine formulation 

that found a slightly higher proportion with diarrhea in vaccinated versus comparison persons. 

Overall, the evidence indicates that systemic adverse events occur at similar rates in vaccinated 

and comparison populations. 

Post-marketing, spontaneously reported, serious unexpected adverse events were rare for 

Orochol®, the older formulation of this vaccine. Of more than 500,000 Orochol® doses

distributed, events included hospitalization with fever, gastroenteritis, vomiting, hemorrhagic 

cerebrospinal fluid in an 11-month old infant; 1 report of Guillain-Barre Syndrome (GBS) in a 

person who received multiple travel vaccines; 1 report of Angioedema; and 1 report of loss of 

hair. Of more than 200,000 Orochol® E doses distributed, there were no spontaneously 

reported adverse reactions. 

Most evidence for serious and systemic adverse events came from studies of an older 

formulation of the vaccine; thus, the evidence type was downgraded for indirectness. There 

have been relatively few recipients of the newer formulation of the vaccine. The evidence type 

for these RCTs was downgraded for imprecision. Overall, SAEs were uncommon, and studies 

with old and new formulations of the vaccine suggest that AEs occur at similar rates in 

vaccinated and comparison populations. The final evidence type was 3 for RCTs and 4 for 

observational studies, and the overall evidence type was 3.

There were 3 RCTs and 1 observational study that evaluated evidence for decrease in the 

effectiveness of co-administered vaccines and medications. No effect was identified on 

antibody response to live attenuated oral typhoid vaccine when co-administered with CVD 103-

HgR. Of people given both vaccines, 62% to 83% developed anti-Typhi antibodies versus 66% 

of people given typhoid vaccine alone. No effect was identified on antibody response to YF 

vaccine when co-administered with CVD 103-HgR. Of people given both vaccines, 100% 

developed anti-YF antibodies. There was 1 additional study that evaluated CVD 103-HgR in 

combination with typhoid, YF, and OPV vaccines, as well as mefloquine, chloroquine, and 

proguanil. There was lower vibriocidal seroconversion in response to the cholera vaccine when 

chloroquine was co-administered with CVD 103-HgR versus CVD 103-HgR alone.

For typhoid or YF vaccine, the evidence type was downgraded for indirectness, as these studies 

used the older formulation of the vaccine. There was no suggestion that CVD 103-HgR 

decreases the effectiveness of typhoid or YF fever vaccines. There was insufficient evidence to 

determine the effect on other co-administered vaccines or medications. The RCTs received a 

final evidence type of 2, and one observational study received a final evidence type of 4. The 

overall evidence type was determined to be 2.

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The following table reflects the full GRADE summary:

Overall, there was insufficient evidence to determine whether the vaccine prevents cholera 

death. The evidence suggests that the vaccine prevents life-threatening and severe cholera 

diarrhea, as well as cholera diarrhea of any severity, with an overall evidence type of 1. The 

evidence suggests that the vaccine induces a vibriocidal antibody response, with an overall 

evidence type of 1. The evidence did not suggest an association between the vaccine and any 

serious or systemic adverse events, with an overall evidence type of 3. The evidence, which 

was available with respect to oral live-attenuated typhoid vaccine and YF vaccine, did not 

suggest that CVD 103-HgR decreases the effectiveness of co-administered vaccines or 

medications. The overall evidence type for this outcome was 2.

In terms of considerations for formulating recommendations for use, cholera is rare in the US. 

Fewer than 25 cases per year have been reported since 2012; however, other years have had 

more cases. There were 42 cases reported in the US in 2011 during a cholera epidemic in 

Haiti, and there was a large outbreak on a flight from Argentina to Peru to the US in 1992. 

Cholera cases in the US are likely underreported. Infections that occur while traveling that 

Outcome Studies Initial 

evidence

Risk of 

bias Inconsistency Indirectness Imprecision Publication Bias Other Final evidence

Overall 

evidence 

type

Prevent 

cholera death

4 RCTs 1 N/A N/A N/A Very serious

(-2) N/A N/A N/A Insufficient 

evidence to 

evaluate 

1 Obs 3 N/A N/A N/A outcome Very serious

(-2) N/A N/A N/A

Prevent lifethreatening 

cholera 

diarrhea

1 RCT 1 No 

serious No serious No serious No serious No serious

Strength of 

assoc. 

