DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION 

Advisory Committee on

Immunization Practices (ACIP) 

Summary Report

June 21-22, 2017 

Atlanta, Georgia 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Table of Contents Page 

Agenda 4-5 

Acronyms 6-9 

Wednesday: June 21, 2017 

Welcome and Introductions 10-13 

Hepatitis Vaccine 

 Introduction 

 Hepatitis A Vaccine Background 

 Cost-Effectiveness Analysis of Catch-Up Hepatitis A Vaccination Among Unvaccinated/Partially 

Vaccinated Children 

 Updated ACIP Routine Recommendations for Use of Hepatitis A Vaccine 

 Updated ACIP Recommendations for Use of Hepatitis A Vaccine and Immune Globulin for PostExposure Prophylaxis and for International Travelers 

14-42 

Influenza 

 Introduction 

 Influenza Surveillance Update 

 Vaccine Effectiveness Update 

 Vaccine Safety Update 

 Flublok® In Pregnancy 

 Public Comment 

 Proposed Recommendations / Vote 

43-73 

Herpes Zoster Vaccines 

 Introduction 

 Zostavax Phase IV Study 

 Zostavax GRADE 

 Herpes Zoster Revaccination Data 

 Cost-Effectiveness Models 

 Consideration for the Use of Herpes Zoster Vaccines 

74-99 

Varicella 

 Impact of the US Varicella Vaccination Program on the Epidemiology of Herpes Zoster 100-105 

Anthrax Vaccine 

 Introduction 

 Anthrax Vaccine Workgroup Information 

106-111 

Vaccine Supply 111-111 

Public Comment 111-123 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Thursday: June 22, 2017 

Tribute to CAPT Jean Smith 123-124 

Agency Updates 

 Centers for Disease Control and Prevention (CDC) 

 Center for Medicare and Medicaid Services (CMS) 

 Department of Defense (DoD) 

 Department of Veteran’s Affairs (DVA) 

 Food and Drug Administration (FDA) 

 Heath Resources and Services Administration (HRSA) 

 Indian Health Services (I HS) 

 National Institutes of Health (NIH) 

 National Vaccine Advisory Committee (NVAC) 

 National Vaccine Program Office (NVPO) 

124-127 

Dengue Virus Vaccines 

 Introduction 

 Dengue Epidemiology in the US and US Territories 

128-133 

Yellow Fever Vaccine 

 Introduction 

 Update on Implementation of IND Protocol and Yellow Fever Vaccine Distribution 

 Review of Protocol Inclusion Criteria and Current ACIP Recommendations 

133-139 

Mumps Disease and Vaccine 

 Introduction 

 Update on Mumps Epidemiology in the United States (2017) and Review of Published Studies of 3rd 

Dose MMR for Mumps Outbreak Control 

 Effectiveness of a 3rd MMR Dose During a Mumps Outbreak in a Highly Vaccinated University 

Population (2015-2016) 

139-152 

Meningococcal Vaccines 

 Introduction 

 Meningococcal Disease and Vaccine Response in Patients Receiving Eculizumab 

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

Disease Outbreaks in the US 

152-162 

Vaccine Adverse Event Reporting System (VAERS) 

 Vaccine Safety: Transition to the New VAERS 2.0 Reporting Form 

162-164 

Public Comment 164-165 

Certification 166 

Membership Roster 167-175 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Acronyms 

AAFP American Academy of Family Physicians 

AAP American Academy of Pediatrics 

ACA Affordable Care Act 

ACCV Advisory Commission on Childhood Vaccines 

ACIP Advisory Committee on Immunization Practices 

ACOG American Congress of Obstetricians and Gynecologists 

ACP American College of Physicians 

ADEM Acute Disseminated Encephalomyelitis 

AE Adverse Events 

AFI Acute Febrile Illness 

AHIP America’s Health Insurance Plans 

aHUS Atypical Hemolytic Uremic Syndrome 

AIGIV Anthrax Immune Globulin Intravenous 

AIM Association of Immunization Managers 

AN Alaska Natives 

ANA American Nurses Association 

ARI Acute Respiratory 

ASM American Society for Microbiology 

BARDA Biomedical Advanced Research and Development Authority 

BIDS Border Infectious Disease Surveillance Program 

BIO Biotechnology Innovation Organization 

BLA Biologics License Application 

BP Blood Pressure 

BSI Bloodstream Infection 

BSPB Bacterial Special Pathogens Branch 

CDC Centers for Disease Control and Prevention 

CFU Colony Forming Units 

CER Cost-Effectiveness Ratio 

CINAHL Cumulative Index to Nursing and Allied Health Literature 

CLD Chronic Liver Disease 

CMS Center for Medicare and Medicaid 

COI Conflict of Interest 

CSTE Council of State and Territorial Epidemiologists 

CVE Center for Vaccine Equity 

DEET N,N-Diethyl-m-toluamide 

DF Dengue Fever 

DHCPP Division of High Consequence Pathogens and Pathology 

DHF Dengue Hemorrhagic Fever 

DHA Defense Health Agency 

DNA Deoxyribonucleic Acid 

DoD Department of Defense 

DSMB Data Safety Monitoring Board 

DSS Dengue Shock Syndrome 

DTaP Diphtheria and Tetanus Toxoid and Pertussis 

DVA Department of Veterans Affairs 

EAP Expanded Access Program 

EIS Epidemic Intelligence Service 

ED Emergency Department 

EHR Electronic Health Record 

EIP Emerging Infections Program 

EMA European Medicines Agency 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

EMR Electronic Medical Record 

EMBASE® Excerpta Medica Database® 

Epi-X Epidemic Information Exchange 

ESG Electronic Submissions Gateway (FDA) 

ESRD End Stage Renal Disease 

FAO (United Nations) Food and Agriculture Organization 

FDA Food and Drug Administration 

FluSurv-NET Influenza Hospitalization Surveillance Network 

GBS Guillain-Barré Syndrome 

GCC (Tom Harkin) Global Communications Center 

gE Glycoprotein E 

GMC Geometric Mean Concentrations 

GMT Geometric Mean Titers 

GRADE Grading of Recommendation Assessment, Development and Evaluation 

GSK GlaxoSmithKline 

GUP General Use Prophylaxis 

HAI Hemagglutinin Inhibition 

HAIVEN Hospitalized Adult Influenza Vaccine Effectiveness Network 

HBsAg Hepatitis B Surface Antigen 

HBV Hepatitis B Vaccine 

HCP Healthcare Personnel 

HCUP Healthcare Cost and Utilization Project 

HD High-Dose 

HEDIS Healthcare Effectiveness Data and Information Set 

HELP (US Senate Committee on) Health, Education, Labor, and Pensions 

HepA Hepatitis A 

HepB Hepatitis B 

HHS (Department of) Health and Human Services 

HMO Health Maintenance Organization 

HPV Human Papillomavirus 

HRSA Health Resources and Services Administration 

hSBA Human Complement Serum Bactericidal Antibody 

HZ Herpes Zoster 

HZ/su HZ Subunit Vaccine 

IAC Immunization Action Coalition 

ICD International Classification of Diseases 

ID Identification 

IDSA Infectious Disease Society of America 

IDU Injection Drug Use 

Ig Immunoglobulin 

IHB Immunization Healthcare Branch 

IHR International Health Regulations 

IHS Indian Health Services 

IIS Immunization Information Systems 

IIV Inactivated Influenza Vaccine 

ILI Influenza-Like Illness 

IND Investigational New Drug 

IPV Inactivated Polio Vaccine 

IT Information Technology 

ITT Intention-To-Treat 

ISO Immunization Safety Office 

JAMA Journal of the American Medical Association 

JEV Japanese Encephalitis Vaccine 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

JID Journal of Infectious Diseases 

KPNC Kaiser Permanente Northern California 

LAIV Live Attenuated Influenza Vaccine 

LLR Log-Likelihood Ratio 

LTPS (SPS) Long-Term Persistence Study 

MedDRA Medical Dictionary for Regulatory Activities 

MCV Meningococcal Vaccine 

MDH Minnesota Department of Health 

MDHHR Michigan Department of Health and Human Resources 

MenB Serogroup B Meningococcal Disease 

MIC Minimal Inhibitory Concentration 

MMR Measles, Mumps and Rubella 

MMWR Morbidity and Mortality Weekly Report 

MSM Men Who Have Sex With Men 

NACCHO National Association of County and City Health Officials 

NAIIS National Adult Influenza and Immunization Summit 

NAPNAP National Association of Pediatric Nurse Practitioners 

NCAI National Coalition of Adult Immunization 

NCEZID National Center for Emerging and Zoonotic Infectious Diseases 

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

NCHS National Center of Health Statistics 

NCIRD National Center for Immunization and Respiratory Diseases 

NEJM New England Journal of Medicine 

NFID National Foundation for Infectious Diseases 

NG Non-Groupable 

NGS Next-Generation Sequencing 

NIAID National Institute of Allergy and Infectious Diseases 

NIH National Institutes of Health 

NIS National Inpatient Sample (HCUP) 

NIS National Immunization Survey 

NNDSS National Notifiable Diseases Surveillance System 

NNT Number-Needed-to-Treat 

NNV Number Needed to Vaccinate 

NVAC National Vaccine Advisory Committee 

NVPO National Vaccine Program Office 

NYC New York City 

ODN Oligonucleotides 

ORISE Oak Ridge Institute for Science and Education 

PA Protective Antigen 

PACCARB Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria 

PCR Polymerase Chain Reaction 

PEP Post-Exposure Prophylaxis 

PhRMA Pharmaceutical Research and Manufacturers of America 

pIMDs Potential Immune Mediated Diseases 

PHL Public Health Laboratories 

PHN Post Herpetic Neuralgia 

PNH Paroxysmal Nocturnal Hemoglobinuria 

PPE Personal Protective Equipment 

PPV Positive Predictive Value 

PrEP Pre-Exposure Prophylaxis 

PSA Probabilistic Sensitivity Analysis 

QALYs Quality-Adjusted Life-Years 

QIV Quadrivalent Influenza Vaccine 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

RCA Rapid Cycle Analysis 

RCT Randomized Controlled Trial 

REMS Risk Evaluation and Mitigation Strategy 

RNA Ribonucleic Acid 

RSV Respiratory Syncytial Virus 

RT-PCR Reverse Transcriptase Polymerase Chain Reaction 

S. aureus Staphylococcus aureus 

SAE Serious Adverse Event 

SAGE Strategic Advisory Group of Experts on Immunization (WHO) 

SAHM Society for Adolescent Health and Medicine 

SASG Slide Agglutination 

SBA Serum Bactericidal Antibody 

SBT Serum Bactericidal Testing 

sBLA Supplemental Biologics License Application 

SME Subject Matter Experts 

SPRT Sequential Probability Ratio Test 

S. pneumoniae Streptococcus pneumoniae 

SPS Shingles Prevention Study 

STPS (SPS) Short-Term Persistence Substudy 

TB Tuberculosis 

Tdap Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis 

TDOC Tauro Deoxycholate 

TIV Trivalent Influenza Vaccine 

TLRs Toll-Like Receptors 

VASP Varicella Active Surveillance Projects 

VZV Varicella Zoster Virus 

UK United Kingdom 

UN United Nations 

US United States 

USVI US Virgin Islands 

VAERS Vaccine Adverse Event Reporting System 

VE Vaccine Efficacy 

VFC Vaccines for Children 

VICP Vaccine Injury Compensation Program 

VRC Vaccine Research Center 

VSD Vaccine Safety Datalink 

VZV Varicella Zoster Virus 

WFS Waterhouse-Friderichsen’s Syndrome 

WG Work Group 

WGS Whole Genome Sequencing 

WHO World Health Organization 

WWII World War II 

YF Yellow Fever 

ZEST ZOSTAVAX® Efficacy and Safety Trial 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

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

Call To Order / Welcome 

Nancy Bennett, MD, MS

ACIP Chair 

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

meeting to order and welcomed those present. 

Overview / Announcements 

Amanda Cohn, MD 

Executive Secretary, ACIP / CDC 

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

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

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

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

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

Chris Caraway. 

She noted that handouts of the presentations were distributed to the ACIP members and were 

made available for others on the tables outside of the auditorium. Slides presented during this 

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

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

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

minutes will be available on the website within approximately 90 to 120 days following this 

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

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

interviews. 

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

(CDC) on Wednesday and Thursday, October 25-26, 2017. Registration for all meeting

attendees is required and may be completed online at www.cdc.gov/acip. The registration

deadline for Non-US citizens is September 25, 2017 and for US citizens registration closes

October 5, 2017. Registration is not required for webcast viewing. As a reminder for nonUnited States (US) citizens attending ACIP meetings, completion of several forms is required for

each meeting at the time of registration. It is important that these forms are submitted within the

required time frame. Stephanie Thomas, the ACIP Committee Management Specialist, will be

able to assist with any questions about the process. Member substitutions and new Liaison and

Ex-Officio representatives announced during this meeting included the following:

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Liaison Representatives 

 Ms. Carol Hayes, representing American Nurses Association (ANA) 

 Dr. Susan Lett, representing the Council of State and Territorial Epidemiologists (CSTE) 

 Dr. Corey Robertson, representing Pharmaceutical Research and Manufacturers of America 

(PhRMA) 

 Dr. Pamela Rockwell will be representing the American Academy of Family Physicians 

(AAFP) 

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

Ex-Officio Members 

 Dr. Angela Shen is representing the National Vaccine Program Office (NVPO) 

 COL Margaret Yacovone is representing the Department of Defense (DoD) 

New ACIP Liaison and Ex Officio Representatives 

 Dr. Linda C. Lambert, National Institutes of Health (NIH) 

 Dr. Caroline Quach-Thanh, Canadian National Advisory Committee on Immunization (NACI) 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

members state any COIs. 

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

beginning July 1, 2018. Detailed instructions for submission of names of potential candidates to 

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

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

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

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

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

complete contact information are required. Questions should be directed to Dr. Cohn or 

Stephanie Thomas. 

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 two ACIP publications since February 2017, which are 

reflected in the following table: 

Visitors / Farewells / Roll Call 

Nancy Bennett, MD, MS

ACIP Chair 

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

 Dr. Wakaba Fukushima, Professor and Chairperson, Department of Public Health, Osaka 

City University Faculty of Medicine, Osaka, Japan 

 Dr. Megumi Matsunaga, Associate Professor, Department of Preventive Medicine, Faculty of 

Medicine, Saga University, Saga, Japan 

 Mr. Kazuya Ito, Research Associate, Department of Public Health, Osaka City University 

Graduate School of Medicine, Osaka, Japan 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

She then wished farewell to and thanked two ACIP members for their service who have 

completed their four-year terms, but agreed to remain until new members are appointed: 

Dr. Allison Kempe 

Dr. Kempe was a fearless leader as the Chair of the Human Papillomavirus (HPV) Vaccines 

Work Group (WG), taking them through a time of great progress and several truly challenging 

decisions. She focused the WG’s attention on new responsibilities as a result of the Affordable 

Care Act (ACA), and pushed them to clarify the impact of their recommendations on health 

equity—a critical consideration. She brought her specific expertise on the realities of 

implementation of vaccine policy—also critical to the WG’s decisions. Finally, she survived the 

Atlanta “snowstorm” during which no snowflakes were observed. However, Dr. Kempe’s 

hometown got six feet of snow that day. Despite all of this, Dr. Kempe has begged for lifetime 

tenure on the ACIP and everyone would love to have her indefinitely. 

Dr. Art Reingold 

Dr. Reingold brought tremendous expertise to the ACIP from his long tenure with the Emerging 

Infections Program (EIP) and as a veteran of the Strategic Advisory Group of Experts on 

Immunization (SAGE). He will be missed tremendously, especially his insightful but disarmingly 

simple questions that seem to summarize the content of any given session. Dr. Reingold also is 

entering the Guinness Book of World Records for having chaired and served on the largest 

number of ACIP WGs. Although he is rarely in the US, he does have a room set aside for him 

in the Tom Harkin Global Communications Center (GCC) at CDC. They knew he was always 

looking for a place to sleep as he has “so few” friends in Atlanta. He will be missed 

tremendously by ACIP, but the waiters at the General Muir are truly heartbroken. 

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

ACIP members had COIs. The following COIs were declared: 

Robert Atmar receives research support from Takeda Vaccines 

The remainder of the ACIP members declared no conflicts 

Dr. Bennett then requested that the Liaison and Ex Officio members introduce themselves. A 

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

the full document from the June 2017 ACIP meeting. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Hepatitis Vaccines 

Introduction 

Art Reingold, MD

Hepatitis Vaccines Work Group 

Dr. Reingold reminded everyone that the last full set of recommendations, Prevention of 

Hepatitis A Through Active or Passive Immunization, was published in 2006. There have been 

several updates since that time relating to specific issues regarding Hepatitis A (HepA) 

vaccination, such as an alternative dosing schedule. Given that the most recent update was in 

2009, those recommendations are ripe for updating. The WG has been working assiduously 

over the past couple of years to assemble the requisite information for ACIP to consider in 

support of the revised recommendations regarding Hepatitis A virus (HAV) infection prevention. 

The WG has considered HepA disease burden and population protection, HepA catch-up 

vaccination for children and teens 2 through 18 years of age, and cost-effectiveness of Hep A 

catch-up vaccination. With that in mind, presentations for this session focused on the following: 

 Hepatitis A vaccine background 

 Cost-effectiveness analysis of catch-up HepA vaccination among unvaccinated and 

partially-vaccinated children 

 Updated ACIP routine recommendations for use of HepA vaccine 

 Updated ACIP recommendations for use of HepA vaccine and immune globulin for postexposure prophylaxis (PEP) and for international travelers 

In terms of next steps, the WG plans to present the full updated HepA vaccine statement for a 

vote in October 2017. In addition, the WG will continue deliberations on adult Hepatitis B 

(HepB) vaccination. 

HepA Vaccine Background 

Noele Nelson, MD, PhD, MPH 

CDC Lead, ACIP Hepatitis Vaccines Work Group

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

Centers for Disease Control and Prevention 

Dr. Nelson discussed HepA epidemiology, background, vaccine recommendations, vaccine 

coverage, an Alaska example, and outbreaks. She indicated that the reported number of acute 

HepA cases in the US has declined substantially. In 2015, 1390 cases were reported. Data 

collection for HepA started in 1966. In 1971, there were approximately 60,000 cases at a rate of 

30 cases per 100,000 population. In 1996 when vaccine was first recommended, there were 

31,000 cases at a rate of about 12 cases per 100,000 population. Between 1996 and 2011, 

there was a 95.5% decline in the rate of cases. In 2015, the rate was about 0.4 and has 

remained stable over the last few years. In terms of the rates of reported acute HepA in the US 

by age, all children 0 through 19 years of age reached 0.3 cases per 100,000 by 2014. This is 

the Healthy People 2020 target. The highest rates are among adults 20 through 29 years and 

30 through 39 years at 0.6 per 100,000. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

The following map shows 2015 state acute HepA incidence compared to the Healthy People 

2020 national goal: 

Of the 50 reporting states, 22 (44%) were at or below the national goal, 28 states were above 

the national goal, and 4 states had rates more than twice the national goal. These states are 

distributed across the country despite the incremental recommendations that have been issued 

in the Western states [National Notifiable Diseases Surveillance System (NNDSS)]. 

About 60% of cases have available data on hospitalizations. The cases hospitalized have 

increased from 2009-2013 from 39.3% to 48%. In 2014, the rate decreased slightly to 45% but 

increased again in 2015 to 47%. That is, close to 50% of cases were hospitalized. A study 

conducted a few years ago assessing the primary discharge diagnosis of HepA in the National 

Inpatient Sample (NIS) from the Healthcare Cost and Utilization Project (HCUP) found that the 

mean age of persons hospitalized for hepatitis A increased significantly over the study time 

period from 37.6 years in 2002-2003 compared to 45.5 years in 2010-2011. This is important 

because disease is worse in older adults. 1This study also showed a number of trends. The 

proportion of HepA hospitalized patients with Medicare coverage increased in 2010-2011 

(22.7%) compared to 2002-2003 (12.4%), had an increase in comorbid liver disease 2010-2011 

(38.3%) compared to 2002-2003 (25.1%), and had an increase in comorbid medical conditions 

in 2010-2011 (38.5%) compared to 2002-2003 (26.8%). However, there were no changes in the 

mean length of stay or in-hospital deaths identified over the study period. 2Another study also 

showed an increase in the percent of HepA cases hospitalized from 1991-2011. Very few 

deaths were associated with HepA. 3Data from the NNDSS also showed that the number of 

deaths reported from HepA were low at about 26 in 2014. [

1Collier MG, Tong X, Xu F. Hepatitis 

A hospitalizations in the United States, 2002 - 2011. Hepatology. 2014 Sep 29; 2Ly et al. JID Jul 

15;212(2):176-82. 2015; 3NNDSS]. 

Based on data from 1999-2000 and 2009-2010, the prevalence of antibody to HepA virus, or the 

seroprevalence, has increased among children due to childhood vaccination. However, it has 

decreased among adults. In children 6 through 11 and 12 through 19 years, there has been a 

significant increase in protection. There has been a minimal change in prevalence among 

adults 20 through 29 and 30 through 39 years of age. However, significant decreases occurred 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

in the proportion of adults with protection for ages 40 through 60 years of age. The overall 

prevalence of antibody among US residents remained about the same between the two surveys 

at 31.2% for 1999-2000 and 26.5% for 2009-2010, indicating that less than 1/3 of the US 

population had protection against HepA in 2009-2010 [NHANES, National Health and Nutrition 

Examination Survey; Murphy TV et al. Progress Toward Eliminating Hepatitis A Disease in the 

United States. MMWR Suppl. 2016 Feb 12;65(1):29-41]. 

The risk factors for HepA include international travel, food/waterborne outbreaks, men who have 

sex with men (MSM), injection drug use (IDU), sexual/household contact with HepA-infected 

persons, child/employee in a daycare center, contact with a daycare child or employee, and 

other contact with an HAV-infected person. These risk factors have informed the HepA vaccine 

risk group recommendations. 

In the US, HepA vaccines are inactivated. These include the following: 

 Monovalent: Merck CR326F strain, VAQTA® 

 Monovalent: GSK HM175 strain, HAVRIX® 

 Combination: GSK HM175 strain and recombinant hepatitis B surface antigen (HBsAg), 

TWINRIX® 

The efficacy of HepA vaccines were studied in 1995 and 1996. Of approximately 1000 children 

2 through 16 years of age in the Merck VAQTA® study, 100% were protected with 1 dose in a 

community while living in a community with a high HAV infection rates. The efficacy of 

HAVRIX® in protecting against clinical HAV infection was 94% among approximately 38,000 

Thai children 1 through 16 years of age who received 2 doses 1 month apart while living in 

villages with high infection rates [1Werzberger, A et al. New Engl J Medicine. 1992;327:453–7; 

2Innis BL, et al. JAMA 1994;271:1328–34]. 

HepA vaccines are administered in a 2-dose schedule. VAQTA® is given on a 0, 6-18 month 

schedule and HAVRIX® on a 0, 6-12 month schedule. Of note when HAVRIX® was first 

licensed, it was given in a 3-dose schedule of 360 EL.U. per dose, which is one-half of the 

number of units given currently. The 3-dose schedule has been determined to be equivalent to 

the 2-dose schedule. TWINRIX® is licensed only for adults 18 years of age and older on an 

accelerated dosing schedule of 4 doses (1 mL each) given on days 0, 7, and 21-30 followed by 

a booster dose at month 12, particularly for travel. TWINRIX® cannot be used for PEP because 

of the decreased dose of the HepA vaccine component [Fiore AE, Wasley A, Bell BP. 

Prevention of hepatitis A through active or passive immunization: recommendations of the 

Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006 May 

19;55(RR-7):1-23]. 

In pre-licensure trials, adverse reactions to HAVRIX®, VAQTA®, and TWINRIX® were mostly 

injection site reactions and mild systemic reactions. The most frequent side effects are 

soreness or erythema at the injection site, fever, headache, and malaise. Multiple studies 

demonstrate no serious adverse events (SAE) definitively attributed to inactivated vaccine. 

Post-marketing surveillance for AEs following receipt of HepA vaccines has been performed 

primarily by two systems in the US, the Vaccine Adverse Event Reporting System (VAERS) and 

the Vaccine Safety Datalink (VSD). Recent analyses of these data show no unusual or 

unexpected safety patterns for any of the HepA vaccines. VAERS pregnancy reports following 

HepA were reviewed and no patterns of concern were observed [MMWR 2006;55(RR-7) IOM 

2011. Moro PL, et al. Am J Obstet Gynecol. 2014 Jun;210(6):561.e1-6]. Currently, the VSD is 

conducting an ongoing safety study of HepA and HepB vaccines in pregnant women. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

The contraindications of HepA vaccines include a history of severe allergic reaction to a 

previous dose of HepA vaccine or vaccine component. Precautions include vaccination of 

persons with moderate or severe acute illness, with or without fever, in whom HepA vaccine 

should be deferred until illness resolves as is the case with other vaccines [Fiore AE, Wasley A, 

Bell BP. Prevention of hepatitis A through active or passive immunization: recommendations of 

the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006 May 

19;55(RR-7):1-23]. 

The duration of protection after vaccination is unknown. Anti-HAV has been shown to persist in 

vaccine recipients for at least 20 years in adults administered inactivated vaccine as children 

with a three-dose schedule. Detectable antibodies are estimated to persist for 40 years or 

longer based on mathematical modeling and anti-HAV kinetic studies. Protection following 

natural infection is lifelong and may also be lifelong following vaccination [Theeten H, et al. 

Vaccine. 2015 Oct 13;33(42):5723-7. Plumb ID, et al. Viral Hepat. 2017;00:1–5]. 

HepA vaccination recommendations were introduced incrementally in the US from 1996-1999. 

In 1996, vaccine was recommended for children at age 2 years in communities with high rates 

of disease and children through teen years in outbreaks. In 1999, vaccine was expanded to 

include children at age 2 years of age in 11 states with average annual HepA rates of two times 

the national average or >20 cases per 100,000 population. Vaccination was to be considered in 

6 states with rates above the national average or >10 cases per 100,000 population. Notably, 

all of these states were in the Western region of the country [MMWR 1996;45(RR-15); MMWR 

1999;48(RR-12); MMWR 2006;55(RR-7)]. 

In 2006, childhood vaccination was recommended for routine use at 12 through 23 months of 

age in all states. Vaccination programs for children 2 through 18 years of age were 

recommended to continue, which refers primarily to the Western states that had the higher rates 

of cases. Catch-up vaccination was to be considered in outbreaks and areas with increasing 

disease rates and for any person wishing to obtain immunity. However, no routine catch-up 

recommendation was made for children ages greater than 23 months [MMWR 2006;55(RR-7)]. 

ACIP HepA vaccine recommendations include groups at increased risk of HAV infection or 

severe HAV disease, including travelers, MSM, users of injection and non-injection drugs, 

persons with clotting-factor disorders, persons who work with non-human primates, persons 

who anticipate close personal contact with an international adoptee, persons with chronic liver 

disease (CLD), and healthy persons 12 months through 40 years of age for PEP [MMWR 

1996;45(RR-15); MMWR 1999;48(RR-12); MMWR 2006;55(RR-7)]. 

Vaccine coverage for HepA is the lowest among childhood vaccines for children 19 through 35 

months of age based on National Immunization Survey (NIS) data for 1994-2014. In 2014, 2-

dose coverage for HepA vaccine among children 19 through 35 months of age was 57.5%. In 

2015, HepA ≥ 1-dose coverage was 85.8% and ≥ 2-dose coverage was 59.6%. The Healthy 

People 2020 goal is 85% for 2-dose coverage, so the 2-dose coverage is still well below that 

goal [Hill HA, Elam-Evans LD, Yankey D, Singleton JA, Dietz V. Vaccination Coverage Among 

Children Aged 19-35 Months - United States, 2015. MMWR Morb Mortal Wkly Rep. 2016 Oct 

7;65(39):1065-1071. doi: 10.15585/mmwr.mm6539a4. PubMed PMID: 27711036]. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

In 2013, national vaccination coverage for 1 and ≥2 doses of HepA vaccine among adolescents

13 through 17 years of age was 62.5% and 51.0%, respectively [unpublished]. The ≥2-dose 

coverage for adults ages 19 through 49 years was low at 12.1% overall, 18.8% among travelers, 

8.1% among non-travelers, and 18.2% among persons with CLD based on 2014 data. As a 

reminder, travelers and persons with CLD are considered high-risk groups for whom vaccine is 

recommended [Williams WW, Lu PJ, O'Halloran A, Kim DK, Grohskopf LA, Pilishvili T, Skoff TH, 

Nelson NP, Harpaz R, Markowitz LE, Rodriguez-Lainz A, Fiebelkorn AP. Surveillance of 

Vaccination Coverage among Adult Populations - United States, 2015. MMWR Surveill Summ. 

2017 May 5;66(11):1-28]. 

One example of vaccine implementation comes from Alaska where from 1950-1990, there were 

cyclic HAV epidemics every 10 to 15 years. Of Alaska Natives (AN) born before 1945, 85% 

were anti-HAV positive. Universal HepA vaccination was introduced in 1996 for persons 2 

through 14 years of age. In 1997, the age was expanded to persons 2 through 18 years of age. 

In 2001, HepA vaccination became a daycare and school attendance requirement. For the 

remainder of the country in 2006, the recommendation was for persons 12 through 23 months of 

age. In 2006, the age was expanded to 1 through 18 years of age. From 2002-2007, an 

estimated 2052 symptomatic cases were prevented with vaccine. In 2006, there was 65% ≥1 

dose vaccine coverage among AN children 2 through 18 years of age. By 2008, there was 94% 

2-dose coverage among AN children 11 through 17 years of age. This resulted in a 99.9% 

reduction in cases among AN people at 0.3/100,000 persons, which is the current Healthy 

People 2020 goal. This illustrates that transmission in Alaska was halted due to high 

vaccination coverage, routine childhood vaccination, and mandatory school vaccination. 

To highlight some recent outbreaks, there was a multi-state outbreak associated with frozen 

pomegranate arils imported from Turkey in 2013. Of 165 cases, 7% were among people <18 

years of age and 93% were among people ≥18 years of age. In terms of complications, 42% 

were hospitalized, there were 2 cases of fulminant hepatitis, and 1 case required a liver 

transplant [Collier MG, et. al. Outbreak of hepatitis A in the USA associated with frozen 

pomegranate arils imported from Turkey: an epidemiological case study. Lancet Infect Dis. 2014 

Oct;14(10):976-81]. A cost analysis of this outbreak was performed, which estimated that the 

per-patient cost of healthcare and productivity loss was approximately $13,500 for hospitalized 

and approximately $2000 for non-hospitalized patients and about $1.3 million for all 165 

outbreak-related cases. State and local public health personnel expenditures included 82 hours 

and about $3200 per outbreak-related case. While this was not a large number of cases, the 

public health resources and expenditures were substantial. 

In 2016, there was a food-associated outbreak in Hawaii. On August 15, 2016, the Hawaii 

Department of Health (HDOH) identified raw scallops served at Chain A restaurants on Oahu 

and Kauai as a likely source of the ongoing outbreak. The product was Sea Port Bay Scallops 

(Wild Harvest, Raw Frozen) that originated in the Philippines and were distributed by Koha 

Oriental Foods and True World Foods. The product was embargoed and there was a temporary 

closure of all Chain A restaurants on Oahu and Kauai. As of January 11, 2017 there were 292 

confirmed cases and 74 hospitalizations. The onset of illness occurred between 6/12/16 to 

10/9/16 [http://health.hawaii.gov/docd/hepatitis-a-outbreak-2016/].

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Also in 2016, there was a multistate outbreak of HepA linked to frozen strawberries in 9 states. 

The likely source was frozen strawberries imported from Egypt. The location was Smoothie 

Restaurant A Cafés. The product was removed on August 8, 2016. As of September 28, 2016 

there were reports from 143 people with HepA from 9 states. Of these cases, 129 reported 

eating a smoothie from Smoothie Restaurant A Café, 14 had no direct exposure to Tropical 

Smoothie Café, 12% were <18 years of age, and 88% were ≥18 years of age. The age range of 

cases was 12 through 70 years of age. Of these cases, 56 were hospitalized and there were no 

deaths [http://www.vdh.virginia.gov/blog/2016/09/10/hepatitis-a-investigation; and 

www.cdc.gov/hepatitis/outbreaks/2016/hav-strawberries.htm]. 

There have been outbreaks in 2017 in San Diego, Southeast Michigan, Colorado, and New 

York City as follows: 

San Diego 

 160 total confirmed or probable outbreak-associated cases 

 Hospitalizations: 120 (75%) 

 Deaths: 4 (2.5%) 

 Primarily in homeless individuals and/or IDU 

 Secondary infections in inmates 

Southeast Michigan 

 144 total confirmed, probable, or secondary outbreak associated cases 

 Hospitalizations: 121 (84%) 

 Deaths: 9 (6%) 

 Primarily in homeless individuals and IDU 

Colorado 

 26 cases 

 Gender: 72% are male 

 Age: median 52 years 

 Primarily in MSM, second cluster in females who consumed smoothies 

New York City 

 16 cases 

 Primarily in MSM 

 Linked to HAV strains circulating in Europe 

In summary, HepA vaccine is largely responsible for the marked reduction in HepA cases. 

However, an increasing proportion of adults in the US are susceptible to HAV. This is due to 

reduced exposure to HAV early in life and significant decreases in seroprevalence in older 

adults ≥ 40 years. In addition, there is low 2-dose vaccination coverage among adults, including 

high risk adults (travelers 18.8%; CLD 18.2%). Morbidity and mortality increases with age. The 

mean age of persons hospitalized for HepA increased significantly from 2002-2003 to 2010-

2011. Hospitalization rates for reported HepA cases increased from 2005 to 2011. There is 

suboptimal HepA vaccination 1- and 2-dose coverage among young children as well, and there 

is no routine HepA vaccine recommendation for adolescents or adults. HAV remains endemic 

in many areas of the world resulting in ongoing risks for travelers to intermediate and high 

endemic countries, as well as the risk for consumption of imported HAV contaminated food from 

global sources. Of note, herd immunity does not protect against foodborne exposure. 

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Regarding the timeline, from February to April 2015, the ACIP Hepatitis Vaccines WG discussed 

HepA vaccination, including the methods and results of this study. The results of the study were 

published in July 2016 in Vaccine1. The ACIP Hepatitis Vaccines WG resumed discussing the 

findings, both these and others, in the context of HepA catch-up vaccination from March to May 

2017 [

1 Hankin-Wei A, Rein DB, Hernandez-Romieu A, Kennedy MJ, Bulkow L, Rosenberg E, 

Trigg M, Nelson NP. Cost-effectiveness analysis of catch-up hepatitis A vaccination among 

unvaccinated/partially-vaccinated children. Vaccine. 2016 Jul 29;34(35):4243-9]. 

 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Cost-Effectiveness Analysis of Catch-Up HepA Vaccination 

Among Unvaccinated and Partially Vaccinated Children 

David B. Rein, PhD, MPA 

Director, Public Health Analytics Program

NORC at the University of Chicago 

Dr. Rein reported on work that he did for the Hepatitis Vaccines WG in 2015. He emphasized 

that the motivation behind the cost-effectiveness analysis of catch-up HepA vaccination among 

unvaccinated and partially vaccinated children was that a large population of adolescents and 

young adults remain unvaccinated against HepA. Due to lower rates of incident infection in 

childhood, there are lower rates of disease-acquired HAV immunity among the US adult 

population. This increases vulnerability to outbreaks. Several HAV outbreaks due to 

contaminated food have been observed as well. An interesting point to note about HepA is that 

the severity of HAV symptoms increases with age of infection. Decreased incidence leads to 

older average age of infection, which has been observed to lead to more severe outcomes 

when infection occurs. Consequently, catch-up vaccination may be necessary due to 

decreasing population anti-HAV seroprevalence. HepA vaccine is the only vaccine on the 

childhood vaccination schedule without a catch-up recommendation. In order to contemplate a 

recommendation change regarding catch-up, the cost-effectiveness of catch-up vaccination 

needed to be assessed. This study assessed the cost-effectiveness of a one-time, age-cohortbased, catch-up vaccination campaign for US children 2 through 17 years of age. 

In terms of the methods for the cost-effectiveness study, a previously published Markov model 

of HepA vaccination was utilized that was used for the 2005 ACIP HepA vaccination 

discussions. The study tested the cost-effectiveness of a policy of catch-up HepA vaccination of 

unvaccinated and partially vaccinated children as compared to no catch-up, with catch-up 

defined as a probability and cost of two doses of HepA vaccine for children with no 

documentation of previous vaccination, and a separate probability and cost of a second dose for 

children with documentation of only a single prior dose. 

Simulated outcomes were used in succession for each age from 2 to 17 and outcomes and 

costs were summed in Excel to calculate final results. The model simulated patient progression 

between eight possible HAV-related states based on the probability of vaccination, HAV 

infection, and health complications due to vaccination or infection. Model parameters included 

vaccine costs, rates of HAV infection, probability of disease complications and associated 

healthcare costs, gradual loss of vaccine-acquired immunity following vaccination, public health 

costs for an HAV-associated outbreak, costs of productivity loss, and all-cause probability of 

death due to non-HAV causes among the lifespan of the age cohort. Costs and quality-adjusted 

life years (QALYs) were assigned by state annually [Rein DB, Hicks KA, Wirth KE, Billah K, 

Finelli L, Fiore AE, et al. Cost-effectiveness of routine childhood vaccination for Hepatitis A in 

the United States. Pediatrics 2007;119:e12–21]. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

The following figure shows the different states included in the model: 

All persons start the model in a susceptible, non-immunized state when born. From that point, 

their lives are simplified into two possible outcomes. They could be infected or not be infected 

and have a probability of vaccination: 1) Those who are infected develop either asymptomatic 

or mildly symptomatic anicteric HepA. The mildly symptomatic cases can incur some work loss 

or outpatient visits with small costs, and then go on to being immune due to disease immunity; 

or 2) Those who are icteric cases with more severe outcomes, including more extensive 

outpatient visits, hospitalization, or fulminant disease. Fulminant disease could result in a liver 

transplant, death, or resolve on its own. Those who are vaccinated acquire immunity, but have 

a probability of losing vaccine-acquired immunity at different stages in their lives from 1 year to 

95 years following vaccination, at which point they become susceptible and immunized. There 

also is a chance that people who developed asymptomatic infection not detected would be 

vaccinated again and incur those costs. 

Like all simulation models, the model is governed by a series of parameters. In terms of 

incidence, probably the most important parameter in the model, the average national incidence 

between 2008 to 2012 was used. This was increased somewhat because the model’s baseline 

settings from when the model was built in the early 2000s would not allow an incidence lower 

than 1 case per 100,000. An incidence of 1 case per 100,000 was used. Unlike earlier 

recommendations, there is no current evidence of regional variation. The annual incidence for 

under-reporting was adjusted using a ratio of 1.95 unreported cases for every 1 reported case 

observed. This also is lower than previous analyses and comes from recent work. The 

probability of symptomatic disease increased with age according to published estimates. The 

distribution of disease severity was updated based on surveillance data, and loss of vaccineacquired immunity was updated by year estimated based on new data obtained from Alaska 

[Klevens RM, Liu S, Roberts H, Jiles RB, Holmberg SD. Estimating acute viral hepatitis 

infections from nationally reported cases. Am J Public Health 2014;104:482–7; Van Herck K, 

Van Damme P. Inactivated hepatitis A vaccine-induced antibodies: follow-up and estimates of 

long-term persistence. J Med Virol 2001;63:1–7; Armstrong GL, Bell BP. Hepatitis A virus 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

infections in the United States: model based estimates and implications for childhood 

immunization. Pediatrics 2002;109:839–45; Rein DB, Hicks KA, Wirth KE, Billah K, Finelli L, 

Fiore AE, et al. Costeffectiveness of routine childhood vaccination for Hepatitis A in the United 

States. Pediatrics 2007;119:e12–21; Taylor RM, Davern T, Munoz S, Han S-H, McGuire B, 

Larson AM, et al. Fulminant hepatitis A virus infection in the United States: incidence, prognosis, 

and outcomes. Hepatol Baltim Md 2006;44:1589–97; McMahon BJ, Williams J, Bulkow L, 

Snowball M, Wainwright R, Kennedy M, et al. Immunogenicity of an inactivated hepatitis A 

vaccine in Alaska Native children and Native and non-Native adults. J Infect Dis 1995;171:676– 

9]. 

In terms of existing coverage levels, NIS estimates for children 19 through 35 months and 13 

through 17 years of age was used. Age-specific coverage was estimated linearly based on the 

two estimates by literally drawing a line between the mid-points of those two estimates and 

using the slope of that line to linearly estimate the expected vaccine coverage rates for each 

individual age between ages 2 through 17. For catch-up vaccination, an assumption was made 

because there is no comparable catch-up program to estimate vaccine uptake. Therefore, an 

assumption was made that 50% of those unvaccinated and unaware of prior infection would 

receive the first dose of vaccine, and that 50% of those who received the first dose would 

receive the second dose. For adult vaccination, it was assumed that adults 18 through 64 years 

of age were vaccinated at a rate of 0.5% per year based on proprietary sales data generously 

provided by GlaxoSmithKline (GSK) [Centers for Disease Control and Prevention (CDC). 

Hepatitis A vaccination rate weighted estimates for 19–35-month-old children in U.S. 50 States 

+ DC, 2003; Centers for Disease Control and Prevention (CDC). Hepatitis A vaccination rate 

weighted estimates for 13–17-year-old children in U.S. 50 States + DC, 2008 

Trofa A, personal communication, 2 April 2015]. 

QALYs were updated using Global Burden of Disease (GBD) study values. Basically, the 

morbidity weight was applied to different disease states based on the viral hepatitis stages 

estimated in the GBD study. Costs were updated using four case studies of US HepA 

outbreaks for mild symptomatic disease, unreported icteric infection, reported icteric infection, 

hospitalization, and fulminant liver failure with and without transplant. Productivity losses were 

estimated for parents/caregivers and death from HAV. The model used a lifetime time horizon 

and a 3% annual discount rate [2011 Health Care Cost and Utilization Report | HCCI n.d. 

http://www.healthcostinstitute.org/2011report (accessed August 31, 2015); Bownds L, 

Lindekugel R, Stepak P. Economic impact of a hepatitis A epidemic in a mid-sized urban 

community: the case of Spokane, Washington. J Community Health 2003;28:233–46; Berge JJ, 

Drennan DP, Jacobs RJ, Jakins A, Meyerhoff AS, Stubblefield W, et al. The cost of hepatitis A 

infections in American adolescents and adults in 1997. Hepatology 2000;31:469–73; Dalton CB, 

Haddix A, Hoffman RE, Mast EE. The cost of a food-borne outbreak of hepatitis A in Denver, 

Colo. Arch Intern Med 1996;156:1013–6; and Rein DB, Hicks KA, Wirth KE, Billah K, Finelli L, 

Fiore AE, et al. Cost-Effectiveness of Routine Childhood Vaccination for Hepatitis A in the 

United States. Pediatrics 2007;119:e12–21. doi:10.1542/peds.2006-1573]. 

As a reminder, incremental difference in costs and QALYs are reported from cost-effectiveness 

studies. The incremental cost-effectiveness ratio is a measure of the incremental difference in 

costs and QALYs between the intervention scenario (in this case, catch-up vaccination) minus 

the baseline scenario (in this case, no catch-up). Costs are assessed in terms of differences in 

vaccine costs, vaccine administration costs, HAV infection and adverse event-related medical 

costs, productivity losses, and public health response costs. Sensitivity analyses were 

performed for the 10-year-old cohort, the midpoint age for catch-up vaccination. Threshold 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

analyses were conducted for disease incidence to determine the incidence that would be 

required to reach certain cost-effectiveness thresholds. 

The following table summarizes outcome measures per age cohort included in the analysis, and 

for all age cohorts pooled together: 

To summarize that information, across all ages 2 through 17, the incremental costs or extra 

costs expected to be associated with catch-up vaccination was $146 million including all 

discounting. The incremental QALYs that would be gained from that were 357. This resulted in 

an overall incremental cost-effectiveness ratio (ICER) of approximately $430,000 per QALY, 

with an ICER range by age of about $190,000 to $750,000. The following graph shows the 

ICER results by age for each individual age cohort: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

In terms of some examples of the results for the Age 10 Cohort, catch-up vaccination reduced 

total HAV infections by 741, with 556,989 additional vaccine doses administered. For every 752 

additional doses administered, one case of HAV infection would be averted. Catch-up 

vaccination increased total discounted QALYs across the 10-year-old cohort by 23, or 0.000006 

QALYs per person. Catch-up vaccination increased net costs by $10.2 million or $2.38 per 

person. The catch-up vaccination intervention increased vaccine and administration costs for 

children, but decreased these costs for adults, as individuals vaccinated by the catch-up 

campaign would not require HAV vaccination in adulthood. The incremental cost of the HAV 

vaccine catch-up at age 10 years was $452,239 per QALY gained. 

Looking across all of the results, cost-effectiveness of catch-up vaccination decreased with the 

age of the cohort targeted for vaccination, with catch-up becoming more cost-effective when 

targeting children in late adolescence. This effect was due to several factors: 

 Higher probability of symptomatic disease among older children 

 Less discounting of future costs of disease 

 Vaccination of older children, which averted the need for higher-cost adult vaccination with 

less delay in averting these costs 

The cost-effectiveness of catch-up vaccination was most favorable at age 12 years, resulting in 

an ICER of $190,000 per QALY gained. The model assumes that the administration costs of 

HepA vaccination were split with other vaccines routinely administered at age 12 years, thus 

lowering the cost of vaccination. 

The results were most sensitive to the following: 

 Discount rate: ICER = $24,000/QALY when the discount rate is 0% 

 Cost of child vaccine in the public and private market 

 Annual rate of adult vaccination; catch-up is more cost-effective when it is assumed to 

replace more adult vaccination 

 Incidence at baseline of 1/100,000, with ICER being $47,000 at an incidence of 5/100,000 

and cost-saving at an incidence of 12/100,000 

These results were similar to and consistent with the results found in the 2005 analysis when 

discussing the national recommendation. Results were insensitive to the rate of catch-up 

adoption, QALY decrements, and rate of loss of vaccine acquired immunity. 

The study has several limitations, as all modeling studies have. The values of certain 

parameters used in the model are uncertain. The most important among these are the rates of 

HepA vaccine catch-up uptake and adult vaccination rates. Sensitivity analyses indicate that 

the ICER of catch-up is insensitive to uptake, but is sensitive to the adult vaccination rate. 

Since catch-up vaccination is assumed to replace adult vaccinations, as the annual rate of adult 

vaccination increases, the cost-savings associated with replacing more expensive adult vaccine 

with less expensive children’s formulations increases. However, some of that is diminished if 

people would be vaccinated again as adults. The annual rate of adult vaccination might be 

underestimated because adult vaccination data could be obtained only from GSK at the time of 

the study. The model output is based on HepA incidence from 2008 to 2012, and the costeffectiveness conclusions are tied to factors related to disease transmission patterns, which 

may change over time and alter future cost. Only the current US ACIP two-dose 

recommendation was used. World Health Organization’s (WHO’s) SAGE has advised that 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

national immunization programs may consider inclusion of single dose HepA vaccine in 

immunization schedules. Herd immunity effects of vaccination were excluded from the model; 

however, previous analyses indicate that herd immunity associated with routine vaccination 

would result in even lower incidence and less favorable cost-effectiveness for catch-up. 