(+2)

1 1 

Prevent 

severe 

cholera 

diarrhea

3 RCTs 1 No 

serious

Serious

(-1) No serious No serious No serious

Strength of 

assoc. 

(+2)

1 1 

Prevent 

cholera 

diarrhea of 

any severity

4 RCTs 1 No 

serious

Serious

(-1) No serious No serious No serious

Strength of 

assoc. 

(+2)

1 

1 

3 Obs 3 Serious (-

1) No serious Serious(-1) No serious No serious

Strength of 

assoc. 

(+2)

3 

Induce 

vibriocidal 

antibody 

response

19 RCTs 1 No 

serious No serious No serious No serious No serious

Strength of 

assoc. 

(+2)

1 

1 

3 Obs 3 No 

serious No serious Serious(-1) No serious No serious

Strength of 

assoc. 

(+2)

2 

Serious/syste

mic adverse 

events

20 RCTs 1 No 

serious No serious Serious (-1) Serious (-1) No serious None 3 

3 

4 Obs 3 No 

serious No serious Serious (-1) No serious No serious None 4 

Decrease 

effectiveness

of coadministered

vaccines and

medications

3 RCTs 1 No 

serious No serious Serious (-1) No serious No serious None 2 

2 

1 Obs 3 No 

serious No serious Serious (-1) No serious No serious None 4 

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resolve before return to the US are not captured by US surveillance. Cholera has a short 

incubation period, and little information is available about cases that occur while traveling. 

Cholera can be severe and rapidly life-threatening. The overall risk of cholera is very low for 

most US travelers, and it is treatable if medical services are readily available. However, certain 

populations may be at higher risk of exposure. These may include HCP, outbreak response 

workers, persons visiting friends or relatives, and persons traveling or living in cholera-affected 

areas for extended periods. Certain populations also may be at higher risk of poor outcomes,

including those with low gastric acidity or blood type O, or persons without ready access to 

medical services. It is important to note that sanitation, hygiene, and safe water and food 

remain critical to preventing cholera and other enteric infections. 

Overall, the evidence type is 1 for prevention of cholera diarrhea and induction of a vibriocidal 

antibody response. Overall, the evidence type is 3 for safety as assessed by serious and 

systemic adverse events and 2 for decreasing the effectiveness of co-administered vaccines 

and medications. There are insufficient data to evaluate whether CVD 103-HgR prevents death 

from cholera. Also, there are no data currently available on the safety and efficacy of this 

vaccine in pregnant women. In terms of the balance between benefits and harms, there is 

strong evidence that CVD 103-HgR prevents cholera diarrhea. SAEs were uncommon with the 

older formulation of vaccine. Limited evidence suggests that SAEs are also uncommon with the 

newer formulation. Systemic adverse events occur at similar rates in vaccinated and 

comparison groups. 

High value is placed on the ability to prevent a severe, life-threatening illness in travelers at risk 

of cholera exposure or severe cholera illness, especially if medical care is not readily 

accessible. Cost-effectiveness was not evaluated in this review. Risk of cholera is very low for 

most travelers to cholera-affected areas. Travel vaccines are usually paid for by employers or 

by the travelers themselves, depending upon the circumstances.

The WG has discussed options for draft recommendations. One option is a broad

recommendation: to recommend or consider the vaccine for adults planning to travel to a 

cholera-affected area. Another option is more targeted: to recommend or consider for adults

who are at high risk of exposure (for example, cholera outbreak response workers) or at risk for 

severe illness. 

Based upon review of the evidence for critical and important outcomes, the WG concluded that 

the vaccine is safe and effective. The WG is continuing to discuss a Category A versus 

Category B recommendation, and whether specific risk groups should be emphasized in the 

recommendations. The WG is evaluating evidence for duration of protection and for reimmunization. Evidence is being evaluated from selected subgroups, such as 

immunocompromised persons, separately from this GRADE review. The WG also is evaluating 

pediatric studies separately from this GRADE review, as a summary of these data may be 

helpful to clinicians considering off-label use in persons less than 18 years of age. 

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In conclusion, Dr. Wong reminded everyone that the original policy question assessed by this 

GRADE evaluation was, “Should CVD 103-HgR be recommended for use in adults at risk of 

travel-related exposure to toxigenic Vibrio cholerae O1?” As ACIP considers these questions, 

she asked the members also to consider whether within the policy option, specific risk groups 

should be emphasized, and whether there were additional data that would be helpful to ACIP to 

inform future discussions. 

Discussion Points

Dr. Karron asked whether a lot of data would be available on duration of protection beyond 6 

months.

Dr. Danzig replied that with the historical formulation, she presented re-immunization data from 

2.5 to 3.5 years. PaxVax currently is negotiating final labeling with the FDA. They anticipate 

post-marketing commitments and will be designing them together with the FDA. However, no 

studies have been initiated to date so no data will be forthcoming soon.

Dr. Ezeanolue asked how soon data on pediatrics would be available. He thought she 

mentioned that these data were already available.

Dr. Danzig responded that PaxVax plans to submit the protocol to FDA by the end of 2016, so it 

will take a couple of years before the pediatric data with the new vaccine formulation are 

available. 

Dr. Wong responded that historical data with the older formulation of the vaccine are available 

for pediatric populations, and these will be summarized while awaiting new pediatric data.

Dr. Jeanne M. Santoli

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

During this session, Dr. Santoli presented an update on Pentacel® vaccine. In December 2015, 

Sanofi Pasteur announced a manufacturing delay with Pentacel® vaccine. As a result, Sanofi 

Pasteur is only able to meet approximately 70% of historical Pentacel® vaccine demand 

throughout the first half of 2016. At this time, sufficient supplies of the relevant individually 

administered vaccines DAPTACEL®, ActHIB®

, and IPOL® are available to address the 

anticipated gap in Pentacel® supply.

CDC’s Vaccine Supply/Shortage Webpage can be found at:

http://www.cdc.gov/vaccines/vac-gen/shortages/default.htm

Vaccine Supply

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Julie Lindberg, Pregnant Mother

Delivered in Person and by Letter Submitted to ACIP for the Record

713 Berkeley Ave NW, Atlanta, GA 30318

julielindberg@yahoo.com 

Injury and Death by Vaccines February 24, 2016 

First of all, I want to thank you for your expertise. Thank you for listening to these public 

comments. It is a privilege to be able to speak to you today. 

I am here to talk about your recommendations in general, but first I want to share with you 

something new that affects me personally today. I am pregnant, and my health care provider 

follows your advice to recommend the inactivated flu vaccine and the Tdap. The CDC website 

tells me that the flu shot is safe for me and my child and that it has been shown to protect us 

from the flu. Unfortunately, the manufacturers for every single flu vaccine on the market today 

publicly state the exact opposite, in writing. Currently, Novartis, GlaxoSmithKline, Sanofi 

Pasteur, Protein Sciences Corporation, and bioCSL, state that safety and effectiveness of their 

flu vaccine have not been established for pregnant women. The same is true for Tdap, 

according to Sanofi Pasteur and GlaxoSmithKline. Both available Tdap vaccines, Adacel and 

Boostrix, contain high levels of aluminum. The World Health Organization states that one of the 

risk factors of heavy metal exposure is that it can cause microcephaly.

But I am not here to talk about the flu vaccine or Tdap. Or Brazil. I want to speak to you about 

all your recommendations. I am asking you today to slow down, maybe stop altogether, and 

reexamine the injury and death that all kinds of vaccines have caused. 

Historically, this advisory committee has recommended vaccines that have not undergone 

safety testing with a true placebo, not another vaccine as a placebo, but a placebo that does 

nothing to the human body. You have recommended vaccines that are not tested for long-term 

effectiveness, vaccines that severely disable and kill. Your recommendations are being applied 

in deceptive, abusive, forceful ways, in our own country and across the globe. True informed 

consent is being sidestepped and ignored. This is wrong. I am asking you today to stop and 

challenge one another to look at these issues in the face. 

The history of vaccines, from 1850 to today, particularly in the U.S., does not show that 

vaccines are responsible for the major decline of disease and death. Clean water, proper 

nutrition, effective sanitation, holistic medicine, and compassionate quarantine have saved 

millions of lives. I am asking you to stop and look at a broader view of history. 

You have been given a position of authority and influence. You shape the beliefs and actions of 

people across the world. You influence the law and the economy. Take some time and turn 

your eyes away from the money and the power and the illusions. Both diseases and vaccines 

have ruined lives. Smallpox, polio, diphtheria, pertussis, and SIDS have not been reduced. 