In conclusion, the findings suggest that given the current US HAV disease incidence, a catch-up 

vaccination program would not be cost-effective at thresholds of $50,000, $100,000 or $200,000 

per QALY saved. The ICER of vaccination falls below $50,000/QALY saved at an HAV 

incidence of 5.0 cases per 100,000 persons. The incremental cost per QALY given current US 

HAV disease incidence ranged from a low of $190,000 per QALY gained at age 12 years to a 

high of $725,000 per QALY gained at age 4 years. Relative to the cost per QALY projected for 

hepatitis A catch-up vaccination, studies assessing the economic impact of catch-up 

interventions for other vaccinations show lower cost per QALY. The improved costeffectiveness of these catch-up vaccination interventions (e.g., HPV vaccine, meningococcal 

conjugate vaccine) relative to HepA are driven by higher baseline disease incidence, higher 

case-fatality ratio, and higher costs of care for complications. Because incidence is so low, the 

cost-effectiveness of catch-up vaccination is poor. However, catch-up vaccination could be 

justified based on offsets to adult vaccination if such substitution occurs. There may be other 

important reasons to consider catch-up vaccination. 

Discussion Points 

Regarding the baseline incidence of 1/100,000, Dr. Atmar pointed out that from the 

epidemiological data, the incidence appeared to be 0.06 or lower for most age groups. He 

wondered whether that would make the ICER even higher. 

Dr. Rein replied that it would make the ICER higher. 

Given that this modeling is of a cohort of children and adolescents, Dr. Kempe said she was 

having difficulty understanding how the herd immunity which affects the elderly, who are the 

expensive cases, is taken into account or if this is not included in the model. 

Dr. Rein replied that no herd immunity effects were accounted for in this modeling exercise. 

Dr. Reingold noted that while the assumption was made in the model that 50% of the children 

who receive a catch-up vaccination would get only one dose, the data in Dr. Nelson’s back-up 

slides show that the efficacy of one dose is actually quite high. With that in mind, he inquired as 

to what efficacy was assumed in the model for a single dose. He also thought it would be more 

cost-effective to administer a vaccine that offers long-term, potentially lifetime, protection at a 

younger age. However, the graph showed the opposite and was counter-intuitive. 

Regarding Dr. Reingold’s first question, Dr. Rein responded that if efficacy is the same or similar 

with 1 dose as 2 doses, the cost would be cut in half and there would be a much more favorable 

cost-effectiveness ratio. He did not have those results to share. In terms of the vaccination 

becoming more cost-effective at older ages, the model behaves oddly at an incidence this low 

and with adult vaccination. This relates to the discounting being done to the adult vaccination 

and the amount of adult vaccination being replaced. Considering vaccination of a 2-year old, 

replacing the adult vaccination that would occur at age 18, which is the first year the model 

would consider that, the cost of adult vaccination would be discounted at a rate of 3% per year 

from age 18 down to age 2. That would probably decrease the cost of the adult vaccination 

below the cost of the child vaccination, so there would still be an incremental cost of the 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

vaccine. Essentially, getting increasingly closer to the date when adult vaccination occurs, the 

present-day value of the adult vaccination increases. This has the effect of making the total 

vaccine cost lower, because adult vaccination costs are subtracted from the childhood 

vaccination cost, which leads to a lower incremental cost-effectiveness ratio. The simplified 

answer is that it is a product of the adult vaccine offsets, which are occurring closer in time in 

older children than in younger children. 

Dr. Messonnier asked whether there is a geographic aspect to current vaccination coverage 

being so low. For example, do the Western states identified as being at higher risk have higher 

coverage? She said she presumed that few states have school requirements for hepatitis. She 

wondered about anticipated coverage with a catch-up campaign. 

Dr. Nelson replied that approximately 50% of states have school mandates. In terms of 

coverage, there is variability across the country. There is higher coverage in the Western 

states, but there is more even distribution as time goes on. 

Dr. Messonnier asked whether the states that have mandates have high coverage. 

Dr. Rein responded that there have been a couple of publications that predicted higher 

coverage in states with mandates. 

Dr. Moore reported that Tennessee has well over 80% coverage at 24 months of age, and has 

had a mandate in place for 1 dose for daycare and 2 doses for kindergarten entry since 2009. 

Compliance with immunization requirements for kindergarten entry is approximately 95%. In 

terms of whether the model’s 50% coverage estimate with a catch-up campaign is a reasonable 

starting point, she thought this would vary by state. The 50% of states with existing mandates 

are going to have much higher coverage. The concept of a national catch-up campaign makes 

sense at 12 years of age when other vaccines are being given. What troubles her about this 

model is that things are so sensitive to the discount. The benefit to adults is discounted so 

much by giving childhood vaccines, she worries about doing this for HepA vaccine when most of 

the disease burden is in older adults. Thus, she thinks the model had to be taken “with a grain 

of salt.” 

Dr. Nelson has a study that has been submitted showing that mandates do influence the 

coverage rates. 

Dr. Szilagyi asked what the effect would be on the ICER if the coverage rate was 60%, 70%, or 

80%. Because the model is so sensitive to the underlying baseline incidences, he also 

wondered whether there was any evidence of a trend in incidence in the US or other similar 

nations. 

Dr. Rein replied that there would be very little effect on the ICER if the coverage rate was 60%, 

70%, or 80%. The ICER pertains to the benefit per person. Since the model does not account 

for extra herd immunity effect, it would be essentially the same. Herd immunity was excluded 

because the current incidence was assumed to be related to foodborne outbreaks or other 

environmental exposures, which would not be affected by herd immunity. By definition, the 

model could only account for herd immunity among people who are already within the cohort. 

The point about children potentially affecting their grandparents for example would be a benefit 

that could possibly be excluded from the model; however, those grandparents would not be 

covered in the catch-up recommendation other than effects from children. 

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Dr. Nelson responded that the incidence has remained relatively stable in the US over the last 

few years between 0.4 to 0.5 cases/100,000 population. Fluctuations have been noted in other 

countries around the world and most recently in terms of infections among MSM. 

Dr. Hunter said he thought there is a cohort of people about 20 to 50 years of age who have low 

immunity because they have not been immunized and have not been exposed to natural 

infection, and if they were trying to prevent infections/complications in that group, he wondered 

how catch-up vaccination of children 2 through 18 years of age would help them. 

Dr. Nelson replied that it would not help that particularly population immediately, but will help 

improve population protection overall. As more children through 18 years of age are 

vaccinated, coverage among adults will increase over time. 

Dr. Wharton (SME) pointed out that the NIS-Child data assesses coverage in children 19 to 35 

months of age, which may not fully capture the impact of school immunization requirements 

implemented at school entry. For instance, as Dr. Moore mentioned, it might capture the first 

dose but not necessarily the second dose. There probably is more variability in how this 

particular program has been implemented state-to-state than is typical with pediatric 

immunization. 

Dr. Jane Zucker (NYC Immunization Program) noted that after the CDC presentation in 2014 

showing the data about HepA epidemiology impact in older groups, NYC changed its 

recommendations for catch-up for everyone through 18 years of age. Basically, that entailed 

changing the NYC Immunization Registry recommendations. At 12 months, there is a “do now” 

recommendation and everyone who was not fully vaccinated after 2 years, received a 

recommendation to be given HepA vaccine to complete their 2 doses. Their coverage for 19 to 

35 months of age ranges about 76% for 1 dose and 49% for 2 doses. For adolescents 11 

through 18 years of age, coverage is approximately 93% coverage for 1 dose and 88% 

coverage for 2 doses. It has been their experience that the numbers are generally much higher 

than typically can be achieved with catch-up vaccination. Catch-up has been very feasible 

because it is allowed to be given at any visit during which a child is receiving other vaccines. 

Dr. Lee noted that the state-based approach appeared to be very effective when implemented in 

a way that allows a systems-based approach to occur. One way to do that is to mimic in the 

model what is being observed in the various states without necessarily changing the model. 

That would help ACIP understand how these recommendations might be implemented. From a 

strategy standpoint, it also would be helpful to have information available from the economic 

models about 1 versus 2 doses. She emphasized that since the incidence is lower nationally on 

average, it would be helpful to have the model go below 0.1. While she recognized that this 

seemed to be a challenge, it would give them some additional information to counterbalance the 

potential for herd immunity effects. Another challenge for ACIP is to understand what the 

QALYs mean. She asked whether the QALY decrements were considered to be temporary 

specifically for mild, symptomatic, or asymptomatic infection or if they were assumed to be 

accumulated over time aside from those who may receive a liver transplant. In addition, she 

wondered whether the number of hospitalizations, liver transplants, and deaths averted had 

been assessed. That would offer more information about what the QALYs mean and would 

help ACIP understand whether the model is calibrated to what is being observed in national 

data. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Dr. Rein replied that the QALY decrements are associated with the duration of the symptoms or 

outcomes. For symptomatic disease, it is related to varying durations of disease ranging from 

very short for mildly symptomatic anicteric disease to longer for fulminant disease with 

hospitalization. For deaths from HepA, it includes full losses of QALYs for each year after 

death. They have and can provide the results for the number of hospitalizations, liver 

transplants, and deaths averted. He was not certain whether they retained all of these from 

each age cohort simulation, but they have the output from each so they can pull those and put 

them together. 

Dr. Reingold clarified that he chaired the SAGE WG that recommended giving 1 dose if 2 

cannot be afforded. SAGE had a tolerance for that, but this is licensed as a 2-dose vaccine in 

the US. Therefore, he did not think ACIP was contemplating recommending a 1-dose schedule. 

However, there is very good evidence that 1 dose offers a high-level of protection. The interest 

is in making sure that it is modeled appropriately. 

It appeared to Ms. Pellegrini that the spacing on the doses would allow for them to be 

administered at the 12- and 13-year old child well visits, which would reduce the burden on 

families. When accounting for administrative costs, she wondered whether they were reduced 

for both doses or just the first. 

Dr. Rein recalled that they had one administration cost that was cut in half. 

Dr. Moore thought administratively, it could be given with both doses of human papillomavirus 

(HPV) vaccine. Since the Healthy People 2020 goal is 0.3/100,000 or less and there is a lot of 

state-to-state variability, she would be interested in seeing how that correlates with states that 

do have mandates and, therefore, are in less need of catch-up because they have a 

consistently high level of coverage. It would be interesting to see whether the states that have 

mandates already have achieved the Health People 2020 coverage goal. 

Dr. Hunter observed that based on slide 22 titled “Long-Term Protection,” in Dr. Nelson’s 

presentation, it seemed like there would not be much of a decline in immunity among the 

immunized younger cohort. This shows that anti-HAV antibodies have been shown to persist at 

least 20 years in adults who received 3 doses of inactivate vaccine as children, and detectable 

antibodies have persisted for 40 years or longer in mathematical models. However, it looked 

like there might be a decline based on Slide 9 of Dr. Rein’s presentation. There seemed to be 

an adjustment in the QALY in the cost-effectiveness for some decline in vaccine-acquired 

immunity by year based on recent data, and he wondered about the magnitude. 

Dr. Rein responded that there is loss of immunity that occurs more rapidly at first and then more 

gradually over time. It is a complicated 3-point spline equation in which there is greater loss of 

immunity in earlier ages, then there is a slower loss of immunity between the next two points, 

followed by an even slower loss of immunity after that. While he did not have the results with 

him, he will share that with ACIP. This was based on new data collected in Alaska on a cohort 

of individuals who were vaccinated 20 years ago and then observed over time. 

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Dr. Hunter clarified that he was trying to understand the 3 general cohorts consisting of those 

who are younger who have been immunized, those who have not been immunized and have not 

been exposed much to natural disease (20 to 50 years of age), and those over 50 who have 

natural disease. He wondered whether the immunized cohort would have less persistent 

immunity than the natural immunity group, and if there would be an ongoing issue of aging 

cohorts having less immunity. 

Dr. Rein replied that this is an ongoing and unknown question that cannot yet be answered. 

This is all speculation and it is not clear what the actual answer is. There has been speculation 

that with severity of disease after infection or level of protection even after antibody titer falls 

below detectable levels, some level of protection persists. 

Dr. Wharton added that based on the NIS, even if the second dose is given exactly at 24 

months, some interviews are conducted at 19 months of age. So, the ability of the survey to 

precisely estimate 2-dose coverage is limited. 

Updated ACIP Routine Recommendations for Use of HepA Vaccine 

Noele Nelson, MD, PhD, MPH 

CDC Lead, ACIP Hepatitis Vaccines Work Group

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

Centers for Disease Control and Prevention 

In terms of HepA vaccine considerations, Dr. Nelson indicated that the Hepatitis Vaccines WG 

has deliberated on the following topics: 

 HepA catch-up vaccination 

 Vaccination of pregnant women 

 Vaccination of persons with CLD 

 Vaccination of persons in institutions for persons with developmental disabilities 

 PEP 

In the future, the WG plans to take into consideration vaccination of HIV and 

immunocompromised persons. 

Despite the cost-effectiveness results, the WG proposes updating the permissive catch-up 

language to a routine catch-up recommendation for children 2 through 18 years of age in order 

to improve population protection from HAV and vaccine uptake in children aged greater than 2 

years. Decreasing HepA incidence in the US and reduced exposure to HAV has resulted in 

decreasing anti-HAV seroprevalence among adults, and an increasing proportion of susceptible 

adults. Vaccinating adolescents will lead to increased adult protection quicker than waiting for 

the universal vaccine cohort to reach adulthood. Of note, the cohort of children vaccinated in 

2006, when HepA vaccine was routinely recommended for all children 12 through 23 months of 

age will reach adolescence (age 13) in 2018 and adulthood (age 19) in 2024. National 

vaccination coverage among adolescents 13 through 17 years in 2013 for 1 and ≥2 doses of 

HepA vaccine was 62.5% and 51.0%, respectively. The current and draft proposed 

recommendations are compared in the following table: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Hepatitis A Catch-Up Vaccination 

Current Recommendation (2006) Draft Proposed Recommendation 

• Recommended for use at age 12-23 

months in all states 

• Continue existing vaccination programs 

for ages 2-18 years 

• Consider catch-up vaccination in 

outbreaks and areas 

with increasing disease rates 

• Any person wishing to obtain immunity 

• Recommended for all children age 12-23 

months 

• Children and adolescents age 2-18 years 

who have not previously received 

hepatitis A vaccine should be vaccinated 

routinely at any age with an appropriate 

dose and schedule 

• [OR Recommended for all children aged 

12 months to 18 years] 

• Consider adult catch-up vaccination in 

outbreaks and areas with increasing 

disease rates 

• Any person wishing to obtain immunity 

The 2006 pregnancy recommendation states that the safety of HepA vaccination during 

pregnancy has not been determined; however, because HepA vaccine is produced from 

inactivated HAV, the theoretic risk to the developing fetus is expected to be low. The risk 

associated with vaccination should be weighed against the risk for hepatitis A infection in 

pregnant women who might be at high risk for exposure to HAV. However, since those 

recommendations more data are available on vaccination during pregnancy. The 2017 

Immunization Schedule states that HepA vaccines during pregnancy should be recommended 

for adults with additional medical conditions or other indications, meaning pregnant women who 

are at risk for HAV infection. The Moro et al study conducted in 2014 searched VAERS for AEs 

reports in pregnant women who received HepA or HepAB vaccines from January 1, 1996 to 

April 5, 2013. VAERS received 139 reports of AEs in pregnant women of which 7 (5.0%) were 

serious. No maternal or infant deaths were identified, and 65 (46.8%) did not describe any AEs. 

The conclusion of the study was that VAERS reports did not identify any concerning pattern of 

AEs in pregnant women or their infants following maternal HepA or HepAB immunizations 

during pregnancy. The current and draft recommendations are compared in the following table: 

Pregnancy 

Current Recommendation (2006) Draft Proposed Recommendation 

• The safety of hepatitis A vaccination 

during pregnancy has not been 

determined; however, because hepatitis A 

vaccine is produced from inactivated 

HAV, the theoretic risk to the developing 

fetus is expected to be low. The risk 

associated with vaccination should be 

weighed against the risk for hepatitis A in 

pregnant women who might be at high 

risk for exposure to HAV. 

• Pregnant women with any of the 

conditions that increase the risk of either 

acquiring or having a severe outcome 

from HAV infection (e.g., having chronic 

liver disease, clotting-factor disorders, 

travelers, users of injection and noninjection drugs, and women who work 

with nonhuman primates) should be 

vaccinated during pregnancy if not 

previously vaccinated. 

• Pregnant women at risk for HAV infection 

during pregnancy should also be 

counseled concerning all options to 

prevent HAV infection. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Regarding CLD, the WG is interested in changing the language to make it parallel with the 

HepB vaccine statement. The current and draft proposed recommendations for CLD are 

compared in the following table: 

Chronic Liver Disease 

Current Recommendation (2006) Draft Proposed Recommendation 

• Susceptible persons with chronic liver 

disease should be vaccinated. Available 

data do not indicate a need for routine 

vaccination of persons with chronic HBV 

or HCV infections without evidence of 

chronic liver disease. Susceptible persons 

who are either awaiting or have received 

liver transplants should be vaccinated 

• Epidemiology: Persons with chronic liver 

disease (e.g., cirrhosis, fatty liver disease, 

alcoholic liver disease, autoimmune 

hepatitis) are not at increased risk for 

HAV infection unless they have fecal-oral 

exposure to hepatitis A. However, 

concurrent acute HAV infection may 

increase the risk for more severe liver 

disease. 

• Vaccination: Vaccination for persons with 

chronic liver disease (including, but not 

limited to, those with hepatitis C virus 

(HCV) infection, hepatitis B virus (HBV) 

infection, cirrhosis, fatty liver disease, 

alcoholic liver disease, autoimmune 

hepatitis, and liver function tests >2 times 

the upper limit of normal). Susceptible 

persons who are either awaiting or have 

received liver transplants. 

Historically, HAV infection was highly endemic in institutions for persons with developmental 

disabilities. As fewer children have been institutionalized and as conditions in institutions have 

improved, the incidence and prevalence of HAV infection have decreased, although outbreaks 

can occur in these settings. 

A study by Bohn et al published in 2015 described a HepA outbreak in group homes in Michigan 

in 2013 in which there were 8 cases among 5 group homes. There were 261 contacts who 

warranted PEP, and 225 (86.2%) were confirmed to have received Ig or HepA vaccine or both 

during this outbreak. Since disabled adults are now typically cared for in group homes, where 

residents live in close quarters, and residents are often incontinent and non-verbal, this is a 

population in which vaccination could be beneficial [Bohm SR, Berger KW, Hackert PB, Renas 

R, Brunette S, Parker N, Padro C, Hocking A, Hedemark M, Edwards R, Bush RL, Khudyakov 

Y, Nelson NP, Teshale EH; Centers for Disease Control and Prevention (CDC). Hepatitis A 

outbreak among adults with developmental disabilities in group homes--Michigan, 2013. MMWR 

Morb Mortal Wkly Rep. 2015 Feb 20;64(6):148-52. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

A study by Lim et al in 2013 described a HepA hepatitis A outbreak in a residential facility for the 

disabled in South Korea that occurred in 2011. There were 16 cases who had contact with 51 

residents and 31 teachers and staff members. The initial source of infection was not identified; 

however, the possibility that the HAV outbreak was started by person-to-person spread is high, 

and volunteers were suspected to be the most likely infection source [Lim HS, Choi K, Lee S. 

Epidemiological investigation of an outbreak of hepatitis A at a residential facility for the 

disabled, 2011. J Prev Med Public Health. 2013 Mar;46(2):62-73. doi: 10.3961/ jpmph.2013. 

46.2.62. Epub 2013 Mar 28. 

The current recommendations and draft proposed recommendations based on these studies for 

settings providing services to children and adults are compared in the following table: 

Settings Providing Services to Children and Adults 

Current Recommendation (2006) Draft Proposed Recommendation 

• Historically, HAV infection was highly 

endemic in institutions for persons with 

developmental disabilities. As fewer 

children have been institutionalized and 

as conditions in institutions have 

improved, the incidence and prevalence 

of HAV infection have decreased, 

although outbreaks can occur in these 

settings. 

• Historically, HAV infection was highly 

endemic in institutions for persons with 

developmental disabilities. Now, persons 

with developmental disabilities typically 

live in group homes or residential 

facilities. Outbreaks can occur in these 

settings. 

• All residents and health care personnel 

should be offered hepatitis A vaccination 

if they have not previously completed 

vaccination. 

Dr. Nelson invited ACIP members to discuss and provide their opinions on the following: 

 Routine hepatitis A catch-up vaccination 

 Vaccination of pregnant women with any of the conditions that increase the risk of either 

acquiring or having a severe outcome from HAV infection 

 Vaccination of persons with chronic liver disease 

 Vaccination of persons in institutions for persons with developmental disabilities 

Discussion Points 

Regarding the pregnancy issue, Dr. Belongia noted that primarily a VAERS analysis was cited 

that assessed 139 reports and there was a suggestion that the WG would be interested in a 

recommendation for women who are considered at risk for complications. He asked whether 

the WG considered parsing that recommendation into first, second, and third trimester. Safety 

data in general for vaccines are much harder to acquire for the first trimester than for the second 

and third. Given that in any 9-month period in a disease with a very low incidence overall, the 

incidence of getting HAV infection in that period is pretty low. He asked what the thinking was 

on this in terms of recommending vaccination throughout pregnancy for women at risk, versus 

deferring it, versus administering it only in the second and third trimester given the lack of data. 

Given the lack of data, Dr. Nelson indicated that the WG did not engage in extensive 

deliberations on administering the vaccine. It was thought that it would be given in the second 

or third trimester, but that is still up for discussion. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Dr. Kempe inquired as to whether this issue has been examined in the VSD, which would offer a 

lot more granularity and better data. 

Dr. Nelson replied that an assessment of VSD data on this issue is in progress. 

Dr. Messonnier suggested that the WG provide more context during the October 2017 meeting 

regarding the burden of disease of HepA in pregnancy, the number of cases that are potentially 

preventable, and other outcomes that are potentially preventable with vaccination. 

Dr. Nelson indicated that one of the primary considerations of the WG was concern about 

complications during pregnancy if a mother was to acquire HepA disease during the pregnancy. 

There are a couple of studies she can present that document this issue. 

In response to the routine catch-up recommendation, Ms. Finley (AIM) noted that only 21 states 

have mandates. Of the states with mandates, 3 or 4 have two times the national goal of 

hepatitis incidence. Therefore, it may be necessary to further consider how to increase the 

rates. 

Dr. Bennett thought that analysis would be helpful. 

Dr. Moore inquired as to how this discussion fits with any consideration of PEP during 

pregnancy. 

Dr. Nelson indicated that this would be addressed in the next presentation by Dr. Link-Gelles. 

Dr. Hunter noted that the current catch-up recommendation was somewhat equivalent to a 

Category B recommendation as he read it, which should mean that the Vaccines For Children 

(VFC) program would cover it, and if the new draft language recommendation would shift it to a 

Category A recommendation. 

Dr. Messonnier clarified that the draft language had not yet been through the Grading of 

Recommendation Assessment, Development and Evaluation (GRADE) process. There will be a 

presentation in October 2017 or February 2018, depending upon how things move, on the 

GRADE findings on the evidence for a catch-up campaign. The Category B recommendation is 

covered in the VFC program, but the goal is to move from a permissive to a proactive 

recommendation. 

Dr. Lee inquired as to whether it would be helpful to expand the recommendation for persons 

with developmental disabilities to residential facilities in order to be broader. 

Regarding the catch-up recommendation, Dr. Atmar expressed interest in knowing what the WG 

thought of the cost-effective analysis, particularly given the limitations of the analysis that were 

discussed. 

Dr. Reingold thought it was fair to say that it turns out to be quite expensive to prevent these 

cases, and the WG felt that ACIP should consider that issue as a full committee. There were 

mixed views among WG members regarding whether this would be a good use of limited funds. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Dr. Whitley-Williams (NMA) requested that the WG consider any data regarding the 

simultaneous use of or the timing of giving the HepA vaccine to pregnant women with Tetanus 

Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis (Tdap) and Inactivated Influenza 

Vaccine (IIV). 

Regarding the catch-up issue, Dr. Kempe requested more information about the WG’s 

considerations of different groups. Essentially, the data presented pointed out increased 

hospitalizations and costs as people age. The cost analysis did not take into account herd 

immunity presumably because most of the disease is being caused by international 

contamination of food, so there is a disconnect. She wondered whether the WG considered 

what the relative cost would be of vaccinating those at highest risk of bad disease, such as the 

elderly. While she understood the rationale in wanting to get adults vaccinated in the future, she 

wondered about how to deal with the current problem. 

Dr. Thompson (NVAC) asked whether there would be an opportunity to perform some additional 

modeling that would integrate cost-effectiveness and transmission modeling in a way that might 

enable ACIP to assess the herd immunity benefits. The fact that the draft catch-up 

recommendations begin with “Despite the cost-effectiveness results . . .” sounded to her like the 

WG was having trouble reconciling these issues. She suggested assessing other specific 

populations with the cost-effectiveness and economic analysis. 

Dr. Belongia noted that the best-case scenario in the analysis presented during this session, 

$189,000 per QALY gained was thought to be optimal at age 12 years. He wondered if there 

were examples of other catch-up recommendations that are comparable in terms of the cost per 

QALY. 

Given the time, Dr. Messonnier invited the members to submit additional suggestions and 

requests to be worked on between now and the October 2017 and February 2018 meetings. 

Updated Recommendations for Use of HepA Vaccine and 

Immune Globulin for PEP and for International Travelers 

Ruth Link-Gelles, PhD, MPH 

Epidemic Intelligence Service Officer, Division of Viral Hepatitis

Lieutenant, US Public Health Service 

Dr. Link-Gelles presented draft updates to the 2007 ACIP recommendations for PEP for HepA 

and prevention of HepA in international travelers. She explained the current ACIP 

recommendations for PEP, discussed the current context and ACIP Hepatitis Vaccine WG 

process, presented draft updates to the recommendations for PEP, presented proposed 

updates for international travelers, and proposed some specific questions for ACIP member 

input. 

According to the 2007 ACIP recommendations, HepA vaccine or Ig is recommended for PEP in 

a variety of circumstances. First, PEP is recommended for previously unvaccinated persons 

who have close personal contact with persons who have serologically confirmed HAV infection 

including household and sexual contacts, and persons who have shared illicit drugs. 

Additionally, persons with other types of ongoing, close personal contact can be considered for 

PEP. 

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For the past 6 months, the ACIP Hepatitis Vaccine WG has been focused on updating the 

existing HepA recommendations. Discussion led to a consensus that concerns about the use of 

Ig for PEP require updated recommendations. There are a number of concerns about the 

current recommendations. First, Ig may have decreased potency in settings such as the US 

with low HepA prevalence1,2. As rates of HepA have decreased in developed countries where 

HepA vaccine has been introduced, so too has the prevalence of HAV antibodies in plasma 

donations, leading to decreased potency of Ig. A recent study from CDC and the Food and 

Drug Administration (FDA) comparing 9 intramuscular Ig preparations from developed countries 

yielded low anti-HAV Ig potencies. Even in lots that achieved protective levels of IgG, modeling 

indicated that immunity would wane before the expected 3 months [1Zaaijer HL, et al. Hepatitis 

A antibody titers after infection and immunization: implications for passive and active 

immunization. J Med Virol. 1993;40(1):22-27; 2 Tejada-Strop A, et al. Evaluation of Potencies of 

Immune Globulin Products Against Hepatitis A. JAMA Intern Med. 2017;177(3):430-432]. 

 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

If HepA is recognized in children or employees of child care centers, PEP should be 

administered to unvaccinated staff and attendees. In outbreak settings, household members of 

children attending child care in diapers should also be vaccinated. In common-source 

outbreaks, food handlers at an institution where another food handler has been diagnosed with 

HepA should be vaccinated, as should patrons after exposure to a food handler who also had 

poor hygiene, but only if the patron can be administered PEP within 2 weeks of exposure. 

Finally, PEP is recommended in schools, hospitals, and work settings only if an epidemiologic 

investigation indicates transmission at the facility. Hospital staff do not need to receive PEP 

after treating a person with HAV infection, as long as staff used appropriate personal protective 

equipment (PPE) [Advisory Committee on Immunization Practices, Centers for Disease Control 

& Prevention. Update: Prevention of hepatitis A after exposure to hepatitis A virus and in 

international travelers. Updated recommendations of the Advisory Committee on Immunization 

Practices (ACIP). MMWR Morb Mortal Wkly Rep 2007;56:1080-1084]. 

According to the 2007 ACIP recommendations, the type of PEP depends on age and immune 

status. Children under 12 months of age, immunocompromised individuals, those with CLD, 

and those with a vaccine contraindication should receive immunoglobulin, or Ig, only. Healthy 

individuals 12 months to 40 years receive vaccine only, and adults over 40 years, regardless of 

immune status, are recommended to receive Ig only, with vaccine as a back-up if Ig cannot be 

obtained. All PEP should be administered as soon as possible after exposure, ideally within 2 

weeks [MMWR. October 19, 2007:mmwr/preview/mmwrhtml/mm5641a3.htm]. 

Second, reports from state and local partners during 3 recent, large outbreaks in the US 

indicated limited availability of Ig for use in outbreak settings, mostly due to health departments 

and providers not keeping Ig in stock. Control of these outbreaks has therefore relied primarily 

on vaccine, regardless of the age or immune status of exposed individuals. Combined with 

identification and recall of the source product, all 3 outbreaks were ended, despite limited 

availability or use of Ig. Additionally, a recent report from New York City (NYC) on the handling 

of hepatitis A cases in food handlers indicated logistical concerns with administration of Ig, 

particularly during a mass exposure. Finally, Ig has a shorter duration of protection than 

vaccine, so administering Ig alone to persons for whom vaccine is not contraindicated 

represents a missed opportunity to provide long-term immunity and increase herd protection. 

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The 2007 ACIP recommendations were largely based on work done by Victor et al in 

Kazakhstan1. The study, published in 2007, randomized household and day-care contacts 2 to 

40 years of age to receive either Ig or hepatitis A vaccine within 14 days of exposure and then 

followed individuals for 56 days to determine effectiveness. Despite slightly higher rates of 

disease in vaccinated individuals, vaccine was found to be non-inferior to Ig. With modeling, the 

authors showed that, assuming 90% efficacy of Ig, vaccine efficacy (VE) was estimated to be 

86%. If IG efficacy was assumed to be 80%, vaccine efficacy (VE) was estimated at 73%. Risk 

of HepA in the vaccine group was never greater than 1.5% above that in the Ig group. No 

studies have been conducted to assess differences between Ig and vaccine or to explore 

effectiveness of Ig alone in discrete age groups over 40 years. With this in mind, a systematic 

review was conducted of available data on HepA vaccine in adults over age 402 [

1 Victor JC, 

Monto AS, Surdina TY, Suleimenova SZ, Vaughan G, Nainan OV, Favorov MO, et al. Hepatitis 

A vaccine versus immune globulin for postexposure prophylaxis. N Engl J Med 2007;357:1685-

1694; 2Link-Gelles, Hofmeister, Nelson, Vaccine (in preparation)]. 

In the Link-Gelles et al study, existing data were reviewed on the use of vaccine versus Ig for 

adults over 40 years of age, including a look at existing guidelines in other countries. PubMed® 

and Excerpta Medica Database® (EMBASE®) were searched for articles and guidelines 

published since 1992 and included only articles with data on HAVRIX® or VAQTA® administered 

to adults over 40 years of age. Articles were included with both immunogenicity and disease 

endpoints, as well as surveillance data and case studies. For immunogenicity data, only results 

within 2 weeks of vaccine or Ig administration were included, which is the window in which PEP 

would need to be administered to be effective. Each abstract was read by 2 reviewers and 

consensus was obtained on inclusion or exclusion of the abstract. Results of this systematic 

review are pending publication and will undergo a GRADE review in the coming months. 

The search yielded 782 abstracts from PubMed® and 257 abstracts from EMBASE®. Of these, 

936 abstracts were excluded, primarily because they focused on children or younger adults or 

did not report data less than 28 days post-vaccination, which is needed for assessing use for 

PEP. More than half of the articles focused on vaccine introduction, including cost-effectiveness 

of routine vaccine, serosurveys before and after vaccine introduction, and opinion pieces that 

did not provide the necessary data. The full articles were reviewed for the remaining 103 

abstracts, of which 8 were retained and 2 additional articles were added from searching 

references of the retained articles. Of these studies, 4 directly compared HepA vaccine 

protection in adults over the age of 40 at 15 days and 30 days after the first dose of vaccine. 

However, it should be noted that there were some differences in the studies. First, some 

studies used Havrix® 1440 ELU, which is currently licensed in the US for adults. Other studies 

used different variations of VAQTA®, including 25, 50, and 100-unit formulations. In the US, the 

50-unit formulation is licensed for adults. Second, because no absolute protective level has 

been defined, the lower limit of detection of the particular assay being used has generally been 

considered the protective level. In the studies presented, some used anti-HAV ≥ 10 mIU/mL as

the cutoff for seroprotection and some used anti-HAV ≥ 20 mIU/mL, which is the common 

standard today. 

Briem et al compared adults aged 20 through 39 years and 40 through 62 years at 15 and 30 

days after the first dose in 1994 as part of an observational cohort study. Seroprotection in this 

study was considered ≥20 mIU per mL. They found that at 15 days, 90% of those in the 

younger age group had responded, compared to 77% in the older age group. By 30 days, 97% 

of individuals in both groups had responded [Briem H, Safary A. Immunogenicity and safety in 

adults of hepatitis A virus vaccine administered as a single dose with a booster 6 months later. J 

Med Virol 1994;44:443-445]. 

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Reuman et al was also an observational cohort study that looked at responses to a 25-unit dose 

of VAQTA® in adults less than 40 years of age compared with adults greater than or equal to 40 

years of age and found, as with Briem, that response was better in younger adults, although the 

cutoff for seroprotection in this study was anti-HAV ≥ 10 mIU/mL versus ≥ 20 mIU/mL in Briem. 

Reuman also provided geometric mean titers (GMTs), which is a measure of average HAV 

antibodies. However, it should be noted that the 25-unit dose of VAQTA used in this study is 

half the dose that is licensed in the US for adults [Reuman PD, Kubilis P, Hurni W, Brown L, 

Nalin D. The effect of age and weight on the response to formalin inactivated, alum-adjuvanted 

hepatitis A vaccine in healthy adults. Vaccine 1997;15:1157-1161. NOTE: 4-week 

seroprotection percentages and all GMTs include only individuals who were not revaccinated at 

2 weeks]. 

In Nelson et al, the authors reanalyzed data from a randomized trial published in 2000 by 

Williams et al that did not include results by age. In Nelson, the results were reported in 3 age 

groups and showed a similar trend to previous studies, with the youngest age group, those 40 

through 49 years of age, having the best response. Although the sample size is small, 

especially in the oldest age category, it should be noted that this is the only study that included 

discrete age groups over 40 years [Nelson NP, Murphy TV, McMahon BJ. Hepatitis A 

vaccination for post-exposure prophylaxis in persons aged 40 years and older. Vaccine 

2014;32:2939. 

Van Der Meeren and colleagues in 2015 did a retrospective pooled analysis of randomized trial 

data and compared 20 through 30 years olds with individuals 40 and over and found relatively 

high seroprotection in both age groups 15 days after the first dose, with almost 100% achieving 

protective antibody levels by 30 days. Geometric mean concentrations (GMCs) were higher in 

both groups than in other studies [Van Der Meeren O, Crasta P, de Ridder M. A retrospective 

pooled analysis assessing the effect of age on the immunogenicity of Havrix in healthy adults. 

Hum Vaccin Immunother 2015;11:1729-1734]. 

The remaining studies included in the systematic review did not directly compare age groups or 

did not provide detailed results by age. In general, age was found to be significantly associated 

with response to vaccine. Three studies looked at surveillance or post-outbreak data, including 

retrospective chart reviews, in which case contacts were vaccinated1,2,3. Very few vaccine 

failures were identified in adults over 40 years of age1,2, but little additional information on timing 

of vaccine administration was provided. Finally, one study looked at 3 VAQTA® formulations, 25 

units, 50 units, and 100 units, and found a clear dose response relationship. Of adults who 

received 50 units, the currently licensed dose in the US, 46% had seroconverted by 2 weeks 

post-vaccine and 89% had seroconverted by 4 weeks4. No studies were identified which 

directly compared vaccine and Ig in adults over 40 years for use as PEP [1 Whelan J, Sonder 

GJ, Bovee L, Speksnijder A, van den Hoek A. Evaluation of hepatitis A vaccine in post-exposure 

prophylaxis, The Netherlands, 2004-2012. PLoS One 2013;8:e78914; 2 Parron I, Planas C, 

Godoy P, Manzanares-Laya S, Martinez A, Sala MR, Manuel S, et al. Effectiveness of hepatitis 

A vaccination as post-exposure prophylaxis. Hum Vaccin Immunother 2016:0; 3 Freeman E, 

Lawrence G, McAnulty J, Tobin S, MacIntyre CR, Torvaldsen S. Field effectiveness of hepatitis 

A vaccine and uptake of post exposure prophylaxis following a change to the Australian 

guidelines. Vaccine 2014;32:5509-5513; and 4 Bertino JS, Jr., Thoelen S, VanDamme P, Bryan 

JP, Becherer PR, Frey S, Hayden FG, et al. A dose response study of hepatitis A vaccine in 

healthy adults who are > or = 30 years old and weigh > or = 77 kg. J Infect Dis 1998;178:1181-

1184]. 

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To summarize, there are a number of potential benefits of vaccine over Ig for PEP. First, 

vaccine provides long-term protection, which Ig does not. Therefore, vaccinating individuals in 

the context of an outbreak helps boost herd protection. Second, while local health departments 

and many provider offices have ready supplies of vaccine, reports from recent outbreak 

investigations to CDC indicate that Ig is frequently not kept in stock, leading to potential delays 

in administration compared to vaccine. Additionally, switching to vaccine would bring the US in 

line with most other countries. Finally, it should be noted that vaccine (HAVRIX®/VAQTA®: VFC 

$26/$28; Private sector $64/$67) and Ig ($75 for 2 mL single dose vial) are very similar in price 

depending upon the Ig dosage required for an individual. 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

In addition to a literature review, the WG reviewed current HepA PEP recommendations in other 

countries. Countries generally agree on use of vaccine for PEP in healthy adults 1 through 40 

years of age. Likewise, there is general agreement that Ig, with or without vaccine, is ideal for 

immunocompromised individuals and those with chronic liver disease. However, the US and 

Israel are the only 2 countries identified which recommend Ig alone for healthy individuals over 

40 years of age. 

With all of this in mind, the WG’s current draft recommendations focus on vaccine wherever 

possible. The following draft recommendations are not exact wording, but summarize the 

current wording: 

Specifically, the draft proposes changing the recommendation for healthy adults over the age of 

40 from Ig, as the preferred method for PEP, to vaccine as the preferred method. Children 

under 12 months of age and persons for whom vaccine is contraindicated would continue to be 

recommended to receive Ig as soon as possible after exposure. Finally, immunocompromised 

persons, who were previously recommended to receive Ig alone, would now be recommended 

to receive both Ig and HepA vaccine simultaneously, if previously unvaccinated. 

Under the draft recommendations, Ig alone would be recommended only for infants and those 

with a vaccine contraindication. Persons with CLD and immunocompromised individuals would 

be recommended to receive vaccine and Ig, including persons with any of the following: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

 Congenital or acquired immunodeficiency 

 HIV/AIDS 

 Chronic renal failure/undergoing hemodialysis 

 Receipt of solid organ, bone marrow, or stem cell transplants 

 Iatrogenic immunosuppression 

 A contraindication for HepA vaccine 

 Those otherwise less capable of developing a normal response to immunization 

As was previously mentioned, inclusion of persons with chronic liver disease is an ongoing WG 

discussion. 

Under the current guidelines, there are no specific pregnancy-related recommendations for 

HepA PEP and the vaccine has not been widely tested in pregnant women, although the 

theoretical risk is low. The WG discussed a number of issues relating to HepA and pregnancy. 

First, an additional study of HepA vaccine safety during pregnancy has been published since 

the 2006 guidelines and found no pattern of AE in pregnant women or their infants following 

vaccination during pregnancy. Second, the WG discussed a review published in 2015 that 

found that generally, infants born to mothers with HepA infection are healthy, with rare 

exceptions. However, the review also found that while HAV infection during pregnancy is 

generally not associated with serious outcomes, there is some association between infection 

and preterm labor, placental abruption, and premature rupture of membranes. There does not 

appear to be an increased risk of mortality for either the mother or baby associated with HAV 

infection during pregnancy. Third, the workgroup discussed adding a specific recommendation 

for vaccinating pregnant women at high risk of HAV infection, including PEP. Finally, the 

workgroup discussed the potential for confusion if both Ig and vaccine are recommended for 

pregnant women given that for other inactivated vaccines, ACIP generally recommends vaccine 

only for pregnant women, the same as for non-pregnant individuals. At this time, the WG had 

not included pregnancy as an indication for Ig for PEP. 

Regarding draft recommendations for prevention of HAV infection before international travel, the 

current recommendation for susceptible persons traveling to countries with intermediate or high 

HepA endemicity is to receive hepatitis A vaccine or Ig. Under the proposed draft 

recommendations, no substantial changes would be made for healthy persons greater than 12 

months. HepA vaccine would continue to be recommended, with clarification added for 

individuals who have previously received one or more doses to complete the series. Currently 

for older adults, immunocompromised persons, and persons with chronic liver disease, vaccine 

is recommended, with a permissive recommendation for Ig if the individual is departing in less 

than 2 weeks. This permissive recommendation has resulted in some confusion, with CDC 

subject matter experts (SMEs) receiving numerous inquiries from providers. Therefore, the 

WG’s draft proposal includes some clarification. Previously unvaccinated adults over 40 years 

of age, immunocompromised persons, and persons with chronic liver disease should be 

vaccinated as soon as possible. If departing in less than 2 weeks, these persons should also 

receive Ig at a separate anatomic injection site. Finally, the recommendation for travelers who 

elect not to receive vaccine will be revised slightly to align the wording with other parts of the 

recommendation as shown here: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

In addition to general discussion of PEP and international travel, the WG posed the following 

specific questions for ACIP members: 

 Based on the evidence presented, what are ACIP members’ opinions on the 

recommendation for PEP for healthy individuals > 40 years? Are there differences in age 

groups over 40? 

 Should pregnancy be considered an indication for administration of both Ig and HepA 

vaccine for PEP or is vaccine alone enough? 

Discussion Points 

Dr. Moore noted that practically, Ig is usually not in stock in health departments when 

recommended and it has to be ordered. In the interest of time, vaccine is always on hand and a 

dose of vaccine is typically given because it can be given right then. Often when someone is in 

need of PEP, they are at the end of the 2-week window. Since time is of the essence, vaccine 

is given while awaiting Ig and Ig is given as soon as it arrives as long as it is within the 2-week 

window for those who really need it because of health conditions. She asked whether that is 

okay since doing this simultaneously was mentioned. Because Ig is usually not in stock, 

simultaneous administration is often a challenge. 

Dr. Nelson said as far as she knows, it is okay to do that. The wording can be clarified that 

indicate that Ig should be given as soon as it is available. 

Dr. Moore asked why a second dose is recommended, noting that the PEP recommendation 

mentions in the first category giving a first dose of vaccine and then a second dose at least 6 

months later. However, the second dose would not be essential for PEP. It should just state “if 

that person remains at risk or is in a category for whom full HepA immunization is 

recommended,” because otherwise if they have no other risk factors a single dose is all that is 

needed for PEP. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Dr. Link-Gelles noted that as discussed earlier, the vaccine is licensed on a 2-dose schedule, 

recommendations would generally be drafted such that a person would have a first dose for 

PEP, but then would complete the licensed schedule. There certainly could be permissive 

wording to encourage the first dose as being the most important for PEP. 

Dr. Moore emphasized the importance of making it clear that the second dose has nothing to do 

with PEP, because that raises an issue of affordability in terms of responding to an outbreak. 

That would be a challenge. 

Dr. Romero inquired as to whether ACIP should consider increasing the prophylactic dose of Ig 

given the low levels of antibody found in the American supply. 

Regarding the use of HepA vaccination during international travel, Dr. Fryhofer (ACP) quoted a 

paragraph written by some of the authors who write the Yellow Book. This is an excerpt from 

“Medical Considerations before International Travel” published in the New England Journal of 

Medicine (NEJM) pertaining to HepA vaccine, “A single dose of hepatitis A vaccine given any 

time before travel, even on the way to the airport, provides more than 94% seroprotection.” 

Dr. Moore strongly questioned the justification for the draft proposed recommendation that 

people over 40 years of age would need both Ig and vaccine before international travel. Just 

because someone is traveling internationally does not mean they already have been exposed to 

HepA. In general, someone over 40 going to the airport being told to get the vaccine is not the 

same thing as PEP in which someone already has been exposed and immediate protection is 

essential. 

Dr. Walter expressed confusion about what was presented in the recommendations. It seemed 

like they saw some data that showed decreased immunogenicity for elderly; however, the 

recommendations for PEP dropped the use of Ig. As mentioned, vaccine for travelers over 40 

years of age included Ig. He was not certain how to reconcile all of that. 

Dr. Nelson clarified that for those who are at increased risk, Ig is recommended. The concern 

was to provide them with long-term protection from vaccine as well as for future potential 

exposure. 

Dr. Riley expressed gratitude to the WG for considering pregnancy, given that these 

conversations often leave out pregnancy. When discussion is left out about pregnancy, 

obstetricians and gynecologists will do nothing because everyone assumes that it is unsafe. If 

there is no comment at all, the assumption will be that it is unsafe and pregnant women who 

need the vaccine will not get it. In an outbreak setting, a bad HAV infection during pregnancy 

would not be in the best interest of the mother or her baby. An increase in her risk for pre-term 

labor probably would be the most common risk. 

From a local public health perspective in terms of responding to these types of events, Dr. Zahn 

(NACCHO) reported that there are two types of events that require PEP. One example would 

be for a batch of tuna that has been found to be infected, which is a risk even if no one has 

gotten sick yet. Another example would be of someone who has HepA and someone in their 

household is exposed. The nature of those exposures is different in terms of the numbers of 

people exposed and the likelihood of the risk. California has told their local health departments 

that for those 40 through 59 years of age, either vaccine or Ig may be given depending upon the 

situation. Functionally what happens is for someone with disease and a 55-year old wife who is 

not immune in the same household, that is only one person and Ig can be found. However, if 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

hundreds of people eat pomegranates, a lot of vaccine would be given. He is on the WG and 

he suggested that at some point consideration be given to the nature of exposures not being 

exactly the same. 

Dr. Messonnier congratulated the team on Herculean effort to conduct the literature review, 

which represented an incredibly impressive amount of work. To ACIP and the WG, she pointed 

out that this is a very specific recommendation to a very narrow subset of people. Generally, 

clinicians in the US are not going to be called upon to interpret these recommendations. It is 

much more narrowly focused on outbreaks and health departments. As such, she felt like they 

should differentiate between an ACIP recommendation versus the implications in terms of 

clinical applications. ACIP cannot possibly get to the granularity of the level that health 

departments need to make decisions. Perhaps they could separate the recommendation and 

then provide guidance that would help health departments as they are trying to make strategic 

decisions about how to implement the recommendation. 

Dr. Kimberlin (AAP Red Book) said he was puzzled because during the June 2007 ACIP 

meeting, the vote taken for Ig being preferred over vaccine for persons 40 years of age and 

older specifically said, “Ig is preferred because of the absence of information regarding vaccine 

performance and the more severe manifestations of HepA.” Data have now been presented 

showing that vaccination is less good in older people; however, a recommendation was being 

proposed to change. Looking historically at how ACIP has deliberated on this in the past 

relative to the current set of data being presented seemed to have a disconnect. 