They have been renamed. Prod one another to greater honesty. Take courage and walk away 

from that revolving door. Challenge each other to do what you can to end the harm and 

Public Comment

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heartbreak in the vaccine industry. We can wait for you. We have a multitude of safe options to 

prevent sickness while you take the time to “First Do No Harm.” 

Disease exists in many forms. But it will not win in the end. Be courageous and ask for deeper 

wisdom in these matters. Thank you for your time.

Mara Berger

Parent of Adam Berger, Deceased

Letter Submitted to ACIP for the Record

February 8, 2016

From: Mara Berger, mother of Adam Berger, deceased

Address: 5801 N. Sheridan Road, Chicago, IL 60660

Email: maraberger@hotmail.com

Subject: To Recommend the Conjugate Vaccine to the Adult Population concerning Neisseria 

Meningitidis strain C

This is the third time I'm requesting that the ACIP recommends the conjugate vaccines 

Menactra and Menveo for routine usage in healthy adults 21-55 years old and to healthcare 

personnel for the purpose of protecting them from contracting meningococcal disease/Neisseria 

meningitidis bacterial strains A, C, Y and W135. The ACIP and CDC have never targeted or 

recommended the conjugate vaccines to them, which appears to be intentional and without 

explanation. The fact is that healthy adults and healthcare personnel do contract meningococcal 

disease and can suffer sequelae or die. The ACIP, CDC and HHS are aware that one of them 

who died two years ago was my son, Adam age 44, who was healthy and a nursing student. He 

had contracted Neisseria meningitidis strain C and died within hours. After he died, I did 

extensive research and learned that Neisseria meningitidis is a vaccine preventable disease, 

which would have prevented his untimely and needless death. The ACIP and CDC cannot 

continue to turn a blind eye and ignore the fact that healthy adults as well as those in the 

healthcare field are at risk for meningococcal disease. Unbeknownst to me, many health 

facilities such as the prestigious teaching hospital that Adam worked at in Chicago didn't 

mention meningococcal disease to Adam or recommend the conjugate vaccines for strains A, 

C, Y and W135 because they follow the CDC, which doesn’t recommend the vaccines to adults 

over 21 years or healthcare personnel for routine use. Healthy adults without medical 

conditions are just as at risk to contract meningococcal disease. Does the ACIP and CDC want 

healthy adults to believe that because they're healthy, that they won't contract the 

disease? Anyone, anytime and anywhere can contract dangerous Neisseria meningitidis 

suddenly and even with proper care, can die within hours. That is why it’s most important to 

prevent the disease before it starts with vaccination and adults should have that choice and 

know the risk of not getting vaccinated. I never heard of meningococcal disease or Neisseria 

meningitidis prior to Adam’s death. I feel duped by the CDC. Since the government’s top health 

agencies don’t recommend the vaccine to protect us, why would they educate the public about 

the disease and vaccines to prevent it. They wouldn’t. Therefore, healthy adults and healthcare 

personnel are at risk for the disease. The ACIP and CDC are supposed to make sound medical 

decisions and protect all people and save lives. The conjugate vaccine Menactra was approved 

by the FDA in 2005 for 9-month to 55 year olds for routine usage and Menveo was approved in 

2010 for 9-month to 55 year olds for routine usage. The ACIP and CDC never recommended 

either one for healthy adults 21-55 and healthcare personnel for routine usage. I want to know 

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the scientific or medical reason that the ACIP and CDC have never recommended those 

conjugate vaccines to them. In my opinion, any other excuse or reason would be egregious and 

irresponsible. They refuse to recommend the vaccines, yet, the CDC’s website states that 

Neisseria meningitidis is the leading cause of infectious disease in the United States; that the 

vaccine is safe, immunogenic and effective; that vaccination in adults is low and that there has 

been no decrease of incidence in adults. My research written by an expert in a reputable 

medical journal states that the average age to contract meningococcal disease is 45 years old 

and male although women contract it also. In terms of incidence of the disease resulting in 

mortality or morbidity, the greatest burden of disease is among adults 25-64 years old in which 