Dr. Link-Gelles clarified that no papers were found that directly compared vaccine and Ig, so the 

situation is still that there are not great data comparing the two head-to-head. Everything 

comes anecdotally from outbreak investigations. In the interim, there have been a lot more 

concerns about Ig potency. There are recent analyses by FDA and CDC showing that Ig 

potency has declined quite a bit in the US. As Dr. Moore pointed out, there are also issues 

regarding the logistics, especially in terms of a mass exposure situation and getting Ig to a 

health department to administer to a wide group of people. She thought the WG weighed the 

limited evidence with the very real logistical problems of getting Ig within the 14 days during 

which it would need to be administered, and the reality that vaccine is almost always readily 

available and can be administered immediately. 

Dr. Bennett thought some of the discomfort they were experiencing was due to inconsistency 

across the recommendations for travelers and PEP. Perhaps the WG could think through that 

further. Also, the question was raised about Ig potency and whether the dosage should be 

changed. 

Regarding whether differences in age groups should be considered, Ms. Pellegrini noted that 

only the Nelson study had data that would allow that type of grouping. In addition, the N for the 

60 through 69-year-old cohort was tiny at 9 or 10 people and that may not be enough to support 

a recommendation. 

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Dr. Walter reminded everyone that during the February ACIP meeting there was an update on 

FluMist® (LAIV4), a presentation on Afluria® (IIV3) and investigation into the Southern 

Hemisphere 2010 AEs of febrile reactions/seizures, and a discussion of the study of Fluzone® 

High-Dose (HD-IIV3) among long-term care residents. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Influenza 

Introduction 

Emmanuel (Chip) Walter, MD, MPH

Chair, Influenza Work Group 

Since the February 2016 ACIP meeting, the WG has engaged in calls twice a month, during 

which members discussed development of 2017-2018 ACIP Influenza Statement and heard 

updates on influenza vaccine effectiveness and safety. 

The agenda for this session included the following topics: 

 Influenza Surveillance Update 

 Influenza Vaccine Effectiveness Update 

 End-of-Season Update: 2016-2017 Influenza Vaccine Safety Monitoring 

 Flublok® Pregnancy data 

 Proposed Recommendations/Vote 

Influenza Surveillance Update 

Alicia P. Budd, MPH 

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention 

During this session, Ms. Budd provided a brief update on influenza activity that occurred in the 

US for the 2016-2017 season. She reminded everyone that these data are preliminary and 

could change slightly as reports continue to come in. 

Based on data reported to CDC by US Clinical Laboratories as of June 16, 2017 that include 

data through the week ending June 10th, testing was done on almost 900,000 specimens for the 

season as a whole. Of the greater than 120,000 of those specimens that were positive for 

influenza, 70% were influenza A viruses and 30% were influenza B viruses. Nationally, the 

percent of specimens testing positive for influenza peaked at approximately 24% during the 3 

weeks from mid- to late-February. Regional differences were observed in timing of influenza 

activity across the country, with the Northwest and West (HHS Regions 8 and 10) peaking in 

late December, followed by the Southwest (Region 9) peaking in January, and the rest of the 

country peaking in February. As often occurs in influenza seasons, there was an increase in 

influenza B later in the season. In fact, each week since late March, influenza B viruses were 

reported more frequently than influenza A viruses. 

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To examine the virologic data in more detail, Ms. Budd presented data from the US Public 

Health Laboratories (PHLs) on the number of influenza positives by influenza A subtype and 

influenza B lineage. So far this season, PHLs have reported testing more than 85,000 

specimens, of which more than 41,000 were positive for influenza. Influenza A(H3N2) was the 

predominant virus overall this season, accounting for 75% of all of the viruses reported by the 

PHLs and 97% of the influenza A viruses reported by these laboratories. These data also show 

the increase in influenza B activity later in the season. Overall, influenza B viruses comprised 

22% of the viruses reported by PHLs. Of those viruses for which lineage information is 

available, 71% were Yamagata lineage and 29% were Victoria lineage viruses. 

CDC performs additional genetic and antigenic characterization of a subset of the viruses 

submitted by the PHLs. The results of genetic characterization of nearly 2500 viruses collected 

in the US since October 1, 2016 are depicted in the following pie charts: 

The single pie chart on the left above depicts the relative proportion of the various subtypes and 

lineages reported by the PHLs. On the right are pie charts showing the distribution of the 

genetic groups within each influenza A subtype and influenza B lineage. There was only a 

small amount of variability in terms of the genetic groups that were circulating this season in the 

US, with 93% of the H3 viruses tested belonging to the 3C.2a genetic group, 99% of the H1 

pdm09 viruses belonging to the 6B.1 genetic group, and all of the B Victoria and B Yamagata 

viruses belonging to the V1A or Y3 genetic groups respectively. 

CDC also performed antigenic characterization on more than 1800 influenza viruses collected in 

the US since October 1, 2016. Of the A (H1N1)pdm09, 294 of 296 (99.3%) were antigenically 

characterized as A/California/07/2009-like, the H1N1 component of the 2016-2017 vaccine. Of 

the A (H3N2), 730 of 772 (94.9%) were antigenically characterized as A/Hong Kong/4801/2014-

like, the H3N2 component of the 2016-2017 vaccine. Of the B/Victoria lineage, 283 of 327 

(86.5%) were antigenically characterized as B/Brisbane/60/2008-like, which is included in 

quadrivalent and trivalent vaccines for the 2016-2017 season. Of the B/Yamagata lineage, all 

429 were antigenically characterized as B/Phuket/3073/2013-like, an influenza B virus included 

in the quadrivalent influenza vaccines for the 2016-2017 season. Some of the B Victoria viruses 

that had reduced titers against the B/Brisbane/60/2008-like virus had similar genetic changes 

that appear to be altering the antigenic properties of the viruses. These viruses in general have 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

comprised a very small proportion of the circulating viruses during this season, but CDC is 

continuing to monitor to see if there is any change in the prevalence of these viruses. All of the 

Yamagata lineage viruses tested were similar to the reference virus included in the vaccine this 

year. 

In terms of the percentage of outpatient visits for influenza-like illness (ILI) reported by 

healthcare personnel (HCP) participating in the ILINet surveillance system, the weekly percent 

of ILI nationally was at or above the national baseline of 2.2% from mid-December through early 

April and peaked at 5.1% during the week ending February 11, 2017. It felt like a particularly 

long influenza season. This was actually borne out by the fact that this season, ILI was at or 

above baseline for 17 consecutive weeks. In comparison, the average over the last 15 seasons 

was above baseline for 13 weeks. 

Through the Influenza Hospitalization Surveillance Network (FluSurv-NET), CDC has 

population-based surveillance for laboratory-confirmed ILI-related hospitalizations for persons 

hospitalized between October 1 and April 30 of each year. This season, more than 18,000 

laboratory-confirmed hospitalizations were reported, resulting in a cumulative incidence for all 

age groups of 64.9 hospitalizations per 100,000. By age group, the cumulative rate to date is 

highest for persons 65 years of age and older at 290.5 hospitalizations per 100,000. 

Hospitalizations in this age group accounted for approximately 60% of all of the reported 

hospitalizations this season. The cumulative rate for the other age groups ranged from a high of 

65.1 per 100,000 among adults 50 through 64 years of age to a low of 16.7 per 100,000 among 

children and adolescents 5 through 17 years of age. 

CDC monitors pneumonia- and influenza-related mortality using data from the National Center 

for Health Statistics (NCHS) Mortality Surveillance System. During this season, the percent of 

deaths attributed to pneumonia and influenza peaked at 8.3% during the week ending January 

21st and was at or above the epidemic threshold for 12 consecutive weeks beginning at the end 

of December and continuing until the middle of March. 

CDC also monitors influenza-associated deaths in children less than 18 years of age. This 

year, 99 influenza-associated pediatric deaths have been reported. This is slightly more deaths 

than were reported during the 2015-2016 season (N=92), but fewer than were reported during 

the 2014-2015 (N=148) and 2013-2014 (N=111) seasons. Of the deaths this season, 64 were 

associated with influenza A virus infection. Of those with subtype information available, 94% 

were H3N2 viruses. Of the deaths this season, 34 were associated with influenza B virus 

infection and 1 was associated with an infection for which the type was not determined. 

In summary, influenza activity during the 2016-2017 season in the US was moderate with 

severity indicators that were within the range of what has been observed during previous 

influenza A (H3N2) predominant seasons. Activity peaked nationally in February, but there 

were regional differences. Western Regions (HHS regions 8, 9 and 10) peaked earlier in the 

season between late December and mid-January. The remainder of the country (HHS regions 

1-7) peaked about a month later in mid- to late-February. Influenza A(H3N2) viruses 

predominated overall, but influenza B viruses have been reported more frequently than 

influenza A viruses since late March. The majority of circulating viruses that were antigenically 

characterized at CDC were similar to the reference viruses included the 2016-2017 influenza 

vaccine. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Vaccine Effectiveness Update 

Jill Ferdinands, PhD 

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention 

Dr. Ferdinands reviewed end-of-season estimates of 2016-2017 influenza VE from the US Flu 

VE Network, introduced the US Hospitalized Adult Influenza Vaccine Effectiveness Network 

(HAIVEN), and presented preliminary 2016-17 VE estimates during this session. 

The US Flu VE Network is CDC’s annual study that estimates influenza vaccine effectiveness 

against outpatient influenza infection. The sites and principal investigators are as follows: 

 Baylor Scott and White Health (Manju Gaglani) 

 Centers for Disease Control and Prevention (Brendan Flannery, Alicia Fry) 

 Kaiser Permanente Washington Health Research Institute (Mike Jackson, Lisa Jackson) 

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

 University of Michigan (Arnold Monto, Emily Martin) 

 University of Pittsburgh (Rick Zimmerman, Tricia Nowalk) 

The network is comprised of outpatients aged 6 months or older who present with acute 

respiratory (ARI) illness with cough of 7 days’ duration or less. It uses a test-negative casecontrol design, with which the odds are estimated of polymerase chain reaction (PCR)-

confirmed influenza among vaccinated compared to unvaccinated enrollees. In this network, 

vaccination is defined as receipt of at least one dose of 2016–2017 influenza vaccine according 

to medical records, immunization registries, and/or self-report from patients who can provide 

both a date and location. The estimation of VE is calculated as 1 – adjusted odds ratio in a 

multivariate logistic regression model x 100%. This is adjusted for a number of confounding 

factors, including age, sex, race/ethnicity, self-rated general health status, days from onset to 

enrollment, and calendar time of illness onset. 

In summary, 7205 patients were enrolled in the US Flu VE study in the 2016-2017 season. 

Overall, the pattern was similar to what was presented by Ms. Budd. It was a late and 

somewhat long season, peaking in mid-February. A little over 2000 cases occurred in the 

outpatient network. Of those, 67% were A/H3N2 infection, 28% were B/Yamagata, and 3% 

were B/Victoria. 

In terms of VE observed this season, about 43% of the influenza-positive cases were 

vaccinated and about 54% of the influenza-negative controls were vaccinated. That resulted in 

an unadjusted VE of 35% and an adjusted VE of 42%, which was statistically significant with a 

confidence interval of 35% to 48%. VE estimates were similar for the various age groups 

included in this network. There were some variations by age, but a significant protective effect 

of the vaccine was observed in children and among those 50 through 64 years of age. Analysis 

of the remainder of the age groups did not show statistically significant effectiveness. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Looking at VE by subtype, the adjusted VE for all ages for A/H3N2 was significant at 34%. 

When stratified by age group, there was some variation with some estimates being statistically 

significant and others not. While there was limited A/H1N1pdm09 this season, there was 

enough to calculate an overall estimate for all ages combined of 54%. In terms of VE for the B 

lineage viruses, adjusted VE for all ages was 56% for all Influenza B, 55% for B/Yamagata, and 

60% for B/Victoria. 

The new platform, HAIVEN, was developed to learn more about the effectiveness of influenza 

vaccine against more severe influenza outcomes. This is a CDC-funded study to estimate the 

effectiveness of influenza vaccine specifically for prevention of influenza hospitalizations among 

adults. CDC has another platform that assesses hospitalizations in children, though this is not 

discussed during this session. The 2015-2016 season was the pilot season for the HAIVEN 

study, which included 7 hospitals. The 2016-2017 season included 10 hospitals and over 5000 

acute care beds. The 4 enrolling sites and investigators include the following: 

 Baylor Scott and White Health (Manju Gaglani) 

 University of Michigan (Arnold Monto, Emily Martin) 

 University of Pittsburgh (Rick Zimmerman, Fernanda Silveira, Don Middleton) 

 Vanderbilt University (Keipp Talbot) 

HAIVEN uses a similar design to the US Flu VE Network. Enrollees are comprised of adults 

aged 18 years of age and older who have been hospitalized for less than 72 hours with an ARI 

with cough ≤10 days duration. HAIVEN also uses the test-negative case-control design and 

estimates the odds of PCR-confirmed influenza among vaccinated compared to unvaccinated 

enrollees. The HAIVEN results presented during this session defined vaccination as receipt of 

at least one dose of 2016–2017 influenza vaccine 14 or more days prior to illness onset by 

patient or patient surrogate self-report. The analysis is similar to that of the US Flu VE Network 

with VE defined as 1 – adjusted odds ratio x 100% and also adjusted for a number of covariates 

(site, age, sex, race/ethnicity, days from onset to enrollment, calendar time of onset, number of 

hospitalizations in past year, frailty, and home oxygen use). 

In 2016–2017, a little over 2200 patients were enrolled in the HAIVEN study. The pattern of 

influenza A and B enrollment was similar to that observed by the US Flu VE Network. This 

analysis includes data only for enrollees through April 14, 2017. However, enrollment continued 

through May 13, 2017. There were approximately 380 cases, which is quite lower than the 

number typically enrolled in a season in the US Flu VE Network. That makes stratification by 

certain subgroups tricky for HAIVEN. In terms of the distribution of the type of influenza 

infections in the HAIVEN study, approximately 70% were A/H3N2, 17% were B/Yamagata, and 

4% were B/Victoria. 

In terms of VE against any influenza A or B, for all ages included in this study, 62% of the 

influenza-positive cases were vaccinated and about 69% of the influenza-negative controls were 

vaccinated. That resulted in an unadjusted VE of 27% and an adjusted VE that was significant 

at 30%. When stratified by age groups, some of the VE estimates are less robust due to the 

sample size. However, a significant protective effect was observed in the oldest age group, 65 

years of age and older, with a VE of 37%. Looking at the HAIVEN VE estimates by virus type 

among those 18 years of age and older, VE was 30% for influenza A and B, 20% for A/H3N2, 

and 53% for influenza B. 

As mentioned earlier, one of the reasons for developing the new HAIVEN network was the 

interest in learning more about VE against more severe influenza outcomes and the desire to 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

assess these outcomes and VE against them over time similar to what is done with the 

outpatient network. There are data from HAIVEN from the 2015-2016 pilot season that have not 

previously been presented to ACIP. VE in HAIVEN during the 2015-2016 timeframe was 50%, 

suggesting that vaccination prevented half of influenza-associated hospitalizations among 

adults in that season. 

CDC also is interested in understanding more about how VE against severe influenza disease 

relates or compares to VE among the milder influenza outcomes typically assessed in the US 

Flu VE network. In a direct side-by-side comparison of the VE estimates from the two networks 

for 2016-2017, the overall VE estimates from the inpatient and outpatient networks are similar 

with VE of 30% in both networks among all adults 18 years of age and over. Because HAIVEN 

did not enroll children, these VE estimates are restricted to adults. 

In summary, vaccine reduced outpatient influenza visits by 42% for influenza A and B viruses 

and by 34% for influenza A/H3N2 viruses. VE was similar to previous A/H3N2 predominant 

seasons when vaccine was antigenically like circulating influenza viruses. Vaccine offered 

significant protection against influenza hospitalizations. Vaccine reduced influenza 

hospitalizations by 30% among all adults and by 37% among adults ≥65 years of age for 

influenza A and B viruses. It is important to note that these results are preliminary and may 

change when final datasets are available. 

Discussion Points 

Dr. Atmar asked whether VE information is available for trivalent versus quadrivalent vaccine for 

influenza B in particular. 

Dr. Ferdinands replied that these data are not available yet because CDC is awaiting some final 

data that will provide details about vaccine type received; however, that is anticipated to come in 

later in the summer and will be evaluated. 

Though the confidence intervals were wide, it appeared to Dr. Reingold that VE increased 

among people over the age of 65 compared to younger adults, which would be surprising. He 

wondered whether that was due to the use of higher potency vaccines, or if it mattered which 

vaccine people over 65 years of age received. 

Dr. Ferdinands replied that there has been some suggestion regarding the 37% VE in the oldest 

age group that perhaps the point estimate may be somewhat higher for that age group. CDC 

will continue to examine this and will assess the uptake of high-dose vaccine in that age group, 

which potentially could be a contributing factor. However, this will not be known until more data 

are received on vaccine type later in the summer. 

Dr. Bennett reminded everyone that this was the opposite in the outpatient setting in the US Flu 

VE Network. 

Dr. Riley asked whether CDC has the ability to assess VE in pregnancy. 

Dr. Ferdinands responded that unfortunately, the outpatient sample is small for pregnant women 

and is almost non-existent in the in-patient network because so few pregnant women are 

enrolled. 

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Knowing that adults do not shed virus as long as children do, Dr. Moore wondered what impact 

the HAIVEN data may have in terms of misclassifying people due to the 10-day window in which 

they may no longer be shedding virus and cannot be PCR-confirmed. 

Dr. Ferdinands indicated that the case definition for HAIVEN was selected to include people 

who had been sick up to and including 10 days, given the smaller number of cases overall and 

the desire to enroll as many as possible to get as precise as possible VE estimate. However, 

the risk is losing accuracy on the outcome definition by doing that. A review of the literature 

suggested that there is not a lot of misclassification by extending out to the 10 days. Some 

additional analyses performed internally suggested that the bias from that in the estimates 

would be minimal by perhaps a couple of points at most. 

Ms. Pellegrini asked whether HAIVEN can enroll pregnant women and if they anticipate 

expanding HAIVEN to enroll more hospitals. 

Dr. Ferdinands indicated that they can enroll pregnant women, but that there are no plans at this 

point to expand. However, after the current 5-year study is over, this will be revaluated to 

determine what can be assessed with this number of hospitals. 

Recognizing that an issue which would arise later is the differential efficacy in the older age 

group of the high-dose vaccines, Dr. Messonnier asked whether either study is robust enough in 

those 65 years of age and older to allow for more specific estimates around different vaccines. 

Dr. Ferdinands replied that this was assessed in HAIVEN during the pilot year, which had a 

smaller sample size. However, there was a signal in the pilot year that high-dose had 

somewhat higher effectiveness. This will be considered carefully in the future. 

Dr. Plotkin (Vaccine Consultant) pointed out that if they were honest about these data, the 

efficacy of the vaccine is only moderate. The question that arose in his mind was, “Why is 

that?” There is a putative correlate of protection. Generally speaking, 1:40 is considered to be 

an adequate response. However, the data suggest that that probably is only about 50% 

protective. It is known that titers wane after vaccination. He asked whether CDC could make 

serological measurements as well as PCR; that is, obtaining blood at the time influenza occurs 

to try to determine whether there is a correlate of protection whether it is hemagglutination 

inhibition (HAI) titer or microneutralization. This would be useful because perhaps the vaccines 

being used do not have sufficient antigen to elicit the type or size of responses desired over the 

period of the influenza outbreak. He wondered whether Dr. Belongia would like to comment on 

this. 

Dr. Belongia agreed and emphasized that there is a need and opportunity to follow large 

community cohorts over multiple seasons with multiple episodes of vaccination. Studies like 

that were conducted in 1970s in Michigan and Seattle, but have not been conducted in any 

recent years to his knowledge. He thinks the virology, immunology, and vaccines have changed 

a lot and it is time to assess that again. However, the Flu VE Network is not really set up to do 

that because the investigators do not know who the people are until they present with a 

respiratory illness so it is not possible to identify them in advance to collect serum. It is 

potentially possible to collect a sample at the time people present, many of whom present within 

2 to 3 days and are in the acute phase of illness. 

Dr. Ferdinands added that during the pilot year and in the second year of HAIVEN, there will be 

the ability to collect residual clinical specimens from the patients who have been hospitalized. 

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Regarding the HAIVEN study, Dr. Whitley-Williams (NMA) requested that Dr. Ferdinands 

comment on the race and ethnicity data collected, whether there is any information on the 

comorbid conditions of the hospitalized patients, and whether the study hospitals are reflective 

of the US population. 

Dr. Ferdinands replied that race and ethnicity data are collected similarly to the way in which the 

US Flu VE Network collects these data using the Census-based categories and self-report from 

the medical records. That sometimes has to be collapsed into a smaller number of categories if 

needed for analytic purposes. While she did not have the exact number readily available, she 

thought about 14% of the HAIVEN enrollees were non-white and will look it up to be certain. 

Data are collected on comorbid conditions in the HAIVEN study. Questions are posed about 

comorbid conditions and use of home oxygen and frailty in order to get at that. Data also are 

collected on the type of medical encounters enrollees had in the year prior to their enrollment. 

From that, it can be determined if they have a history of any number of chronic diseases. In this 

network, approximately 94% to 95% of enrollees do have a chronic condition. The 10 hospitals 

are located in 4 geographic sites, so it is difficult to say that this is completely representative. 

There is some geographic variation in influenza circulation, so that will be captured. 

Dr. David Greenberg (Sanofi Pasteur) wondered if anything is known from the Flu VE Network 

and HAIVEN sites about what proportion of the cases and controls have received high-dose. 

Overall, it is about 60% nationally. 

Dr. Ferdinands indicated that these data are not yet available from the 2016-2017 season on 

vaccine type for HIAVEN. It is known from the pilot season, 2015-2016, that about 40% of the 

vaccinees over 65 years of age had received high-dose vaccine. That is similar for the US Flu 

VE Network. 

In terms of contemplating the suboptimal VE, Dr. Szilagyi requested a reminder of the extent to 

which there are data about vaccination in prior years and how many years this may go back in 

order to further explore the question regarding the potential impact of previous vaccine on VE. 

Dr. Ferdinands responded that this is a tricky methodologic issue. Especially in HAIVEN in 

which two-thirds of enrollees are vaccinated, information is being collected about vaccination 

history. CDC would like to acquire at least 5 seasons’ worth of vaccine information. The data 

quality becomes sketchier the further back it is collected, but an evaluation will be done for this 

first full year of enrollment to assess prior vaccination effects. 

Dr. Sun (FDA) asked whether inter-center variability in the criteria for hospitalization is 

examined for the 10 hospitals in the 4 geographic areas. 

Dr. Ferdinands replied that of the 10 hospitals, 5 or 6 are large tertiary care referral centers and 

the others are community hospitals. There are differences in the patient populations between 

those two groups. A standard case definition was used across the entire study, so each study 

site used exactly the same set of symptoms to determine which patients might be eligible. From 

that perspective, they should be fairly consistent. Perhaps there could be some differences in 

the types of patients who are hospitalized at the various facilities. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Vaccine Safety Update 

Tom Shimabukuro, MD, MPH, MBA 

Immunization Safety Office

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention 

Dr. Shimabukuro provided the end of season updates for the 2016-2017 season influenza 

vaccine safety monitoring. He provided the following table of US influenza vaccine 

abbreviations, highlighting that high-dose trivalent and adjuvanted trivalent vaccines are 

approved for use in individuals 65 years of age and older, with some variability on the lower end 

of the age spectrum for the other vaccines: 

Vaccine Abbreviation 

Trivalent inactivated influenza vaccine IIV3 

Quadrivalent inactivated influenza vaccine IIV4 

High-dose trivalent inactivated influenza vaccine 

(approved for use in individuals 65+ years old) IIV3-HD 

Intradermal trivalent and quadrivalent inactivated 

influenza vaccines 

IIV3-ID 

IIV4-ID 

Cell culture-based trivalent and quadrivalent 

inactivated influenza vaccine 

ccIIV3 

ccIIV4 

Recombinant trivalent and quadrivalent inactivated 

influenza vaccine 

RIV3 

RIV4 

Adjuvanted trivalent inactivated influenza vaccine 

(approved for use in individuals 65+ years old) aIIV3 

He reminded everyone that VAERS is a passive reporting system that is co-administered by the 

CDC and FDA. The strengths are that it includes national data, is good for rapid signal 

detection, and can detect rare AEs. The limitations include reporting bias, inconsistent data 

quality and completeness, and lack of an unvaccinated comparison group. Because of the 

limitations, whether a vaccine caused an AE generally cannot be assessed from VAERS data 

alone. 

Included for this season were US influenza vaccine reports received in VAERS through May 26, 

2017 for individuals vaccinated July 1, 2016 through May 1, 2017. Signs, symptoms, and 

diagnoses are coded using the Medical Dictionary for Regulatory Activities (MedDRA) terms. 

Clinical review of reports, which includes review of medical records when available, were 

performed for the following: 

 All serious reports after IIV3, IIV3-HD, IIV4, IIV4-ID, ccIIV3, RIV3, aIIV3 

 All anaphylaxis reports in persons with a history of egg allergy 

 Pregnancy reports for spontaneous abortion, stillbirth, congenital anomalies, and serious 

pregnancy reports 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Serious reports are based on the Code of Federal Regulations and include death, lifethreatening illness, hospitalization or prolongation of hospitalization, or permanent disability. 

Empirical Bayesian data mining is utilized to detect disproportional reporting for vaccine AE 

event pairings. 

Following IIV3, IIV4, and IIV3-HD in 2016-2017, US serious reports ranged from 4% to 6% and 

correspondingly non-serious reports were 94% to 96%. Dr. Shimabukuro emphasized that this 

does not mean that 4% to 6% of people who got an influenza vaccination had an SAE. VAERS 

is a partial numerator system only, which means that of the VAERS reports for these products, 

4% to 6% met the regulatory definition for serious. Guillain-Barré Syndrome (GBS) reports 

comprised a very small percentage of total reports from 0.9% to 1% for these products. 

Anaphylaxis reports are rare in VAERS, ranging from 0.2% to 0.6%. There were no data mining 

safety signals for GBS or anaphylaxis in association with trivalent, quadrivalent, or trivalent highdose. Of the 27 IIV4 reports, 3 were in persons with a history of egg allergy. Following ccIIV4, 

RIV3, aIIV3-ID, and IIV4-ID, serious reports ranged from 4% to 7%. GBS was rarely reported 

and there were some anaphylaxis reports, but it is important to keep in mind that these small 

numbers can make big differences in percents. Importantly, there were no data mining signals 

for GBS or anaphylaxis for these influenza products either. One of the RIV3 anaphylaxis 

reports was in a person with a history of egg allergy. The breakdown for IIV3, IIV4, IIV3-HD, 

ccIIV4, RIV3, aIIV3-ID, and IIV4-ID is similar to previous seasons. 

In terms of the anaphylaxis reports in persons with a history of egg allergy, one case was a 6-

year-old female who received Fluzone® (IIV4) alone. Her medical history was significant for 

asthma, eczema, food allergies to eggs (signs symptoms not reported), peanuts, wheat, corn, 

and shellfish. The patient received “a flu shot” of unknown type 2 years prior, with no reported 

reactions. Symptom onset occurred within 30 to 35 minutes, including hives and tachycardia, 

but no wheezing. This was classified as a Brighton Level 3 anaphylaxis case. The Brighton 

classification ranges from 1 to 4, with Level 1 being the highest level of diagnostic certainty. 

The next case was a 37-year-old female who received Flublok® (RIV3) alone. As a reminder, 

Flublok® is egg-free. Her medical history was significant for hives to “flu shots” (unknown type) 

in the past and diarrhea and hives after eating eggs. Symptom onset occurred within minutes, 

including swelling of upper throat, difficulty swallowing, pruritus in tongue, throat, and chest and 

loss of consciousness. This case was classified as a Brighton Level 1. 

The next case was in a 2-year-old female who received Fluzone® (IIV4) and HepA vaccine. Her 

medical history was significant for anaphylaxis with milk and a “positive” but unspecified reaction 

to eggs, although it was reported that the patient can eat eggs. She had previously received an 

IIV influenza vaccine of an unknown type and HepA vaccines without any problems. Symptom 

onset occurred within minutes, including vomiting, red rash on back, paleness, low 

responsiveness, and initial blood pressure (BP) of 84/40 that dropped to 70/30. This case was 

classified as a Brighton Level 1. The final report of anaphylaxis in a patient with egg allergy 

occurred in an 18-year-old female who received Afluria® (IIV4), inactivated polio vaccine (IPV), 

MCV, and Tdap in the same visit. She had a known history of egg allergy, but the signs and 

symptoms were not reported. This was known prior to receiving a “flu vaccine” of an unknown 

type in the past. The history is somewhat unclear, but that is what was in the report. No contraindication to receiving IIV could be identified in the report. Symptom onset was within hours and 

included hives, severe respiratory distress with wheezing, and angioedema of face and throat 

swelling. This case was classified as a Brighton Level 1. 

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Of the 37 total pregnancy reports, 36 were with standard IIV3 or IIV4 and one was with ccIIV4. 

The median maternal age was 29 years. The median gestational age when reported was 21 

weeks. The breakdown for trimester of vaccine was 5 (36%) in the first trimester, 4 (28%) in the 

second trimester, and 5 (36%) in the third trimester. Of the 37 reports, 7 (19%) included a 

pregnancy-specific outcome. Of these 7, 5 were spontaneous abortion and 2 were vaginal 

bleeding. Roughly half of the reports, 18 (49%), were non-pregnancy-specific AEs. This 

includes the one ccIIV4 report. There were 12 (32%) vaccination error reports. These 

vaccination error reports could be true error reports; reports in which a patient received an 

influenza vaccine and the person reporting it perceived this to be an error; and patients who 

received multiple vaccines, one of which may have been the vaccine given in error. To 

summarize VAERS surveillance for the 2016-2017 influenza season and plans for 2017-2018, 

no new safety concerns were detected for IIVs, ccIIV3, RIV3, or aIIV3 during the 2016-2017 

influenza season. Surveillance for the 2017-2018 influenza season will include enhanced safety 

monitoring for aIIV3 (FLUADTM), IIV4-ID (Fluzone® Intradermal Quadrivalent), RIV4 (Flublok® 

Quadrivalent), pregnancy reports, and anaphylaxis reports in persons with history of egg allergy. 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Moving on to FDA surveillance for GBS, FDA conducts near real-time surveillance for GBS after 

influenza vaccination every influenza season in collaboration with the Center for Medicare and 

Medicaid (CMS). About half of these beneficiaries receive influenza vaccination every season. 

The population under surveillance is about 15 to 16 million beneficiaries per season, almost 

99% of whom are 65 years of age and older. FDA compares the current seasons’ GBS rates 

with historic rates. Previously, this has been for three seasons. However, in the 2016-2017 

season, FDA used the past five seasons to help with stability of data. FDA uses updated 

sequential probability ratio test (SPRT) to account for claims and clinical delays. If the observed 

rate exceeds a critical limit, that constitutes a statistical signal. CMS data are refreshed each 

week, although it takes up to 10 weeks for data to mature. 

In week 17 of surveillance, which includes data as of December 9, 2016, the current GBS rate 

for the primary outcome was greater than the historical rate. By Week 20, the GBS rate in the 

current season declined and was very close to the historical rate. This is illustrated in the 

following graphic: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

The current season is represented by the orange line, while the light green solid line is last 

season when there was a signal for GBS in FDA’s GBS monitoring of the CMS data. As a 

reminder, there also was a signal detected in the Vaccine Safety Datalink (VSD) Rapid Cycle 

Analysis (RCA) for GBS as well. The spike in the orange line was an anomaly early in the 

season, which when looked into was resolved and is why there was a drop back down to zero. 

The GBS in the current season is very close to the average of the past five seasons. However, 

the GBS rate is lower than the GBS rate in the 2015-2016 season when it was 7.25 GBS 

cases/million vaccines. FDA plans to conduct an end-of-season self-controlled risk interval 

analysis. However, there are not sufficient data for 80% power yet, indicating that the number 

of GBS cases was quite small this season. 

In week 40 of surveillance, GBS rate in a 6-week risk window was 5.96/million vaccinees, 

compared to an average of 5.70/million vaccinees for the prior five seasons. End-of-season 

analysis using a self-controlled design is to be conducted when 99% of the fee-for-service 

beneficiaries have been vaccinated. Limitations of surveillance include comparison to historical 

data, claims-based analysis, and no control for confounders. 

Turning to VSD RCA for the current season, the VSD was established in 1990 as a 

collaboration between CDC and 9 integrated healthcare plans. It includes data on over 9 million 

persons per year (~3% of US population) and links vaccination data to health outcomes data 

(hospitalization, emergency department visits, outpatient visits). Patient characteristics are 

linked by unique identification (ID) numbers. Two methods are used to conduct RCA in VSD, 

self-controlled design and current versus historical design. In a self-controlled risk interval 

design, each patient serves as his/her own control, and events in the risk window and 

comparison window are assessed. In this particular case, vaccination occurs on Day 0, the risk 

window extends from Day 0 to Day 1, and the comparison window (control window) is Day 14 to 

Day 15. The time period in the risk window is considered exposed time and the time period in 

the comparison window is considered unexposed time. The current versus historical design 

assesses events in the risk window in patients in the current season versus patients during the 

historical comparison period. 

The VSD RCA outcomes for the current season include acute disseminated encephalomyelitis 

(ADEM), anaphylaxis, Bell’s palsy, encephalitis, GBS, seizures, and transverse myelitis. A total 

of 4,554,828 doses were administered in the VSD through April 29, 2017 broken down as 

follows: IIV3 (2,655,071), IIV4 (1,359,059), IIV High-Dose (456,043), ccIIV3 (78,002), IIV 

Intradermal (5,549), and RIV3 (1,104). IIV3 and IIV4 dominated, approaching 90% of all 

influenza vaccine doses administered in the VSD during the season. 

Regarding the 2016-2017 VSD RCA results, it is important to note that the log-likelihood ratio 

(LLR) is the test statistic. If the LLR exceeds the critical value for any pre-specified outcome, 

there is a signal. To address this question in advance, that is not always a simple ratio for a 

self-controlled risk interval. There are different lengths of windows and adjustments have to be 

made for data lags. If the relative risk exceeds 1, there is a value for the LLR. None of the 

LLRs exceeded the critical value for IIV3 or IIV4 for any of the pre-specified endpoints, so there 

was no signal in the self-control design for IIV3 or IIV4 for this season. In the case of the 

current versus historical design, the relative risk is a simple ratio. None of the LLRs exceeded 

the critical values for any of the pre-specified outcomes for IIV3 or IIV4 in the current versus 

historical design, so there were no signals in this design either in the current season. 

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In summary of the 2016-2017 VSD influenza vaccine RCA, no RCA signals were identified in 

either the self-controlled risk interval or current versus historical designs for any of the prespecified outcomes for IIV3 or IIV4. For IIV3 high-dose, a limited number of doses were 

administered in VSD for the 2016-2017 influenza season (n=450,242). There were no statistical 

signals or elevated relative risks for any pre-specified outcomes being monitored, which 

includes GBS, in either the self-controlled risk interval or current versus historical designs for 

high-dose. Data for ccIIV3, IIV Intradermal, and RIV3 are limited due to low use of these 

vaccines, but were generally reassuring. 

A self-controlled risk interval and current versus historical RCA was conducted for the prespecified conditions (anaphylaxis, Bell’s palsy, encephalitis, GBS, seizures, transverse myelitis, 

acute disseminated encephalomyelitis) for the 2017-2018 influenza season. Work continues on 

a comprehensive analysis to evaluate the risk of GBS following pH1N1-containing seasonal 

influenza vaccines for the years 2010-2016. This study is a follow-up to the RCA signal in the 

self-controlled risk interval design for GBS following IIV3 detected during the 2015-2016 

influenza season. 

To summarize influenza vaccine safety monitoring for 2016-2017, no new safety concerns were 

detected in VAERS monitoring. There were reassuring results in FDA’s near real-time 

monitoring for GBS following influenza vaccination in Medicare beneficiaries in CMS data. No 

signals were identified for any pre-specified outcomes being monitored in the VSD RCA. 

Discussion Points 

Dr. Romero asked whether Dr. Shimabukuro had information about the trimesters in which the 5 

spontaneous abortions occurred in the 2016-2017 season. He also noted that no data were 

included on the RCA self-control results for IIV3 or IIV4. 

Dr. Shimabukuro replied that the spontaneous abortions were clinically reviewed. They would 

have that information if it was included in the reports, which he will provide to Dr. Grohskopf. 

For the endpoint of ADEM, only the current versus historical design was used. ADEM is so 

rare, there were no meaningful data to present for the self-control risk interval design. 

Dr. Lee asked whether the current versus historical comparisons actually accommodated for the 

transition between International Classification of Diseases (ICD-9) to ICD-10 that occurred 

during that historical period and whether that contributed to the elevated GBS risk observed in 

the 2015-2016 season. Related to that, she wondered whether it would be useful to consider a 

case-centered approach to account for seasonality and secular trend. This might result in a 

slightly different answer than what would be found with a self-controlled risk interval analysis. 

Dr. Shimabukuro confirmed that the 2015-2016 season does span the ICD-9 to ICD-10 

transition. His understanding from speaking with the statisticians and epidemiologists in VSD is 

that the problem, at least with GBS, is minimal. However, they cannot exclude that the 

transition from ICD-9 to ICD-10 may have played some role in what was seen in the data for 

that season. Multiple methods are being considered to analyze the data for that study, one of 

which is case-centered. 

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Kevin Ault (ACOG) noted that spontaneous abortion typically would occur in the first trimester 

up to 12 weeks or less than 20 weeks. Beyond those gestational ages, it would be referred to 

as stillbirth or pre-term delivery. There are good data showing that influenza vaccination during 

pregnancy prevents stillbirths and prematurity. He assumed that standard definitions of 

spontaneous abortion are being used. 

Dr. Shimabukuro replied that they use the standard definition for spontaneous abortion. If there 

was a stillbirth, it would have been reported as such. Fetal demise is not being combined into 

one category. Those are spontaneous abortions based on the review of the report. 

Flublok® in Pregnancy 

Wayne E. Hachey, DO, MPH

Head Government and Clinical Services 

Protein Sciences Corporation 

Dr. Hachey indicated that Protein Sciences Corporation maintains a pregnancy registry, which 

includes all pregnancies reported during clinical trials and those reported voluntarily during 

seasonal use. Subject tracking during clinical trials is an active process, which ensures capture. 

However, for seasonal use, the package insert includes a request for notification of all Flublok® 

vaccine exposures during pregnancy. Again, this is voluntary and assumes that people are 

reading the package insert. There are some limited data from a vaccine coverage program 

conducted in Mongolia by the Center for Vaccine Equity (CVE). 

Regarding pregnancies reported during clinical trials, Protein Sciences Corporation’s first study 

was PSC 01 that was conducted in the 2004-2005 influenza season. For the 181 doses 

administered to women of childbearing age, there were 3 pregnancies. One subject received 

vaccine at 5 weeks gestation and had an uneventful term pregnancy. One subject became 

pregnant 3 months after receiving Flublok® and underwent an elective termination at 12 weeks. 

The third subject became pregnant 20 weeks following immunization and underwent an elective 

termination at 12 weeks. 

The second study that involved women of childbearing age was PSC 04 that occurred in the 

2007-2008 season. This involved 1371 doses to women of childbearing age, among whom 

there were 20 pregnancies. Of the 20, there were 12 uneventful live births. There was 1 

spontaneous abortion in a woman who received vaccine 2 months prior to pregnancy and 

experienced the spontaneous abortion at 5 weeks. There were 2 elective terminations, 3 were 

lost to follow-up, and 2 withdrew from the study and would not provide pregnancy outcome data. 

Study PSC 16 occurred during the 2013-2014 season. This involved 7 pregnancies among 675 

women of childbearing age. Of these, 1 subject reported pregnancy 3 weeks following 

immunization and a spontaneous abortion 6 weeks later. The remaining 6 were uncomplicated 

live births. 

In terms of pregnancies after routine seasonal influenza immunization, 5 pregnancies were 

reported. Of these, 4 were uneventful and 1 experienced a spontaneous abortion 2 days after 

immunization. At the time the pregnancy loss was reported to Protein Sciences Corporation, 

approximately 1,000,000 total doses had been administered. 

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The last data group comes from a vaccine coverage project in Mongolia. This program was 

conducted by CVE at the Task Force for Global Health. The goal was to increase influenza 

vaccine coverage in Mongolia. Protein Sciences Corporation donated 40,000 doses of Flublok® 

vaccine, which was given to 330 pregnant women. No serious AEs were reported; however, it 

is important to note that this was a passive surveillance network with a number of limitations. 

There was no active follow-up of pregnancies and the surveillance network capability to capture 

pregnancy-related AEs are uncertain. At best, these are somewhat reassuring data. However, 

it is hardly the same follow-up that would be experienced by someone reporting a pregnancy 

directly to Protein Sciences Corporation. With continued participation in this project, Protein 

Sciences Corporation hopes to include active follow up of individuals who received Flublok® 

during pregnancy in order to acquire better data. 

In summary, excluding the Mongolia data, there were 35 Pregnancies. Of these, 23 resulted in 

normal outcomes, 3 ended in spontaneous abortions, 4 were electively terminated, 3 were lost 

to follow-up, and 2 withdrew from the study. 

Influenza WG Considerations and Proposed Recommendations 

Lisa Grohskopf, MD, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention 

Dr. Grohskopf provided an overview of the draft 2017-2018 ACIP influenza statement, which is 

anticipated to be published sometime in August 2017. It will be included in the Morbidity and 

Mortality Weekly Report (MMWR) Recommendations and Reports document. 

One aspect of the statement not being proposed for change is the core recommendation. The 

draft statement re-iterates the core recommendation that annual influenza vaccination is 

recommended for all persons aged 6 months and older who do not have contraindications. 

As is done each year, the statement will include the US influenza vaccine composition for 2017-

2018: 

Trivalent Vaccines 

 A/Michigan/45/2015 (H1N1)pdm09-like virus (updated) 

 A/Hong Kong/4801/2014 (H3N2)-like virus 

 B/Brisbane/60/2008-like virus (Victoria lineage) 

Quadrivalent Vaccines 

 A/Michigan/45/2015 (H1N1)pdm09-like virus (updated) 

 A/Hong Kong/4801/2014 (H3N2)-like virus 

 B/Brisbane/60/2008-like virus (Victoria lineage) 

 B/Phuket/3073/2013-like virus (Yamagata lineage) 

This composition represents an update in the (H1N1)pdm09-like virus for 2017-2018. 

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Next, there is a discussion of products licensed and changes in existing approval since 

publication of the last statement on August 26, 2016. These include: 

 Afluria® Quadrivalent (IIV4, Seqirus), for persons aged ≥18 years

 Flublok® Quadrivalent (RIV4, Protein Sciences), for persons aged ≥18 years

 FluLaval® Quadrivalent (at 0.5cc dose) for children aged ≥6 months (previously licensed 

for ≥3 years)

Notably, prior to this licensure change for FluLaval®, the only influenza vaccine approved for 6-

to 35-month-olds has been a 0.25cc dose of Fluzone® and Fluzone® Quadrivalent. That 

approval still exists, but there are now 2 options for children in the 6- to 35-month-old age group. 

With regard to LAIV4 Flumist® Quadrivalent, during the June 2016 ACIP meeting, ACIP made 

the recommendation that LAIV not be used for the 2016-2017 season due to concerns about its 

effectiveness against (H1N1)pdm09-like viruses during the 2013-2014 and 2015-2016 seasons. 

The draft recommendation extends this recommendation that LAIV not be used into the 2017-

2018 season while further data are awaited on LAIV4, which are anticipated to be presented to 

ACIP during the October 2017 meeting. 

At the time the recommendation was made not to use LAIV for the 2016-2017 season, one 

question raised regarded whether this would adversely affect pediatric vaccine coverage rates 

for influenza. With that in mind, preliminary influenza vaccination coverage for the 2016-2017 

season compared with 2015-2016 final season estimates are shown in the following graph, 

which shows considerable overlap and indicating that as the season progressed, coverage 

overall remained similar: 

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Notably, there was a difference in the 5- through 12-year-old age group of 2.3% lower for 2016-

2017 compared to 2015-2016. Though a small difference, it was statistically significant. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

The following table summarizes data from the same source; however, this time there is 

stratification by age group within the pediatric population that shows similar coverage estimates 

for the two seasons: 

Returning to the content of the 2017-2018 statement, Dr. Grohskopf discussed the two areas for 

which language changes were proposed for consideration. The first of these related to Afluria® 

(IIV3). Afluria is licensed by FDA for persons aged 5 years and older. However, since the 

2010-2011 influenza season, ACIP has recommended Afluria® only for persons aged 9 years 

and older following reports of febrile seizures and reactions that occurred in association with its 

use in Australia with the 2010 Southern Hemisphere formulation. The seizures were confined 

largely to those under 5 years of age; however, there were febrile reactions among children 

aged 5 through 8 years. In February 2017, ACIP heard a presentation from SeqirusTM that 

summarized the investigation into the root cause of these reactions and some manufacturing 

changes that were made as a result. 

Because these data were presented several months ago, Dr. Grohskopf reviewed the main 

findings from the SeqirusTM presentation in February 2017. With the initial investigation into the 

happenings in Australia, CSL Biotherapies, the company at the time that held Afluria®, 

concluded that two factors probably in combination were associated with these events. One 

factor was that for the 2010-2011 season, the composition of the vaccine changed such that all 

three viruses in the seasonal vaccine changed. There was the introduction of the 

(H1N1)pdm09-like viruses, A/California/07/2009, into the seasonal vaccine. That had been the 

same virus in the monovalent vaccine. There also was the introduction of B/Brisbane/60/2008 

for the B virus. 

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The second factor that was initially implicated pertained to residual lipid and ribonucleic acid 

(RNA) complexes that were in the vaccine product following splitting. This is an inactivated 

vaccine product. The viruses are split or disrupted. In this case, it is with a compound called 

taurodeoxycholate (TDOC). As presented to ACIP by SeqirusTM in February 2017, a study was 

conducted using an in vitro cell cytokine release model in which several different experimental 

settings altering the concentration of TDOC used on the various viruses was done. The original 

standard formulation used 0.9% for H1N1, 0.5% for B, and a higher concentration of 1.5% for 

H3N2. The take-home message is that raising the concentration of TDOC used to 1.5% for all 

viruses resulted in the greatest attenuation of the inflammatory signal. These data are also 

summarized in the paper by Rockman from Vaccine 2014 [Rockman S et al. / Vaccine 32 

(2014) 3869-3876]. 

Also presented to ACIP in February 2017 were data from 2 studies in children 5 through 8 years 

of age. The first study compared a modified Afluria® trivalent in which the TDOC concentration 

was raised to 1.5% for the B strain to a licensed comparator quadrivalent vaccine. In this study, 

fever rates were similar. In addition, the fever prevalences were compared with historical fever 

data from previous formulations of trivalent CSL vaccine. In the new experimental Afluria® TIV, 

the fever prevalence was lower [https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-

000175-27/results]. 

A similar study was conducted in the same age group in which a quadrivalent Afluria® with a 

concentration of TDOC raised to 1.5% for all 4 viruses was compared with a licensed 

comparator quadrivalent. Again, there were similar fever rates and lower fever rates than were 

observed with the historical TIV fever data [Leong J, et al.

As was summarized for ACIP by SeqirusTM, it was felt that with the change in the TDOC content 

for use in treating the viruses, fever rates for children 5 through 8 years of age with the TIV and 

QIV were similar to comparator QIV and were less than observed historically with older TIV 

formulations of Afluria® IIV3. In consideration of discussion of these data that were presented to 

ACIP and also were discussed within the WG, the first proposed change is that Table 1, the 

large table that has been in the guidance for a number of years that summarizes information on 

all of the vaccine products anticipated to be available for the season, be modified to state that 

Afluria® is indicated for persons ≥5 years of age rather than ≥9 years of age as it currently 

states. In addition, the footnote that occurs that the bottom of that table stating ≥9 years of age 

and the reason why is recommended to be removed. 

The second proposed modification relates to vaccination of pregnant women and choice of 

vaccine. Before going into the proposed language, Dr. Grohskopf presented a high-level 

summary of the recommendation for influenza vaccine in pregnant women. Pregnant women 

with risk factors for severe influenza illness have been recommended to receive influenza 

vaccine since the 1960s. Between that time and roughly the 1990s, vaccination was generally 

recommended for those who had another risk factor, for example, a chronic medical condition 

such as heart or lung disease that conferred a higher risk for severe influenza illness. Over 

time, it became increasingly recognized that pregnancy, particularly the second and third 

trimesters, were risk factors in and of themselves for severe illness and negative pregnancy 

outcomes in some studies. In 1995 and 1997, the third and second trimesters were added as 

risk factors themselves without regard to having another risk factors. Influenza vaccination has 

been recommended by ACIP for women who will be pregnant during influenza season without 

regard to trimester since 2004. Information that was considered for this recommendation 

included increased risk for severe influenza illness in pregnant women, particularly during 

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second and third trimesters; adverse pregnancy outcomes noted in some studies; and an 

association of some birth defects with maternal fever. Current language regarding pregnancy in 

the ACIP statement indicates that pregnant women should receive IIV specifically. 

The WG discussed the information on pregnancy reports presented by Protein Sciences 

concerning Flublok® (RIV). The information on Mongolia was not available at the time, so that 

was not discussed. In addition, there have been three VAERS reports since 2013 of pregnant 

women who received Flublok®. In two of these reports, no AE was reported. In one report, a 

woman presented in clinic with vaginal bleeding and a suspected spontaneous abortion. In their 

discussions, the WG considered that there are relatively few data concerning the use of 

Flublok® in pregnancy. There is more experience and more data relating to IIVs. Although the 

evidence base consists largely of observational studies and safety surveillance data, it is overall 

reassuring on balance. There is a much longer clinical experience with the use of IIVs than with 

RIV. The WG also acknowledged that even for the inactivated vaccines, data are somewhat 

more limited for the first trimester and also for some newer inactivated vaccines, such as 

quadrivalents and cell-based vaccines. 

While there are few data relating specific to the use of Flublok® in pregnancy, it was noted that 

the general overall safety profile of Flublok® in comparison to IIVs is reassuring. For example, 

one concern that arises is reactogenicity and inflammation. Overall, reactogenicity in the 

studies in which Flublok® inactivated vaccines have been compared, rates of most of the local 

and systemic AEs are similar to that observed with IIVs in clinical studies. Relatively few 

additives are listed in the RIV package insert (e.g., preservatives, antibiotics, gelatin, egg 

protein). However, not all inactivated vaccines contain these agents either. Flublok® does 

contain some residual insect cell and Baculovirus proteins in DNA, which is cited on the 

package insert. The inactivated vaccines do not contain these residuals. On initial licensure, 

Flublok® RIV3 received a Pregnancy Category B destination, which is similar to most of the 

other IIVs available. The Flublok® RIV4 was approved in fall 2016. That package insert 

incorporates the new FDA Pregnancy and Lactation Labeling language, so it is not quite directly 

comparable to the previous language. 

Based on these considerations, the WG proposed the following recommendation for vaccination 

of pregnant women shown in comparison to the 2016-2017 language with the proposed 

changes underlined: 

2016-2017 Language 

“Because pregnant and postpartum women are at higher risk for severe illness and 

complications from influenza than women who are not pregnant, the ACIP recommends that all 

women who are pregnant or who might be pregnant in the upcoming influenza season receive 

IIV. Influenza vaccination can be administered at any time during pregnancy, before and during 

the influenza season.” 

Proposed New Language for 2017-2018 

“Because pregnant and postpartum women are at higher risk for severe illness and 

complications from influenza than women who are not pregnant, the ACIP recommends that all 

women who are pregnant or who might be pregnant in the upcoming influenza season receive 

influenza vaccine. Any licensed, recommended, and age-appropriate, trivalent or quadrivalent 

IIV or RIV may be used. Influenza vaccination can be administered at any time during 

pregnancy, before and during the influenza season.” 

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Discussion Points 

Dr. Kempe requested clarity regarding whether the FDA licensure wording for the use of IIV3 

and IIV4 influenza vaccines in pregnancy is exactly the same. 

Dr. Grohskopf replied that the recommendations have not made a distinction with regard to 

pregnancy and IIV3 or IIV4, so either would be feasible. 

Ms. Pellegrini observed a nuance that she wished to better understand. In general, most any 

vaccine may be used for any purpose for which it is licensed. These are licensed for use in 

anyone above a certain age. There is a subtle but important difference in the proposed 

language in making what would appear to be an affirmative statement that RIV is safe in 

pregnant women versus remaining silent on it or stating that ACIP is not saying it should not be 

used, but there are not enough data to affirmatively say it is safe. It seemed that they were 

heading there, and she wondered whether the rest of the group was comfortable with that. 

Dr. Kempe said her understanding was that the FDA makes decisions about safety and that it is 

not necessarily ACIP’s job, so she was somewhat confused about why the proposed language 

was calling this out. 

Dr. Sun (FDA) clarified that in order for a vaccine to be indicated for pregnant women, it has to 

be in the package insert specifically for that population. When new vaccines were licensed for 

adults, which includes women who are pregnant, that is not considered to be inclusive of 

pregnant women. In other words, one would have to show safety for pregnant women in order 

for the label to state that it is safe in pregnant women. That is not to say that they are not safe. 

It is that there are not sufficient data to state that they are safe. The distinction here is that it is 

not in the label. 

Dr. Bennett clarified that this change is simply to make Flublok® consistent with all of the other 

vaccines, because essentially there are not a lot of data, but there are no safety signals to 

distinguish Flublok® from the other vaccines that ACIP recommends. 

Dr. Lee agreed with Ms. Pellegrini in that the proposed language makes an affirmative 

statement as opposed to the absence of a clear statement for it. It seemed that the sentence 

could be moved to a generic section to state that ACIP would be in favor of any of the influenza 

vaccines period for any people. However, because it was in this section, it seemed to implicate 

that ACIP has a certainty of the benefits, risks, and balance of that. However, only 1000 doses 

have been administered. It felt like they did not have enough information. It was not that it 

should not be used, but calling it out specifically seemed to indicate its use in the particular 

population. 

Dr. Walter thought part of it had to do with the way the rest of the recommendations read. They 

do mention all of these vaccine products. It was meant to be inclusive and not give an 

endorsement of safety. 

Dr. Belongia agreed and thought it was a matter of being equivalent to IIV. Especially in the first 

trimester, there is a relative paucity of data for IIV as well. Flublok® is a recombinant vaccine. 

Theoretically, it should not be any worse than IIV in terms of the potential to cause harm 

because it is theoretically pure HA, recognizing with any manufacturing process nothing is 100% 

pure. Afluria® is a split vaccine with RNA, lipids, and other things that Flublok® does not have. 

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Based on that, he would not penalize Flublok® and it would be at least equivalent to IIV in the 

absence of any evidence. 

Dr. Hunter asked whether the WG acknowledged the implications of a lack of preference 

between vaccines, based on the fact that there is a ratio of 2:1 trivalent to quadrivalent being 

used. Because the trivalent is less expensive than the quadrivalent and large systems often will 

purchase only one or the other, clinicians often do not get to choose what, in their opinion, is 

necessarily appropriate for particular patients because of the health system in which they 

practice. That decision feeds into the manufacturing process of what is produced. 

Dr. Walter said he thought the intent of the WG was to allow use of whatever product was 

available. 

Dr. Bennett thought it was implicit in the proposed recommendation language that the WG did 

not choose to make any preferential recommendations. 

Dr. Walter confirmed that this was correct. 

Dr. Lee asked if put into the context of the reset of the recommendations, the intent of the 

proposed language reflected the differential uncertainty in the different vaccines, but ACIP 

would not be making any preference statement. 

Dr. Walter said he thought the pregnancy section discussed experience. The proposed 

language just puts it into context with the rest of the recommendations as outlined. 

Dr. Grohskopf clarified that the draft recommendations are divided into two sections, the 

Recommendation Summary and the Background. The Background discusses in some detail 

what literature base is available for each vaccine. 

Ms. Pellegrini remained uncomfortable with the new pregnancy language and wondered 

whether there was an option to separate it out as a distinct issue or vote. 

Dr. Bennett pointed out that because there was no motion on the floor, Ms. Pellegrini could 

propose any option she liked. 

Ms. Pellegrini made a motion to separate the proposed pregnancy language for an individual 

vote from the rest of the recommendations. Dr. Hunter seconded the motion for the purpose of 

further discussion. 

Dr. Messonnier clarified that if there is a motion on the floor, it would be permissible in the 

context of that motion to make a recommended change to the language. 

Dr. Bennett called for discussion on separating the pregnancy language and voting on it 

separately from the full statement. 

Dr. Kempe wondered whether if the proposed language simply stated, “a recommended 

influenza vaccine product may be used” and did not single anything out it would make it more 

comfortable. The safety issues are FDA’s not ACIP’s decisions. That is true for any vaccine 

during pregnancy. 

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Dr. Hunter asked whether the suggestion was to remove “trivalent or quadrivalent IIV or RIV” 

and retaining “Any licensed, recommended, and age appropriate vaccine may be used.” 

Dr. Kempe thought that would take it out of the realm of suggesting that they have carefully 

looked at all of these different products. 

Dr. Grohskopf pointed out that the one complication is that she would need to insert language 

about LAIV. This past season, LAIV was not recommended but was available, so language had 

to be included referencing previous recommendations for its use or not use. So, to say “any 

licensed, recommended . . .” is probably okay, but there should probably be a sentence stating 

that LAIV should not be used in pregnancy because of the general recommendation to not use 

live virus vaccines. 

Dr. Belongia thought it would be acceptable alternative wording to say “Any licensed, 

recommended, age-appropriate vaccine may be used. LAIV should not be used in pregnancy.” 

As an obstetrician, Dr. Riley interpreted the language to mean that she could use anything that 

is available in pregnancy other than LAIV. She read it as more choices and that more women 

would get vaccinated. The materials sent to ACIP members go through the limits to the data 

available. 

Dr. Atmar did not see that the proposed language change really changed anything. The 

proposed language is more specific about which types of vaccines would be age- and 

pregnancy-appropriate. The other language required the addition of another sentence to state 

specifically that LAIV should not be used. The statement did not address the relative paucity of 

data in either choice. Therefore, he saw no reason to change the language as originally 

proposed. 

Dr. Fryhofer (ACP) said that as a clinician who sees patients, she does not have the knowledge 

base that the researchers have. Therefore, she tries to think of the recommendations in terms 

of what clinicians will think when they read them. She thinks clinicians appreciate as much 

detail as possible. Looking at the proposed language, it was not clear to her whether ccIIV 

would be included. 

Ms. Hayes (ACNM) agreed that it is helpful for clinicians if more data are provided on what drug 

or vaccine is or is not appropriate to give. She also thought they must remind people that live 

vaccine is not to be given during pregnancy. To her, the exclusion was almost more important 

than the inclusion. 

Dr. Grohskopf clarified that the sentence about the exclusion falls immediately after this material 

and will be there regardless. 

It seemed to Dr. Thompson (NVAC) that the full sentence proposed for revision was adding 

complexity. The sentence above it states that all pregnant women should receive influenza 

vaccine and her inference is that it should be licensed, age-appropriate, and recommended. It 

was not clear to her why there was an extra sentence or what it added. 

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Dr. Belongia thought the WG’s issue with the 2016-2017 recommendation was that it stated 

“IIV.” The goal was to get away from that. He thought stating “any licensed influenza vaccine 

and not LAIV” pretty much said the same thing. 

Dr. Messonnier thought they were back to a problem that ACIP discussed generically in the 

past, which regarded how most providers make their decisions. While she completely 

understood the detail-orientation of ACIP, which is what it should be, in the end most providers 

are not reading these recommendations at the level ACIP is reading them. What matters 

equally is what is in the schedule, and hopefully the eventual maternal schedule that will be 

created and how things are articulated. The current schedule states, “Pregnant women should 

receive IIV.” In some ways, it seemed that the request was for ACIP’s intensions to be clearer 

in the materials being used. Perhaps more importantly is how the intent is communicated rather 

than what it actually says. 

Dr. Bennett agreed. In an effort to move forward, she asked Ms. Pellegrini to make a motion for 

the wording she would like, determine whether others agreed, and then move forward with the 

vote. 

Following additional discussion, Ms. Pellegrini withdrew the original motion and Dr. Hunter 

seconded the withdrawal. 

Dr. Atmar made a new motion to approve the 2017-2018 Influenza Vaccine Recommendations 

as presented. 

Dr. Kempe recommended that the more general statement be made to read, “Any licensed, 

recommended and age-appropriate vaccine. LAIV should not be used.” 

Dr. Lee pointed out that intent was clearer in the preliminary information provided to ACIP and 

she wondered whether that could be posted. Dr. Bennett indicated that they did not have it to 

put up on the screen, but that the wordsmithing could be done post hoc and sent to all members 

to ensure that everyone is comfortable with it. 

Public Comment 

The following letters were submitted by Alachua County Board of County Commissioners prior 

to the meeting for consideration by ACIP: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Pam Rockwell 

Parent of a Child with Autism 

Presented During the Meeting 

I want to encourage the ACIP to change the recommendation for flu vaccine to add a 

contraindication for the first trimester of pregnancy. Most studies of flu vaccine safety in 

pregnancy only follow the child for first year of life, but you can’t tell if someone has a 

developmental disability until they are at least 2 two years old. Last November, researchers at 

Kaiser Permanente published a study that showed and increased risk of autism in children 

whose mothers were vaccinated during the first trimester of pregnancy. It was 4/1000 increase. 

It’s about 20% of the regular risk for autism. This is the only published data that you have to 

make recommendations on. The FDA has not tested any vaccines for flu after 1 year, so 

whether that’s Flublok® or any other vaccine, no one knows what happens after 1 year right 

now, except for this study. I would really like you to make your recommendations on actual data 

and not on wishful thinking. I know you think there is probably no chance that autism could be 

caused by a maternal vaccine, but autism experts will tell you that the genetics alone can’t 

explain why autism develops, that there is an environment component, and that early pregnancy 

an extremely vulnerable time. A human fetus does not develop a blood brain barrier (BBB) until 

the second trimester, so it is more vulnerable to toxins and infections. There are studies that 

link fever during pregnancy with autism. There are studies that link maternal infections with 

autism, including influenza infections. Individuals with autism tend to have biomarkers of 

inflammation and have more activated glial cells in their brains, indicating more immune activity. 

Women who have had children with regressive autism even have antibodies in their blood that 

bind human brain cells. These antibodies have been used to make animal models of autism. 

Pregnant moneys or mice that have been exposed to these antibodies in early pregnancy have 

mostly male offspring that show autistic-like behaviors. Even the genetics of autism point to 

immune dysfunction. Female relatives of autistic people are more likely to have autoimmune 

disorders like rheumatoid arthritis (RA), multiple sclerosis (MS), lupus, or thyroid disease. 

I’m not an anti-vaxer, but infections could cause an autoimmune version of autism, then the 

vaccines for those infections could also potentially trigger that. But, if you picked the right 

antigen, something that didn’t cause autoantibodies or cause a fever at the wrong time, you 

might actually end up with a vaccine that not only prevents influenza, but it prevents the autism 

that is caused by influenza. But, if you’re not actually tracking which vaccines cause these 

secondary autoimmune disorders like autism or lupus, then you’re not ever going to find out 

which ones could be used to prevent those secondary endpoints. I’m a housewife. I am not a 

doctor or a scientist. I have a 17-year old autistic son. He was diagnosed at 20 months old. He 

is not a vaccine injury. They were not vaccinating pregnant women 17 years ago. But, the drug 

that made the biggest difference in his life when he was 7 years old was amantadine, which is 

used to treat influenza, and it wasn’t used because he had influenza. It was used because it 

also binds human N-methyl-D-aspartate (NMDA) receptors. This circuit, the NMDA receptor 

circuit, is a really well-studied circuit that is a problem in autism. It’s also a problem in 

Alzheimer’s disease. Memantine is a very close cousin of amantadine. If you had an antibody 

that was shaped like amantadine that bound M2 proton-selective ion channels, you could fight 

the flu really well and you make great antibodies to the flu, but you also have a risk of an 

autoimmune disorder. So, this is one of those cases that’s actually bad news for you, because 

that would mean that functionally, you would have a good vaccine—if you actually got rid of the 

autoimmune problems, you would reduce the effectiveness of your vaccine. 

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 0 Opposed: N/A 

0 Abstained: N/A 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

So, I’m going to point out that the H1N1 vaccine, when it came out in 2009, it was 75% effective. 

These days, it’s only around 50% effective—maybe less than that. But, there have been a lot of 

vaccine changes in the meantime. There have been HA concentrations so that you don’t have 

as many of the M2 protons pumps in the vaccine, and there have been innovations like Flublok® 

that don’t even have the M2 pumps in the first place. It’s possible that those vaccines actually 

already reduce the risk of autism, but you really need to look. In the meantime, the only thing 

you have on the table right now is that you have data that says in the first trimester of pregnancy 

if you use a flu vaccine, you have a much higher risk of autism. Really, if you just made it 

second trimester and third trimester only, maybe you could actually improve some people’s 

lives. Thank you. 

Discussion Points 

Dr. Bennett indicated that Ms. Rockwell’s full comments will be available to the committee. 

Regarding the letters submitted from Alachua County for public comment, Ms. Pellegrini 

emphasized that this county has gone through a lot of work to provide ACIP with some 

disparities data. There was a significant reduction in their school-based immunization program 

because they could not use LAIV. 

Motion/Vote: 2017-2018 Influenza Vaccine Recommendations 

The Motion for the 2017-2018 Influenza Vaccine Recommendations had a number of nuances raised 

during the discussion before the final vote was cast. The progression follows: 

 Ms. Pellegrini initially made a motion to separate the proposed pregnancy language for an individual 

vote from the rest of the recommendations. Dr. Hunter seconded the motion for the purpose of 

further discussion. 

 Following additional discussion, Ms. Pellegrini withdrew the original motion and Dr. Hunter seconded 

the withdrawal. 

 Dr. Atmar made a new motion to approve the 2017-2018 Influenza Vaccine Recommendations as 

presented. Dr. Riley seconded the new motion. 

 Dr. Kempe recommended that a more general statement be made to the pregnancy component to 

read, “Any licensed, recommended and age-appropriate vaccine may be used. LAIV should not be 

used.” 

 Dr. Bennett indicated that precise language to reflect the sentiment of the vote would be crafted posthoc and sent to all members to ensure that everyone is comfortable with it. 

Following public comment, a vote was taken and the new motion to include the suggested revision carried 

unanimously with 15 affirmative votes, 0 negative vote, and 0 abstentions. The disposition of the vote 

was as follows: 

15 Favored: Atmar, Belongia, Bennett, Ezeanolue, Hunter, Kempe, Moore, Pellegrini, Reingold, 

Riley, Romero, Stephens, Szilagyi, Walter 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

VFC Resolution Update: Influenza Vaccines 

Dr. Jeanne M. Santoli 

Immunization Services Division 

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention 

Dr. Santoli indicated that the purpose of this resolution was to: 1) update the Recommended 

Vaccination Schedule section with the addition of a table of age-indications for currently 

available influenza vaccines covered under this resolution; and 2) update the information in the 

Contraindications and Precautions section. 

Eligible groups include all children aged 6 months through 18 years. The recommended 

vaccination schedule for children 6 months through 8 years of age to receive 1 or 2 doses and 

children 9 through 18 years of age to receive 1 dose. The following table has been added to list 

the currently approved influenza vaccines in the VFC program, including the age indications for 

each vaccine: 

The brand names are listed in the table in alphabetical order. The first two rows for Afluria® 

vaccine now have an age indication of >5 years of age to reflect the discussion that just 

occurred. In addition, a note will be added to indicate that the use of brand names is not meant 

to preclude the use of other comparable licensed vaccines. 

The recommended intervals and doses language follows and will not change: 

Recommended Intervals 

 Minimum Age: 6 months 

 Minimum interval between dose 1 and dose 2 (where applicable): 4 weeks 

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The Contraindications and Precautions section previously pointed to the most recent influenza 

recommendation. However, because that recommendation includes the information about 

Afluria®, which is not current now that a new recommendation has been passed, there is not a 

published reference that can be pointed to. When that occurs, the language is included. The 

following is the language for the Contraindications and Precautions section that is taken from 

the existing ACIP recommendation for the 2016-2017 season, which will not necessarily be 

changed. However, a statement also is included that when a recommendation is published by 

ACIP within 6 months of the passing of this resolution, that language is included by reference: 



 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Recommended Dosage 

 Refer to product package insert. 

Contraindications: 

History of severe allergic reaction to any component of the vaccine or after previous 

dose of any influenza vaccine. However, ACIP makes specific recommendations for the 

use of influenza vaccine in persons with egg allergy (see Influenza Vaccination of 

Persons with a History of Egg Allergy, in www.cdc.gov/mmwr/volumes/65/rr/ 

rr6505a1.htm) 

Precautions: 

 Moderate or severe acute illness with or without fever 

 GBS within 6 weeks following a previous dose of influenza vaccine 

[If an ACIP recommendation regarding influenza vaccination is published within 6 months 

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

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

URL]. 

Motion/Vote: VFC Resolution for the 2017-2018 Influenza Vaccine Recommendations 

Dr. Hunter motioned to approve the VFC Resolution for the 2017-2018 Influenza Vaccine 

Recommendations. Dr. Moore seconded the motion. The motion carried unanimously with 15 

affirmative votes, 0 negative vote, and 0 abstentions. The disposition of the vote was as 

follows: 

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

Reingold, Riley, Romero, Stephens, Szilagyi, Walter 

0 Opposed: N/A 

0 Abstained: N/A 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Introduction 

Edward Belongia, MD

Chair, Herpes Zoster Work Group

Center for Clinical Epidemiology & Population Health

Marshfield Clinic Research Foundation 

Dr. Belongia reminded everyone that the primary objective of the Herpes Zoster (HZ) WG is to 

develop evidence-informed vaccine policy for the use of HZ vaccines. The WG will: 

 Consider vaccine and programmatic performance of the currently licensed live attenuated 

vaccine by Merck, which is trade-named Zostavax® and also is referred to as ZLV 

 Consider the efficacy, safety, and duration of protection of the adjuvanted HZ subunit 

vaccine by GSK, which is trade-named Shingrix and also is known as HZ/su vaccine that is 

currently under FDA review, with a decision expected by this fall 

 Identify programmatic options for both vaccines that incorporate cost-effectiveness analyses 

and the potential impact on disease burden in the US 

The WG has convened 28 conference calls since August 2015 and received a variety of 

presentations by manufactures and researchers on the effectiveness, safety, immunogenicity, 

cost-effectiveness, and programmatic barriers of HZ vaccines. The WG has considered the 

body of evidence regarding both vaccines, and has identified key zoster vaccine policy 

questions and discussed options. In addition, there will be upcoming presentations and data for 

discussions on the CDC cost-effectiveness analysis and GSK plans regarding program 

implementation, including vaccine price, efforts to assure completion for this 2-dose vaccine, 

efforts to inform and prepare vaccine providers and patients regarding reactogenicity, and 

efforts to minimize disparities. 

ACIP received presentations during the October 2016 meeting on HZ epidemiology and 

Zostavax® performance and coverage and Phase III efficacy studies of HZ/su vaccine (ZOE-50 

& ZOE-70). In February 2017, ACIP heard presentations on the safety summary of HZ/su, the 

GRADE evaluation of HZ/su, and considerations for policy by CDC. During this meeting, 

presentations were provided on Zostavax® Phase IV effectiveness studies, the GRADE 

evaluation of Zostavax®, immunogenicity of HZ/su in prior Zostavax® recipients, a costeffectiveness analysis summary, and considerations for policy. A vote is planned for the 

October 2017 ACIP meeting. 

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Zostavax® Phase IV Study 

 

 

 

 

 

 

 

 

 

 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Nicola Klein, MD, PhD 

Director, Kaiser Permanente Vaccine Study Center

Kaiser Permanent Northern California 

Dr. Klein presented the first results on up to 8 years of follow-up (2007-2014) from Kaiser 

Permanente’s long-term effectiveness study for Zostavax® funded by Merck. This study is a 

post-licensure commitment to FDA and the European Medicines Agency (EMA). The primary 

objective of the study is to estimate VE against HZ by age at vaccination and time since 

vaccination, while the secondary objective is to estimate VE against PHN by age at vaccination 

and time since vaccination. The study is being conducted within Kaiser Permanente Northern 

California (KPNC). KPNC has more than 1 million members 50 years of age or older, as well as 

complete electronic healthcare records (EHRs). KPNC has offered Zostavax® vaccine, or ZVL, 

free of charge since mid-2006. Since July 2013, KPNC has had a database health prompt for 

vaccination for persons 60 years of age and above. 

The study design is a continuous accrual of people as they become age-eligible for ZVL, 

starting in January 2007. That includes May 2006 for those 60 years of age and above and 

March 2011 for those 50 through 59 years of age. The study cohort is updated annually to 

include newly eligible members. The members are unvaccinated at study entry, and then switch 

to vaccinated status after they receive ZVL. Vaccinated and unvaccinated individuals in the 

study are followed for the occurrence of HZ and PHN. 

In terms of the statistical analysis plan, VE is estimated against incident HZ or PHN using Cox 

regression. VE is calculated by 1 – the hazard ratio. The Cox regression is on a calendar 

timeline and is stratified by birth year. Models also were adjusted for demographic 

characteristics, time-varying comorbidities, immunocompromised status, and use of health 

services. VE was estimated for vaccines for the following analyses: overall, by time since 

vaccination, by age at vaccination, by age at vaccination and time since vaccination, and by 

immunocompromised status at the time of vaccination. In terms of age and time since 

vaccination, KPNC hypothesized that both age at vaccination and time since vaccination matter 

to VE. 

Regarding uptake of ZVL from 2007 through 2014, there was a reasonably steady increase in 

uptake until the database health prompt in July 2013 for those 60 years of age and older when 

there was a much sharper increase. There continues to be very low uptake amongst individuals 

50 through 59 years of age. For the study population, from January 2007 to December 2014, 

1.3 million persons ≥ 50 years contributed approximately 5.8 million person-years of follow-up. 

The average duration of follow-up was 4.3 years, while the average duration of vaccinated 

follow-up was 2.6 years. Of the 1.3 million people, 29% received ZVL. Of the nearly 400,000 

people vaccinated, most (222,517) were 60 through 69 years of age. 

For the primary objective of VE against HZ, for the case definition, an HZ diagnosis code was 

used accompanied by a prescription for an antiviral medication or a laboratory test positive for 

varicella zoster virus. Nearly 49,000 incident cases of HZ were identified. A random sample of 

charts was reviewed to verify the definition, and there was a very high positive predictive value 

(PPV) of 98%. These are the cases included in the primary analysis. Also identified were just 

over 5,900 less-certain HZ cases. These were primary HZ diagnosis without an antiviral 

prescription. PPV for these cases was 86%. These cases were included only in the sensitivity 

analyses and did not contribute to the primary analysis. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Regarding HZ incidence by age group and vaccine status, there was an increase by age and 

quite clearly incidence was less in vaccinated versus unvaccinated. The incidence of HZ is 

consistent with other population-based studies. Overall VE of ZVL against HZ was 49.1% with 

confidence intervals of 47.5% to 50.6% and a significant P-value. These models were adjusted 

for calendar time, age, sex, race/ethnic group, influenza vaccination, immunocompromised 

status during follow-up, outpatient visits, and comorbid conditions. They were not adjusted for 

age at vaccination or time since vaccination. 

Looking at VE of ZVL against HZ by time since vaccination, there was high VE in the first year, 

a drop in the second year, and then gradual decreases through the course of study. By 7 to 8 

years out, VE is still statistically significant but the confidence intervals are wide due to the 

smaller number of cases. In every age group, VE of ZVL is similarly high in the first year, drops 

substantially in the second year, and then decreases more gradually after the first year. For 

those 65 years of age and above, the VE is between 45% and 50%. Combining VE against HZ 

by age at vaccination and time since vaccination, most notable is that every age group starts off 

with high VE, with VE dropping fairly dramatically in the second year and then decreasing more 

gradually thereafter. For those 50 through 59 years of age, there was not enough time to trace 

the trajectory of waning with precision more than 3 years. 

For VE of ZVL against HZ by immunocompromised status at the time of vaccination, it is 

important to note that KPNC does not advocate administering ZVL to persons who are 

immunocompromised because it is contraindicated. However, this is a study conducted with 

real-world data and people who are immunocompromised do receive vaccination on occasion 

for a variety of reasons. Regardless of low (mild) or high (more serious) immunocompromised 

status, there is substantial protection against HZ following ZVL. In addition, protection is similar 

to that of persons who are not immunocompromised at the time of vaccination. 

For the second objective, VE against PHN, the PHN case definition began with the nearly 

49,000 incident HZ cases and identified those with a PHN diagnosis based on ICD and internal 

Kaiser codes. Codes were included that were associated with a visit and/or prescription, and 

that occurred 90 days to 1 year after the HZ case index date. A total of 3,316 PHN cases 

(6.8%) were identified. Cases with a PHN code for both a visit and a prescription were 

accepted electronically (N=1551). A sample of charts was reviewed to verify that algorithm, with 

a very high confirmation rate of 96%. For cases with a PHN code for only a visit or a 

prescription (N=1987), all of the charts were reviewed and 89% (1765) of those were confirmed 

and were included in the analysis. 

Incidence of PHN by age group and vaccination status was similar to the HZ story in that the 

vaccinated appeared to have a lower incidence than the unvaccinated. There is an increase in 

PHN for each age group as well. The overall VE of ZVL against PHN is 68.7%, which is higher 

than the overall VE of 49.1% for HZ. Again, this model is not adjusted for age at vaccination or 

time since vaccination but is adjusted for all of the other covariates, including: calendar time, 

age, sex, race/ethnic group, influenza vaccination, immunocompromised status during followup, outpatient visits, and comorbid conditions. 

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Zostavax® GRADE 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

In terms of time since vaccination for VE of ZVL against PHN, like HZ, there is a similar pattern 

for PHN. The VE against PHN is highest in the first year and drops after the first year. After the 

second year, there is less evidence of waning for PHN than HZ. Currently, the case numbers 

are much fewer for PHN. More will be learned as the study continues over time and this 

information can be updated. Like HZ, the VE against PHN by age at vaccination shows a 

similar pattern with similar protection levels across all age groups 50 years of age and above at 

60% to 70%. 

It is important to note the overall VE estimate includes all of the cases in the study, but the 

average is the best approximation to crudely estimate the average VE over 3 or 5 years if 

everyone in the study can be followed for 3 or 5 years. For HZ across the age groups and 

certainly for 65 years of age and above, VE averages 45% to 50% for 3 and 5 years. For PHN, 

VE averages 60% to 70% for 3 and 5 years. 

In conclusion, these results are consistent with clinical trials and other real-world studies. VE 

against HZ was greater than 60% in all age groups in the first year after vaccination, wanes in 

the second year in all age groups, and decreases gradually thereafter. By year 7 or 8, VE is 

about half as effective as during year 1, but is still clinically important and statistically significant. 

There is no clear timepoint when protection ends; that is, there is no clear point at which there is 

an obvious increase in risk that may suggest an obvious time to revaccinate. Average VE for 

HZ over 5 years following vaccination was approximately 45% to 50% in all age groups 60 years 

of age and above, and for PHN was approximately 60% to 70% in all age groups 60 years of 

age and above. There is less evidence for waning against PHN than against HZ. There may be 

waning, but more time may be needed to see it. Persons vaccinated at 80 years and older have 

similar protection against HZ and PHN to younger vaccinees. In this study of routine use, 

persons immunocompromised at the time of vaccination have similar levels of protection against 

HZ and PHN. For time reasons, the 80 and above data were not presented but were provided 

in the ACIP members’ packets. 

Angela Guo, MPH

Oak Ridge Institute for Science and Education (ORISE) Fellow

Division of Viral Diseases 

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention 

Ms. Guo presented the results from the GRADE analysis of live attenuated HZ vaccine, ZVL. 

She reminded everyone that the GRADE process is used to develop policy questions, consider 

critical outcomes, review and summarize evidence of benefits and harms, and evaluate the 

quality of evidence. The remaining steps to assess population benefit, evaluate values and 

preferences, review health economic data, consider formulating recommendations, and ACIP 

recommendation and GRADE category will be presented during a future meeting. 

The policy question for consideration is, “Is the live attenuated herpes zoster vaccine (ZVL) safe 

and effective at preventing herpes zoster?” The population of interest is immunocompetent 

adults aged 50 years and older. The intervention of interest is one dose of ZVL. The WG 

looked for studies that compared this intervention to placebo or no vaccine. The outcomes the 

WG considered most important were HZ, PHN, duration of protection against HZ defined as 

protection four or more years post vaccination, SAEs, and reactogenicity. Outcomes included in 

the evidence profile can be divided into benefits and harms. The benefits of prevention of HZ 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

and PHN were deemed critical and duration of protection considered important. In the harm 

category, SAEs were deemed critical and reactogenicity was considered important. 

The WG completed a systematic review of studies in any language from PubMed, Embase, the 

Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane, Scopus, and 

clinicaltrials.gov. Efforts also were made to obtain unpublished or other relevant data. Initial 

search terms included “zostavax”, or “zoster” and “vaccine ADJ2 live”, or “zoster” and 

“attenuated ADJ2 live”, or “zoster” and “vaccine ADJ2 attenuated”, or “zoster vaccine live”, or 

“zoster vaccine attenuated.” Articles were included if they presented data on ZVL and involved 

immunocompetent adults aged 50 years or older, included data for relevant intervention (ZVL, 

one dose, minimum of 19,400 PFU), included data relevant to the outcome measures being 

assessed, and reported primary data. Working with an expert in Library Sciences, the WG 

identified 1113 references via database searches. An additional 158 references were identified 

from clinicaltrials.gov. Another 8 references were identified from searching reference lists and 

reviewing conference abstracts. Title and abstracts were then screened for all 1279 references, 

and records were excluded if there was no primary data reported or if the study did not include 

the population or intervention of interest. Following that step, the WG conducted full text 

screenings of 159 articles of which 119 were excluded because the study did not report data for 

the intervention or outcomes of interest, was ongoing, had results reported in another study that 

was reviewed, or were case reports of individual AEs. 

For reference, the evidence types outlined in the GRADE process are as follows: 

Initial Evidence Type Study Design 

1 Randomized controlled trials (RCTs) or 

overwhelming evidence from observational studies 

2 RCTs with important limitations, or exceptionally 

strong evidence from observational studies 

3 Observational studies, or RCTs with notable 

limitations 

4 Clinical experience and observations, 

observational studies with important limitations, or 

RCTs with several major limitations 

Regarding the GRADEing of evidence of ZVL starting with potential benefits, Outcome #1 is 

vaccine efficacy or effectiveness against herpes zoster. There were two randomized controlled 

trials (RCTs) included for assessment. Oxman et al reported an RCT in adults 60 years of age 

and older, also known as the Shingles Prevention Study (SPS). Schmader et al reported an 

RCT in adults aged 50 through 59 years of age, also known as the ZOSTAVAX® Efficacy and 

Safety Trial (ZEST). There were an additional 7 observational studies included in the 

assessment, which looked at real-world effectiveness of ZVL. These studies were mainly 

conducted in managed care settings or using Medicare administrative data. 

This forest plot demonstrates the varying estimates of effect from the studies included in the 

analysis for this outcome: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

The x-axis represents the risk, odds, or hazards ratios and their 95% confidence intervals that 

were either reported directly from the study or calculated based on the reported VE. Also 

included on this figure are the VE estimates from each study and their 95% confidence intervals, 

the mean age of study participants, and the mean follow-up time post vaccination. Schmader 

2012a was an RCT in adults aged 50 through 59 years of age. It is important to note that this 

age group is younger than the rest of the studies which looked at adults aged 60 and older. 

Overall, the estimates were relatively consistent among studies and demonstrated the vaccine 

to be protective against herpes zoster. 

The type of evidence supporting the prevention of herpes zoster is type 1. For the two RCTs, 

there were no serious risk of bias concerns and no concerns of inconsistency, given that the 

study population for Schmader 2012a was younger than the other studies. There also were no 

concerns of indirectness and imprecision. This led to an evidence type 1 for the RCTs. The 

observational studies were downgraded for risk of bias because outcomes assessors were likely 

aware of the intervention received by participants. There were no concerns related to 

inconsistency, indirectness, and imprecision. This led to an evidence type of 4 for observational 

studies. The overall evidence type for this outcome was 1, following ACIP GRADE guidelines in 

which the overall evidence type for each outcome is based on the strongest evidence within that 

outcome. 

Moving on to Outcome #2, duration of protection against HZ looking specifically at 4 or more 

years post-vaccination, there were two RCTs included for assessment. Schmader et al reported 

follow-up data from participants in the SPS 3 to 8 years post-vaccination in the Short-Term 

Persistence Substudy (STPS). Morrison et al reported follow-up data from the participants of 

the SPS 4 to 12 years post-vaccination in the Long-Term Persistence Study (LTPS). Both 

studies had important limitations regarding their comparison groups. In the STPS, participants 

were un-blinded during the study period and placebo recipients were eligible to receive the 

vaccine. Once placebo participants received ZVL, they were no longer able to serve as 

controls, limiting the placebo group available for follow-up. In the LTPS, there were no placebo 

controls since participants already had been un-blinded. Instead, a comparison group was 

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modeled using data from the placebo groups in the SPS and STP. There were an additional 3 

observational studies included in this assessment. 

This forest plot demonstrates the varying estimates of effect from the studies included in the 

analysis for this outcome, by years since vaccination: 

The top half of the forest plot includes studies that looked at VE during the first four years post 

vaccination. This is what was presented earlier for Outcome #1. The bottom half of the forest 

plot includes studies that looked at VE four or more years post vaccination. These studies that 

looked at long-term protection were included in GRADE analysis for this outcome. Overall, the 

WG found that the estimates for protection 4 or more years post-vaccination to be relatively 

consistent among studies and to demonstrate that the vaccine was still protective against HZ 

after four years, although not as protective as during the first four years post-vaccination. 

While the SPS, STPS, and LTPS were conducted in different time periods and among different 

study populations with different age structures, overall, they are consistent in showing a decline 

in VE over time. The WG determined that the 2 RCTs had serious limitations in regard to their 

comparison groups as discussed previously, and thus were given an initial evidence level of 2. 

The observational studies were downgraded for risk of bias, because outcome assessors were 

likely aware of the intervention received by participants. The WG found no other serious 

concerns and found that the evidence type for this outcome is 2. 

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Moving on to Outcome #3, VE against PHN, there were 8 studies that reported estimates for VE 

against PHN. There were 3 RCTs included for assessment: SPS, STPS, and LTPS, discussed 

previously. There were an additional 5 observational studies included for assessment. This 

forest plot demonstrates the varying estimates of effect from the studies included in the analysis 

for the prevention of PHN: 

The first 3 studies on the figure are experimental, and the remaining studies observational. 

Overall, the WG found that the estimates for prevention of PHN to be relatively consistent 

among studies, although some studies had large confidence intervals. 

The WG deemed Oxman 2005, SPS, as the only RCT without major limitations. The STPS and 

LTPS were graded as RCTs with serious limitations given concerns around their comparison 

groups, and thus were given an initial evidence level of 2. These studies also had large 95% 

confidence intervals and were downgraded for imprecision. Observational studies were 

downgraded for risk of bias because outcome assessors were aware of the intervention 

received by participants, and because PHN was likely underreported because PHN diagnosis 

was often based on healthcare encounters and not self-report. The WG found the overall 

evidence type for this outcome to be 1. 

For the two harm outcomes, SAEs and reactogenicity, there were 11 studies that directly met 

the WG’s PICO (population, intervention, comparison, outcomes) question and had a 

comparison group that was either placebo or no vaccine. Of these studies, 9 were RCTs and 2 

were large observational studies. There were 10 studies with comparison groups that reported 

data on SAEs related to vaccination. In 8 placebo-controlled RCTs with over 36,000 

participants receiving ZVL, there were no imbalances in SAEs between vaccine and placebo 

groups. The 2 large observation studies found no increased risk post-vaccination for 

cardiovascular, neurologic, or infectious conditions studied among over 222,000 participants 

receiving ZVL. Overall, the WG found no SAEs associated with ZVL. 

There were additional studies that reported SAEs related to ZVL live that did not have 

comparison groups. However, the WG included these studies in the GRADE analysis since 

they had at least one study arm that received the vaccine. There were an additional 7 RCTs, 6 

non-randomized clinical trials, and 5 observational studies. Overall, the findings are consistent 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

with findings from the placebo-controlled studies, with no SAEs found to be associated with 

zoster vaccine live. Overall, there were 28 studies included in the GRADE analysis for SAEs 

related to vaccination. The 8 RCTs with comparison groups were given an evidence type 1. 

The 13 RCTs with limitations included randomized trials with no comparison group and nonrandomized clinical trials as mentioned earlier. These were given an initial evidence level of 2. 

The trials with limitations and observational studies were downgraded for risk of bias because 

outcome assessors were likely aware of the intervention received by participants. The overall 

evidence type for this outcome is 1. 

There was additional safety data from case reports related to SAEs and Oka-caused AEs. 

Merck’s 10-year post-marketing review reported 13 cases of PCR-confirmed VZV rash caused 

by the Oka vaccine strain. In clinical trials, 2 subjects with varicella-like rashes and zoster-like 

rashes had PCR-confirmed Oka strain varicella. An additional 7 case reports of SAEs related to 

ZVL were not included in the GRADE analysis. None of these events have been substantiated 

as a safety signal for ZVL through additional research or reporting through VAERS. 

For Outcome #5, reactogenicity, there were 25 studies that reported data on reactogenicity, 

defined as injection-site reactions or systemic reactions related to vaccination. Injection-site 

reactions were the most common AEs related to vaccination. One large RCT in adults 60 years 

and older reported injection-site reactions among 48% of vaccine recipients compared to 17% 

among placebo. One large RCT in adults aged 50 through 59 reported injection-site reactions 

among 64% of vaccine recipients compared to 14% among placebo. The range of injection-site 

reactions reported among the remaining studies was 8% to 62%, with the large variation likely 

due to the large differences in sample sizes among the remaining studies. However, the 

majority of studies reported an estimate between 35% and 55%. There were 4 studies that 

reported moderate/severe (grade 3) injection-site reactions that ranged between 0% to 4% of 

vaccine recipients. This includes a post-hoc analysis of the SPS that found that <1% of 

participants reported grade 3 reactions post vaccination. There were 7 studies that reported 

vaccine-related systemic AEs, with reactions reported among 0% to 8% of vaccine recipients. 

There were 25 studies included in the assessment for reactogenicity. The 15 RCTs were given 

an evidence type of 1. Non-RCT and observational studies were downgraded for risk of bias 

because outcome assessors were aware of the intervention received by participants. This lead 

to an evidence type 3 for non-randomized trials and an evidence type 4 for observational 

studies. The overall evidence type for this outcome was 1. 

In summary, first to provide some context of how to interpret the different evidence types: 

 Evidence Type 1: The WG is very confident that the true effect lies close to that of the 

estimate of effect. 

 Evidence Type 2: The WG is moderately confident in the effect estimate. 

 Evidence Type 3: The WG’s confidence in the effect estimate is limited. 

 Evidence Type 4: The WG has very little confidence in the effect estimate. 

As a reminder, the WG is not measuring how good the intervention is, but rather how much 

confidence they have in the estimates of effect. 

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In terms of the GRADE summary for one dose of ZVL compared to placebo or no vaccine in 

adults aged 50 and older, the critical outcomes of HZ, PHN, and SAEs related to vaccination are 

all supported by at least one good quality large RCT and were given an evidence type 1. For 

these critical outcomes, the overall evidence type is 1. In other words, the WG’s level of 

confidence in the estimate of effect of these outcomes is high. For important outcomes, 

reactogenicity and duration of protection were assigned an evidence type of 1 and 2, 

respectively. To recap, the findings were that ZVL is effective in preventing herpes zoster and 

PHN and no safety concerns of SAEs related to the vaccine were observed in real-world or 

clinical settings. 

Herpes Zoster Vaccine Revaccination Data 

Romulo Colindres, MD, MPH 

Global Medical Affairs Lead 

Zoster Vaccine Program

Glaxo/Smith/Kline 

Dr. Colindres noted that he would be presenting to ACIP on behalf of a very large team at GSK 

and many study investigators on the immunogenicity and safety of Shingrix in adults previously 

vaccinated with ZVL. To place this presentation into context, he reminded everyone that the 

ZOE-50 and ZOE-70 Phase III clinical trials were previously presented at the June 2015 and 

October 2016 ACIP meetings. In February 2017, a broad overview of HZ/su safety was 

presented to ACIP with no major safety concerns today. The presentation for this June 2017 

session focused on the Zoster-048 study evaluating revaccination with HZ/su in terms of the 

context and rationale for why the revaccination study was conducted, the objectives and study 

design, results, and important conclusions and key take-away messages. 

The following graphic illustrates the composition of the non-live, HZ/su vaccine candidate: 

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On the left in turquois is the antigen, which is 50 μg of recombinant glycoprotein E. This is the 

most abundant protein found on the envelope of VZV, which elicits a specific immune response. 

On the right is the adjuvant system ASO1B, which serves to enhance the glycoprotein E (gE)-

specific immune response. ASO1B is a liposome-based adjuvant system containing the 

immunostimulants MPL and QS-21. Synergistically, MPL and QS-21 induce a stronger and 

long-lasting both humoral and cell-mediated immune response. 

To begin, some context and rationale for why the ZVL revaccination study was conducted. ZVL 

has been licensed in the US since 2006. Approximately 31% of US adults ≥60 years of age 

have received ZVL1. Vaccination with ZVL, the current standard, offers protection against HZ 

with a VE of 51% in adults ≥60 years of age2. However, as has been published in the literature 

and was presented by Dr. Klein earlier, this protection wanes over time3. Therefore, 

revaccination with a different HZ vaccine may be required to attain optimal and sustained 

protection against shingles. The Zoster-048 study was designed to generate immunogenicity 

and safety data in persons who received ZVL at least 5 years prior [

1CDC. Vaccination coverage 

among adults in the United States, NHIS, 2015. www.cdc.gov/vaccines. Accessed June 7, 

2017; 22016 Zostavax PI; 3Morrison VA, et al. Clin Infect Dis. 2015;60:900-999]. 