60% of the cases and 70% of fatalities occur. The ACIP and CDC omitting that information on 

their website is very troubling because omission is a lie. The federal government appoints 

individuals to represent and protect the public and physicians take an oath to “Do No Harm.” In 

my opinion, much harm has been done over the years. What I already knew, but Health 

Secretary Burwell confirmed in a letter to me stated that “Based on its comprehensive analysis 

of the available evidence, it is possible that ACIP might not recommend an FDA-licensed 

vaccine for routine use. However, physicians or other healthcare providers would still be able to 

administer the FDA-licensed vaccine according to the labeled indications.” Therefore, it 

appears that physicians can act in their patients’ best interests and bring up the subject of 

meningococcal disease and the vaccine to prevent it to their healthy patients and those persons 

entering the healthcare field. If physicians don’t want to supply and store the vaccine, they can 

send their patients to the pharmacy for the inoculations. In my opinion, someone must be held 

accountable and responsible for the intentional and irrational decision to not recommend a lifesaving vaccine to prevent maiming and death. In memory of Adam, I’m going to educate adults 

about the risks of meningococcal disease and the conjugate vaccines to prevent it. I say to the 

ACIP...It’s time to recommend the meningococcal conjugate vaccines to healthy adults 21-55 

and healthcare personnel for routine usage.

Frankie Milley

Founder / National Director 

Meningitis Angels

Letter Submitted to ACIP for the Record

 Meningitis Angels

Website www.Meningitis-Angels.org 

Address PO Box 448, Porter, Texas 77365

Phone 713-444-1074 

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Ref: Meningococcal B Vaccines

Dear Dr. Nancy Bennett and ACIP Committee:

First let me say thank you for you service to all of us for your most important work on vaccines. 

The work you all do insures our country and the world we will be protected from vaccine 

preventable diseases.

Today, I am writing to ask you to strongly consider full recommendations for the use of 

MenACWY vaccines in HIV-infected persons and among men who have sex with men (MSM). 

At the same time though not on the agenda. I am asking you to also reconsider stronger 

recommendations for the use of the meningococcal B vaccines among teens and young adults. 

The US, as you know, is still experiencing outbreaks with the most recent in California. Each 

time this happens another life is at risk. Another family may have to bury a child, as I did 

needlessly, or care for one severely disabled. 

The current recommendation for this age group is not working as well as it should. It leaves 

health care providers confused and afraid of the liability of giving a vaccine not fully 

recommended by the ACIP Committee. The permissive recommendations do NOT allow for 

proper education on the disease and vaccines. Affordability and accessibility due to permissive 

recommendations as always are an issue. 

I am asking the committee to please once and for all to do the right thing. Please give strong 

recommendations for all 3 of the high risk groups listed above. The decision to protect lives 

from disease and death are never the wrong ones. 

Respectfully, Thank You, Frankie Milley, Mom to Ryan, 

Meningitis Angels, National Executive Director

Hollie Smith and Laura Matrka

Letter Submitted to ACIP for the Record

NOTICE OF DENIAL

(To Hollie Smith)

Dear 

Catamaran, an OptumRx company ("OptumRx"), on behalf of L Brands Inc, is responsible 

for reviewing pharmacy services provided to L Brands Inc members. OptumRx received a 

request on 2/1/2016 and reviewed it to provide the following medication, GARDASIL INJ, at 

a zero dollar cost to you. 

http://www.cdc.gov/vaccines/hcp/acip-recs/vaccspecificlindex.html for specific details). 

The reason(s) OptumRx did not approve this medication can be found above. This denial 

is based on the GARDASIL drug coverage policy. 

126 

Why was my request denied? 

This request was denied because you did not meet the following clinical requirements: 

In order for the plan to cover a vaccine at zero copay, the requested vaccine must 

be listed as recommended per the Advisory Committee on Immunization 

Practices (ACIP) guidelines (see

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Advisory Committee on Immunization Practices (ACIP) Summary Report February 24, 2016

What if I need help understanding why my request was denied? 

Contact OptumRx at 8776656609 for assistance with understanding this letter and the 

decision to deny you a service or coverage. 

How can I obtain the material(s) used to review this request? 