Moving on to the objectives and study design, Zoster-048 is a Phase III, prospective, nonrandomized, group-matched study conducted in the US. Subjects ≥65 years of age were 

enrolled in parallel in two groups, the previous ZVL or no previous ZVL groups. As the name 

implies, previous ZVLs were subjects who received the ZVL live ≥5 years prior and the no 

previous ZVL were those who did not receive the live vaccine. There were two co-primary 

objectives. The first was to compare anti-gE antibody concentrations 1 month post-dose 2 of 

HZ/su between the two groups, and the second was to evaluate safety and reactogenicity up to 

1 month post-dose 2. There were also secondary objectives, which were to assess humoral 

and cell-mediated immune responses at different time points, as well as an ongoing safety 

assessment up to 12 months post-dose 2. 

Prior to vaccination, potential subjects went to a screening visit for eligibility, ZVL history, and 

matching variables. Based on this information, 215 subjects each were enrolled in the previous 

ZVL group and the no previous ZVL group. Subsequently, all subjects received HZ/su at Month 

0 and Month 2. In order to assess humoral and cellular immune responses, blood samples 

were taken at baseline or pre-vaccination, 1 month post-dose 1, and 1 month post-dose 2. 

There also will be a blood sample taken at the end of the study 12 months post the second 

dose. As the study is ongoing, the results presented during this meeting were through the 

Active Phase or through Visit 4, Month 3. 

For participant enrollment, 822 participants were screened for eligibility, ZVL vaccination, and 

matching variables. The matching variables include age (65-69, 70-79, ≥80), gender, race, and 

medical condition as appropriate (in hierarchical order: immune mediated diseases, diabetes 

mellitus, depression, pulmonary conditions, heart conditions, and none of the above). The 

result was that out of 822 participants screened, 430 subjects (215 in each group) were 

matched and vaccinated. There were 213 subjects who received Dose 2 and completed the 

Active Phase of the study in the previous ZVL group versus 212 in the no previous ZVL group. 

Turning to the study results, the mean age of subjects upon receipt of the first dose of HZ/su 

was 70.9 years. There was nearly an equivalent number of males and females enrolled in the 

study, all subjects were Caucasian. The mean time since previous ZVL vaccination was 6.7 

years. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

In terms of the primary endpoint, non-inferiority of previous ZVL to no previous ZVL in terms of 

humoral immune response 1 month post the second dose of HZ/su, the GMCs of approximately 

48,000 for the previous ZVL group compared to the GMCs of approximately 50,000 in the no 

previous ZVL group, the GMC ratio total value was 1.04 with an upper limit of the 95% 

confidence interval of 1.17. This is well below the preset criterion of 1.5 for non-inferiority. 

Clearly, the primary endpoint of this study was met. 

Next, there were secondary objectives pertaining to the humoral immune response at separate 

time points. There was virtually no difference between the two groups for any of the timepoints. 

Furthermore, the GMC results from the ZOE-50 and ZOE-70 clinical studies for both time points 

(pre-vaccination or baseline, and 1-month post-dose 2) are remarkably similar to those of the 

Zoster-048 study. 

Cellular immune responses also were assessed by measuring gE-specific CD4 T-cell 

frequencies. Similar to the patterns that were seen for the humoral immune responses, the Tcell frequencies are similar between the groups at all of the time points studied in the Zoster-048 

study. In the ZOE-50 study, the cell-mediated immune responses are similar to those in the 

Zoster-048 study. 

Transitioning to the safety results, solicited local and systemic symptoms were collected for 7 

days after each dose, while unsolicited AEs were collected for 30 days after each dose. SAEs 

and potential immune-mediated diseases (pIMDs) are being collected and followed through the 

entire study period or 12 months post the second dose. Again, as this is an ongoing study, the 

results presented during this meeting were through Month 3 analysis or 30 days post the 

second dose. 

In terms of SAEs and unsolicited AEs up to 30 days post last vaccination, there appeared to be 

a higher point estimate in the previous ZVL group compared to the no previous ZVL group. 

Although there was some overlap in the confidence intervals, the investigators looked more 

closely into these unsolicited AEs, and there are two points to make. The first is that the 

absolute number of AEs was relatively small, and these AEs were widely dispersed over more 

than 20 system organ classes with no apparent clustering or biologic plausibility. Lastly and of 

note, there were no pIMDs or related SAEs reported from first vaccination up to 30 days post 

last vaccination. 

Regarding the local or injection site symptoms within 7 days post-vaccination of any grade, the 

results are consistent with the Phase III clinical trials with pain being the most commonly 

reported injection site symptom in both groups. All symptoms were of a duration of 2 to 3 days, 

and the majority were mild to moderate in intensity. Looking specifically at Grade 3 injection site 

symptoms, again pain was the most common solicited injection site symptom for both groups 

and all groups showed similar reporting for all symptoms. The median duration for these Grade 

3 symptoms was 1 day. 

For solicited systemic symptoms of any grade, the most commonly reported symptoms were 

fatigue, headache, and myalgia all of which were reported similarly between both groups and all 

had a duration between 1 and 2 days. These results also are consistent with the Phase III 

clinical trials. For Grade 3 solicited systemic systems, the two most commonly reported 

symptoms were fatigue and myalgia and they were transient with a median duration of 1 to 1.5 

days. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Regarding the conclusions, Shingrix induced a strong humoral and cellular immune response 

consistent with Phase III ZOE trials, regardless of previous vaccination with ZVL. There were 

no clinically significant safety differences observed between the study groups within 30 days 

post-dose 2 of Shingrix. Solicited local and systemic symptoms also were similar between the 

two groups. 

In summary, the results of Shingrix Phase III clinical trials ZOE-50 and ZOE-70 demonstrated 

unprecedented age-independent efficacy of > 90% even in those above 70 and above 80 years 

of age. This high vaccine efficacy has been shown to persist through at least 4 years postvaccination. Earlier in 2017, GSK presented the well-characterized safety profile of Shingrix 

with no concerns to date. Although solicited local and systemic symptoms are more common in 

the vaccine than the placebo group, the majority were mild to moderate in intensity and of short 

duration. In addition, there were reassuring immune persistence data going up to 9 years, 

which was presented in February 2017. The results of the Zoster-048 revaccination study have 

demonstrated that having been previously vaccinated with ZVL does not negatively impact the 

immunogenicity or safety of Shingrix. Given that the immunogenicity and safety results of this 

study are consistent with the ZOE clinical trials, GSK is encouraged that Shingrix may become 

an option for individuals who have previously received ZVL and may benefit from the high 

vaccine efficacy of Shingrix observed in previous trials. 

Discussion Points 

Dr. Reingold asked whether any of the people enrolled in the study had a history of HZ before 

they were enrolled and, if so, what the effects of the vaccine were in people with a history 

versus no history of HZ. 

Dr. Colindres replied that in the GSK study, a history of HZ was an exclusion criterion and they 

would not have been included in the study. 

Dr. Klein responded that Merck also excluded people with a history of HZ. 

With respect to the Kaiser study, Dr. Moore recalled that Dr. Klein mentioned 5900 cases that 

were borderline that had an 86% PPV and were excluded, but were included in the sensitivity 

analysis. She inquired as to how they impacted the sensitivity analyses. 

Dr. Klein replied that the findings were essentially the same in those cases as with the primary 

analysis. 

Dr. Hunter asked whether the Kaiser study really had only 29% uptake of the ZVL vaccine in 

people over 50 who did not have to pay anything for the vaccine. 

Dr. Klein confirmed that this was correct even though it is a free vaccine. Uptake definitely 

increased when the database prompt was implemented for those 65 years of age and above. 

All of Kaiser’s vaccines are free, but reminding physicians and patients with the prompt is 

important to increasing uptake. 

Dr. Hunter observed that the national data on HZ vaccine uptake is based on 60 years and 

older, not 50 years and older. He wondered if Kaiser reanalyzed the data for 60 and older it 

would be higher than 30%. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Dr. Klein acknowledged that it is much higher than 29% for those 60 years of age and older, 

although she did not have the exact percentage. 

Cost-Effectiveness Models 

Andrew J. Leidner, PhD 

Berry Technology Solutions

Federal Contractor for CDC/NCIRD/ISD 

Dr. Leidner described two cost-effectiveness models, which were developed by two different 

teams, Merck and GSK. Each of these models was described in a report submitted to the ACIP 

HZ WG, as well as in a presentation given to the ACIP HZ WG. Both reports went through the 

CDC economic review following the ACIP Guidance for Health Economics Studies. An earlier 

draft of these slides circulated to Merck and GSK for review. A cost-effectiveness analysis by 

the CDC team is forthcoming in October 2017. 

A cost-effectiveness ratio (CER) can be considered a price paid per unit of health gained. In 

some models, health gained is thought of as a cost per case avoided. Outcomes considered in 

this presentation are quality-adjusted life-years (QALYs). A QALY is suitable for HZ because 

QALY accounts for morbidity loss and the main disease burden of HZ is in pain, which is a 

morbidity outcome. CERs always compare two potential strategies, for example, vaccination 

versus no vaccination. Dr. Leidner explained that throughout the presentation, he would be 

using the notation of Strategy 1 versus Strategy 2 to define the scenarios. 

The CER is the result of calculations based on several assumptions, or parameters, or inputs. 

The assumptions, combined with how they are calculated, is the cost-effectiveness model. The 

output of that model is the CER. Parameters can include intervention (i.e., vaccine) 

effectiveness, costs of intervention, costs of disease outcomes, and many others. An important 

aspect of these two things is that the availability of relevant data varies by parameter. As a 

quick concrete example of how CERs work, imagine Intervention A having a CER of $1 

million/QALY and Intervention B having a CER of $10,000/QALY. If this were the case, one 

would say that if CERA > CERB, then intervention A is less cost-effective than B. 

Regarding the background of the model and base case results, the current vaccine, ZVL or 

Zostavax® by Merck, is licensed and recommended. Zostavax® is a 1-dose vaccine that has 

been received by 20 to 25 million people. The candidate vaccine is a HZ/su vaccine, Shingrix, 

by GSK. Shingrix is a 2-dose vaccine. The GSK model and Merck model cost-effectiveness 

research objectives were to assess adults 60 years of age and older who have never received a 

vaccine for HZ in terms of the cost-effectiveness of ZVL versus no vaccine, HZ/su versus no 

vaccine, and HZ/su versus ZVL (head-to-head). Both models contain several additional subanalyses that were not included in this presentation due to time restrictions. 

In terms of the base case scenario, the findings for ZVL versus no vaccine were a cost of 

$120,000/QALY for GSK and $125,000/QALY for Merck. This is a fairly close finding for two 

separately made cost-effectiveness models. Regarding the HZ/su versus no vaccine, the Merck 

model identified a CER for the HZ/su vaccine of $74,000/QALY. This is greater than the GSK 

model finding of $12,000/QALY. The next step was to determine exactly why these two values 

differed. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Regarding initial VE for HZ/su, the GSK model assumes a single dose of the HZ/su confers 90% 

VE initially and the Merck model assumes 73%. That difference is contrasted with how similar 

these are in the 2-dose assumption. In terms of VE through time, the GSK model starts at 90% 

and then declines gradually to 0% by Year 16. By contrast, the Merck model starts at 73% and 

declines to 0% after 1 year. For 2 doses of the HZ/su vaccine, the models are very similar for 

the first 5 years and then both decline, with the GSK model declining at a more gradual rate. 

As a reminder for the HZ/su versus no vaccine scenario, the GSK model base case result is 

$12,000/QALY and the Merck model result is $74,000/QALY as seen earlier. If in the GSK 

model a sensitivity analysis is produced, the parameters would be affected by lowering of the 

second dose compliance rate, lowering the first dose efficacy, and increasing the rate of waning 

following a single dose of the HZ/su vaccine. Changing these inputs results in an increase in 

the CER bringing it much closer to the Merck base case results. To foreshadow the discussion 

later, this type of sensitivity analysis is pretty common in these models. 

In terms of the vaccine cost assumptions, vaccine costs are very important for costeffectiveness in general. For ZVL, both models assume a comparable cost about $200 per 

single dose (GSK $197; Merck $213). For the HZ/su vaccine, the GSK model assumes that a 

single dose costs $140 and the Merck model assumes that a single dose costs $106. 

Accounting for the fact that there are 2 doses of the HZ/su vaccine and vaccine administration 

fees, the total 2-dose cost of the HZ/su vaccine is $320 for the GSK model and $250 for the 

Merck model. 

Regarding cost-effectiveness in general, the scenario comparing HZ/su vaccine to no vaccine 

includes the base case model at $12,000/QALY for GSK and $74,000 for Merck. For the 

sensitivity analyses, the extreme values were identified. The two takeaways from this are that 

the error bars overlap and all extreme points are lower than $150,000/QALY. 

Moving to the head-to-head comparison of the HZ/su vaccine to ZVL, in both base cases in both 

models the HZ/su vaccine was found to be cost-saving relative to ZVL. The only case in which 

ZVL was found to be cost-saving relative to the HZ/su vaccine was in the scenario in the Merck 

model that favored ZVL. 

In summary, for the HZ/su versus no vaccine scenario, the base case ranged from $12,000 to 

$74,000 per QALY gained. The sensitivity analyses brought this from cost-saving to $150,000 

per QALY gained. In the ZVL versus no vaccine scenario, the base case cost-effectives ranged 

from $120,000 to $125,000 per QALY gained. In the sensitivity analyses, the range was from 

$60,000 to $260,000 per QALY gained. In the HZ/su versus ZVL scenario, the base case of 

both models found that HZ/su is cost-saving relative to ZVL. In one case, ZVL was cost-saving 

relative to the HZ/su, which was in the Merck model with parameters that favored ZVL. 

Important factors influencing the observed range in values between the two models include 

efficacy and waning immunity for the first dose of HZ/su vaccine and long-term waning immunity 

for 2doses of HZ/su vaccine. Important factors influencing the observed range in overall costeffectiveness include the HZ/su vaccine cost, HZ/su regimen completion, HZ incidence, cost to 

treat a case of HZ with and without PHN, initial efficacy of a single dose of HZ/su, and rate of 

waning immunity from HZ/su. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

The limitations of the study are uncertainty around several key parameters, including limited 

empirical data for efficacy and waning immunity for the first dose of HZ/su vaccine, 2-dose 

regimen completion of HZ/su outside of clinical trials, and long-term waning immunity for 2 

doses of HZ/su vaccine. In addition, the price for the HZ/su vaccine has not been published. 

Discussion Points 

Dr. Kempe observed that the Merck base case assumed only one immunization. The rationale 

for that was not clear to her, given that the vaccine license application is as a 2-dose vaccine. 

Dr. Leidner replied that both models account for the fact that regimen completion may not be 

100% and what the immunity would be for the portion who did not complete the series. 

Dr. Hunter asked whether there were criteria in the sensitivity analyses for various levels of 

completion (e.g., 0%, 50%, 100% of the population finished the second dose). 

Dr. Leidner indicated that there were such criteria in the sensitivity analyses. The base case 

assumption for second dose completion for the Merck model was 73% and for the GSK model it 

was 68%. The lower bounds for both were about 45% and the upper bounds were 90% plus or 

minus 1% or 2%. 

Dr. Thompson (NVAC) wondered whether Dr. Leidner could offer some intuition behind the 

different assumptions on the waning, and the logic and evidence behind why the two companies 

appear to be looking at this very differently. 

Dr. Leidner replied that in terms of the literature on a single dose of HZ/su, there are no data on 

what that efficacy would be. GSK based their results on some internal data and Merck based 

their results on an assumption. He deferred to the manufacturers to respond regarding the 

motivation of their selection of particular wane rates. 

Dr. Bresnitz (Merck) confirmed that there are no data published for the 1-dose subunit vaccine, 

so they basically have to guess or try to come up with some estimate not only in terms of 1-dose 

efficacy, but also the durability of that dose. The waning immunity shown was based on the 

Phase II study results on the immunogenicity data published by GSK, which led them to conduct 

their pivotal trials with the 2-dose vaccine. GSK’s Phase II study showed that after 1 dose, they 

did not reach what the peak was after 2 doses, and after 3 years it basically returned to close to 

baseline. That is what Merck used to assess what they thought might be efficacy and durability. 

Dr. Friedland (GSK) replied that when they reviewed their data, they needed to come up with an 

assumption for what VE would be for 1 dose even though this is a 2-dose vaccine, and what the 

waning rates would be. For Phase II, GSK conducted a study that assessed 1 dose and 

showed that immunity was maintained above baseline out to 3 years for cellular and humoral 

immunity. In addition, the rate of waning was assessed. The assumption regarded why the rate 

of waning would be any different for the subunit versus the live vaccine. The live vaccine wanes 

at approximately 5.1% to 5.4% per year, which was the rate included in the GSK model for 1 

dose. 

Dr. Lee asked what types of models were built for the two different analyses, what the time 

horizon was, and whether discounting was used. Related to that, the estimates for ZVL versus 

no vaccine were quite similar for the two, which was reassuring on one hand, but also because 

the functions might be different that go into those models, she wondered whether they looked 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

further to determine if the same assumptions were used, or if the results were the same 

because they just happened to get to the same results. She thought it would be helpful to 

understand the price assumptions, the range of the sensitivity analyses, and whether a 

probabilistic sensitivity analysis (PSA) would be typically used in this situation or these types of 

models or if there would be reliance on one way to help understand the robustness of these 

analyses. 

Dr. Leidner replied that both were lifetime models, both included discounting, and they were 

Markov models. A lot of the assumptions were very comparable between the two models. 

There were very similar costs per case, waning immunity and efficacy assumptions for ZVL 

were extremely close. To him, it appeared that the two manufacturers relied on the published 

evidence and used the same or very similar parameters. While he did not present any PSA 

results, both models did produce PSA results. The error bars he presented contained 80% to 

90% of the PSA results. In terms of price, the Merck model assumed a price parity of the HZ/su 

vaccine with ZVL. Around that price parity, they expanded plus or minus 20%. For the GSK 

model, a base case was assumed of $145 [$140] with an upper bound of $175 and lower bound 

of $125 [per dose]. He deferred to the manufacturers to discuss the motivation behind those 

ranges. 

Regarding the pattern of waning after vaccination and assuming a constant rate of waning, it 

seemed to Dr. Reingold that the data Dr. Klein presented showed that there is a dramatic 

decrease in the first year that remains relative constant after that. From a clinical protection 

point of view, that seemed to be a better model of what is going to occur than constant waning. 

In terms of the 2-dose waning, Dr. Bresnitz (Merck) reminded ACIP that data were presented 

during the February 2017 ACIP meeting that were based on a Phase II study of immunologic 

data involving a group of 70 people in the Phase II trial that was homogenous from Europe. 

That is not representative of what was in the ZOE-50 and ZOE-70 studies, which he thought 

was the basis of the model for the durability of the vaccine that goes out to 30 years. There is 

about a 4-fold decrease from the response immediately after 2 doses to what is observed at 9 

years. The bottom quartile of the point estimate at 9 years overlaps with the top quartile of the 

estimate at baseline. Given that there is no correlate of protection, he did not know whether 

they could say anything about the real durability or effectiveness of those data, but it does 

decline over time. This information is available on the ACIP website. He also noted that the 

cost-effectiveness model was for those 60 years of age and older, but the policy question 

addressed in the GRADE analysis presented earlier in the session for Zostavax® and for 

Shingrix during the last ACIP meeting was for persons 50 years of age and over. 

For the waning assumptions in the model, Dr. Friedland (GSK) noted that everyone had the full 

report submitted and reviewed by the CDC Economic Team. The data for waning came from 

the ZOE-50 and Zoe-70 studies, so the actual numbers are that the rate of waning for the first 4 

years for people 50 through 70 years of age was 1%, and then was 2.3% in years 5 and 

beyond. For individuals over 70 years of age, the rate of waning was 3.6% throughout the 

model. Those data come from the Phase III RCT vaccine efficacy studies. 

Dr. Bennett observed that it will be interesting to see the CDC model having seen these two 

models, and to see how the decisions are made about the data to use in the new model. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Consideration for the Use of HZ Vaccines 

Kathleen Dooling, MD, MPH

Medical Epidemiologist

Division of Viral Diseases 

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention 

Dr. Dooling began with a review of HZ and PHN epidemiology in the US. The annual rate of HZ 

is approximately 4 cases of HZ per 1000 population or roughly 1 million cases annually1,2. 

Incidence increases with age, ranging from about 1 case/1000 children to about 15 cases/1000 

population 80 years and older.

2,3 For adults 50 years and older with HZ, about 10% to 18% will 

go on to develop PHN. Similar to HZ, incidence increases with age3. For many, the pain of HZ 

and the unrelenting persistence of PHN can be debilitating [1Jumaan et al., JID, 2005, 

191:2002-7; 2Yawn, et al., Mayo Clin Proc. 2007; 82:1341-9; and 3Insinga et al., J Gen Intern 

Med. 2005, 20:748-53]. 

In terms of vaccination coverage for ZVL among adults 60 years of age and older in the US 

between 2007-2015, starting from FDA licensure in 2006, ZVL has shown a slow and steady 

increase in trend in coverage to approximately 31% by 2015. Dr. Dooling indicated that she 

would not review safety and efficacy as they were discussed in previous presentations. 

Regarding the GRADE evaluation of HZ/su that was presented to ACIP in February 2017, the 

vaccine was significantly efficacious in preventing both HZ and PHN. The estimates for VE 

against HZ were 97% for individuals 50 through 69 years of age and 91% for individuals 70 

years of age and older. The estimates for VE in preventing PHN were 91% for those 50 years 

of age and older and 89% for those 70 years of age and older. The protection against HZ was 

at least 85% in the 4 years study. Regarding SAEs, no difference was detected between 

vaccinated and comparison population. However, Grade 3 reactions were reported more 

commonly in vaccinated groups compared to placebo. All of the outcomes examined were 

supported by Type 1 evidence. 

The following are key HZ vaccine policy questions before the ACIP: 

 Should ACIP recommend HZ/su for vaccination of immunocompetent adults either as a 

Category A or a Category B? 

 At what age should HZ/su age-based recommendations start: 50 years of age or 60 years 

of age? 

 Should ACIP recommend a preference for HZ/su over ZVL? 

 Should ACIP recommend that individuals previously vaccinated with ZVL receive HZ/su? 

In order to address these policy questions, Dr. Dooling presented the WG’s interpretation of the 

data, the WG’s deliberations, and the WG’s current perspective on the policy. However, the 

WG is awaiting a final price for HZ/su in order to complete final cost-effectiveness analyses, as 

well as strategies to achieve high 2-dose adherence for HZ/su. Therefore, the interim work 

group perspective was expressed during this session. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

With respect to the first policy question regarding whether ACIP should recommend HZ/su for 

vaccination of immunocompetent adults, the WG interpretation of the data is as follows. Based 

on 1 large Phase III RCT, HZ/su demonstrated high VE against HZ of 97% and 91% for 50 

through 69 year olds and ≥70 year olds, respectively; high vaccine efficacy against PHN at 91% 

for >50 year olds; and maintenance of efficacy above 85% for 4 years following vaccination in ≥

70 year olds. Based on 1 large Phase III RCT and additional small studies, HZ/su 

demonstrated no differences detected between vaccinated and comparison populations for 

SAEs and more commonly reported Grade 3 reactions in vaccinated groups (17%) compared to 

placebo (3%). 

What does all of this mean in terms of the burden of disease that can be expected to be 

prevented through the use of HZ/su vaccine? In terms of health outcomes comparing HZ/su to 

no vaccine in a cohort of 10,000 60-year-olds over 4 years, simplifying assumptions were made 

that VE is stable over 4 years at 97% for HZ and 93% for PHN, disease incidence is stable over 

4 years (HZ= 8:1000, PHN= 0.9:1000), and all vaccinees completed 2 doses of HZ/su. In 4 

years under these parameters, approximately 320 cases of HZ and 36 cases of PHN would be 

expected in an unvaccinated cohort of 10,000. If vaccinated with HZ/su, cases expected would 

decrease to 10 for HZ and 3 for PHN thus preventing 310 cases of HZ and 33 cases of PHN 

over 4 years. Under these simplistic parameters, the number needed to vaccinate (NNV) to 

prevent 1 case of HZ in 4 years would be 32 and NNV to prevent 1 case of PHN in 4 years 

would be 303. 

Looking at the same health outcomes in the same cohort with the expected cases of HZ and 

PHN modeled over the lifespan, a number of assumptions were made regarding 2-dose 

compliance and 1-dose effectiveness of HZ/su and rates of waning of the vaccination. Those 

assumptions were introduced in the previous cost-effectiveness analysis presentation. The 

estimates were derived from the Merck and GSK models. Estimates for HZ cases expected 

over the lifespan in an unvaccinated cohort range from 1961 to 2020. Estimates of PHN cases 

expected range from 200 to 226. Estimates of disease in the HZ/su vaccinated group range 

from 925 to 1250 for HZ and 114 to 130 for PHN. The number of HZ cases expected to be 

prevented over the lifespan through HZ/su ranges from 780 to 1036, and the number of PHN 

cases expected to be prevented over the lifespan ranges from 70 to 112. Therefore, over the 

lifespan, the NNV to prevent 1 cases of HZ is 10 to 13 and the NNV to prevent 1 case of PHN is 

89 to 142. 

Returning the focus to the first policy question regarding whether ACIP should recommend 

HZ/su for vaccination of immunocompetent adults, based on review and GRADE assessment of 

the evidence for critical and important outcomes, the WG is confident that the vaccine is safe, 

efficacious, and maintains high protection against HZ 4 years following vaccination. WG 

members acknowledged the importance of clear ACIP recommendations. Under most 

assumptions, HZ/su demonstrates NNV and cost-effectiveness similar to or more favorable than 

other adult vaccines. The WG is favorable to vaccinating immunocompetent adults with HZ/su 

as a Category A. 

In terms of the second question regarding whether the HZ/su age-based recommendations 

should start at 50 or 60 years of age, the WG interpretation of the data was that HZ/su efficacy 

is very high in the 50 through 59-year-old group at 97%. There is minimal waning in the first 4 

years following vaccine receipt. Waning beyond 4 years is unknown. In a small Phase II study 

of participants 60 years of age and older, immunogenicity data at years 4, 6, and 9 years 

following HZ/su vaccination shows similar CD4+ T-cell response with a >3-fold rise above 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

baseline. These data were presented to ACIP in February 2017. However, there is no 

established correlate of protection. 

WG deliberations on this question included a number of points. HZ and PHN incidence 

increases with age. In 2011, ACIP did not recommend ZVL for 50 through 59-year-olds 

because there was evidence of waning in the first 4 years and beyond. HZ/su VE is very high in 

this age group (97%) with minimal waning in the first 4 years. The degree of waning beyond 4 

years is uncertain. However, durability has been demonstrated for cellular and humoral 

immunological outcomes at 6 and 9 years. There are about 42 million people who are 50 

through 59 years of age in this country, and about 21% of all HZ episodes occur in this age 

group annually. The WG is favorable toward an age-based recommendation starting at 50 

years old; however, policy proposals are awaiting a final price for HZ/su and accompanying 

cost-effectiveness analyses for this subgroup. 

The next question considered regarded whether ACIP should recommend a preference for 

HZ/su over ZVL. In terms of the WG interpretation of the data, it is important to note that these 

vaccines have not been studied in a head-to-head efficacy trial. HZ/su estimates of efficacy are 

higher than ZVL estimates across all age groups. HZ/su appears to wane at a slower rate than 

ZVL over the first 4 years. With respect to safety outcomes, it should be noted that HZ/su 

vaccine has been studied in approximately 16,000 participants in clinical trials; whereas, ZVL 

has been administered to more than 20 million people in the US following its clinical trials. 

Neither vaccine is associated with SAEs in immunocompetent persons. HZ/su is more 

reactogenic than ZVL. ZVL is a live-attenuated virus, which can cause HZ in rare 

circumstances. In terms of economics, HZ/su is more cost-effective than ZVL under most 

assumptions. 

This graph depicts VE and effectiveness against HZ for HZ/su and ZVL by age group during the 

first 4 years following vaccination: 

As shown on the graph, the HZ/su vaccine is more efficacious in each age category and the 

difference is larger amongst older recipients. 

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Returning to the simple cohort of 10,000 people 60 years of age and older followed over 4 years 

comparing no vaccine, ZVL, and HZ/su, the same simplifying assumptions were made that VE 

is stable over 4 years, disease incidence is stable over 4 years, and HZ/su recipients completed 

2 doses. Already presented was what would be expected for the unvaccinated and HZ/su 

cohorts. After 4 years in the cohort vaccinated with ZVL, approximately 150 cases of HZ and 12 

cases of PHN would be expected. Therefore, for every 10,000 people vaccinated, HZ/su is 

expected to prevent an additional 105 cases of HZ and 9 cases of PHN compared to ZVL over 4 

years. 

Looking at those same 3 cohorts modeled over the lifespan, a number of assumptions have 

been made regarding 2-dose compliance and 1-dose effectiveness of HZ/su, as well as the 

rates of waning of both vaccines. Again, these were discussed in the previous presentation. 

The following estimates are derived from Merck and GSK analyses. The number of cases 

expected was presented for the no vaccination and HZ/su cohorts. Over the lifetime in the ZVL 

cohort, estimates of HZ cases expected ranged from 1600 to 1640 and expected cases of PHN 

ranged from 140 to 177. Therefore, for every 10,000 people vaccinated, HZ/su is expected to 

prevent an additional 360 to 715 cases of HZ and 10 to 63 cases of PHN compared to ZVL over 

the lifespan. 

The two policies under consideration by the WG were a preference for HZ/su vaccine or no 

preference for either vaccine. Dr. Dooling reviewed the pros and cons of each of these options 

as deliberated by the WG. 

Under a preference for HZ/su, the pros would be substantially more prevention of HZ, PHN, and 

other complications. This is a particularly important issue for seniors 80 years and older who 

are most vulnerable and at highest risk for HZ and PHN. HZ/su is more cost-effective than ZVL 

under most assumptions. However, the price has not been finalized and a cost-effectiveness 

analysis is pending. HZ/su is refrigerator-stable, which may decrease provider barriers. Cons 

of a preferential recommendation are that HZ/su vaccine may be removed from the market if an 

unexpected safety signal is observed with HZ/su. This policy may lead to more Grade 3 

reactions following vaccination. HZ/su requires 2 doses, which will likely increase programmatic 

barriers. 

In terms of a no preference policy, this would support competition and safeguard a stable 

vaccine supply in the event of an unexpected safety signal. On the con side, large difference in 

VE will result in thousands of preventable HZ cases and hundreds of PHN cases. Additionally, 

some insurers or delivery systems may choose to cover only the less expensive vaccine if no 

preference is stated. Finally, a non-preferential policy places the onus on providers to compare 

safety and efficacy. 

Ultimately, there are a number of unknowns in this decision analysis. There is always a 

possibility that an unexpected safety event with HZ/su may occur. The VE of HZ/su beyond 4 

years is unknown. The real-world 2-dose compliance of HZ/su is unknown, and the VE and 

durability of 1 dose of HZ/su are both unknown. With regard to programmatic and 

implementation factors, price, insurance coverage details, and healthcare seeking among 

vaccinees with reactions are all unknown. 

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In terms of how long it will take to answer the unknowns, assuming that HZ vaccine uptake 

continues at its current pace of about 3 to 4 million doses annually, a 1- to 2-year period may be 

sufficient to accumulate real-world safety data of HZ/su vaccine for surveillance for rare AEs. 

For 2-dose compliance of HZ/su, again a 1- to 2-year period probably will be needed as 

compliance will likely change as the program matures and providers become familiar with the 

HZ/su reactogenicity profile. For VE, a 4- to 8-year period beyond licensure would be 

necessary to study and report on long-term effectiveness. VE of 1 dose of HZ/su would require 

at least a 2- to 3-year period for an observational study in, for example, a large health 

maintenance organization (HMO) with at least 1 million unvaccinated adults to accumulate 

sufficient 1-dose HZ/su recipients. At least 4 years would be required for age-specific estimates 

and duration of protection. During this period, preventable cases of HZ and PHN may continue 

to occur if a less effective vaccine is used. 

To recap the WG deliberations regarding a preference for HZ/su vaccine over ZVL, HZ/su can 

prevent significantly more HZ and PHN than ZVL. HZ/su is more cost-effective than ZVL under 

most assumptions. A preference would safeguard access to the more efficacious vaccine; 

whereas, insurers or delivery systems may choose to carry only the less expensive vaccine if no 

preference is stated. An equivalent recommendation puts the onus on clinicians to review the 

literature on both vaccines to compare safety and efficacy. However, there are a number of key 

unknowns, including 2-dose compliance, VE of 1 dose, long-term waning, and the possibility of 

an unexpected safety signal. The majority of WG member favored that a preference be stated 

for HZ/su over ZVL. A minority of WG members thought no preference should be stated at this 

time. The WG is awaiting a final price for HZ/su and accompanying cost-effectiveness 

analyses. 

In terms of the final policy question regarding whether individuals previously vaccinated with 

ZVL should receive HZ/su, the WG’s interpretation of the data was as follows. HZ/su is more 

efficacious than ZVL in all age categories. Experimental and observational studies indicate 

significant waning of protection from ZVL. VE drops the first year after receipt by 15% to 25%. 

By 6 years post-vaccination, most studies estimate that VE is less than 35%. There may be 

negligible protection by 10 years post-vaccination. HZ/su is significantly more efficacious over 4 

years with a VE of greater than 97% in the first year, which is maintained above 85% in the 

subsequent 3 years for all ages. In a small study presented to ACIP earlier in this session, 

vaccination with HZ/su 5 years following ZVL did not alter the safety or immunogenicity of 

HZ/su. There is a significant gap in HZ protection between that provided by HZ/su and that 

provided by ZVL. 

The WG deliberations on this policy question were as follows. Prior ZVL receipt should not be a 

contraindication to receiving HZ/su. For prior ZVL recipients, HZ/su is a new vaccine. A 

substantial amount of HZ and PHN could be prevented by vaccinating this population with 

HZ/su. Prior ZVL did not alter the safety or immunogenicity of HZ/su. Of the US population, 

31% of individuals 60 years of age and older have already followed ACIP recommendations and 

received ZVL. A significant fraction of ZVL recipients now have very low vaccine protection for 

HZ and PHN. The WG’s perspective was that HZ/su should be considered for people who have 

already received ZVL. The WG is awaiting a final price for HZ/su and accompanying costeffectiveness analyses. 

Looking forward, the WG will review a summary of the GRADE analyses of both vaccines, the 

CDC cost-effectiveness model, and considerations for policy during the October 2017 ACIP 

meeting. In addition, and FDA licensure decision for HZ/su vaccine is expected prior to the 

ACIP October 2017 meeting. At the ACIP’s discretion, a vote on HZ vaccine recommendations 

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may be taken in October 2017. In closing, Dr. Dooling requested feedback on whether there 

are additional data that would help ACIP develop policy for the use of HZ vaccines in adults. 

Discussion Points 

Dr. Atmar recalled that a question was raised during the meeting in February regarding the 

racial make-up of the ZOE trials, which included only 1% African Americans. The revaccination 

study presented during this session included 100% Caucasians. This remains a major gap in 

terms of understanding whether the vaccine will perform similarly in all groups. 

Dr. Dooling replied that the data presented represented all of the data accumulated up to this 

point. 

Dr. Kempe pointed out that many of the analyses presented during this session were helpful 

and straightforward, but these analyses assumed that everyone would receive 2 doses. The 

previous analyses heard earlier were based on 1 dose. She would like to see these data with 

25% and 50% of individuals receiving 2 doses. 

Dr. Dooling clarified that she presented the cohort based over 4 years in which everybody 

received 2 doses, which she referred to as the simplified cohort. The subsequent cohorts, 

which were modeled by both GSK and Merck did assume real-world estimates of what they 

expect to be 2-dose compliance. As Dr. Leidner previously presented, for GSK the estimate 

was 69% 2-dose compliance and for Merck was 72% 2-dose compliance. Some sensitivity 

analyses were performed for those as well, which were not presented. 

Dr. Bennett noted that in the simplified cohort, the 60 year and above age group was used. She 

wondered why this did not begin at 50 years of age and above, given that the recommendation 

of the WG was to begin at 50 years of age. 

Dr. Dooling replied that they wanted to use as much current real-world data as possible, so the 

current recommendation was modeled. The 50 through 59-year-old cohort will be modeled, 

included a cost-effectiveness analysis, to be presented during the October 2017 ACIP meeting. 

Dr. Kempe said she would like to see it lower than 75%, because that is potentially unrealistic. 

Dr. Walter inquired as to whether there would be any costing for a revaccination scenario. 

Dr. Dooling indicated that revaccination costing would be done as well. It was provided by one 

of the manufacturers, but was not presented during this session due to time constraints. This 

also will be done in the CDC cost-effectiveness model. 

Dr. Lee asked whether they would be able to see if Dr. Klein’s data, presented during this 

session, would make any difference in the outcomes of the models, which she thought would be 

very helpful. To follow up on the disparities issue, she inquired as to whether there are currently 

any disparities occurring with regard to HZ and PHN. As they are making considerations about 

preferences, she worried that there may be some unintended consequences, particularly if there 

are underinsured adults who have to pay out-of-pocket. She wants to make sure that they think 

through considerations such as this to understand whether cost does make a difference, and if it 

is Medicare D versus B how that might impact the implementation of a program. 

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Dr. Dooling responded that this remains an unknown as well. From some of the informal 

qualitative outreach CDC has done and input from partners, many clinicians will still want to give 

the vaccine with which they are most familiar and have experience. The intent is for Zostavax® 

to retain its Category A recommendation and clinicians would continue to have access to that 

vaccine. She stated that she could not predict the distribution of market share under the case of 

a preferential vaccine recommendation. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Dr. Dooling replied that ZVL is currently covered under Part D as part of Medicare, and no 

indication has been received that this would change if a new vaccine is licensed for that 

indication. Regarding the question about the Phase IV studies from KPNC, those data were 

used to inform the longer-term waning of Zostavax® in the Merck model. 

Referring to a slide, Ms. Pellegrini observed that Dr. Dooling noted that the rate of HZ among 

those 50 through 59 year of age represents 21% of the cases. She wondered whether similar 

data are available on PHN. 

Dr. Dooling replied that less than 21% of PHN will occur in those 50 through 59 years of age. 

Dr. Harpaz added that the rates of PHN accelerate at the age of 60. The rates of PHN among 

those 50 through 59 years of age is considerably lower than the rates among older adults. 

Dr. Schmader (AGS) added that he did not have any specifics, but agreed that the PHN rate 

among persons 50 through 59 years of age is much lower. 

Regarding Dr. Kempe’s point about 2-dose coverage, Dr. Moore reported that the WG 

discussed extensively what constitutes realistic 2-dose coverage. They look at HepB coverage 

and completion of the series. There are some encouraging aspects to think about in terms of 2-

dose coverage in this population. Those 50 years of age and older see their pharmacists a lot, 

and pharmacies are a source of immunization for that group. She Googled how many people 

over 50 years of age have a regular daily prescription. Based on data from 2005, she found that 

76% of people over 50 years of age take a daily prescription, which means they see their 

pharmacists very regularly. The average number of prescriptions was 4, and it is probably 

higher now than it was in 2005. In other words, there are many opportunities for encounters 

with the healthcare community where immunizations can be given. This is in stark contrast to 

younger adults who may be at high risk for pneumococcal disease or younger adults who are 

getting HPV vaccine for whom there are harder challenges in terms of getting them in. She is 

hopeful that if there is a preference, programmatically people can be coached and helped with 

programmatic opportunities to increase the numbers. 

Dr. Foster (APhA) observed that one of the major problems with getting people vaccinated with 

Zostavax® currently is the fact that the ages 60 through 65 are not covered under Medicare. 

Many pharmacies have difficulty billing for people in that age group. If this is lowered to age 50, 

unless insurance mechanisms are developed along with this, it is still going to be a very difficult 

process for pharmacists. 

Dr. Hunter inquired as to what the likelihood would be during the first 1 to 4 years after a 

recommendation is made, if it is preferential, they would be “burning a bridge” and would not be 

able to reverse that and still have live vaccine available if something goes wrong from an 

implementation and market share point of view. 

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Dr. Reingold thought surely there must be observational data on the rates and VE in groups 

other than Caucasians. Instead of controlling for race and ethnicity, perhaps they could produce 

race- and ethnicity-specific VE estimates even if they have wide confidence intervals. 

Dr. Bennett noted that this would be difficult with HZ/su because the numbers are so small, but 

it would be possible with the live vaccine. 

Regarding the framing of the cost-effectiveness analyses, Dr. Thompson (NVAC) observed that 

in the evolution of HZ vaccines, there was first the introduction of ZVL and to her, that is 

currently the status quo. She thought if ACIP was considering a change in the 

recommendation, the way to frame the economic analysis would be to consider the new vaccine 

relative to the status quo. She thought that was done to some extent in the head-to-head 

comparison, but it would be better to do this much more directly. In that regard, some of the 

uncertainty lies in the unknowns mentioned that potentially would be significant factors. She 

thought some sensitivity or uncertainty analyses could be performed around some of those with 

input from members of the WG to explore how that changes the preferential option based on a 

comparison of the current status quo to a subunit vaccine. Regarding the challenges with the 

uncertainty about how people will receive the vaccine and whether there are issues with side 

effects, adjuvant irritation, or anything that could change how people respond to the vaccination, 

that is obviously a major uncertainty that is difficult to guess at. One thing that triggers for her is 

that if it is known that the vaccine feels different or behaves differently, that would be a very 

important opportunity to communicate this to people to head off some of the potential issues. 

Dr. Dooling agreed that 2-dose compliance will be affected by many factors, one of which is the 

ability to communicate with clinicians and the public about what will be expected in terms of 

reactogenicity. The WG is aware of that issue and will be working on it before the October 2017 

ACIP meeting. 

Regarding programmatic, implementation, and preferential issues, Dr. Bresnitz (Merck) pointed 

out that ACIP rarely makes a preferential recommendation. They have not done so for 

influenza, never did it for the HPV vaccine, and the last time it was done for LAIV, they had to 

go back on that for different reasons that had nothing to do with AEs. The safety database for 

Shingrix with about 16,000 people is very similar to when Zostavax® was licensed following the 

SPS, so the Shingrix safety database is probably adequate for licensure, though he left that to 

FDA to decide. Zostavax® has had experience with 20 to 25 million people over the last 10 plus 

years in the US and 36 million individuals globally. It is unknown with a vaccine that has a novel

adjuvant in terms of the target population, comorbidities, and doses being used, the long-term 

SAEs remain unknown. Clearly, in the pivotal trials, there have been no differences with the 

placebo. There has been reactogenicity, which is probably because of the adjuvant. One of the 

first things he had to deal with when he was the State Epidemiologist in New Jersey was 

RotaShield® where it went to market, and after a couple of million doses it had to be taken off of 

the market due to an acute event immediately post-vaccination. There was not another vaccine 

at the time to replace it. He said he could speculate on the answer to the question of what 

would happen if there is a preferential to Merck’s vaccine, demand clearly will go down. When 

demand goes down, production will go down. Live attenuated vaccine cannot be ramped up 

that quickly. Over time, if an SAE presents a year or two later, it would be hard to ramp up if 

production has been reduced. 

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He clarified that Merck was asked to include the 73% completion rate in its model. They do not 

think it is going to be 73%, but in deference to CDC who wanted to have a more comparable 

rate to what GSK was developing, Merck included this in its model as the base case. At that 

time, it was based on data from the Nelson paper that examined series completion for HepA 

and HepB that was more than 10 years old. Since then, there have been two publications. One 

was by GSK that was presented in May 2017 on this particular issue with Truven data and 

Merck did the same analysis, which showed that completion rates are less than 73%. He urged 

the WG to use the more recent data that has been validated by two separate analyses 

sponsored by two separate manufacturers. While he thought the pros and cons statement was 

great and agreed with most of them, with the exception of the insurance issue. He did not think 

that the insurance statement was accurate. He suggested that Zostavax® should be divided into 

3 categories (commercial, Medicaid, Medicare), given that these are different in terms of 

reimbursement. His understanding under ACA is that when a vaccine is recommended by 

ACIP, it has to be covered by commercial insurance. There is not a preference for one over the 

other. It has to be covered. Medicaid is not an issue because most states do not cover 

Zostavax®. They have to include it in their formulary, but they tier it. He emphasized that a 

preferential recommendation would make a difference, and that ACIP has not done this 

previously. These two vaccines have different attributes and the market should be allowed to 

determine what is going to happen. There are advantages for one and there are advantages for 

the other that are obvious. That is what happened with the HPV vaccine. They let the market 

dictate and Cervarix® is no longer on the market. 

Dr. Friedland (GSK) reported that in the model presented during this session, there were a wide 

range of sensitivity analyses, varying second dose compliance and many other variables. 

Across all of the various sensitivity analyses pertaining to compliance, cost-effectiveness is 

generally maintained. Regarding compliance and preparing the patient for the experience of the 

vaccination in terms of reactogenicity, second dose compliance will be great if they all work 

together. GSK will be discussing with the WG its plans to help bring education to providers, 

pharmacists, and patients so that there is a benefit from the full vaccination series that this 

vaccine provides. While they have to put something into a model for compliance rates, they can 

aim higher to achieve very high compliance rates for a vaccine that has great potential to offer 

very high efficacy for people of all ages. 

Dr. Netoskie (AHIP) concurred with the comment about payers and whether they can prefer one 

over another. If Shingrix is approved, it would be covered. The confusion in the marketplace is 

that there may be variability in the year following approval in terms of which plans may adopt 

sooner versus later. He also thinks when physicians are evaluating their choices as far as 

physician preference, they also may choose to take a “wait and see” approach. That also may 

limit access to patients who may wish to receive the newer vaccine. He thinks there will be a lot 

of variability in the marketplace as this vaccine enters it, but health insurance plans would 

provide both options. In those 50 through 60 years of age, only the new vaccine would be 

covered if approved. Grandfather plans still exist and may fall outside of this process. 

Dr. Belongia added that his understanding is that large healthcare systems could choose one 

product for a variety of cost and logistical reasons. 

Dr. Moore added that those healthcare delivery systems with so many quality measures might, 

in the absence of a preferential recommendation for a 2-dose product, prefer to use a 1-dose 

product because it is easier to achieve quality benchmarks with 1 dose than with 2. There may 

be pressure because of the way they are measured nowadays to do the easier rather than the 

more efficacious thing. 

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Dr. Bennett observed that there have been some difficulties with pneumococcal vaccine in 

nursing homes because pneumococcal polysaccharide vaccine (PPSV) is considerably less 

expensive than PCV. Despite the recommendations, people are receiving pneumococcal 

polysaccharide vaccine (PPSV23) first. 

Varicella Vaccines 

Rafael Harpaz, MD, MPH

Medical Epidemiologist, Division of Viral Diseases

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention 

Dr. Harpaz reported on the impact of the US varicella vaccination program on the incidence of 

HZ. In terms of background, Dr. Edgar Hope-Simpson was a brilliant clinician and researcher in 

the United Kingdom (UK) during the post-war era. He developed a particular interest in varicella 

and HZ. While he had no formal training in epidemiology, he was a keen observer and he drew 

many conclusions regarding the complex natural history of varicella that still hold true today. 

Some 50 years ago, Dr. Hope-Simpson published his hypothesis regarding the interaction of 

varicella and HZ. By 1965, there was evidence that HZ was caused by reactivation of varicella 

zoster virus (VZV) present in latent form in dorsal root ganglia. Dr. Hope-Simpson postulated 

that VZV reactivation occurred years to decades after initial varicella infection, and that 

reactivation and subsequent development of HZ were under immunological control. He 

speculated that that control is maintained by two processes, endogenous boosting of immunity 

due to subclinical VZV reactivation without the development of HZ and/or by exogenous 

boosting due to exposure to children with chickenpox. 

Decades later in the early 1990s, as ACIP and FDA deliberated about varicella vaccination, they 

considered that if Dr. Hope-Simpson was correct, the program would reduce VZV circulation 

and thus exposure, and the decline in exogenous boosting might then plausibly lead to an 

increase in the risk of HZ. The same concern continues to make vaccine policy-makers in 

Europe and elsewhere cautious about introducing varicella vaccination even today. An early 

influential infectious disease model to evaluate the implications of the Hope-Simpson hypothesis 

by Brisson et al published in Vaccine in 2002 stated in the abstract, “. . . Mass varicella 

vaccination is expected to cause a major epidemic of herpes-zoster, affecting more than 50% of 

those aged 10-44 years at the introduction of vaccination [M. Bisson, et al, Exposure to varicella 

boosts immunity to herpes-zoster: implications for mass vaccination against chickenpox, 

Vaccine 20 (2002) 2500-2507]. The following is a key figure from the Brisson et al analysis 

illustrating the predictive incidence of zoster in the general population following the introduction 

of routine varicella vaccination: 

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An immediate decline in varicella rates is assumed in the above model. The dashed horizontal 

line shows zoster rates assuming no varicella vaccination, the violet curve representing the 

base case assumes zoster risk is reduced for 20 years following exposure to varicella. The two 

gray lines representing sensitivity analyses assume that zoster risk is reduced for either 7 or 41 

years following varicella exposure. The base case model predicts that zoster rates will increase 

for the first 20 years after launch of varicella vaccination, peaking at levels about 50% higher 

than during the pre-vaccine era. Rates increase immediately and most rapidly immediately 

upon introduction of vaccination. Incidence then declines as fewer and fewer individuals remain 

latently infected with wild-type VZV. Numerous models have been published over the last two 

decades to evaluate the implications of the Hope-Simpson model. Most show that the results 

are qualitatively similar to these, with rapid increases in zoster rates immediately following 

introduction of varicella vaccination and peaking between 20 and 30 years later. 

It has now been just over 20 years since ACIP first recommended varicella vaccine in 1996. 

Having framed the issues, Dr. Harpaz went on to discuss: 1) the background of varicella in the 

US in terms of the burden, introduction of varicella vaccination, and the impact on VZV 

circulation; 2) HZ in the US with regard to the epidemiology and risk factors, including baseline 

rates, and the introduction of zoster vaccination and vaccine uptake; and 3) the impact of the 

US varicella program on HZ trends. He discussed zoster in adults only since there has been no 

speculation that varicella vaccination would increase zoster rates among children born after 

launch of the program. However, he indicated that he would be happy to answer questions 

about this during the discussion period. 

Regarding the burden of varicella during the pre-vaccine era, by young adulthood almost all 

persons in the US had evidence of prior infection. This is an indication that at that time 

averaged over several years in the entire US birth cohort of 4 million experienced varicella 

infection annually. Aside from service as a source of exogenous boosting, these cases 

translated to the large burden of disease annually, including approximately 11,000 to 13,500 

hospitalizations and approximately 100 to 150 deaths. The greatest disease burden was in 

children who experienced greater than 90% of cases, 70% of hospitalizations, and 50% of 

deaths. There also were approximately 44 cases of congenital varicella syndrome annually. 

The large burden of disease was the rationale for introduction of varicella vaccine to begin with 

[Refs: Wharton ID Clin N Am 1996; Galil PIDJ 2002; Davis Pediatrics 2004; Meyer JID 2000; 

Nguyen NEJM 2005; Enders G & Miller E (2000) Varicella and herpes zoster in pregnancy and 

the newborn. In: Arvin AM and Gershon AA (eds) Varicella-zoster virus]. 

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The varicella vaccines used in the US are Merck’s VARIVAX® and ProQuad® licensed in 1995 

and 2005, respectively. Both are comprised of live-attenuated VZV. In 1996, ACIP 

recommended 1 dose of varicella vaccine for all children 12 through 18 months of age1. The 1-

dose program effectively prevented severe varicella, but school-based outbreaks persisted, so 

ACIP added a second dose recommendation in 2006 for all children 4 through 6 years of age2 

[

1MMWR 1996;45(RR-11); 2MMWR 2007;56(RR-4):1-39]. 

Regarding varicella vaccine coverage with 1-dose uptake in children 19 through 35 months of 

age in the US for the years 1996 to 2015, by 2006 or so uptake approached 90% in this cohort 

and was considerably higher at the age of school entry. By 2012, uptake for the second dose 

reached 88% among 7-year old children and subsequently reached 94% [http://www.cdc.gov]. 

In terms of how all of this vaccination has affected varicella circulation, four states have 

engaged in continuous varicella reporting (Illinois, Michigan, Texas, West Virginia) from 1990 or 

earlier. Incidence declined by an average of 97% (range 93%-98%) between 1993 to 2014. 

This reduction obviously translated to huge reductions in the total burden of varicella disease, 

including hospitalizations, deaths, and outbreaks [Lopez et al. MMWR 2016]. 

In 1995, CDC established Varicella Active Surveillance Projects (VASP) to more carefully 

monitor the impacts of the varicella vaccine program. This table shows the aggregated data for 

sites stratified by age group: 

Antelope 

Valley, CA

(%) 

West 

Philadelphia

(%) 

Age Group 

<1 -97 -94 

1-4 -98 -97 

5-9 -99 -99 

10-14 -93 -99 

15-19 -86 -94 

20+ -94 -91 

Total -97.5 -98 

Both sites reported 98% declines. Indeed, circulation already was down by about 90% at the 

beginning of the last decade. There were huge declines in all age groups, including infants 

under 1 year of age. Since infants are not eligible for varicella vaccine, the reduction in this age 

group is presumably due to the reduction in VZV infection resulting in herd protection. 

Moving on to HZ in the US, prior to licensure of zoster vaccine, HZ incidence was about 4 per 

1000 population annually with an annual risk of about 30%)1. There were approximately 1 

million cases of HZ annually, approximately 110,000 cases of post-herpetic neuralgia of 90 days 

in duration, approximately 10,000 to 30,000 hospitalizations, and about 90,000 eye 

complications2. Risk factors include age, immunosuppression, gender, race, and 

genetics/family history1. Age is the key risk factor for zoster. Risk varies by an order of 

magnitude across the age spectrum, and age affects everybody. Those who are 

immunocompromised bear a substantial portion of the total zoster burden in the US at up to 20-

fold for some conditions. Women are at a 25% to 35% increased risk of zoster compared to 

men regardless of age, though it is unclear why. Caucasians are at 40% to 50% higher risk of 

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zoster compared to African Americans, which is presumed to be related to genetics. Though 

family history appears to be a risk factor for zoster, the fold increase in risk varies widely across 

different studies from 2-fold to about 20-fold. A key point regarding zoster risk is that just as 

there is not a mechanistic explanation for why VZV suddenly reactivates after decades of 

latency, what distinguishes most of the approximately 1/3 individuals who develop HZ from the 

approximately 2/3 individuals who do not also is unkown1 [

1Harpaz et al., MMWR Recomm Rep. 

2008; 2Yawn et al. Mayo Clin Proc 2013]. 

There is another major unknown about HZ. The incidence of HZ has been increasing from 

years to decades preceding the availability of varicella vaccine. This has been noted in 5 of 6 

US studies1 and involves all adult age groups. The obvious causes have been ruled-out for 

these increases and there are no explanations 1,2. Comparable increases have been seen prior 

to varicella vaccination in most studies conducted in Canada, the UK, Spain, Taiwan, Japan, 

Australia, Czech Republic, and S. Korea3. This phenomenon obviously makes it a lot harder to 

interpret the impacts of varicella vaccination on HZ rates [1Ragozzino MW, Medicine 

(Baltimore), 61(1982):310-6; Kawai K, CID, 63(2016):221-6; Singleton J, 41ST Annual Meeting 

IDSA 2003, Abstract 899; Leung J, CID, 52(2011):332-40; Hales CM, Ann Intern Med 

160(2014):582-3; Hales CM (unpublished thesis, 2015, http://scholarworks.gsu.edu/ math 

theses/149/); Jumaan AO, JID 191(2005):2002-7; 2Joesoef RM, Mayo Clin Proc. 87(2012):961-

7; and Kawai K, BMJ Open. 4(2014):e004833; Park SY, Korean J Dermatol, 42(2004):1531-5 

(in Korean); Smetana J, Epidemiol Mikrobiol Imunol, 59(2010):138-146 (in Czech)]. 

Another factor that can complicate this determination is HZ vaccine itself. Merck’s ZOSTAVAX® 

was licensed in 2006 and was recommended by ACIP for adults 60 years of age and older in 

2008. In 2010, FDA extended the ZOSTAVAX® license to persons 50 through 59 years of age 

based on additional clinical trial data. ACIP has maintained the age-based at 60 years of age 

and older. It is believed that to date, ZOSTAVAX® has not had a substantial impact on 

population-wide HZ incidence for several reasons. First, uptake has been modest. Uptake 

reached 31% in 2015 amongst persons 60 years of age and older. In addition, VE for 

prevention of HZ is 51% for persons 60 years of age and older and is much lower for the oldest 

cohorts. Also, that protection appears to wane to baseline levels at about 10 years [Lu P, 

Vaccine, 2009; Lu P, AJPM, 2011; Williams W, MMWR, 2012; Williams W, MMWR, 2014; Lu P, 

Vaccine, 2015; Williams W, MMWR, 2016; Williams W, MMWR, 2017]. 

From a policy perspective, the key question for decision makers is not whether exogenous 

boosting controls HZ risk within certain households or in certain subgroups, but instead whether 

varicella vaccination leads to increases in HZ in the population at large. The US, with a 

population of 320 million, an effective national varicella vaccination program lasting over 20 

years, and several sources of data regarding HZ incidence is the ideal setting to test this 

question. In terms of the information regarding the impact of varicella vaccine on HZ rates in 

the US, there have been 7 US studies showing HZ trends following availability of varicella 

vaccine that include an adequate number of years of data following introduction of varicella 

vaccination to be informative. None of these 7 studies shows evidence of an accelerating trend 

following introduction of varicella vaccination1, and 5 of the 7 studies suggest a deceleration, at 

least in certain age groups2 [

1Kawai K, CID, 63(2016):221-6; Jumaan AO, JID 191(2005):2002-

7; Leung J, CID, 52(2011):332-40; Harpaz R, OFID 2015:2 (suppl_1): 1052; Hales CM, Ann 

Intern Med 160(2014):582-3; Zhang J (unpublished); Izurieta HS, CID, 64(2017):785-793; 

Moanna A, OFID 2016: 3 (suppl_1): 628; Yih WK, BMC Public Health. 5(2005):68; Mass DPH 

(unpublished); Tseng HF, JID, 213(2016):1872-5; 2Leung J, CID, 52(2011):332-40; Harpaz R, 

OFID 2015:2 (suppl_1): 1052; Hales CM, Ann Intern Med 160(2014):582-3; Zhang J 

(unpublished); Izurieta HS, CID, 64(2017):785-793; Moanna A, OFID 2016: 3 (suppl_1): 628; 

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Yih WK, BMC Public Health. 5(2005):68; Mass DPH (unpublished); Tseng HF, JID, 

213(2016):1872-5]. 

Data on incidence in adults 35 years of age and older for the years 1993-2014 were updated 

through 2006 in 2011. The results for the last 8 years have not yet been published. These data 

are from MarketScan® databases, which contain health insurance claims data on 230 million 

unique patients since the early 1990s acquired from over 100 self-insured employers, state 

governments, hospitals, health insurance plans, and Medicare in all states and represent 

current and former employees, retirees, and beneficiaries. The data covers ages 35 years and 

older with ages stratified into 30-44 years, 45-54 years, 55-64 years, and 65 years and older. 

There was a significant upward trend in HZ incidence in all age strata from the very start of the 

observation time to several years before varicella vaccine was introduced. While these data are 

not adjusted, earlier published analyses showing almost identical patterns were adjusted for 

sex, region, urban versus rural, and immunosuppression status. A series of negative controls 

were used to assure that the results were not due to secular changes in health-seeing behavior 

or in case finding. Not only has there been no evidence of varicella vaccination in plummeting 

varicella rates contributed to increasing HZ incidence, but also rates appear to have plateaued 

for persons 65 years of age and older beginning around 2007. As mentioned earlier, it is not 

really feasible that this plateauing could be attributable to ZOSTAVAX®. There are two other 

points. First, in the 2011 paper to look for varicella vaccine impact on HZ incidence, the 50 

states were stratified into those with high varicella vaccine coverage and low varicella vaccine 

coverage. There were no differences in HZ rates in these two groupings of states. Second, 

mean age at occurrence of HZ did not change over time. If exogenous boosting was important, 

one might speculate or predict that mean age would have declined in the absence of exposure 

to varicella, but that did not happen. The age stayed stable [Harpaz R, IDWEEK 2015]. 

The results of analysis of HZ incidence from 1992-2010 amongst Medicare beneficiaries 65 

years of age and older were published in 2013. All key variables were adjusted for and negative 

controls were used to look for secular changes in health-seeking or case finding. These results 

amongst older adults are very similar to the MarketScan® results, with a large increase in 

incidence amongst all age strata from the very beginning of the study starting several years 

before licensure of varicella vaccine. These results also provided no evidence that varicella 

vaccination has contributed to an increase in HZ incidence, and also show the plateauing 

phenomenon beginning in 2007. Also in this study, HZ rates did not vary in states with high 

versus low varicella vaccination uptake and median age at the development of HZ remained 

stable throughout the entire observation period1. The Medicare analysis was recently extended 

to 2014, though the results have not yet been published. In these unadjusted aggregated data 

for Medicare beneficiaries 65 years of age and older, the plateauing continues and rates appear 

to be declining. As noted earlier, it is not feasible that uptake of ZOSTAVAX® could be bending 

the curve so abruptly in 20072 [

1Hales C. et al., Ann Intern Med. 2013;159:739-745; 2CDC, 

Unpublished]. 

From data presented at IDWEEK in October 2016 on age-specific HZ rates 2000-2014 amongst 

the 5 to 6 million veterans who received their healthcare in the Veterans Administration (VA) 

system, the authors reported that by 2015, ZOSTAVAX® uptake was just 6% in persons 60 

years of age and older and just 5% in persons 50 through 59 years of age. The authors noted 

that HZ rates stabilized in recent years after years of increase, and even decreased significantly 

in persons 60 through 69 years of age. Once again, there is no indication from this analysis that 

varicella vaccination has led to an increase in the incidence of HZ in this population [Moanna A, 

IDWEEK, 2016]. The VA population and healthcare system are quite different from those of 

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MarketScan® and Medicare, so the consistency of the findings across these different platforms 

suggests that they are very robust. 

In summary, there has not been any evidence that varicella vaccination has led to a noticeable 

increase in HZ rates in the general US population. There are several potential explanations. 

Frist, Hope-Simpson’s hypothesis may be incorrect. VZV exposure has little to no impact on HZ 

control, or any impact may be of short duration. Perhaps subclinical VZV reactivation and 

endogenous boosting compensate when exogenous boosting declines. Second, perhaps there 

were too few sufficiently-intense VZV exposures during the pre-vaccine era to noticeably alter 

HZ rates at the population level. The effects may have been limited to smaller subgroups such 

as parents of young children or occupational groups. Or, perhaps the population base for HZ is 

concentrated in older adults who have fewer VZV contacts and who also may respond less 

robustly due to immune senescence. Third, perhaps Hope-Simpson’s hypothesis partially 

manifests as a reduction in the mean age of development of HZ due to less exogenous 

boosting. HZ tends to be milder in younger adults, so they may be less inclined to seek care, 

masking the effect. It would be hard to rule out that possibility, but there is also no evidence to 

support that it is true and there is soft evidence to suggest that it is not likely. Fourth, some 

might suggest that it is too early to see an impact of the varicella vaccination program. One 

could argue that it has only been 12 to 13 years since rates of varicella have declined by 80% or 

more and more years are needed to see an effect. However, most models predicted an effect 

much sooner than 20 years. In household studies suggesting that exogenous boosting reduces 

the risk of HZ, the effect is immediate. Finally, perhaps all of the US studies are wrong and true 

HZ incidence is being missed due to overriding artifacts across all sites and all study designs. 

Data on HZ rates after introduction of varicella vaccination have also been published for 

Australia and Canada. To date, the Australia data are somewhat hard to interpret because of a 

lack of data on baseline trends and because public varicella vaccine programs in Australia were 

introduced more recently in 2005. Regarding Canada, varicella vaccine was marketed starting 

in 1998 to 1999. However, publicly funded programs were launched much later on a provinceby-province basis, so the duration of follow-up is still not that long. Studies have been published 

for 4 provinces, 3 of which have shown no evidence of acceleration of HZ rates. A study was 

published two weeks ago from Manitoba that does suggest an abrupt increase in recent years. 

In conclusion, varicella incidence, outbreaks, and severe disease have declined to low levels in 

all age groups. Among children, HZ rates have declined to very low levels though data were not 

presented during this session on this aspect. In terms of HZ amongst adults, there is no specific 

evidence that the varicella program has increased HZ rates in the general population. The 

epidemiology does seem to be changing and cannot be explained, just as what distinguishes 

persons who experience HZ from those who do not, cannot be explained. In theory, it is 

possible that the US data have not revealed an increase either because it is not powered to see 

a small increase or because more time is needed to see an effect for some reason. This seems 

unlikely, but at a minimum, models can be updated and constrained using the US data to allow 

for more realistic assumptions regarding varicella vaccine impact. Finally, the US experience 

can provide reassurance for countries considering adoption of varicella vaccination. 

Discussion Points 

Dr. Thompson (NVPO) requested clarification regarding the VA data, specifically about the 

portion of VA patients that had received the zoster vaccine. 

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Dr. Harpaz clarified that the authors presented that in the VA population, only 6% of individuals 

60 years of age and older and only 5% of those 50 through 59 years of age had received 

ZOSTAVAX®. Thus, this is essentially an unvaccinated population. 

Dr. Plotkin (Vaccine Consultant) said that for amusement, he wanted to mention that a French 

friend of his conducted a study in sequestered monks in which he showed that there was no 

increase in HZ in those sequestered monks who had never seen children by and large. 

Perhaps that should remind ACIP that modeling is supposition and epidemiology is fact. 

Dr. Harpaz thanked Dr. Plotkin and, in jest, noted that the sequestered monk population had a 

very low rate of genital herpes as well. 

Anthrax Vaccine 

Dr. Kate Hendricks 

Medical Officer, Bacterial Special Pathogens Branch

Division of High Consequence Pathogens and Pathology

National Center for Emerging and Zoonotic Infectious Diseases 

Centers for Disease Control and Prevention 

Dr. Hendrix discussed updating recommendations for use of anthrax vaccine in the US. In 

terms of background, she briefly discussed the disease anthrax, the vaccine, the current 

recommendations, and approval of two antitoxins for PEP. She then discussed the rationale for 

reconvening the Anthrax Vaccine WG and the WG’s terms of reference, as well as a new 

formulation of anthrax vaccine adsorbed (AVA). 

With regard to background, Bacillus anthracis is the causative agent of anthrax. It is a Grampositive spore-forming bacterium. Spores are the infective form and are similar in size (3-5 

micrometers in length) to the tuberculosis bacilli (2-4 micrometers in length), which makes them 

respirable. The vegetative form produces two major toxins, lethal toxin and edema toxin. In 

nature, anthrax is primarily a disease of herbivores. In the late 19th and early 20th Centuries, it 

was an important occupational disease in humans. Since then, it has occurred primarily among 

people who have butchered and /or eaten diseased animals and very sporadically among 

people who incidentally inhale the spores during the course of their work or hobby. 

In terms of the natural cycle, herbivores graze on land contaminated with spores, which 

germinate and cause anthrax. They then die, exsanguinate, and further contaminate the 

grazing land. As just mentioned, humans are infected by butchering and or eating the dead or 

dying animals. Biting flies can also carry the bacterium from carcasses to healthy animals. 

Spores introduced through the skin lead to cutaneous anthrax; those that are swallowed lead to 

ingestion anthrax; those introduced through the lungs to inhalation anthrax; and those 

introduced in a percutaneous manner to injection anthrax. Meningitis may also complicate 

primary anthrax infections of the skin, gastrointestinal tract, and soft tissue. In addition, a 

substantial number of cases (32 from 1900-2005) occurred in patients with systemic anthrax 

without a recognized port of entry (i.e., primary anthrax meningitis). After gaining entry, B. 

anthracis spores are thought to either germinate locally or to be transported by phagocytic cells 

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to the lymphatics and regional lymph nodes, where they can germinate. Bacteria begin 

producing toxin within hours of germination. 

Cutaneous anthrax is by far the most common form of anthrax. Spores are introduced through 

the skin, usually but not always through pre-existing abrasions. Infections can remain local or 

can lead to systemic illness in about a third of the cases. Germination occurs 1 to 3 hours after 

inoculation, while incubation takes 1 to 17 days. In the early 1900s, the case fatality rate 

without treatment was 24%. With treatment, less than 2% of patients with cutaneous anthrax 

die. Ingestion anthrax is the second most common form of naturally occurring anthrax. 

Following a 1- to 14-day incubation, the infection can manifest either in the oropharynx or lower 

in the gastrointestinal system. The case fatality rate is 40%, but may be higher in children. 

Inhalation of aerosolized spores from hair, hides, animals or biowarfare (BW)- or bioterrorism 

(BT)-related events leads to inhalation anthrax. Most of the cases described in the medical 

literature are either occupational or BW- or BT-related. The range for the observed incubation 

period in humans is longer than those observed for other forms of anthrax. In 1979, there was 

an anthrax outbreak that occurred following an accidental release of B. anthracis from a 

biowarfare program in Sverdlovsk, Union of Soviet Socialist Republics (USSR). The incubation 

period there ranged from 2 to 43 days. In 2001, there were anthrax letter incidents in the US in 

which incubations ranged from 5 to 13 days. Data from non-human primates are consistent with 

slightly longer incubations. The case fatality rate has improved somewhat with modern critical 

care, but is still very high. In the 20th Century, the case fatality rate exceeded 90%. Since then, 

with modern critical care that includes combination antimicrobials and drainage of pleural fluid, it 

has still approached 50%. 

A new type of anthrax has been identified in the last decade or two in heroin-injecting drug 

users in northern Europe. These are severe soft tissue infections that are deep under the skin 

or in the muscle where the drug was injected. It is not uncommon for these to present with 

meningeal or abdominal symptoms. This type of anthrax has never been reported in the US. 

Transmission is from injection of contaminated heroin. The incubation is from 2 to 10 days, and 

the case fatality rate with treatment approaches 40%. Meningitis is a very common 

complication of inhalation, ingestion, injection, and systemic cutaneous anthrax. More than half 

of the autopsies done on patients who died with inhalation anthrax in Sverdlosk showed 

hemorrhagic meningitis. Meningitis can also occur as a primary manifestation of anthrax (i.e., 

no other route of transmission) and it is thought to be a form of inhalation anthrax. Based on 

data for 1900-2005, the case fatality rate for inhalation anthrax with meningitis was 100% versus 

about 80% for inhalation anthrax without meningitis. 

This distribution map color codes countries by numbers of outbreaks reported during the 2005-

2016 time period and includes livestock, wildlife, and human data. Purple and red countries 

have the most reported outbreaks; green and yellow countries have the fewest reported 

outbreaks. The data come from the Food and Agriculture Organization (FAO) of the United 

Nations (UN). The map likely under-represents the true disease distribution: 

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In terms of human anthrax cases reported in the US in the latter half of the 20th Century, a large 

epizootic outbreak in Oklahoma in 1957 sparked national annual vaccination of livestock against 

anthrax. Only 5 cases occurred from 1980 through 1999. The anthrax letter incident occurred 

in 2001, and there have been no cases from 2014-2017. 

For a variety of reasons, anthrax spores are the most likely bioweapon. Anthrax spores are 

relatively easy to produce; can be stored for a long time; can be dispersed in the air through a 

variety of means; and are odorless, colorless, tasteless, and difficult to detect. The resulting 

disease, inhalation anthrax, is highly lethal. The spores may survive for greater than 40 years. 

An aerosol release can cause widespread illness and death among unprotected persons. A 

1979 release of anthrax spores from a laboratory in Sverdlosk led to least 77 cases of anthrax 

and 66 deaths in the nearby community. The 2001 US mail incident led to 22 cases of anthrax, 

11 of which were inhalation anthrax, with 5 deaths. In a simulated unmitigated wide area 

anthrax release in a subway system, it is estimated that there would be 100,000 or more 

casualties. 

AVA (BioThrax®), was manufactured for a few decades by the Michigan Department of Health 

and Human Resources (MDHHR). However, it is now manufactured by Emergent Biosolutions. 

AVA is a sterile, cell-free filtrate made from an avirulent (toxigenic, but non-encapsulated) strain 

of B. anthracis*. The final product contains 1.2 mg/ml of aluminum for an adjuvant and 

benzethonium chloride and formaldehyde as preservatives [*http://www.biothrax.com/]. 

The formation and activity of main anthrax toxins are depicted in the following graphic: 

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The two main toxins produced by Bacillus anthracis each come in two parts. One of the parts is 

protective antigen, depicted in the above graphic as a red oval. For either toxin to enter the cell, 

protective antigen needs to bind to the anthrax toxin receptor, then form a heptamer, and have 

the toxins attached. The cell surface invaginates and protective antigen forms a pore through 

which the edema factor and lethal factor escape to wreak havoc. If an antibody interferes with 

protective antigen and keeps it from binding to the anthrax toxin receptor, this whole cascade 

can be stopped. 

The vaccine under discussion during this session, AVA, primes the immune system to recognize 

and block protective antigen (PA), which is common to all anthrax strains. Vaccine efficacy 

against numerous anthrax strains has been demonstrated in many animal studies. This vaccine 

has a long history. In the mid-1950s, there was the Ft. Detrick formulation. This first US 

product was a cell-free filtrate from an aerobic culture of the Vollum strain of B. anthracis, 

precipitated with alum. This vaccine provided protection in monkeys, caused minimal reactivity 

and short-term adverse events in humans, and was used in Dr. Brachman’s efficacy study of 

human vaccination against anthrax in millworkers. In the 1960s, the manufacturing process was 

improved, resulting in increased PA concentration and increased purity and potency. This new 

formulation was referred to as the “Lansing” formulation. In the 1970s, the “Lansing” formulation 

was licensed by NIH using data from the Brachman studies. The vaccine was recommended 

for those at high risk of exposure to anthrax. AVA was reapproved for licensure by FDA in 1985. 

Immunogenicity and reactogenicity data on AVA were reviewed by ACIP in 2007-2009, and the 

current guidelines were published in 2010. 

New data are available for post-exposure use of AVA plus CPG 7909, aka Nuthrax®. Synthetic 

oligonucleotides (ODN) with “CpG motifs” trigger cells with toll-like receptors (TLRs). TLRs are 

a type of pathogen recognition receptor that are expressed primarily on immune cells. The 

utility of CpG oligonucleotides as vaccine adjuvants has been evaluated in a number of clinical 

trials. Results indicate that CpG ODN improve antigen presentation and the generation of 

vaccine-specific cellular and humoral responses. Compared with AVA, AVA plus CPG 7909 is 

expected to achieve an accelerated immune response, necessitating fewer injections and a 

reduced amount of antigen to confer protection. 

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Referring to the graphic of the formation and activity of main anthrax toxins shown earlier, 

antibodies that interfere with protective antigen binding to the anthrax receptor, whether they are 

from vaccination or passive transfer, keep the two main toxins from being released. Three 

antitoxins are approved for treatment of inhalation anthrax in combination with antimicrobials: 

Raxibacumab, Anthim, and Anthrax Immune Globulin Intravenous (AIGIV). AIGIV is polyclonal 

and the other two are monoclonal. 

Anthrax vaccine adsorbed has two uses. It is used for pre-exposure prophylaxis (PrEP), which 

used to be called general use prophylaxis (GUP), in person with occupational risk of exposure 

to Bacillus anthracis. It is also used for PEP for persons potentially exposed to Bacillus 

anthracis. For PrEP, AVA is recommended for the prevention of disease caused by Bacillus 

anthracis in persons 18 through 65 years of age at high risk of exposure. For this indication, it is 

administered intramuscularly at a 0.5ml dose at 0, 1, and 6 months for the primary series, and at 

12 and 18 months after the start of the primary series and at 1-years intervals thereafter for 

persons at continued risk of infection. 

Groups considered to be at high risk of infection include: 1) persons handling potentially infected 

animals in research settings or in areas with a high incidence of enzootic anthrax, or when 

standards and restrictions are insufficient to prevent exposure to B. anthracis; 2) persons who 

perform certain types of laboratory work involving B. anthracis; 3) persons involved in anthrax 

environmental investigations or remediation efforts; 4) certain military personnel; and 5) may be 

offered to persons involved in emergency response activities. For PEP, AVA is recommended 

for unvaccinated persons after exposure to aerosolized B. anthracis spores. For this indication, 

it is administered subcutaneously at a 0.5ml dose at 0, 2, and 4 weeks in combination with 60 

days of oral antimicrobials. This series results in rapid anti-PA antibody production and 

augments the antimicrobial portion of PEP. By combining vaccine and antimicrobials, the 

individual is protected from the germinating spores and vegetative cells of B. anthracis while 

their immune system is being “primed” and developing anamnestic capability. 

As previously mentioned, three antitoxins are approved for treatment of inhalation anthrax in 

combination with antimicrobials: Raxibacumab, Anthim, and AIGIV. Two of the three antitoxins 

that are approved for treatment are also FDA-approved for prophylaxis. When alternatives are 

not available or inappropriate, Raxibacumab and Anthim are recommended. 

The WG is being asked to discuss a number of issues related to mass vaccination following a 

wide-area release of B. anthracis spores. A variety of new data have become available since 

publication of the last set of ACIP recommendations for AVA. These include data on increased 

intervals between booster doses for PrEP, an alternative administration route for PEP, and 

modeling for an adequate immune response in humans based on non-human primate studies. 

Additionally, there are data for a new formulation of AVA that is currently being developed in 

pursuit of eventual FDA licensure. The WG also would like ACIP to review and advise on using 

anthrax antitoxins for PEP. The ACIP Anthrax Vaccine WG was reconvened in the spring of 

2017. The WG’s terms of reference are to review the following: 

 AVA data on a reduced booster schedule for pre-exposure prophylaxis 

 Immunogenicity, safety, and logistical considerations for providing AVA via intramuscular 

versus a subcutaneous route and to provide evidence-based recommendations for 

administration as a post-exposure prophylaxis 

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 AVA with CPG 7909 Adjuvant data and to provide evidence-based recommendations for

post-exposure prophylaxis

 Efficacy and immunogenicity data on a reduced schedule and half-dose AVA use for postexposure prophylaxis to prepare for a potential emergency meeting for a mass casualty

incident when AVA is a limited resource

 Review and advise on the use of AVA and antitoxin for post-exposure prophylaxis when no

effective antimicrobials are available or have an absolute contraindication

Discussion Points 

Dr. Belongia requested information regarding the current use of AVA in the US Military. 

Dr. Yacovone (DoD) replied that the DoD currently uses AVA in the protocol for certain identified 

people who are considered at high risk for certain geographic locations, and also in certain 

groups that respond to incidents. 

Dr. Reingold inquired as to where the efficacy data would come from. 

Dr. Messonnier responded that efficacy will be based on correlates of protection. 

Dr. Plotkin (Vaccine Consultant) indicated that he worked with Dr. Philip Brachman. The 

efficacy study was conducted on workers receiving goat hair, basically, and the efficacy was 

quite high. Although, there were not enough inhalation cases for statistical power, it did appear 

that it did work against both cutaneous and pulmonary exposure. 

Dr. Messonnier said she thought what Dr. Reingold was asking referred to the future since 

natural experiences will not be occurring. The answer to that is the WG is reviewing 

immunological studies and correlates of protection in animal challenge studies. 

Vaccine Supply 

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 the HepB vaccine supply. She reported 

that Merck is not currently distributing its adult HepB vaccine and will not be distributing vaccine 

through the end of 2017. The dialysis formulation of HepB vaccine is not affected. GSK has 

sufficient supplies of adult HepB vaccine to address the anticipated gap in Merck’s adult HepB 

vaccine supply; however, preferences for a specific presentation (i.e., vial versus syringe) may 

not be met uniformly during this time. 

CDC’s Vaccine Supply/Shortage Webpage can be found 

at: www.cdc.gov/vaccines/vac-gen/shortages/default.htm

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Day 1: Public Comment 

Andrea Woodruff 

Sales Director 

Optimized Financial System 

I am here to request that all de-identified data as well as models, and I mean full models, not 

models referred to in part in a paper or partially presented, but that the full models along with 

corresponding data be publicly available, and that you ensure that the statistics presented here 

at these meetings are statistically significant with widely accepted statistical methods. 

Essentially, I am asking that you ensure that you are not using snapshot data, but full picture 

data. Formerly, I worked for one of the largest vaccine manufacturers selling vaccines. 

Afterwards, I interned at the US Senate Committee on Health, Education, Labor, and Pensions 

(HELP) following vaccine legislation. Additionally, I worked for the Council on Foreign Relations 

(CRF) doing corporate fundraising that included vaccine manufacturers. 

I am not anti-vaccine. I couldn’t be better trained to be pro-vaccine. However, it became 

impossible to ignore that the current vaccine vetting process hurt me and my family. While I am 

pro the concept of vaccination, I believe in transparency of data, models, and statistically 

significant information and presentations. I now own a company that does applied analytics, 

specifically operations research. I wanted answers to questions that were not adequately 

provided. In order to start getting used to the data, I started by asking, “Do increased 

vaccination rates decrease vaccine-preventable disease?” I thought this would be easy. Surely 

the data would be publicly available and prove that this is so. 

Everyone I spoke to at the CDC seemed to think that this is available. But when I went to go 

look for the data, I essentially found snapshot reports with incomplete data and it was not 

downloadable. Nothing was convincing when I looked at it critically. We wrote 7 models on 

GitHub. GitHub is a public repository for models and data that uses linear regressions, auto 

regressions, and Bayesian Hierarchical models. I have no financial interest here. I provided the 

work at no cost publicly to be criticized publicly to ensure common understanding and to get 

some answers for myself and my family. 

We had problems accessing MMWR data, so we used WHO data. My tax dollars were used to 

gather MMWR data, and to collect all of the data actually that the CDC uses. So, why don’t I 

have access to it? Please listen to me. Nothing showing that the higher the vaccination rate, 

the lower the disease incidence were statistically significant in the United States—nothing that 

we’ve run so far. If you are making recommendations, you should have downloadable data that 

is publicly available to anyone to check the work that is being done here. Thank you. 

Discussion Points 

Dr. Bennett thanked Ms. Woodruff, acknowledging that the CDC has been working with her and 

will continue to do so. She expressed ACIP’s appreciation for Ms. Woodruff’s comments. 

Ms. Woodruff also submitted the following letter to ACIP: 

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Dear ACIP Members, 

I appreciate you taking the time and thank you for reading. My goal is to bring the medical 

community, public health, the vaccine injured, and the vaccine choice advocates together to a 

common understanding. I know that will not be easy, but I feel that it is vital to bring various 

opinions together so we can move forward. I am deeply concerned about the bubbles I see 

being formed around the pro-vaccine movement and the vaccine choice groups. I believe that 

there are huge strides in medicine that can be achieved if we can learn to understand each 

other’s prospective. I understand both sides of this debate. 

When I looked at peer reviewed articles and slides showing data from both sides of the vaccine 

debate, I realized the problem. I see people showing a snapshot of a problem that fits into their 

presentation. My hope is to mathematically show when we are looking at a snapshot or the 

whole picture. I think this will open minds and hearts on both sides of the argument and get us 

closer to resolution. 

I do not believe that any data will calm a mother who lost their child soon after receiving his or 

her vaccinations. Nor will any data calm a mother who has lost a child to a vaccine preventable 

disease. You, as the ACIP, need to know true data in order to advise the CDC appropriately. I 

will be very clear about my philosophy. I believe that people have the right to be vaccinated and 

vaccinate their children. Additionally, from looking at this for the past 18 years from all 

perspectives and looking at the numbers, people have the right not to be vaccinated and not to 

vaccinate their children. We have entered the world of the insane by trying to push this further. 

You may be thinking about herd immunity. Prove it with model ready downloadable public data. 

It is my hope that my initial models create discourse on the matter of vaccination. I am making 

the models public for both criticism and collaboration. People from other disciplines can suggest 

their own models, changes to the existing models, and provide more data points. I ask that you 

do the same with data in order to shift the debate and advance scientific inquiry. I ask that you 

link all models and data sources to the site on GitHub. https://github.com/vaccinemomma (I 

purposely chose this name and spelling for this site to remind me that this is personal. This is 

about me, my family, you, and your loved ones.) 

I ask that the medical community and vaccine critics engage in healthy debate to gain common 

understandings and improve the welfare of our people. I do not know how these models will turn 

out with more granular data or the accuracy of the data. I do know that this data was collected 

with tax payer money and should be available to anyone wanting to do research. 

However, I hope that we can find common ground, develop trust, and encourage trustworthy 

people to be the guardians of this information. Additionally, I hope that this is the beginning of 

discovery into infectious disease as there is much to be learned when looking at larger and 

larger data sets. I welcome any comments on flaws in logic of this report to further everyone’s 

understanding of this issue. I purposely chose graphs that leaned more toward a vaccine choice 

stance because my audience for the report is you, the medical community and public health. I 

wanted to show you what your patients are seeing. I wanted to show how data can be 

manipulated for or against in the absence of statistically relevant boundaries in order to advance 

vaccine related scientific methodology. 

Sincerely, 

Andrea Woodruff 

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ADVANCING VACCINE RELATED SCIENTIFIC METHODOLOGY 

Understanding Immunization and Infectious Diseases Modeling 

Goal 1: Determine if an increase in immunization rates reduces preventable infectious disease 

in a statistically significant way. 

Data components needed for determining if an increase in immunization rates reduces 

preventable infectious disease. 

• Population: UN Data or Census.gov 

• Immunization Rates by Age: WHO Data, CDC-NIS and NHIS Data, and State Data 

• Vaccine Preventable Disease Incidence by Age: WHO Data, CDC MMWR Data, and 

State Data 

What we found 

WHO and UN data was downloadable, but not broken down by age and only going back to 

1980 for some of the diseases on the US schedule. I would prefer to see before the vaccine 

was introduced and before the trials began. 

Census, NIS-NHIS, and MMWR data were needed. I ran into problems when trying to 

access MMWR data in any format that can run through a model. MMWR data does not 

utilize a formal surveillance study design so this may not be the best source of data. Tycho 

may be the best source, but I have not received a note back from them that this is good 

data. Neither had statistically significant results in any of the models that I ran. (I have not 

finished running all the vaccines on the US schedule.) My guess is because it is not granular 

enough. Essentially, the MMWR data is virtually unusable because it only goes back to 

2014. I am working with the department in charge, but this data should be easily publicly 

available back to the point where it actually proves the point that matches the policy 

decisions. 

Some states keep records and others do not. For the states that do keep records, I would 

need to go through several approvals. I have not heard of a state equipped to run any 

models. If there are any, please let me know. I emailed all of them. Some said all their 

information was public, but it was not set up to run data through. If information is not 

downloadable, it is not helpful to someone running a model to check for statistical 

significance. 

Considering the problems that have occurred with several CDC researchers regarding 

vaccine data. Usable public data would go a long way with re-establishing public trust. It 

seems from an outsider’s prospective that in order to get good data that is not even 

identifiable that you have to be in agreement with the status quo. I paid for all of this with my 

tax dollars. Why do I not have access to it? Is it impossible to clean out the identifiable 

information and give make relevant information public? If there was one case of rubella in 

one state, how am I supposed to identify that person? I am told that the law there is to 

protect personal privacy, but is it? This is not one child with rubella in a school of 300 

children. It is a person with rubella in a state. All the roadblocks simply instill a feeling of 

distrust. 

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What models have we run? 

 

 

 

 

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UN-WHO Data 

1. Linear Regression 

2. Linear Regression US Data Only 

3. Autoregressive Using World Data 

4. Autoregressive Using US Data Only 

5. Hierarchical model using the world and countries as the hierarchies for the Intercepts 

and a Global Disease Reduction Factor Based on the Vaccination Rate. 

6. Hierarchical model using the world, region, and country as the hierarchies for the 

intercepts and a global disease reduction factor based on the vaccination rate 

7. AR1 Hierarchical Model 

8. Others, depending on data availability and new hypothesis 

Census, NIS, NHIS, MMWR or (non-public data) 

• Similar to UN-WHO Data 

Census, State Immunization Rates, State (non-public data) 

• Similar to UN-WHO Data 

How should the data be accessed? 

In order to access all the data, CDC reports should be accessible either in a large file, like the 

WHO data, or should be available through an API, so that analytics toolkits like python and R 

can download them programmatically. 

How is statistical significance determined when running data through models? 

1. R-Squared: Goodness of model fit. How much of the variability in the data is explained 

in the model. Usually, the R-squared value should be at least 50%, which would be over 

.5. 

2. T-Statistic on the parameters: The degree of confidence that we can have that each 

model parameter is not zero. Zero means no effect. Not zero means there is some effect 

either decreasing or increasing the rate of incidences. 

3. F-Statistic on the model itself: How likely is it that any model parameter is not zero? 

Means that if it is not zero then at least something is affecting it. 

4. These are in order of importance: R-squared and T are more important than F. 

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5. For a Bayesian Model: DIC-Deviance Information Criteria. This is more relative when 

comparing models. The more negative the better the fit. 

Example of Lack of Fit for US Measles Data with WHO UN Data (1980-2015) 

Residuals: 

Min 1Q Median 3Q Max 

-1.354e-05 -1.099e-05 -1.055e-05 4.200e-08 9.784e-05 

Coefficients: 

Estimate Std. Error t value Pr(>|t|) 

(Intercept) 5.218e-05 9.264e-05 0.563 0.577 

coverage -4.458e-05 1.010e-04 -0.441 0.662 

Residual standard error: 2.378e-05 on 34 degrees of freedom 

Multiple R-squared: 0.005698, Adjusted R-squared: -0.02355 

F-statistic: 0.1949 on 1 and 34 DF, p-value: 0.6617 

Graph of a Poor Fit 

Please tell us what is wrong with the models? I see there are clearly other factors at play. We 

could not get any of the models to fit with the data publicly available when trying to see if the 

higher the vaccination rate the lower the disease rate. The example above is a standard linear 

model. What models are you doing that are fitting better? What assumptions are you making? 

Who is checking those assumptions? 

Data 

Models are only as good as the data fed into them. This is why comparing multiple data sources 

is important at the state, federal, and global level. There should be a central repository for all 

public data internationally. The WHO has started this, but improvement is needed to truly reach 

a logical conclusion. The ACIP says that they only recommend vaccines and anyone is free to 

decline, but that is not what is happening. We are moving toward mandates with California 

being the most prominent example in the United States, but where are the budgets at the state 

level to actually verify that what is presented is accurate and significant? Some of the states do 

not even keep their own statistics much less have the ability to run models. Essentially, the 

recommendations from the ACIP are not questioned by the medical community and financially 

encouraged lawmakers. 

Goal 2: Determining if There is a Better Way to Reduce Disease Rates 

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Look at anomalies in known vaccine data to see if any patterns exist that can improve policy. 

Determine what data is lacking and what needs to be kept in order to find novel ways to tackle 

infectious disease. 

Determine what assumptions are used in current modeling for lives saved, diseases prevented, 

healthcare costs, and indirect costs. Analyze the effects of changes in assumptions on the 

outcome. 

Determine if the results from Healthy People 2010 are statistically significant regarding their 

ability to reduce disease. 

Determine if the recommendations included in Interventions and Resources give statistically 

significant results and what is their magnitude. 

Goal 3: Have publicly available downloadable data (CSV format), models, and conclusions in 

order to increase transparency and encourage debate, generating new ways to approach 

vaccine related problems. (GitHub) 

Emerging Issues in Immunization and Infectious Diseases 

Determine if the Health People 2020 goals are likely the best way to look at the problem or if 

there are other outcomes in data that suggest a different path. Gather buy-in by various vaccine 

choice groups to the information presented by allowing all information to be transparent. 

Examples of “Snapshot” Data 

I cannot confirm all the data in the graphs is accurate because not all data is publicly available 

from government sources. This does not instill confidence in the vaccine choice groups or the 

next generation of medical professionals who know how to use some of the methodologies that I 

have suggested. However, these are the charts that vaccine recipients are seeing. 

Measles 

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The measles vaccine was marketed in the US as a convenience vaccine. Mainly due to the data 

above. It looks like it worked for that purpose. How did we get to the point where children must 

get two doses before they are allowed to attend school in California? One thought is that, we 

developed a fear of Subacute Sclerosing Panencephalitis and maybe rightfully so. I do not know 

because I am not a virologist or a medical professional qualified to ensure the accuracy of these 

reports, but anyone thinking can see that the CDC report is shaky. How many doctors would 

really look at a patient and think that a patient seems to be presenting with SSPE especially with 

a seven-year lag in symptoms? I believe SSPE exists from the autopsy reports. I just would not 

start taking away parents’ rights to make decisions for their children over an accumulation 

“evidence” no matter how much money is put into repeating the same reports or how pretty the 

power point slides are www.cdc.gov/mmwr/preview/mmwrhtml/00001185.htm 

“The average interval between onset of measles and onset of SSPE is approximately 7 years.” 

I have not seen complete numbers on this, but with the low numbers of measles and high 

number of vaccination rates I would ask what the risk of each is now. It seems that there is 

missing information when I read the proof behind certain policies. The information seems 

slanted very much toward the pro-vaccine side and anyone who questions any aspect of 

vaccine policy is discredited. I do not hear debate at the ACIP meetings. I hear one or two 

weakly worded mild questions or comments that are quickly dismissed because there is “data” 

showing evidence. 

This is why we need diverse thought and statistically valid information when presenting graphs 

and referring to data. It may be relevant or it may not be. If it is, then it supports the idea of 

making all the data public in the interest of public health. 

As far as SSPE showing up seven years later, does the Department of Health and Human 

Services have this in the vaccine injury table? 

I am not as interested in compensation for individuals if there are cofactors or if a higher 

percentage would get the illness from the disease. The ability to choose a vaccine with publicly 

available data gives the patient some of the responsibility. Coercion, mandates, hidden 

information gives culpability to the people making the decisions for the public. I would like 

honest people looking at the data critically who have different viewpoints and then see them 

come together to debate. For the vaccine injured, I would like better diagnosis and treatment. 

We are caught up on compensation and liability. The liability has already been removed for the 

doctors and manufactures. This is a false concern keeping us from moving forward. Allow 

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known policy mistakes to continue should be the biggest financial concern of the vaccine injury 

court. 

The further back the data goes the more complete picture we get. Modeling shows us when we 

have enough data points that we are actually looking at a full picture and when there are other 

factors than just the vaccine at work. It occurred to me that maybe the historical data presented 

online was “fake news” or propaganda. 

I spot checked the measles death information above with vital statistics on the CDC website. 

www.cdc.gov/nchs/products/vsus/vsus_1890_1938.htm 

www.cdc.gov/nchs/data/vsushistorical/mortstatsh_1936.pdf (Measles 1934-1.0 and 1936-3.1) 

www.cdc.gov/nchs/data/vsushistorical/mortstatsh_1917.pdf (Measles 1917-14.3 and 1915-5.4) 

The screen shots turned out like this so please check yourself. The measles graph at least 

seemed accurate to me. 

Mumps 

Diseases do not recognize borders, but they still have statistically different transmission rates 

within borders. The first chart shows the US National Outbreak. The second chart compares the 

Czech Republic to the US. 