You may request, free of charge, a copy of the drug coverage policy, actual benefit 

provision, guideline, protocol or other similar criterion on which the denial decision is 

based, including the diagnosis code and the treatment code and their corresponding 

meanings, by calling OptumRx at 8776656609, or by writing to OptumRx at the address 

below: 

OptumRx Prior Authorization 

Department 

P.O. Box 5252 

Lisle, IL 60532-5252 

All OptumlM trademarks and logos are owned by Optum, Inc. All other brand or product 

names are trademarks or registered marks of their respective owners. 

© 2016 Optum. Inc. All rights reserved. 

Page 3 of 7 02/03/2016 10:08AM (GMT-05:00)

 

To Whom it May Concern:

I am writing to request coverage of the Gardasil vaccine for patient _____________ for the 

condition of Recurrent Respiratory Papillomatosis, caused by HPV strains 6 and 11, for the 

following reasons.

1. Patients with RRP fail to clear the HPV virus, whereas normal people typically clear it 

within 9 months or so. They have an incompletely-understood susceptibility to HPV that 

may put them at increased risk of other HPV-mediated disease such as infection with 

HPV 16 or 18 leading to oropharyngeal or cervical malignancy.

2. Recent data indicates that RRP patients who receive the Gardasil vaccine have a 

decreased number of surgeries per year and a longer interval between surgeries. The 

average interval between procedures in the non-vaccinated group was 271.2 days; after 

vaccination, this increased to 537.4 days. The average number of surgeries per year 

prior to vaccination was 2.16; this dropped to 0.93 surgeries per year after vaccination. 

(Hocevar-Boltezar et al Eur Arch Otorhinolaryngol “Human papilloma virus vaccination in 

patients with an aggressive course of recurrent respiratory papillomatosis.” 

2014;271:3255–3262.)

Decreased number of procedures would lead both to better health for these patients and 

obvious financial benefit to the insurance companies who cover them.

Thank you for your consideration,

Laura Matrka, MD

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Upon reviewing the foregoing version of the February 24, 2016 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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February 18, 2016

Department of Health and Human Services

Centers for Disease Control and Prevention

Advisory Committee on Immunization Practices

July 1, 2015 – June 30, 2016

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

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

HARRIMAN, Kathleen, PhD, MPH, RN

Chief, Vaccine Preventable Disease Epidemiology Section

Immunization Branch

California Department of Public Health

Richmond, CA

Term: 07/01/2012 – 06/30/2016

ACIP Membership Roster

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HARRISON, Lee H., MD 

Professor of Medicine and Epidemiology

Infectious Diseases Epidemiology Research Unit 

University of Pittsburgh

Pittsburgh, PA

Term: 07/01/2012 – 06/30/2016

KARRON, Ruth A., MD

Professor and Director

Center for Immunization Research 

Department of International Health

Johns Hopkins Bloomberg School of Public Health 

Baltimore, MD

Term: 07/01/2012 – 06/30/2016

KEMPE, Allison, MD, MPH

Professor of Pediatrics

Director of Primary Care Fellowship

University of Colorado School of Medicine

Director of Research

Division of General Academic Pediatrics

Director of Children’s Outcomes Research Program

The Children’s Hospital of Denver

Denver, CO

Term: 07/01/2013 - 06/30/2017

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

RUBIN, Lorry, MD

Director 

Pediatric Infectious Diseases

Steven and Alexandra Cohen Children’s Medical Center of New York

North Shore-Long Island Jewish Health System

New Hyde Park, NY

Professor of Pediatrics, Hofstra-North Shore LIJ School of Medicine

Hempstead, NY

Term: 07/01/2012 – 06/30/2016

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

WALTER, Emmanuel (Chip), Jr., MD, MPH

Professor of Pediatrics

Duke University School of Medicine

Durham, NC

Term: 07/01/2015-06/30/2019

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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

Department of Defense (DoD)

SERGIENKO, Eric, MD, MPH

CAPT, 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

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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

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

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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

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

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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

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

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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

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

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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

National Vaccine Advisory Committee (NVAC)

ORENSTEIN, Walt, MD

Chair, NVAC 

Associate Director, Emory Vaccine Center

Emory University

Atlanta, GA

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

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Society for Healthcare Epidemiology of America (SHEA)

WEBER, David, MD, MPH

Professor of Medicine, Pediatrics, and Epidemiology

University of North Carolina Schools of Medicine and Public Health

Medical Director, Hospital Epidemiology and Occupational Health, UNC Health Care

University of North Carolina

Chapel Hill, NC

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