The main concern with the mumps outbreak is that generally vaccines show to have waning 

immunity. We should be asking, “Are the real risks of complications statistically significant?” 

There were 37 deaths from mumps ages not specified when the mumps vaccine was first 

released. To put that in prospective, approximately 3500 infants die annually in the United 

States from sleep-related infant deaths, including sudden infant death syndrome (SIDS; 

International Classification of Diseases, 10th Revision [ICD-10], R95), ill-defined deaths (ICD-10 

R99), and accidental suffocation and strangulation in bed (ICD-10 W75). One question to ask is 

how much of a danger is it to choose to have natural immunity? We are concerned about the 

immunocompromised and rightfully so. I am interested in knowing if there are higher rates of 

immunocompromised people and why? I am also interested in knowing if these viruses have 

mutated over the years? Are these viruses somehow deadlier now? If not, why the push for 

mandates now? 

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Rubella 

When presenting graphs, it is important to tell when the trials began and look at the disease 

incidence several years before. 

1941: Gregg identifies rubella 

1947: First known trials of serum or IGIM 

1962: Pandemic strikes Europe, reaching US in 1963 to 1964. 

1969: Three rubella vaccines licensed. 

Are the trial dates and locations made public? Are we clear when vaccines are being licensed 

globally? This would help confirm that the vaccine was not causing the pandemic. 

Polio 

Viral etiology of poliomyelitis by 1909. Trials began in 1935. As stated before a public repository 

of all trials in order for the vaccine to be released is important in maintaining public trust. 

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As presented in the CDC Pink Book: 

This is a perfect example of “snap shot” data: 

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Other Examples of “Snapshot” Data: 

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I hope you see the need for looking at the whole picture and this requires more data points. I will 

feel comfortable when I see something statistically significant in the models. After that, I would 

like to look at the analytics within that. There is so much to learn, but we need data sets in 

formats that are available for anyone not financially tied to the vaccine industry. No matter what 

the outcome, there will be those who want vaccines and there will be those who do not. The 

choice should be theirs because there are no certainties in science. It is my sincere hope that 

your committee benefits from this information and can advance vaccine related scientific 

methodology. 

Tribute to CAPT Jean Clare Smith 

Amanda Cohn, MD 

Executive Secretary, ACIP / CDC 

Dr. Cohn indicated that they wanted to take the opportunity to acknowledge someone who has 

been the heart and soul of ACIP for many years, CAPT Jean Clare Smith. Given that Dr. Smith 

is moving into a new position at CDC, they wanted to take a moment to acknowledge her. Dr. 

Smith joined CDC 25 years ago as an Epidemic Intelligence Service (EIS) Officer. Dr. Smith 

started saving the world many years ago. In 1992, she was featured in an article regarding a 

foodborne outbreak that she worked on that broke out among bankers. She traced the 

foodborne illness back to the eggs of a caterer who was making homemade mayonnaise. After 

EIS, Dr. Smith’s dedication to public health led her to live in India-Nepal, where she worked 

tirelessly for years on polio eradication during a time when enormous progress toward 

elimination was made in the region. In 2006, Dr. Smith became a Medical Officer for ACIP 

Secretariat. This is what the childhood immunization schedule looked like in that year 

compared to the current schedule 11 years later: 

There is so much behind each of these recommendations. Dr. Smith has spearheaded the 

many critical improvements in terms of the way ACIP functions, including GRADE evidencebased recommendations and the way economic analyses are presented to ACIP. More than 

anything, Dr. Smith has been an advisor, mentor, and supporter for dozens of CDC staff and 

over 40 ACIP members over the years. 

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While Dr. Smith will always be part of the ACIP family, everyone is so grateful for her tireless 

efforts to bring ACIP to where it is today, all while raising her beautiful daughter pictured here: 

Everyone is excited for Dr. Smith in her new role. She will not be far away as she continues to 

work on educating providers about ACIP recommendations. 

Dr. Smith thanked everyone and quipped that as a 65-year-old mother of a 19-year-old 

daughter, there is no retirement for her anytime soon, and she has started receiving piles of 

Medicare mailings. 

Dr. Bennett expressed her gratitude and emphasized that there is no way they could ever 

express how much Dr. Smith has meant to all of them. On a personal note, Dr. Bennett said 

she would never have taken this job if not for Dr. Smith. 

Agency Updates 

Centers for Disease Control and Prevention (CDC) 

Dr. Messonnier reported that a number of important and great things are going on in NCIRD, 

which were described in a 2-page report provided to ACIP members. She conceded her time to 

Dr. Cohn for the tribute to CAPT Jean Smith. 

Centers for Medicare and Medicaid Services (CMS) 

Ms. Hahn indicated that there were no updates for CMS. 

Department of Defense (DoD) 

Dr. Yacovone reported that the Defense Health Agency (DHA) Immunization Healthcare Branch 

(IHB) continues to work with all branches of the service on mitigating strategies to conserve 

available doses of yellow fever (YF) vaccine due to the YF vaccine shortages. DoD has 

reduced utilization by more than 60%, maximized its stock with an aggressive redistribution 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

program, and worked in partnership with Sanofi Pasteur on strategies to help delay a national 

stock-out. The DoD routinely vaccinates recruits to protect against Adenovirus Types 4 and 7 

early in initial entry training. Recently completed FDA-mandated post-licensure surveillance 

studies reported sustained reductions in acute respiratory disease and an excellent safety 

profile in this population following reinstatement of a universal vaccination of recruits. These 

publications include one in Infectious Disease and another in Vaccine on the incidence of 

respiratory illness and safety. 

Future goals of the Adenovirus Vaccine Program include modernization of the Adenovirus 

vaccine production in partnership with industry, and consideration for expansion of vaccination 

to military service academies in addition to DoD’s recruit population. For its Japanese 

Encephalitis Vaccine (JEV) Program, DoD has completed all of JEV IXIARO® FDA required 

post-licensure studies. A final manuscript of surveillance of AEs was submitted to the FDA this 

week for review and comments. In terms of metabolomics research, DoD completed a pilot 

study to assess metabolites as markers of AEs following smallpox vaccination. This study 

demonstrates the potential for metabolites to identify mechanisms associated with subjects who 

developed AEs following immunizations that was published in Vaccine in March 2017. 

Food and Drug Administration (FDA) 

Dr. Sun reported that the FDA held an advisory committee meeting on May 17, 2017 for which 

the topic of discussion regarded how to move forward with the development of vaccines for 

infant immunization with respiratory syncytial virus (RSV) vaccine, given the past history of the 

formalin-inactivated vaccine causing enhanced disease. FDA has the advisory committee’s 

feedback and is working with several manufacturers on developing RSV vaccines for that 

population. 

Regarding the 21st Century Cures Act 2016 and how it impacts vaccines, there are numerous 

provisions. The provision that is most relevant to ACIP is Title III Subtitle C: Modern Trial 

Design Evidence and Development Section 3022—Real World Evidence. The act requires FDA 

to establish a program to evaluate potential use of real world evidence for two purposes, which 

are to: 1) help to support the approval of a new indication for a drug approved under section 

505(c); and 2) help to support or satisfy post-approval study requirements. “Real world 

evidence” is defined as “data regarding the usage, or the potential benefits or risks, of a drug 

derived from sources other than randomized clinical trials.” The act goes on to state that “The 

framework shall include sources of real world evidence, including ongoing safety surveillance, 

observational studies, registries, claims, and patient-centered outcomes research activities.” 

The implication for this is that the impact of ACIP recommendations will be enhanced because 

the FDA believes that the nature of ACIP recommendations will dictate how real-world evidence 

will be able to be developed. 

FDA is also charged with developing a guidance on this topic, and there is likely to be additional 

collaboration with ACIP on doing this. On March 13, 2017, FDA approved the supplement for 

the 3-dose Trumenba® series and the confirmatory study for the accelerated approval. Pfizer 

presented data from their breadth of coverage using additional Serogroup B meningococcal 

(MenB) strains as measured by the serum bactericidal antibody (SBA) levels. That supplement 

also included data on concomitant administration of Menactra®, which also was approved. Drs. 

Walter Ornstein, Larry Pickering, Carol Baker, and Sun have submitted an article to Vaccine on 

the topic of ACIP and FDA collaborations on vaccines in the US, and how they have reviewed 

the approvals over the last 10 years and ACIP recommendations. This should be published in 

the next 3 months. 

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Health Resources and Services Administration (HRSA) 

Dr. Nair reported that HRSA has been very busy in the National Vaccine Injury Compensation 

Program (VICP). Thus far, 853 claims have been received in 2017. As of March 2017, $127 

million in awards have been paid to petitioners and $13 million have been paid in attorney fees 

and costs. That includes costs for compensations, dismissed claims, and interim fees. HRSA’s 

website includes current information about the program. The Final Rule that made revisions to 

the Vaccine Injury Table was published in January 2017 and is effective for claims that are filed 

after March 21, 2017. HRSA continues its outreach efforts to make people aware of this 

program. 

Indian Health Services (IHS) 

Ms. Groom reported that IHS had full implementation of their mandatory HCP influenza 

vaccination policy this influenza season. Their final data shows that the agency did achieve the 

Healthy People 2020 goal of 90% coverage for HCP across IHS. For FY2018, IHS is 

implementing a composite measure agency-wide to monitor compliance with adult 

immunizations for Tdap, Td-containing vaccine in the last 10 years, zoster, and pneumococcal 

vaccine. 

National Institutes of Health (NIH) 

Dr. Lambert reported that a Phase I clinical trial has been initiated of the new recombinant RSV 

vaccine. This effort is under the development of the Vaccine Research Center at the National 

Institution of Allergy and Infectious Diseases (NAIAD). NIH also initiated a Phase II clinical trial 

of a zika vaccination, which is a DNA-based vaccine that showed promise in Phase I clinical 

trials. The Phase II clinical trial has a 2-staged study design. Part A will enroll healthy adults 

that will show safety and immunogenicity, and will help determine the optimal dosage. Part B 

will enroll up to 2400 healthy adults 15 through 35 years of age. This part of the trial aims to 

determine if the vaccine can effectively protect against Zika-related disease when someone is 

naturally exposed to the virus. Sites will include the three locations from Part A (Houston, 

Miami, and San Juan) and six additional countries that have had zika (two additional sites in 

San Juan, two sites in Costa Rica, and one site each in Peru, Brazil, Panama and Mexico). 

Late last year, NIH supported a workshop on waning immunity associated with microbial 

vaccines. That was published in May 2017 in an American Society for Microbiology (ASM) 

Journal, and compared and contrasted 6 microbial vaccines (Bordetella pertussis, Salmonella 

typhi, Neisseria meningitidis, influenza, mumps, malaria) in terms of what is known about them 

and their duration of protection. The articles also included recommendations for opportunities 

for additional research support. 

National Vaccine Program Office (NVPO) / National Vaccine Advisory Committee (NVAC) 

Dr. Shen reported that since departing NVPO, Dr. Gellin has left federal service and is now 

serving as a leader at the Sabin Vaccine Institute. On May 9, 2017, NVPO along with CDC and 

the Immunization Action Coalition (IAC) co-chaired the IAC-hosted 6th annual National Adult 

Influenza and Immunization Summit (NAIIS). There were over 350 attendees who represented 

150 organizations across the federal space, local and state health departments, professional 

associations, foundations, networks, academia, et cetera. This year’s theme was “Prioritizing 

Prevention: Strategies to Improve Adult Vaccination within the Transforming Health System.” 

This year, there also was a pre-meeting on leveraging and transforming health systems to 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

improve adult vaccination, which was co-sponsored by AMGATM and NAIIS. NVPO will be 

producing a white paper from that pre-meeting, and the slides are on the NAIIS website. 

Also related to adults, NVPO and IHS co-lead the NAIIS Quality and Performance Measures 

Workgroup. NVPO has a contract through the National Committee for Quality Assurance 

(NCQA) and has completed recruitment. Through the summer, NCQU will be testing NVPO’s 

maternal immunization composite measure that includes Tdap and influenza. This measure will 

be included in the Healthcare Effectiveness Data and Information Set (HEDIS). Many who work 

in health systems appreciate the implications of being part of HEDIS. 

Through the NAIIS, NVPO will have its End-Stage Renal Disease (ESRD) Measure Working 

Group and has engaged with CMS’s ESRD program, including their Quality Incentives Program 

and Networks Program for Quality Improvement and Programs. NVPO will update ACIP in the 

fall on the adult composite. This composite is comprised of Tdap, pneumococcal, zoster, and 

potentially influenza. 

Regarding the 21st Century Cures Act, NVPO is leading the HHS Inter-Agency Working Group, 

which is comprised of FDA, CDC, NIH, and Biomedical Advanced Research and Development 

Authority (BARDA) on delivering on Section 3093. This section requires the Secretary of HHS 

to deliver a report to Congress pertaining to vaccine innovation, which is due in December 2017 

one year from the enactment of the law. 

Earlier in June, NVPO announced the winners of its inaugural UpShot Awards celebrating the 

great work being done to enhance the vaccine immunization system. Excellence in Vaccine 

Safety went to Dr. Roger Baxter, Co-Director, Kaiser Permanente Vaccine Study Center; 

Excellence in Vaccine Communication went to Dr. William Schaffner, Medical Director, NFID; 

Excellence in Vaccine Supply, Access, and Use went to HLN Consulting; and Excellence in 

Global Prevention went to PATH. 

NVAC held its meeting on June 6, 2017. The meeting was framed around the top 3 opportunity 

areas as identified by the NVAC Midcourse Review: Immunization Information Systems (IIS), 

Vaccine Confidence, Financial and Systems Barriers to Administration of Vaccine. Slides will 

be available on the NVPO website in about one week. 

The Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria (PACCARB) is 

charged with developing recommendations on incentivizing development for therapeutics, 

diagnostics, and vaccines. The Vaccines Working Group draft report was presented during the 

May public meeting, but did not include their recommendations. Their full report will be 

presented this fall at the September 13-14, 2017 PACCARB meeting for a full vote of the 

PACCARB. The recommendations of PACCARB go to the Secretary of HHS, who then 

transmits them to the President. A number of NVAC members also sit on that working group. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Dengue Virus Vaccine 

Introduction 

Emmanuel (Chip) Walter, MD, MPH

Chair, Flavivirus Vaccines Work Group 

Advisory Committee on Immunization Practices 

Dr. Walter reminded everyone that during the February 2017 ACIP meeting, there was an 

update on general dengue epidemiology and vaccine development. Since that time, the WG 

has met about every two weeks and continued review of dengue epidemiology, immunology, 

and diagnostics to prepare for submission of the dengue vaccine Biologics License Application 

(BLA). They have learned that the dengue vaccine BLA submission has been delayed. Though 

initially the submission was anticipated to be in 2017, it will probably be sometime in 2018. 

Future WG plans are to continue review DENGVAXIA® clinical trials, the cost-effectiveness of 

dengue vaccines, and GRADE; hear presentations by Sanofi Pasteur; and draft 

recommendations for use. In preparation for all of this, a presentation was delivered during this 

session on dengue epidemiology in the US, Puerto Rico (PR), and other US territories. 

Dengue Virus Vaccines 

Steve Waterman, MD, MPH 

Chief, Dengue Branch 

Centers for Disease Control and Prevention 

San Juan, Puerto Rico 

Dr. Waterman presented available data on dengue epidemiology in the US and its territories. It 

is important to note dengue was only made reportable by CSTE in 2010. After recapitulating the 

fundamentals of dengue epidemiology, he covered the jurisdictions and geographic areas in the 

US affected by dengue, roughly in order of transmission intensity and burden. 

Dengue viruses (DENV) comprise four related serotypes. Zika is closely related to dengue. An 

infection with a given serotype provides long-term protection, and a short period of up to about 6 

months of cross-protective immunity. Thus, theoretically, one can experience four dengue 

infections in a lifetime. Humans acquire dengue through the bite of dengue-infected Aedes 

mosquitoes, principally Aedes aegypti, in a man-mosquito-man transmission cycle without 

intermediate hosts. The incubation period in both man and mosquitoes before becoming 

infectious is about a week. 

Dengue is arguably the most important arbovirus in terms of worldwide morbidity and mortality 

across the tropical and sub-tropical Western Hemisphere, Africa, the Middle East, Asia, and the 

Pacific, with an estimated 100 million dengue cases including 2 million severe illnesses and 

20,000 deaths a year: 

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Dengue is an acute febrile illness (AFI) syndrome resembling many other infectious diseases 

such as measles, leptospirosis, and rickettsial disease. Epidemics typically have a cyclical 

pattern over years and with seasonal incidence correlated with higher rainfall months. In highly 

endemic areas, multiple serotypes may circulate simultaneously. The peak age of incidence 

varies by region, the more endemic, the younger the median age incidence in general. Severe 

dengue often manifests as a capillary leakage syndrome known as dengue hemorrhagic fever 

(DHF)/dengue shock syndrome (DSS) which occurs precipitously several days into the illness 

and is potentially fatal, although with adequate fluid support, mortality should be reduced to less 

than 1% [Guidelines for Clinical Evaluation of Dengue Vaccine in Dengue Endemic Areas. 

Vaccine 2008;26:4113-4119]. 

Secondary infection, a second dengue infection with a different serotype with the associated 

immune response mediated in part by the prior infection, is a documented important risk factor 

but is not necessary a condition for severe disease. In addition to this likely immune system 

mediated risk factor, viral strain and host characteristics (co-morbidities, young age, female) are 

risk factors for disease severity. 

The framework for thinking about dengue risk and possible vaccine recommendations centers 

on presence of the vector. Again, the principal vector is Aedes aegypti, but other Aedes species 

such as albopictus in Hawaii and polynesiensis in the Pacific are vectors as well. The history of 

and potential for virus transmission is also important. Puerto Rico is highly endemic for dengue. 

The Virgin Islands and Pacific territories also have high, if not endemic, levels of transmission. 

Southern US states, such as Texas and Florida, have experienced dengue outbreaks in recent 

years, as has Hawaii. A number of other Southern and Southern border states, such as 

Louisiana and Arizona respectively, are at risk for dengue because of an abundance of Aedes 

aegypti, imported infections, and proximity to endemic areas. Of course, imported cases can 

occur where the vector is not present. 

Puerto Rico has a history of major epidemics. Puerto Rico’s first major epidemics were reported 

in 1915 and 1945. The Commonwealth of Puerto Rico has had a population of over 3 million 

persons since the late 1970s. In 1963, DENV was first isolated in Puerto Rico during a DENV 3 

outbreak. The first laboratory-confirmed case of DHF was reported in 1975. The first time 

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circulation of more than one DENV type was documented was in a 1977 outbreak. During that 

outbreak 12,733 cases were reported (3.75/1000 population) and 355,000 were estimated to 

have occurred. DENV-1, -2, and -3 were detected. Six large, island-wide outbreaks took place 

between 1969-1986. 

The only documented dengue vector in Puerto Rico is Aedes aegypti. Dengue is endemic in 

Puerto Rico, with typically two to three epidemics each decade. Up to 27,000 cases have been 

reported through passive surveillance in an epidemic year, with several thousand cases even in 

some non-epidemic years. Three to four dengue viruses have circulated simultaneously in 

Puerto Rico since the mid-1980s. Seasonal peak dengue activity is in the late summer to fall 

months. Incidence is, as expected, highest in urban areas. Clinical disease report rates are 

highest in those 10 through 19 years of age, with no incidence difference by sex. 

Again, dengue incidence cycles as serotype specific susceptibles are depleted and build back 

up over several years. There were two large outbreaks in the 1990s with multiple serotypes, 

which were predominantly DENV-2 in 1995 and DENV-4 in 1998. There were three large 

outbreaks in the 2000s, with the last occurring in 2012-2013. DENV-1 and DENV-3 

predominated in those outbreaks. DENV-1, -2, and -4 dominated in Puerto Rico from 1986 

through 1997. DENV-3 reappeared in the 1998 outbreak and remained in circulation until early 

2010. By 2000, few cases of DENV-4 and DENV-1 were detected until reappearing during the 

2007 outbreak. DENV-2 has been detected every year; however, the proportion of isolates 

typing as DENV-2 were low from 2000-2002 and recently in 2011-2012. All four viruses were 

circulating in 2015-2016 when DENV-2 seemed to be on the increase again, with DENV-4 being 

the most common subtype. 

Typically, about half (49%) of all laboratory-positive cases reported through passive surveillance 

are among adults 20 years of age or older, as occurred in 2010-2012. The median age was 18 

years and the range spanned from infancy to centenarians. The highest number of cases and 

rate of laboratory positive dengue was among children and adolescents 10 through 19 years of 

age. Laboratory-positive cases during 2010-2012 track with dengue deaths. The mortality rate 

per 100,000 was highest in 2010 with 39 deaths (1.05 deaths/100,000). There were 6 deaths in 

2011 (0.16 deaths/100,000) and 13 deaths in 2012 (0.35 deaths/100,000). The case fatality in 

2010 (39 deaths/10,970 laboratory-positive cases) and 2011 (6 deaths/1547 laboratory-positive 

cases) was 0.4 deaths/100 laboratory-positive cases and 0.2% in 2012 (13 deaths/6057 LP 

cases). In contrast to the higher rate of disease reports in adolescents, only 6 of the 58 

laboratory-confirmed deaths were in children and only one was in those 10 through 19 years of 

age. Rather, deaths were most common in adults between 20 to 88 years of age. In Puerto 

Rico, 52 of 58 (90%) of laboratory-positive deaths occurred in adults from 2010 through 2012. 

The seroprevalence of dengue infection and the proportion of primary and secondary infections 

is an important consideration in thinking about the DENGVAXIA® vaccine. In a 2006 Puerto 

Rico blood donor serosurvey among adults, 92% were seropositive for past dengue infection 

and most of the infections were secondary. The antibody pattern result indicated that 96% of 

those tested had had two or more dengue infections1. Among Puerto Rico laboratory-positive 

dengue cases in 2010, 80% of all infections had a secondary dengue antibody pattern. Primary 

infection was more common in those 1 through 4 years of age, and more than 80% of cases 

had secondary antibody responses2 [

1Mohammed et al., Transfusion, 2012; 2Sharp et al., PLoS 

NTD, 2013]. 

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Moving to the US Virgin Islands (USVI), about 60 miles east of Puerto Rico, based on their 

passive case reporting, USVI has experienced periodic outbreaks between 1986-2012. During 

the last outbreak in 2012, CDC DB assisted the USVI DOH in conducting a seroincidence study 

in schools in St. Croix. Of school-aged children/adolescents and teachers, 20% and 17% 

respectively were acutely or recently infected with dengue virus, and 80% of school aged 

children and adolescents and 98% of teachers had serologic evidence of prior flavivirus 

infection. 

Multiple Aedes species are present in the US Pacific territories which include American Samoa, 

Guam, the Northern Mariana Islands, Palau, the Marshall Islands, and the Federated States of 

Micronesia. Periodic dengue outbreaks have been detected among the Pacific Islands since 

1958, usually with only one dengue serotype at a time1. A 2010 serosurvey in American Samoa 

among adults found that 96% percent of the sampled population had dengue antibody2. CDC 

collaborated on an outbreak investigation in American Samoa in 2015 where 479 (1% of the 

population) suspected dengue cases were reported. Reverse transcriptase polymerase chain 

reaction (RT-PCR) testing detected DENV-3 only. Four persons died, for a case fatality rate of 

about 1%. The most common vectors were Aedes aegypti and Aedes albopictus [

1Hammon et 

al., Am J Trop Med Hyg, 1958; 2Lau, EID, 2013]. 

The region of the continental US most at risk for dengue is the Southeastern US-Mexico border 

in the so-called Lower Rio Grande Valley. Mexico has become increasingly endemic for dengue 

since the 1980s. US transmission stems from Northward movement of DENV across the border 

during large outbreaks in Northern Mexican border states such as Tamaulipas and Nuevo Leon. 

South Texas is the only US border region with documented local transmission. However, 

dengue outbreaks have occurred along the border of Arizona and California in recent years 

where Aedes aegypti has been recently introduced, so these areas are at risk in the future. 

Texas has an impressive history of several large dengue outbreaks, including a 1885-1886 

outbreak in Austin during which an estimated 70% of residents were affected and in 1922 in a 

statewide outbreak involving an estimated 500,000 cases throughout the state. The first 

dengue post World War II (WWII) outbreak occurred in the lower Rio Grande Valley of Texas in 

1980 when a number of cases were identified that did not have a travel history across the 

border to Mexico [Ehrenkranz et al., NEJM 1971]. 

CDC worked with Texas and Mexico to investigate a 1999 dengue outbreak in the sister cities of 

Laredo, Texas and Nuevo Laredo, Tamaulipas. The following satellite image shows the Rio 

Grande river dividing these adjacent communities: 

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Using a modified WHO cluster sampling approach, a serosurvey on both sides of the border 

showed higher incidence of IgM positive recent infections on the Mexico side despite higher 

mosquito density indices on the US side. While most cases on the US side had a travel history 

to Mexico, a number did not. The IgG antibody prevalence indicating prior dengue infection 

among sampled US residents of Laredo was 22.5%. This often cited study by Reiter found 

suggested household environmental characteristics, such as lack of air conditioning, was an 

important risk factor for dengue infection in this setting [Reiter et al. Emerging Infectious 

Diseases 2003]. 

The CDC Border Infectious Disease Surveillance (BIDS) Program enhanced AFI surveillance 

collaboration with Texas detected the first locally-acquired case of DHF in the continental US in 

2005 during a DENV-2 outbreak with the Southeast Asia strain associated with severe disease. 

Again, higher rates of recent infections were seen on the Matamoros, Mexico side, but 38% of 

surveyed Cameron County residents had IgG antibody of 38% and 25% of persons participating 

in the serosurvey who had not traveled out of the US were seropositive for dengue. This was 

the first time DHF was reported in the US. Of cases reported to the Cameron County Health 

Department, 25 (89%) were hospitalized, 16 of whom had DHF syndrome1. The most recent 

Texas outbreak, again in Cameron County, was in 2013 with 53 laboratory-confirmed cases, 

with 55% of whom were hospitalized. Almost half of the reported cases were locally acquired. 

Local transmission was also documented by a serosurvey among household members of 

dengue cases2 [

1Ramos et al Am J Trop Med Hyg 78(3) 2008; MMWR 56 2007; 2Thomas et al. 

Emerg Inf Dis 2016]. 

Florida has had a number of outbreaks since 2009. In 2009, Florida had its first dengue 

outbreak in 64 years detected after a traveler from New York was diagnosed with dengue after 

returning home from Key West, the string of islands extending off the southern tip of Florida. 

The 2009 investigation revealed 27 laboratory-positive locally-acquired cases in Key West 

residents and 5% of residents surveyed at the end of the outbreak (n=240) had had a recent 

dengue infection. DENV-1 was the only type identified. In 2010, during March to November, 66 

locally-acquired dengue cases were identified in Monroe County. 

Two sporadic locally-acquired dengue cases occurred in Florida in 2010. One DENV-1 case 

was detected in Miami-Dade County, and one DENV-3 case was detected in Broward county. 

In 2011, the Florida Department of Health reported 7 dengue cases with no travel history in the 

2 weeks prior to illness onset. The cases resided in Hillsborough (1), Martin (1), Miami-Dade 

(3), and Palm Beach (2) counties. In 2012, Florida had 4 sporadic locally-acquired dengue 

cases, with two in Miami-Dade and one each in Seminole and Osceola Counties. A locallyacquired dengue outbreak took place in Martin and Saint Lucie Counties beginning in June 

2013 and continuing through September 2013. There was one sporadic case that year in 

Miami-Dade County. Of the ill cases initially identified, 21 had DENV-1 and no travel history. 

The median age was 48 years, with a range of 4 through 63 years. More than 85% were white 

non-Hispanic. A seroincidence study suggested that 7% of the residents were infected. 

Sequencing studies in Martin County in 2013 compared to the 2009 virus in Key West, the 

viruses were different, so this was reintroduction not ongoing endemic transmission in Florida 

[CDC Dengue Branch and Florida Department of Health]. 

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Hawaii also has a history of dengue outbreaks, but was quiescent after WWII for a period of 

time. Aedes aegypti was the vector implicated in these early outbreaks. However, sometime 

early in the 20th Century, Aedes albopictus was introduced into Hawaii and has become the 

dominant mosquito in Hawaii. Hawaii experienced a dengue outbreak in 2001 that affected 

three islands. From May 2011 to February of the following year, 1644 suspected dengue cases 

with no recent travel history were tested for dengue, of which 122 were laboratory positive. 

Laboratory-positive cases were detected on 3 of the 6 islands, Kauai, Oahu, and Maui, with 2/3 

of the cases on Maui. A serosurvey in the small Maui rural community of Nahiku showed a 39% 

attack rate with evidence of prior undetected transmission. DENV-1 was the only serotype 

identified and was thought to be most closely related to a strain from Tahiti, which is important. 

The median age of laboratory-positive cases was 41 years. Three of the 122 cases were 

hospitalized, there were no DHF/DSS cases, and there were no deaths. A small cluster of 5 

non-severe dengue cases, two confirmed with DENV-1, was identified in early 2011 in the 

neighborhood of Pearl City, Oahu. The index case was a traveler and subsequently 4 local 

residents without travel history became ill and had confirmed dengue. A dengue outbreak 

occurred recently in 2015 on the Big Island of Hawaii, with 264 laboratory-confirmed infections. 

Cases had a median age of 29 years, and early data indicated a 14% hospitalization rate. The 

outbreak strain was a DENV-1 strain different from the 2001 Hawaii outbreak strain. Dengue 

was the isolated virus from Aedes albopictus. Possible focal areas with Aedes aegpyti 

contributed to outbreak transmission. 

In summary, dengue is highly endemic in Puerto Rico with simultaneous circulation of multiple 

serotypes. Limited seroprevalence data strongly suggest that most of the population has had at 

least one dengue infection by the second decade of life. During large outbreaks, hundreds of 

hospitalizations and tens of deaths occur. Dengue is common and may be endemic in the 

Virgin Islands and American Samoa and other US Pacific territories. Seroprevalence data are 

limited. South Texas has had repeated small dengue outbreaks with local transmission since 

the 1980s. Seroprevalence data over 10 years old suggests that there is a border crossing subpopulation with significant past exposure to dengue. Other US-Mexico border states are at risk 

for dengue, but there is no evidence of local transmission to date. South Florida has had 

repeated small dengue outbreaks since 2009. Hawaii has had two outbreaks and a small 

cluster of cases since 2001, that was transmitted primarily by Aedes albopictus. 

Yellow Fever Vaccine 

Introduction 

Emmanuel (Chip) Walter, MD, MPH

Chair, Flavivirus Vaccines Work Group 

Advisory Committee on Immunization Practices 

Dr. Walter reminded everyone that intermittent production issues have periodically resulted in 

temporary supply shortages of yellow fever (YF) vaccine, YF-VAX®, in the US. Since November 

2015, ordering restrictions have been in place for YF-VAX® due to supply shortages. In October 

2016 and February 2017, the WG briefed ACIP about YF-VAX® production and contingency 

plans to address any supply shortages. Presentations during the June 2017 ACIP Meeting 

included: 1) an update on implementation of an Investigational New Drug (IND) and YF vaccine 

distribution; and 2) a review of protocol inclusion criteria and the current ACIP 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

recommendations. 

Update on YF Vaccine Supply 

David Greenberg, MD

Associate Vice President and Regional Medical Head, North America

Sanofi Pasteur 

Dr. David Greenberg reported that to improve supply of yellow fever vaccine in the US, Sanofi 

Pasteur is transitioning manufacturing of YF-VAX® to a new state-of-the-art facility that is 

expected to be operational by mid-2018. Manufacturing issues resulted in a gap in YF-VAX® 

vaccine supply from the time of the shutdown of the old facility to operation of the new facility. 

Ordering restrictions have stretched the remaining supply of YF-VAX® vaccine. Sanofi Pasteur 

expects to stock-out of YF-VAX® in early July 2017. 

Sanofi Pasteur’s focus has been to provide a continuous supply of YF vaccine in the US for 

travelers, government employees, military, and other response groups who need to be 

immunized. To this end, they have held stakeholder discussions for over a year with CDC, 

FDA, DoD, and others to manage the remaining supply of YF-VAX® vaccine and to import an 

alternative YF vaccine. 

An essential component of the stakeholder discussions has been to work closely with the FDA 

to import Stamaril®, the YF vaccine Sanofi Pasteur manufactures in France that is not licensed 

in the US, under an IND and distribute it in the US via an Expanded Access Program (EAP). 

The EAP protocol allows for Stamaril® vaccine to be used by authorized healthcare providers 

who undergo training. As a result of these efforts, and to maintain supply of YF vaccine in the 

US, Sanofi Pasteur started shipping Stamaril® vaccine to EAP-certified sites on May 23, 2017. 

As noted previously, Stamaril® vaccine is the YF vaccine manufactured by Sanofi Pasteur in 

France. It is a live attenuated vaccine that contains the YF virus 17D-204 strain. This is the 

same strain contained in YF-VAX®. Stamaril® vaccine is used globally in more than 70 

countries, and has been licensed for more than 30 years. More than 430 million doses have 

been distributed globally. Stamaril® vaccine is supplied as a vial of lyophilized powder and a 

syringe prefilled with diluent. 

CDC staff collaborated with Sanofi Pasteur to publish this report on the YF fever vaccine 

shortage in the MMWR, appeared online on April 28, 2017. It reviews the events leading up to 

the shortage, the collective efforts to provide a continuous supply of YF vaccine in the US 

despite the shortage, and the process of selecting and certifying Stamaril® sites. 

Sanofi Pasteur is in the process of enrolling approximately 250 clinical sites to administer 

Stamaril® vaccine to patients under the EAP. Sanofi Pasteur sought to have Stamaril® vaccine 

available at the highest volume clinical sites in the country because they would likely be the best 

equipped and staffed to handle many patients seeking vaccination. Therefore, sites where 

more than 250 doses were ordered in 2016 were asked to participate in the EAP. In addition, 

multi-site organizations that collectively ordered at least 250 doses in 2016 were offered a single 

site. Lower volume sites were added, especially in states and territories that otherwise would 

have been without a site based on the high-volume requirement. All 50 states; Washington, 

DC; and territories are covered. Site personnel are required to follow the EAP protocol, undergo 

training, obtain informed consent from vaccinees or parents if the recipient is aged <18 years, 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

track use of the vaccine, and report AEs. HCPs in clinics not participating have been notified to 

direct their patients to Stamaril® sites listed on the CDC website as shown: 

wwwnc.cdc.gov/travel/page/search-for-stamaril-clinics 

As of June 15th, 250 sites have confirmed their interest in participation. Of these, 207 sites have 

signed the protocol agreement. The remaining 43 sites are waiting for their internal 

management approval or IRB approval. Training has been completed by 199 sites, 175 sites 

have IRB approval, and 128 sites have ordered about 13,000 doses so far. Of the originally 

invited sites, 17 have declined participation. They are mutually exclusive of the 250 sites who 

have confirmed their participation. 

In summary, Sanofi Pasteur expects to stock-out of YF-VAX® in early July 2017. Stamaril® 

vaccine is now being distributed in the US under an expanded access IND that was approved 

by the FDA. Sanofi Pasteur is in the process of enrolling 250 sites and many are up and 

running. As of June 15th, 250 sites have confirmed their interest in participating, 199 sites are 

trained, and 128 have Stamaril® in their refrigerators for their incoming patients. The CDC YF 

website with the URL shown earlier is updated regularly with Stamaril® sites as they are 

approved and trained. Sanofi Pasteur will supply Stamaril® vaccine to the EAP-certified sites 

until the new production of YF-VAX® becomes available in mid-2018. 

Review of Current ACIP Recommendations for YF 

Vaccine and EAP Program Protocol Criteria for Stamaril® 

J. Erin Staples, MD, PhD

Arboviral Diseases Branch 

Division of Vector-borne Diseases 

Dr. Staples indicated that the objective of this session was to highlight the differences between 

current ACIP recommendations and the EAP IND protocol for Stamaril® for ACIP’s awareness. 

The current ACIP recommendations were published in 2010 and recommend the use of YF 

vaccine for persons aged ≥9 months who are traveling to or living in areas at risk for YF virus

transmission. Because of rare but serious AEs, healthcare providers should vaccinate only 

persons at risk for exposure to YF virus or who require proof of vaccination for entry. To 

minimize risk for SAE, healthcare providers should observe contraindications and consider 

precautions to vaccination before administering this live-attenuated viral vaccine. 

During the period while YF-VAX® is unavailable in the US, Stamaril® will be available only at 

selected clinics through an IRB-approved protocol. Persons needing vaccination will be 

screened for inclusion and exclusion criteria. Consent and, when applicable, assent will be 

obtained prior to administering Stamaril®. Since Stamaril® has been available for decades 

outside of the US and has a safety profile similar to YF-VAX®, AE possibly related to vaccination 

and SAE will be passively collected rather than solicited. Persons who receive vaccines in 

clinics that are administering Stamaril® are recommended to report AE to Sanofi Pasteur rather 

than VAERS. 

Overall, ACIP recommendations and the protocol criteria are very similar. Contraindications or 

exclusionary criteria under the ACIP recommendations and the EAP protocol criteria for 

receiving Stamaril® under the EAP protocol are very similar and include: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

 Allergy to vaccine components 

 Age <6 months 

 Symptomatic HIV or asymptomatic HIV with severe immune suppression 

 Thymus disorder 

 Primary immunodeficiencies 

 Malignant neoplasms 

 Transplantation 

 Immunosuppressive and immunomodulatory therapies 

Three precautions are also common to the ACIP recommendations and the EAP protocol, which 

include: 

 Pregnancy 

 Age ≥60 years

 Asymptomatic HIV with moderate immune suppression 

With these groups in particular, there will be counseling about the risk of the disease versus the 

risk of vaccination. The decision to vaccinate will be based on that. 

There are three differences between the current ACIP recommendations and the EAP protocol 

criteria. The first is persons with asymptomatic HIV infection with no evidence of immune 

suppression. Under the current ACIP recommendations, these individuals should receive the 

vaccine if they are at risk for coming in contact with YF virus or need it for proof for country 

entry. Under the current EAP protocol, however, they are listed as a precaution to vaccination. 

However, this should not necessarily impact the ability of persons with these conditions to 

receive the vaccine if they are truly at risk for acquiring the disease. Being 6 through 8 months 

of age is currently listed as a precaution under the ACIP recommendations, but this is an 

exclusionary criterion in the EAP protocol, meaning infants 6 through 8 months of age will not be 

able to receive Stamaril® while YF-VAX® is unavailable in the US. This is also true for 

breastfeeding, which is listed as a precaution in the ACIP recommendations for vaccination, but 

is an exclusionary criterion for EAP protocol unless breastfeeding can be discontinued for 14 

days following vaccination. Since infants 6 through 8 months of age and breastfeeding women 

could previously receive YF vaccine but will be excluded under the EAP protocol, these groups 

are advised to defer travel to risk areas if possible. If that is not possible, strict mosquito 

prevention measures should be used to lower their risk of disease. 

Discussion Points 

Dr. Schaffner (NFID) said he was under the impression that one dose of YF vaccine would be 

sufficient for lifetime protection, and wondered whether that should be a deferral criterion if 

someone did not really need it. 

Dr. Staples replied that in the current ACIP recommendation that was approved in 2015, the 

booster dose of YF vaccine previously recommended every 10 years has been removed for 

most individuals. The EAP protocol specifically addresses people who have not received the 

vaccine previously and are seeking the vaccine to protect themselves against the disease. 

Dr. Reingold requested clarity regarding whether if travel could not be avoided, those 6 through 

8 months of age and breastfeeding mothers would go unvaccinated and would rely strictly on 

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mosquito prevention measures. In many countries, they would not be allowed to enter without 

the yellow card showing that they had received YF vaccine. 

Dr. Staples clarified that they will not be able to receive the vaccine, so the alternative 

prevention measure is to use mosquito precaution. The preference is for them to defer travel if 

possible, but not everybody can. 

Regarding the selection of the Stamaril® sites, Dr. Hunter asked what percentage of travelers 

receive the recommended vaccine and whether non-adherent travelers are geographically 

concentrated. If so, it seems that the site selection process that emphasizes previous highutilization clinics potentially increases non-adherence by decreasing access. 

Dr. Greenberg responded that, indeed, it made sense for Sanofi Pasteur to seek out the highest 

volume centers because they traditionally and historically have ordered the greatest number of 

doses and were thought to be the most apt to handle individuals who might otherwise not have 

gone to that clinic from the surrounding area. The high-volume sites are spread across the 

country and an effort has been made to fill gaps with lower volume sites. 

Dr. Stapes added that some surveys have been conducted of travelers who present to travel 

clinics and are seeking advice about receiving vaccines, so that is already a selective 

population. The group that tends not to be aware of or potentially even will not want to accept 

the YF vaccine tends to be people who are originally from or are visiting friends and family in 

endemic areas. Understanding that the actual proportion of travelers who choose not to get the 

vaccine or never get the vaccine is challenging, CDC tried to conduct a pilot survey previously 

among airports that would get at the population who will be traveling to an at-risk area, but do 

not have good information about the overall acceptance among just anybody getting on an 

airplane. Geographic concentration is a challenging question, but many of the people 

potentially at-risk will be in high-population centers where there are several Stamaril® clinics. 

CDC is working very closely with Sanofi Pasteur as they phase into running out of YF-VAX® to 

understand if there are going to be critical gaps that need to be filled. 

Dr. Fryhofer (ACP) pointed out that while ACIP recommends a single lifetime dose of YF 

vaccine, some of the countries to which people may travel have not shifted to a single dose 

even though WHO has approved a single lifetime vaccination. She inquired as to whether any 

steps are being taken to help those countries understand that a single lifetime dose is sufficient 

so that patients who have had YF vaccine can travel. Given that a booster previously was 

required every 10 years, some patients may have received a YF vaccine years ago and may not 

have the documentation. She wondered whether there is anything their physician can do to 

renew that documentation and certification. 

Dr. Staples replied that WHO is working with countries that are still requiring booster doses. 

CDC tries to keep the most current information available on the travel website so that travelers 

can find out what countries are requiring. This is an ongoing discussion with certain countries 

about that regulation and the need to show proof of vaccination. People historically have lost 

their yellow cards and there is specific information under the International Heath Regulations 

(IHR) that a physician can reissue it, but it should be done with validation that the person 

received the vaccine. Preferably, the clinic that initially administered the card should replace the 

card. 

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Dr. Greenberg clarified that the EAP protocol is agnostic to prior doses. If the HCP at the 

Stamaril® site believes it is appropriate to immunize a person, they will follow the EAP protocol 

based on the inclusion/exclusion criteria. There is no exclusion for someone who previously 

received vaccine many years ago. They are to follow the ACIP recommendations, but 

ultimately, it is the HCP’s decision regarding whether to administer the vaccine and they will 

administer the vaccine under the EAP protocol. 

Dr. Moore indicated that in her state, two of the clinics that will be providing Stamaril® are public 

health departments. They have discussed the fact that this is a public service, and that because 

they are high-volume travel centers, it is important to make sure that vaccine is available in their 

area. Otherwise, people would be traveling hours to reach a clinic if they did not participate. 

Their hesitation had to do with the extra amount of time it would take to administer Stamaril® to 

a patient compared to a routine YF vaccination. Because they are high-volume, that extra time 

is amplified because they will be dealing with so many more patients. She wondered about how 

much extra time it takes to administer Stamaril® in terms of going through the EAP process. 

Dr. Greenberg responded that it really is a matter of the informed consent. It may take an extra 

20 minutes for the first patient, but by the time a clinic gets to patient 10 or 100, it should not 

take that long. The informed consent process is, of course, important but is the same 

counseling that the HCP should have provided when administering YF-VAX®. He does not 

believe it will be a burden. 

Dr. Thompson (NVAC) commented that according to the current WHO-UNICEF vaccine 

schedule, the countries that have YF vaccine in their schedules generally deliver one dose at 9 

months of age and after. Children 6 through 8 months of age would not be eligible even incountry. There would be an interesting discussion about whether those children could be 

excluded from country entry because they do not have proof of vaccine. She also wondered 

what the evidence was behind the exclusion of breastfeeding women in terms of whether there 

was a study showing that there is risk of transmitting the virus from the vaccine to the infant, or if 

it has not been studied and is precautionary. 

Dr. Staples responded that most countries do not require proof of vaccination for those under 9 

months of age, and some do not require it for those less than 12 months of age. Regarding the 

evidence related to breastfeeding, the first case of an infant who acquired vaccine-induced 

encephalitis occurred in 2010. The mother had been vaccinated, but the child had not been and 

was approximately 4 weeks old when they were exposed through breastfeeding. Subsequent to 

that, there were two additional case reports published out of Brazil of infants with encephalitis. 

They were less than 6 weeks of age when exposed. Because the vaccine is known to be 

neurotropic in very young infants, that is why it is contraindicated for children less than 6 months 

of age. That has led to the precautions and, in this case, the EAP protocol contraindication. 

Dr. Grogg (AOA) asked what vaccine someone would receive if they arrived at the border of 

Uganda and had not had YF vaccine. Where he is in the “Bible Belt,” there are mission teams 

leaving the country who need YF vaccine, so public education is necessary. One of the sites 

nationwide is the most expensive for travel site consultation and travel vaccines. A lot of 

patients cannot afford that particular site that was chosen throughout the US. 

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Regarding some of the sites being the most expensive, Dr. Greenberg said they are sensitive to 

that but had to make decisions months ago about how to set up this program of 250 sites. 

There is no way for them to know what a site charges for travel counseling or administration. 

Those decisions had to be made independent of that sort of information. However, Sanofi 

Pasteur is receptive and does want to collect that information. The imperative was to get the 

sites up and running, but he welcomes comments pertaining cost. 

In terms of receiving vaccines outside of the US, Dr. Staples indicated that short of YF-VAX® 

and a vaccine produced in China, the rest of the vaccines available in all other locations are 

WHO pre-qualified vaccines. Stamaril® is one of those. The other WHO pre-qualified 

manufactures include: 1) Bio-Manguinhos in Brazil, which makes a 17DD vaccine; 2) Institute 

Pasteur of Dakar in Senegal that produces vaccine, but is currently offline; and 3) Chumakov 

Institute in Russia. These vaccines are widely available throughout the rest of the world. In 

terms of public education, CDC has been engaged in a lot of outreach with various partners to 

keep information updated. Another MMWR will be published soon on the shortages and the 

implications of that. Additional outreach will be done with specific travel medicine clinics and 

state health departments to ensure that they are aware of the need to switch over to the 

Stamaril® protocol, which is allowing the US to continue to provide YF vaccine to at-risk 

travelers. 

Dr. Sun (FDA) acknowledged Sanofi Pasteur, CDC, and DoD for working to address the 

shortage issue. Unfortunately, this is a situation in which a vaccine has only one supplier and 

illustrates what can occur when there is disruption. 

Mumps 

Introduction 

Kelly L. Moore MD, MPH

Director, Tennessee Immunization Program

Chair, Mumps ACIP Work Group 

Dr. Moore reminded everyone that the objective for the Mumps WG is to evaluate and propose 

policy options to prevent or control mumps outbreaks in the US. The activities related to that 

are focused on: 1) Review the epidemiology of mumps in the 2-dose vaccine era, including the 

international experience; 2) Review available evidence on duration of immunity for mumps after 

2 doses of MMR and other risk factors for vaccine failure; 3) Review the available evidence on 

the benefit provided by a third dose of MMR for mumps outbreak control; and 4) Evaluate 

programmatic implications and the cost of various policy options for a third dose of MMR to 

prevent or control mumps outbreaks. 

The Mumps WG has been quite busy over the last few months, engaging in biweekly 

conference calls and a brief on-line survey to obtain feedback from members of the WG. The 

focus in the past few months has been on reviewing the literature and unpublished data on the 

following: 

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

 

Update on Mumps Epidemiology in the US for 2017 and Review of

Published Studies of 3rd Dose MMR for Mumps Outbreak Control 

In this presentation, Dr. Marin provided an update on mumps epidemiology in the US in 2017 

and presented the evidence reviewed by the WG concerning immune response to the 3rd dose 

of MMR vaccine, referred to hereafter as MMR3; published studies on use of MMR3 for mumps 

outbreak control; and safety of MMR3. Along with the next presentation, the information 

presented covers the evidence currently available on the use of MMR3. The WG deliberations 

and interpretation of the evidence on use of MMR3 are ongoing and will be presented during the 

October 2017 ACIP meeting. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

 Mumps epidemiology in the US in the 2-dose era 

 Immune response to mumps virus and mumps vaccination 

 Persistence of immune response after 2-dose vaccination 

 2-dose VE and risk factors for vaccine failure 

 Molecular epidemiology and antigenic differences between vaccine and circulating mumps 

strains 

 Immune response to a 3rd dose of MMR vaccine 

 Clinical studies after administration of a 3rd dose of MMR vaccine 

3rd dose for mumps outbreak control 

Safety of the 3rd dose 

 US military experience with mumps disease and vaccination 

Regarding the timeline, the goal for the June 2017 meeting was to update ACIP on mumps 

epidemiology in the US in 2017, and discuss the evidence reviewed by the WG concerning 

laboratory and clinical studies of the 3rd dose of MMR vaccine. During the October 2017 

meeting, the WG plans to summarize the evidence reviewed by the WG and present the WG’s 

interpretation of the evidence. During the February 2018 meeting, the WG will present 

additional evidence from ongoing studies (e.g., cost of various policy options), and will present 

the WG’s considerations and options in preparation for an ACIP vote. 

This session included two presentations: 1) an update on mumps epidemiology and review of 

studies of a 3rd dose of MMR vaccine; and 2) the effectiveness of the 3rd dose of MMR vaccine 

in a mumps outbreak in a highly vaccinated university population in Iowa in 2015-2016. 

Mona Marin, MD 

Division of Viral Diseases 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

This figure, presented during the February 2017 ACIP meeting, shows the reported mumps 

cases in the US during the vaccine era: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Overall, since vaccine program introduction, reported mumps cases declined by approximately 

99%. However, several large mumps outbreaks have been reported from 2006 through 2016 

resulting in an increased number of cases in certain years, as shown in the inset. 

Examining more closely the most recent 6 years, since 2011 there has been an increasing trend 

in cases and outbreaks as reflected by a number of epidemiologic characteristics (case count, 

incidence, number of outbreak cases, proportion of outbreak-related cases among all reported 

cases, and number of jurisdictions reporting outbreak cases), with 2016 having the highest 

number of cases and jurisdictions with outbreak cases reported, not only within the past 6 years, 

but also within the past decade. 

Comparing 2017 with 2016, preliminary data through the end of May suggest that 2017 appears 

on track with the trend seen in 2016 for the same characteristics. In 2017, the case count is 

already at 3300, half the number of cases reported in 2016, incidence is lower than in 2016 but 

higher than in any other year before 2016, outbreak cases represent two-thirds of all cases, and 

the number of jurisdictions with outbreak cases is the same as in 2016. It is important to note 

that a large mumps outbreak with more than 3500 cases in Arkansas, primarily among the 

Marshallese population, a close-knit community in Northwest Arkansas, accounted for about 

2400 of the cases reported in 2016 and approximately 500 of the cases reported in 2017. 

However, even if the cases from this large outbreak were excluded, 2016 still continues to have 

the highest incidence and number of cases compared to previous years and 2017 has a similar 

trend. 

In 2017, the highest incidence continues to be in the 18 to 22 age group, similar to previous 

years. The median age of patients with mumps is 23 years and 73% of those with known 

number of doses have 2 or more doses of MMR vaccine. To date in 2017, CDC is aware of at 

least 40 outbreaks, with about half (19) occurring in university settings and one third (14) 

community-wide, of which 8 have been in Marshallese communities which spread from the 

Arkansas outbreak. Other close contact settings also experienced outbreaks in 2017, including 

a military facility. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Several factors have been hypothesized to contribute to the increasing number of mumps 

outbreaks. As discussed during the last ACIP meeting, the vaccine effectiveness for 2 doses is 

estimated to be 88%, and therefore cases can still occur among vaccinated persons. Second, 

waning of vaccine-induced immunity, especially in the era of low disease incidence and 

absence of boosting from wild disease, has been demonstrated. Serologic evidence has shown 

that neutralizing antibody titers do decline over time; however, there are no established 

correlates of protection. Therefore, the implications of declining titers remain uncertain. 

Epidemiologic evidence also suggests waning of immunity with decreased VE and increased 

odds of contracting disease with time since vaccination, but evidence is still limited. Waning of 

immunity, however, does not explain the typically focal nature of outbreaks. Increased force of 

infection from intense exposure settings, such as college campuses or close-knit communities, 

where there is high population density and contact rates that facilitate transmission is frequently 

postulated as a risk factor for current mumps outbreaks. Concern also was raised that antigenic 

differences between the circulating and vaccine strains may lead to mumps vaccine-induced 

immunity being less effective against other strains. To date, studies showed that all sera from 

vaccinated children neutralized diverse mumps virus strains. However, the antibody levels 

against non-vaccine strains are lower than the levels against the vaccine strain and these 

differences may become more important over time. Lastly, the WG acknowledges the 

uncertainty and that there may be other factors not identified or measured. 

Because waning of immunity after 2 doses of MMR vaccine is one of the hypotheses considered 

to explain the current mumps epidemiology, there is increased interest regarding the effect of 

the 3rd dose of MMR vaccine. Dr. Marin summarized the evidence related to the MMR3 

reviewed by the WG, beginning with the laboratory evidence which describes the antibody 

response to MMR3. 

Most of the available evidence on antibody response after MMR3 comes from the study by 

Parker Fiebelkorn et al that included a cohort of 656 young adults who received care at the 

Marshfield Clinic, a large HMO in rural Wisconsin. The median age at MMR3 was 21 years and 

the mean years since the second dose of MMR (or MMR2) was 15. This study examined GMTs 

for neutralizing antibody against the Jeryl Lynn vaccine virus and the proportion of participants 

seronegative or with low titers pre-MMR3 (defined as baseline), at 1 month and 1 year after 

MMR3. Compared with baseline, GMTs were significantly higher, albeit modestly, at 1 month 

and 1 year after MMR3. However, only 6% of subjects had a 4-fold rise or more from baseline 

to 1 month after MMR3 and 2% had a 4-fold rise or more from baseline to 1 year. At baseline, 

very few subjects had low or negative titers (7%). One year after MMR3 this proportion declined 

to 3%. 

One other observation from this study was that post-vaccination titers were highly correlated 

with baseline titers, meaning that subjects with lower baseline titers were more likely to have 

lower titers at 1 month and 1 year after MMR3; whereas, subjects with higher baseline titers 

were more likely to have higher titers at 1 month and 1 year. These results were obtained when 

testing for whole virus neutralizing antibodies, but nearly identical findings were observed when 

antibodies to mumps-specific proteins were studied. Altogether, these findings may indicate an 

inherent trajectory for mumps titers or a set point for individual antibody levels that is minimally 

affected by MMR3 [Parker Fiebelkorn et al. Open Forum Infect Dis, 2014; unpublished data; 

Don Latner, PhD, [CDC] presentation to the Work Group, May 11, 2017]. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

In a much smaller study of 17 subjects aged 19 through 30 years of age who were seronegative 

for mumps despite 2 documented doses of MMR and received MMR3, all but one subject 

developed an IgG response when tested 2 to 3 months after MMR3. The response was rapid, 

observed at 7 to 10 days, with peak antibody activity present sometime between 7 to 10 days 

and 2 to 3 months. Antibody kinetics 2 to 3 months after MMR3 was not evaluated in this study 

[Date et al. J Infect Dis, 2008]. 

To date, the laboratory evidence on MMR3 use remains limited. In addition to the lack of a 

correlate of protection against which to assess the changes in antibody titers, in the studies 

conducted until now, the qualitative aspects of the immune response (antibody avidity, B-cell 

memory) or the strain-specific immune responses were not assessed. 

In terms of the epidemiologic evidence related to the impact of MMR3 for mumps outbreak 

control, the WG is aware there have been outbreaks in which MMR3 was not administered as 

part of outbreak control and only standard outbreak control measures were implemented. All of 

these data will be considered as part of the WG’s deliberations for use of MMR3 and will be 

presented in October. This session focused on the evidence related to impact of MMR3 use. 

Although several states have implemented MMR3 vaccination campaigns to control mumps 

outbreaks, there are only three studies that formally assessed the impact of MMR3 for outbreak 

control. Two were school-based, which Dr. Marin described. The other was conducted in a 

university setting and is described in the next presentation by Dr. Cardemil. 

Third dose intervention campaigns were conducted in Orange County, New York where 81% of 

eligible students aged 11 through 17 years were vaccinated with MMR31 and in Guam where 

33% of eligible students aged 9 through 14 yeas received MMR32. In both studies, the attack 

rates were lower among MMR3 recipients than among MMR2 recipients. However, the results 

were not statistically significantly different. The small number of cases post-MMR3 intervention 

limited the power of the studies to detect a difference if one truly existed. In the Orange County 

study, the incremental VE of MMR3 was calculated as 88% although there was a large 

confidence interval that included zero. Additionally, in Orange County, the attack rates declined 

post-intervention among all age groups in the community, with the highest and significant 

decline among the age group targeted by vaccination in the schools, 11- through 17-year-olds 

followed by the 5- through 10-year-olds. While the attack rates declined after MMR3 

administration, the MMR3 intervention occurred after the peak of each outbreak and the 

possibility of the declines being unrelated to the intervention could not be excluded [

1Ogbuanu 

IU et al. Pediatrics 2012; 2 Nelson GE et al. Pediatr Infect Dis J 2013]. 

The safety data on MMR3 vaccine were collected as part of the same study that was conducted 

at the Marshfield Clinic to assess immune response to MMR3. A total of 662 young adults, with 

a median age of 21 years, received MMR3 and completed safety diaries. Data on 14 solicited 

symptoms were collected 2 weeks before and 4 weeks after MMR3. Significantly higher rates of 

AEs after MMR3 were demonstrated for 4 symptoms: headache, joint pain, diarrhea, and 

swollen glands. Overall, the proportion of subjects who reported these symptoms was low and 

the duration of symptoms was short. No SAEs requiring medical attention occurred. MMR3 

appears safe and is well-tolerated in a young adult population [Unpublished data, Janell Routh, 

MD (CDC) presentation to the Work Group, May 11, 2017]. 

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Effectiveness of a 3rd MMR Dose During a Mumps Outbreak

In a Highly Vaccinated University Population, 2015-2016 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

In terms of knowledge gaps, planned and ongoing studies to inform third dose deliberations 

include the following: 

 Cost of public health response to contain a mumps outbreak in a university setting, including 

the MMR3 intervention at the University of Iowa in 2015-2016 and active pursuit of other 

settings 

 Cost effectiveness analyses of various policy options for MMR3 to prevent or control mumps 

outbreaks 

 Modeling of the impact of MMR3 on burden of mumps during a mumps outbreak 

 Genotyping G-strain specific immune response to MMR3 and MMR2 >10 years 

 More complete national data on epidemiology of and response to mumps outbreaks 

In closing, Dr. Marin asked ACIP what additional 3rd dose data would be helpful to inform their 

deliberations. 

Cristina Cardemil, MD, MPH 

Division of Viral Diseases 

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention 

Dr. Cardemil presented the investigation into the effectiveness of a 3rd dose of MMR used 

during a mumps outbreak in a highly vaccinated student population in Iowa. In 2015, a mumps 

outbreak was reported from Johnson County, Iowa. Most cases were in the University of Iowa, 

a setting with over 22,000 undergraduates and a 2-dose MMR requirement since 2012, with 

provider-verified doses uploaded to their electronic database. Health officials decided to 

implement a widespread 3rd dose campaign in the university, making this outbreak a good 

opportunity to evaluate the effectiveness of the 3rd dose. 

There were 453 mumps cases reported during the outbreak, with 300 of these confirmed. The 

vaccination campaign was held in 8 clinics over six days from November 10-19, 2015 and was 

university-wide. Vaccine was offered free of charge for students under 25 years of age, during 

the daytime and evening hours, and at centralized locations (student union, large dormitories, 

large classroom buildings, sports medicine center). Most cases in the county, about 2/3, were 

in University of Iowa students. 

The primary objective of this study was to estimate the VE of 3 versus 2 doses of MMR against 

mumps. Secondary objectives included assessing for waning immunity, as well as estimating 

the VE of 2 versus 0 doses. Case status was determined from the outbreak investigation, which 

was conducted as a separate investigation in parallel to this analysis, based on the CSTE case 

definition that included probable and confirmed mumps cases. The outbreak period was 

defined as starting on the first day of the academic fall semester and ending on the last day of 

the spring semester. University vaccination records were merged with student registration 

records, which included student demographic information, and vaccine records were verified as 

mentioned previously by a medically-trained provider who uploaded valid doses to the electronic 

database. A subset of vaccine dates was verified manually, including for students who did not 

have 2 MMR doses on file, for closely spaced vaccines and for implausible dates. Exemption 

status also was reviewed, if applicable. Students were included in the analysis if they were ageeligible for the MMR vaccination campaign, meaning they were 18 through 24 years of age by 

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Fisher’s exact test was used to compare unadjusted attack rates, and multivariable Cox 

proportional hazards models were developed to determine risk-adjusted VE. The variables 

examined by case and vaccine status included: age, gender, race, undergraduate status, study 

program, receipt of campaign vaccination, years since MMR administration, age at vaccination. 

For the primary analysis of 3 versus 2 doses, the dataset was limited to students who had 

received 2 doses by the start of the outbreak period. A subset of these students received a 3rd 

dose during the outbreak. Incremental VE was defined as the additional reduction in mumps 

disease experienced by 3-dose recipients compared to 2-dose recipients. The 3rd dose receipt 

was treated as a time-varying covariate, and 4 models were utilized, each with a different postvaccination timeframe based on the expected immune response at 7, 14, 21 and 28 days postvaccination. To evaluate the VE of 2 versus 0 doses, a separate model was created with a 

shorter timeframe for analysis from the start of the outbreak period to just prior to the date of the 

first campaign, to avoid the influence of any change in exposure and risk during and after the 

campaign. Relative risk was estimated using the hazard ratio, and VE was calculated as 1 

minus the relative risk times 100. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

the date of the first campaign, and enrolled full time in the 2015-2016 academic year. Students 

with positive titers in lieu of vaccination records or records that were not required by the 

university (prior military, part-time) were excluded from analysis. 

Regarding the time-varying covariate in this analysis, students analyzed entered the outbreak 

period with 2 doses. During the analysis period, 4 distinct possibilities existed. In the first 

scenario, a student enters the outbreak period with 2 doses, did not develop mumps or receive 

a 3rd dose and their person-time continued until the end of the outbreak period. In the second 

scenario, a student enters the outbreak period with 2 doses, develops mumps symptoms, and 

their person-time ends at the date of symptom onset. In the third scenario, a student enters with 

2 doses, receives a 3rd dose, and after the specified time-period post-vaccination, continues 

their person-time in the analysis as a 3rd dose recipient. The final scenario is similar to the 

previous, but a 3-dose recipient develops mumps symptoms, so their person-time ends before 

the end of the outbreak period. Four models were developed to specify the start of 

immunological protection beginning at 7, 14, 21, or 28 days post-vaccination. Previous studies 

used 21 days to cover the average mumps incubation period of 16 to 18 days. However, the 

range for the incubation period is up to 25 days, and it may take a few weeks to develop an 

immune response post-vaccination. They also wanted to examine a slightly shorter period to 

allow for a more rapid anamnestic response. 

Regarding the results, of those who received a first dose of MMR, 83% were administered at 12 

through 23 months of age. Of those who received a 2nd dose of MMR, 82% were administered 

at 4 through 6 years of age, aligning with ACIP recommendations at the time of administration. 

A second wave of administrations for the 1st and 2nd doses were seen in the university age 

group, close to when the majority of 3rd doses were administered. In terms of the years since 

the 2nd dose of MMR by age at time of administration, the distribution of the variable years since 

receipt of MMR2 was clustered in 2 periods (administration at 4 through 6 years of age as per 

CDC recommendations, and just prior to and during university enrollment at 17 through 24 

years of age), with a few students falling outside of the bimodal distribution. Years since receipt 

of MMR2 was examined as a continuous variable, a dichotomous variable (<13 years and ≥13 

years since receipt of MMR2), and categorical variable (0-2 years, 3-12 years, 13-15 years, and 

16-24 years since receipt of MMR2). Regardless of the variable type used in the model, the 

result was statistically significant for the primary analysis. Because the data are not linear, yet 

there is an increase in risk of disease with years since MMR2 administration, the results are 

reported using the categorical variable in order to demonstrate this stepwise increase in risk. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

For the 2 versus 0 doses analysis, because of the smaller sample size of the 0-dose group, this 

4-level stratification was not possible and the results are reported using the dichotomous 

variable. 

Prior to the outbreak, 98.1% of students had 2 or more MMR doses, and 2.0% had 3 or more 

doses. At the end of the outbreak, 99.5% of students had 2 or more doses and 25.3% had 3 or 

more doses. The attack rate is inversely proportional to the number of MMR doses received, 

with the highest attack rate in the unvaccinated. The overall attack rate was 12.6 per 1,000 

population. More distant receipt of MMR2 was associated with a higher attack rate. Both of 

these trends in attack rates were statistically significant. At the start of the outbreak, 19,705 

students had 2 doses. Of these, 4778 (24%) students received a 3rd dose. Of the 4778 3rd 

doses that were administered during the outbreak period, 94% were administered during the fall 

campaign.

In the model which includes an immune response window of 28 days, students who received 

the 3rd MMR dose had a hazard ratio of 0.22. In other words, receipt of the 3rd dose was 

associated with lower risk of mumps disease as compared to 2-dose recipients. More distant 

receipt of MMR2 of 13 to 24 years prior to the outbreak was associated with higher risk of being 

a case. That is, students who received the 2nd dose 13 or more years prior to the outbreak had 

9- to 14-fold increased risk of being a case as compared to students who received the 2nd dose 

more recently. The other 3 models with time period post-vaccinations of 7, 14 and 21 had very 

similar results. The main difference was in the risk of being a case by receipt of 3rd dose. The 

hazard ratios ranged from 0.22-0.40, indicating a reduction in risk of being a case with receipt of 

a 3rd dose. 

The incremental VE of the 3rd versus 2nd MMR dose ranged from 60.2% at 7 days postvaccination up to 78.2% at 28 days post-vaccination. The finding of an incremental VE of 

60.2% at 7 days post-vaccination suggests there is benefit shortly after the campaign due to the 

anamnestic immune response. However, given the long incubation period for mumps of up to 

25 days and the time needed to develop the immune response, an incremental VE of 78% at 28 

days post-vaccination might be a better representation of the full effect of the 3rd dose. The one 

prior published study, which was mentioned by Dr. Marin, reported an incremental VE of the 3rd 

dose with a comparable point estimate of 88% using a 21-day post-vaccination window, but had 

wide confidence intervals that crossed zero. The probability of remaining mumps-free was 

higher with receipt of the 3rd MMR dose for all 4 post-vaccination timeframes examined. All 

models controlled for years since 2nd MMR dose. 

VE of 2 versus 0 MMR doses differed by years since the second dose. VE was 89.4% (95% CI 

-2, 99) for students who received the second dose more recently (defined as less than 13 years 

prior to the outbreak), and 31.8% (95% CI -389, 91) for students who received the second dose 

13 years or greater prior to the outbreak (past). These estimates had wide confidence intervals, 

particularly the past estimate, but when compared head-to-head, the difference between these 2 

estimates was statistically significant. 

There are limitations to this investigation. Perhaps most importantly, this was an observational 

study with possible unmeasured factors that could have led to over- or underestimation of VE. 

For example, it is possible that there was differential receipt of the 3rd dose based on risk. 

There were anecdotal reports that some students sought receipt of the MMR vaccine after a 

friend or roommate was diagnosed with mumps, or were urged by a parent to obtain the 

vaccine. If 3rd dose recipients were more frequently exposed to mumps than students who did 

not receive a 3rd dose, the estimates of the incremental VE of the 3rd dose would be 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

underestimated. To address the possibility of other unmeasured factors affecting VE, such as 

differential intensity among different ages, sensitivity analyses were conducted with time since 

MMR2 examined as a continuous and dichotomous variable and in a narrower age group. The 

effect of time since the second dose was maintained in these analyses. Second, because 

immunization status during the outbreak period was dynamic, and the student population was 

highly vaccinated with a small number of 0-dose students, the 2 vs 0 doses VE estimates had 

wide confidence intervals. The authors chose not to exclude any 0-dosers from the 2 versus 0 

VE estimates, even though a large proportion of them received 1 or 2 doses during the outbreak 

period, and were unable to control for the receipt of any outbreak dose in this group, because 

the standard error for the covariate was very large, making the regression model unstable. 

However, even without this covariate, the estimates were very similar, giving the authors 

confidence that if anything, these estimates are more conservative, meaning that VE could be 

underestimated. 

In conclusion, there are three main take home points from this investigation. First, in this highly 

vaccinated university setting, the vast majority of students had 2 or more MMR doses. 

However, this was not sufficient to prevent an outbreak in this close contact setting. Second, 

the 3rd dose of MMR that was administered as part of the university-wide campaign free of 

charge to all age eligible students was associated with a significantly decreased risk of mumps. 

The magnitude of that reduction is shown in the incremental VE estimate, which ranged from 

60% to 78%. Third, waning immunity likely played a role in outbreak propagation, and the 

investigation revealed 3 pieces of evidence to support this. Cases were more likely to have 

received the second dose 13 or more years prior to the outbreak. Attack rates correlated 

significantly with time since the second dose, and the VE of 2 versus 0 doses was lower with 

more distant receipt of the second dose. 

There are some considerations worth mentioning in the interpretation of the findings from this 

investigation. First, approximately 1 in 4 targeted students received the 3rd dose, and while that 

at first might appear to be a small proportion, it is within the range of previous additional dose 

interventions in similar settings in which anywhere from 16% to 81% of the target population 

was reached. Second, a campaign of this magnitude is no small achievement. It is no secret 

that it can be very time- and resource-intensive. While feasible in some settings, this might not 

be possible in others. Third, it is likely that other factors contributed to outbreak control, other 

than the use of the 3rd dose. Iowa is no stranger to mumps, having lived through the 2006 

resurgence. This was a highly organized outbreak response with very strong participation and 

frequent communication between the public health officials at the state, local, and university 

levels. The student health center, fairly early in the outbreak, determined the need for 

standardized protocols for case identification, testing, and isolation recommendations. The 

student body was made aware of the outbreak by university officials through various modalities, 

and results from the outbreak investigation indicated very high self-reported adherence to 

isolation recommendations. Finally, and perhaps most importantly, the pre-existing 2-dose 

MMR requirement for the next semester’s registration, without which this outbreak would have 

undoubtedly been much larger. 

Discussion Points 

Ms. Pellegrini inquired as to where the authors would have considered the peak of the Johnson 

County, Iowa outbreak to have occurred. It appeared that the vaccination campaign took place 

only among university students and about a month afterward there was a significant decline in 

the cases, which then dwindled over the next semester. 

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Dr. Cardemil replied that there were several peaks throughout this outbreak, but she was 

referring to the peak that had the highest number of cases for university students and the 

outbreak as a whole. 

Dr. Patel (SME) added that the data in the study suggest that vaccination controlled the 

outbreak. CDC, the university, and the health department feel that in terms of control 

measures, vaccination response did help control this outbreak. 

Dr. Stephens asked Dr. Cardemil to comment on genotype and whether there was any evidence 

of genotype drift, and whether antibody was assessed in the Iowa study. 

Dr. Cardemil replied that they did not have the opportunity to examine serologic data in this 

investigation. 

Dr. Rota (SME) added that CDC has been monitoring the sequences of most strains that have 

been circulating in the US since 2006, and there has been remarkably little sequence variation 

in the small region CDC is sequencing. The genotype has been consistently detected through 

the last several years. CDC is beginning to introduce next-generation sequencing (NGS) 

methods in order to develop WGS. He expects that there probably will be a large number of 

WGS available very soon. But at this time, based on what they are looking at in a small 

window, there are only 1 or 2 nucleotide changes in the region used to determine the genotype. 

Dr. Patel (SME) clarified that no serologic studies were conducted with this outbreak. 

Dr. Walter inquired as to the timing of the cases amongst those who had three doses relative to 

vaccination. 

Dr. Cardemil replied that there were a number of 3-dose vaccine failures spread throughout the 

outbreak period. Most of the 3rd doses in this outbreak investigation were given during the 

vaccination campaign, so the majority of the 3rd dose failures followed that. 

Dr. Lee inquired about secular trend as a potential confounder and whether another sensitivity 

analysis was or could be done to compare the 2-dose versus 3-dose recipients starting from the 

time of the initiation of the MMR 3rd dose vaccination campaign to determine whether the results 

were similar. 

Dr. Cardemil responded that they did consider several potential other methods for analysis, 

taking into consideration how data such as these had been analyzed in previous outbreak 

settings with a 3rd dose campaign and ultimately decided on the use of a time-varying covariate 

because it allowed for underlying change in the hazard over time. What was challenging in this 

type of analysis, and in many of these similar analyses, is that the vaccination campaign does 

not occur all on one date. This campaign started on November 10th and through a series of 

different clinics, there was administration to a number of students through November 19th. If 

everyone was vaccinated on the same day, they could have chosen a 3-week period postintervention and then looked before and after. That has been used previously, but in this 

scenario, due to the fluid nature of how the outbreak progressed as well as the vaccination 

campaign, the authors thought this method allowed for a much more granular look at the data. 

It also allowed the authors to look at the immune response post-vaccination, not just following 

the campaign which occurred over a number of days, but also for those students who received 

3rd doses before and after the campaign. 

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Dr. Reingold asked whether there were enough outbreaks to look ecologically in terms of 

duration of outbreaks or attack rates in outbreaks where there has been response with 

vaccination versus those in which there has not. That might be more interesting to assess than 

what occurred in the context of one outbreak. 

Dr. Patel (SME) replied that CDC plans to model this particular outbreak to assess what the 

impact would have been if there was not an implementation of a 3rd dose, as well as varying 

coverage rates of the 3rd dose. As Dr. Marin mentioned earlier, the WG is deliberating a number 

of outbreaks, such as the New York City outbreak which did not implement a 3rd dose and 

looking at that ecologically. Also as Dr. Marin mentioned, a data call will be going out to the 

states to understand a couple of epidemiologic factors (settings in which outbreaks occurred, 

age groups, interventions implemented), because not all states are doing the same thing. 

Hopefully, the WG will have more information for ACIP during the October 2017 meeting. 

Dr. Atmar pointed out that the vaccine intervention occurred at the peak or back end of the 

outbreak. One issue he was struggling with was that those persons who received a 3rd dose 

and were included may have had a lower risk of infection. The type of analysis Dr. Lee 

proposed could address that. Even though it might be difficult, it would be reassuring if the 2-

dose people after the end of the campaign plus some period for an immune response to have 

occurred still had higher risk than the 3-dose recipients. It may not be the primary analysis, but 

it would be a reassuring secondary analysis. 

Dr. Cardemil responded that the authors did a number of sensitivity analyses with those specific 

questions in mind. One thing that is important to consider in this type of analysis is that the 

underlying risk is allowed to change over time when using the Cox regression. However, a 

number of other analyses were done. One thing they did was exclude cases prior to the 

campaign and analyze the data starting on the first date of the campaign and going forward. 

That basically reduces the sample size of the number of cases being kept in the analysis, 

keeping all of the students in the analysis who had 2 doses at the start of the outbreak. In that 

analysis, all of the incremental VE estimates for all 4 models continued to be statistically 

significant. 

Dr. Plotkin (Vaccine Consultant) said he did not doubt that the trouble with the Jeryl Lynn strain 

is the poor B-cell memory that has been demonstrated. That is pretty clear as far as why there 

is waning. However, he pointed out that there were a lot of specific data that were important 

about strains. The Rubini strain was promoted as a vaccine, but had zero efficacy. The point is 

that in contrast to measles and rubella, little is known about the protective factors that generate 

protection from an attenuated mumps strain. They do differ quite a lot and are not like measles 

and rubella. He suggested asking countries that use other strains, such as Hoshino and Urabe, 

what their experience is with persistence of protection and epidemics in those who have 

received the vaccine. That might suggest a way of dealing with this situation. Of course, the 

advantage of Jeryl Lynn is its safety. Mumps is a Paramyxovirus and has many differences 

from other viruses. Dr. Plotkin’s counsel is that a third dose may be useful to deal with an 

emergency, but they need to delve deeper into this problem. 

Dr. Messonnier responded that CDC has thought about countries other than the US. 

Unfortunately, few of them have as high coverage as the US. CDC plans to contact other 

countries, and will be presenting some of those data during a future ACIP meeting. 

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Regarding re-immunization, Dr. Marin said she was not aware of other studies. One of the 

questions that arose in the WG discussion regarded whether there is replication following the 3rd 

dose or if it just boosts the two. Other than the data she presented, there are no other data. 

The fold rise was low. Very few people had a 4-fold rise, but it is not clear what that means. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Dr. Schaffner (NFID) noted that in the pre-vaccine era, it was known that mumps often infected 

individuals asymptomatically. In fact, only about a third of people developed symptoms. He 

wondered whether anyone had conducted a study of asymptomatic transmission in the setting 

of an immunized population. Regarding re-immunization, he wondered whether anyone had 

studied the dynamics of what happens to the inoculated virus dose in terms of whether it has a 

chance to replicate, and how much, in the recipient who has already been previously 

immunized. He also suggested that perhaps one of the interventions might be to encourage 

countries such as those in Europe and perhaps the Philippines where these viruses may come 

from, to immunize their children so that there is less mumps in the US as well. 

Dr. Patel (SME) replied that CDC worked with Washington to conduct an asymptomatic 

shedding study during an outbreak they experienced earlier in 2017, and found zero shedding 

among the individuals who were in a fraternity/sorority type of setting. They only looked at 

shedding and did not assess serologic response in this particular study. 

Dr. Hunter said he was struggling with the VE of 60% at 1 week after the 3rd dose, which 

seemed high to him and made him wonder whether the VE in the 25% of students who received 

the 3rd dose had to do with other behaviors, such as not sharing saliva, that would lead to a 

limitation in the study being an overestimate because of those reasons. 

Dr. Cardemil noted that one thing that would be useful in future investigations whenever 

possible, which was considered at length when designing this particular study, would be to 

survey the members of the student body who were and were not vaccinated to determine 

exposures and behaviors for each of the students to examine whether there were differences in 

the 2- versus 3-dose recipients. When the authors came into this investigation, it was several 

months post the peak of the outbreak as well as post the vaccination campaign. In speaking 

with the university officials and looking back at their experiences in surveys of the study body, 

the authors anticipated that a very low response rate would be achieved. By the time the survey 

would have been done, it essentially would have been conducted a year post-outbreak. This 

raised issues such as recall bias. Going forward, it would be informative and instructive to be 

able to conduct that type of survey from the outset. In terms of interpreting the finding of a 

response post-vaccination, there are limited data from prior studies. The one Dr. Marin 

presented showed evidence of seroconversion at 7 to 10 days post-MMR3. It would be very 

instructive to have more to support that. 

Dr. Zahn (NACCHO) recognized that having a vaccine campaign at that point helped, but the 

question from the local public health perspective will regard what to do thereafter. If there are 

only 10 cases, a large campaign may not be sensible. However, if a local small university has 

only 10 cases, it will still be in the newspaper and the decision will have to be made about 

whether to wait until there are a much larger number of cases before moving forward. 

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Dr. Decker (Sanofi Pasteur) said he shared the authors’ conviction that the vaccination 

campaign and 3rd dose must have helped. Looking at the epi-curve, it seems that the ability to 

trust the analysis is shaken by an event over which they had no control and which is almost 

impossible to model. There is a full generation of cases after the vaccination campaign, most of 

whom went home for a month. When they returned, the outbreak was over. It is not clear how 

to model that. In addition, there are some numerators during Christmas break, so someone 

stayed. He did not know what the denominator was or if the attack rate was actually higher 

during the Christmas break when 90% of the students went home and 10% stayed behind and 

they all got mumps or not. 

Dr. Messonnier responded that they could speak for an entire hour about this paper, and CDC 

staff would certainly be happy to stay around after the break for questions. However, she 

redirected everyone to the initial presentation and what the WG was really looking for during this 

session from ACIP members, which pertained to what else ACIP members would like to see 

that would help them make a decision. 

Dr. Lee said she thought this was a very answerable question and that they have the data in 

hand. She suggested a matched cohort design matching on the date of vaccination to those 

who only received 2 doses. The 3rd dose campaign appears to have been effective, but this 

would provide an additional level of certainty around the information. She recognized that they 

would lose power, but that is why this would be helpful as a secondary analysis. 

Understanding that a vote is anticipated in February 2018, Dr. Kimberlin (AAP) inquired as to 

what additional data are anticipated in October 2017 that would delay making a 

recommendation as hundreds of thousands of college students are preparing to go off to 

college, or if this could be done sooner. 

Dr. Moore responded that the WG is working as quickly as they can. Through the last few 

months, they have heard the bulk of the data available now. In the coming months, they plan to 

further deliberate what they feel about those data and what else might be available to them in 

the near-term that could help make a clear decision. What has been presented to ACIP are a 

few pieces of the puzzle, but some pieces are still missing. She personally would like to 

understand the quality of the antibodies that are produced by a 3rd dose rather than just a 

quantitative minor bump that is shifting the curve. It is not clear whether that shift represents 

higher quality antibodies that might have greater avidity for the G strain as opposed to the A 

strain. Those are questions for which there are no answers yet. The WG is interested in 

making a decision as quickly as possible, but it has to be based on evidence not on speculation. 

Some of the information the WG hopes for will be done over the summer, such as the cost 

modeling. She also wants to understand what is occurring in the natural experiments that are 

occurring, and the data requests to the states that was mentioned. Every state is operating 

somewhat differently. Tennessee has some experience as do others from which they may be 

able to glean some additional information beyond the results presented that could help support 

a decision one way or the other. However, the WG generally likes to be able to present 

information to ACIP a session before a vote without having a lot of new critical information 

presented at the time of the vote. If there is a way to parse out some piece in October that the 

WG feels is relevant, they will push to do that. At this point, they are awaiting more information 

to support their decision. 

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Dr. Kimberlin (AAP) said with ongoing epidemic outbreaks, this could be the type of 

circumstance that would support the idea of moving more quickly in terms of not having a 4-

month delay between the presentations, deliberations, and vote. He also pointed out that in 

2012, these same discussions and presentations, though of prior outbreaks, occurred and over 

the course of a year ACIP deliberated on it. Ultimately, ACIP voted on a permissive use of a 3rd 

dose that health departments seemed to want to receive. He presumed the WG is utilizing that 

historic memory as well. 

Dr. Moore replied that the WG is very keen to get to evidence-based recommendations as 

quickly as possible, and hopefully the ongoing outbreaks will give them the opportunity to gather 

more data to support a decision. 

Meningococcal Vaccines 

Introduction 

David S. Stephens, MD

Chair, Meningococcal Work Group

Advisory Committee on Immunization Practices 

Dr. Stephens reminded everyone that during the February 2017 ACIP meeting, the WG 

discussed considerations for MenB booster doses for groups at increased risk for MenB 

disease. There is concern about the rapid decline in the immune correlate of protection by 12 

months after completion of the initial vaccination series. However, cases of MenB after 

vaccination have not been reported in persons at increased risk, except for patients receiving 

eculizumab. Additional data on antibody persistence and booster responses were felt to be 

needed. 

In contacting the manufacturers, additional data will be forthcoming within the next few months 

for MenB-4C (Bexsero®), including: 1) persistence 4 years after the 2-dose series and immune 

response 3, 7, and 30 days after booster from Canadian and Australian adolescents, anticipated 

July 2017; and 2) persistence up to 7 years after a 2-dose series and immune responses 3, 7, 

and 30 days after booster from Chilean adolescents, anticipated September 2017. Additional 

information anticipated for MenB-FHbp (Trumenba®) regards persistence 1 year after a booster 

dose, with full data anticipated March 2018. 

In terms of future activities, the WG will continue to review new data as it becomes available. In 

addition, the WG will review the complete GRADE evaluation for MenB boosters and will 

present their considerations to ACIP once additional data are evaluated and GRADE is 

complete. 

A Policy Note regarding the updated recommendations for the use of MenB-FHbp (Trumenba®)

was published in the MMWR on May 19, 2017. 

The agenda for this session focused on meningococcal disease and vaccine response in 

patients receiving eculizumab (Soliris®). This was an informational session only. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Considerations for Serogroup B Meningococcal (MenB) Vaccine Booster

Doses in Persons at Increased Risk for Serogroup B Meningococcal Disease 

Lucy McNamara, PhD, MS

Epidemiologist, Meningitis and Vaccine Preventable Diseases Branch

Division of Bacterial Diseases 

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention 

Dr. McNamara shared information about some work CDC has been doing to understand 

meningococcal disease cases in patients receiving the medication eculizumab, with the hope of 

having some discussion afterward about the best way to protect these patients moving forward. 

As a reminder, meningococcal disease is caused by the bacterium Neisseria meningitidis. It 

presents as meningitis, bloodstream infection (BSI), or both. The disease often starts with 

influenza-like symptoms but can progress within hours to a serious illness that can include high 

fever, severe headache, stiff neck, confusion, and a rash. Meningococcal disease has a rapid 

onset and progression even in previously healthy people, and in some cases death can occur 

less than a day after onset. About 10% to 20% of meningococcal disease patients die even with 

appropriate antibiotic treatment, and 11% to 19% of survivors have serious long-term health 

issues such as cognitive deficits, hearing loss, or amputations due to necrosis of the extremities. 

Eculizumab, or Soliris®, is a complement component inhibitor, specifically a monoclonal 

antibody against complement component C5, which is licensed in the US for the treatment of 

two rare, life-threatening illnesses. The first is paroxysmal nocturnal hemoglobinuria (PNH), for 

which eculizumab was licensed in 2007. For this illness, once a patient becomes ill enough to 

need eculizumab therapy, a lifelong course of eculizumab treatment is typically expected. The 

second illness is atypical hemolytic uremic syndrome (aHUS), for which eculizumab was 

approved in 2011. The optimal course of eculizumab therapy for aHUS is not clear. For some 

patients, lifelong treatment may be necessary, but for other patients a shorter course of 

treatment may be viable1. Both PNH and aHUS have an annual incidence of about 0.1-0.2 

cases per 100,000 population2,3. As a late complement component inhibitor, eculizumab is 

known to be associated with an increased risk of meningococcal disease, and the FDAapproved prescribing information includes a black box warning for increased risk of 

meningococcal disease in recipients [1Zuber et al. 2012, Nat Rev Nephrol 8(11):643-57. 2UK: 

Hill et al. 2006: http://www.bloodjournal.org/content/108/11/985 3Region not specified: Noris 

and Remuzzi: http://www.nejm.org/doi/full/10.1056/NEJMra0902814]. 

The manufacturer shared data on post-licensure cases of meningococcal disease among 

eculizumab recipients with FDA in 2014, and these data are publicly available online. The 

manufacturer reported 16 meningococcal disease cases, including 1 death, out of 5207 personyears of eculizumab exposure between 2007 and the first quarter of 2014. The age range of 

these patients was 17 to 45 years. All of these patients had reportedly received meningococcal 

vaccination. This report was prior to licensure of serogroup B meningococcal vaccines, so 

presumably the patients received serogroup ACWY conjugate or polysaccharide vaccines. Of 

the 16 cases, 1 was caused by serogroup B, 2 by serogroup C, 2 by serogroup Y, and 11 were 

reported to be due to an unknown serogroup. Overall, this is a meningococcal disease 

incidence in eculizumab recipients of 307 per 100,000 person-years, which is 1 to 2000 times 

greater than the baseline risk of meningococcal disease for healthy individuals in the US 

[http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugS 

afetyandRiskManagementAdvisoryCommittee/UCM423031.pdf]. 

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Due to this increased risk of meningococcal disease with eculizumab, there is a Risk Evaluation 

and Mitigation Strategy (REMS) program in place for eculizumab. A REMS program is a 

program required by FDA to manage known or potential serious risks associated with a drug 

product. For Soliris®, the purpose of the REMS program is to mitigate the occurrence and 

morbidity associated with meningococcal infections by informing healthcare providers and 

patients about the increased risk for meningococcal infections with Soliris®, the early signs of 

invasive meningococcal infections, and the need for immediate medical evaluation of signs and 

symptoms consistent with possible meningococcal infections. 

The Soliris® REMS program includes a patient medication guide, which is FDA-approved 

patient-focused labeling to help the patient understand the risk of meningococcal disease 

associated with Soliris®, as well as a patient safety information card that patients can carry in 

their wallet for their own reference and to alert providers to their increased risk of 

meningococcal disease. The program also includes prescriber certification in which providers 

must agree to counsel patients and provide the patients with educational materials, provide the 

medication guide to patients prior to each infusion, and review the educational materials and 

product labeling themselves and comply with directions for safe use, including ensuring that 

patients receive a meningococcal vaccine. However, the program materials do not include 

specific information about the different serogroup ACWY versus serogroup B meningococcal 

vaccines now available. In addition, providers must promptly report meningococcal disease 

cases to FDA or Alexion®, the manufacturer. Monitoring of the REMS program is ongoing, and 

REMS assessments are submitted to FDA by the manufacturer every two years. 

Current ACIP guidelines indicate that eculizumab recipients should receive both serogroup 

ACWY(MenACWY)1 and MenB2 vaccines. The eculizumab product insert indicates that 

meningococcal vaccination should be administered at least 2 weeks prior to initiating 

eculizumab treatment.3 If eculizumab treatment is initiated within 2 weeks of vaccination, the 

eculizumab product insert indicates that in clinical trials, antibiotic prophylaxis was usually 

provided until at least 2 weeks after vaccination. The insert further states that the “benefits and 

risks of antibiotic prophylaxis have not been established” [

1Cohn et al. 2013 

www.cdc.gov/mmwr/preview/mmwrhtml/rr6202a1.htm 2Folaranmi et al. 2015 

www.cdc.gov/mmwr/preview/mmwrhtml/mm6422a3.htm 3Available at: 

www.accessdata.fda.gov/drugsatfda_docs/label/2007/125166lbl.pdf]. 

Turning to a case report that CDC became aware of late last year, Dr. McNamara explained that 

this report was of a tragic fatal meningococcal disease case in a 16-year-old girl with PNH who 

had just begun receiving eculizumab for PNH treatment. The case was initially reported to CDC 

as serogroup B. The patient had received both MenACWY and MenB vaccines about 6 months 

prior to beginning treatment with eculizumab. Just 1 week after starting eculizumab therapy, the 

patient developed meningococcal disease. Initially she presented with headache, one episode 

of vomiting, and generalized body pain and she quickly went to the ER; however, she had no 

fever and her symptoms resolved completely after treatment with a non-steroidal antiinflammatory drug (NSAID) and anti-nausea medication. She was therefore discharged. Later 

that night, however, she developed purpura and became unresponsive. She was transported to 

an ED, but unfortunately died from Waterhouse-Friderichsen’s syndrome (WFS). 

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The infecting meningococcal strain was sent to CDC, where additional testing showed that this 

strain was actually non-groupable (NG), not serogroup B. Meningococcal bacteria are classified 

into serogroups based on their polysaccharide capsule, which is a key virulence factor that 

helps the bacterium evade the host immune response. There are 12 serogroups, but 6 of these 

(A, B, C, W, X, and Y) are the primary causes of meningococcal disease worldwide. NG 

meningococcal bacteria are those that do not express the polysaccharide capsule at all. There 

are two reasons that a Neisseria meningitidis isolate might be classified as NG. First, the 

bacteria might have a functional capsule gene and just not be expressing it, but they may have 

the capacity to turn the capsule gene back on at a later point. Alternatively, the bacteria might 

lack the capsule gene altogether or have another major defect in the capsule expression 

machinery, and therefore be incapable of turning on capsule expression. NG meningococci 

very rarely cause invasive disease; however, asymptomatic carriage of NG meningococci is 

very common1,2. CDC recently performed several carriage evaluations among US college 

students and found that 10% to 24% of students have asymptomatic carriage of Neisseria 

meningitidis at any given time. The vast majority of these carried meningococci were NG 

[

1Soeters et al. 2017 Clin Infect Dis 64(8):1115-22. 2CDC unpublished data]. 

Returning to the case report, in this instance the strain was determined to be NG by slide 

agglutination (SASG), which looks for expression of the capsule; as well as by PCR, which 

looks for the capsule gene; and by whole genome sequencing (WGS). WGS, in fact, 

demonstrated a complete absence of the capsule gene, showing that this strain really had no 

capacity to turn capsule expression back on. WGS also showed that the sequence type, or 

strain, of the isolate was ST-2578, which is more commonly associated with asymptomatic 

carriage rather than invasive disease. 

The meningococcal serogroup ACWY vaccines are based on the polysaccharide capsule 

antigen, so of course they do not provide any protection against NG meningococci. The MenB 

vaccines, though, are based on proteins that are not unique to serogroup B meningococci and 

that are potentially found in NG meningococci as well. However, the extent of MenB vaccine 

potential cross-protection for NG meningococcal strains has not been assessed. CDC’s 

laboratory looked at the MenB-4C antigen sequences in the strain isolated from this case and 

determined that, in fact, the sequences of two of the antigens (FHbp and NhbA) were extremely 

similar or identical to the antigens contained in MenB-4C. NadA was not present and the PorA 

sequence in the strain did not match the PorA antigen in the vaccine. Dr. Dan Granoff’s 

laboratory performed additional testing and showed that there was high expression of both 

FHbp and NhbA on the isolate based on flow cytometry1 [

1Data from Dan Granoff’s laboratory, 

UCSF Benioff Children’s Hospital Oakland]. 

To better understand the capacity of MenB-4C to protect against this strain, CDC sent the strain 

to Dr. Granoff for serum bactericidal activity (SBA) testing. He assessed serum bactericidal 

activity (SBA) in serum collected from 6 healthy adults before, 1 month after, and 4 to 6 months 

after receipt of either 2 or 3 doses of MenB-4C vaccine. A titer of 1:4 is usually considered 

protective. All 6 adults had pre-immunization titers of greater than 1:16, showing that even 

without immunization, the serum from all 6 of these adults was easily able to kill this bacterial 

strain. Titers further increased following MenB-4C immunization, although in most subjects they 

decreased to near baseline by 4 to 6 months after vaccination. Like the WGS data, these data 

suggest that this is not a meningococcal strain that would typically be able to cause disease 

[Data courtesy of Dr. Granoff]. 

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Finally, CDC also was interested in looking at the patient’s antibody levels to the antigens in the 

MenB-4C vaccine. The patient had a serum sample collected 3 days post-mortem, and CDC 

sent the serum sample to Dr. Granoff’s laboratory for characterization. He compared the level 

of antibodies observed in the patient’s serum specimen to the levels observed in specimens 

from other healthy adolescents who either had not received MenB-4C vaccine or who were 7 

months out from receiving the second MenB-4C vaccine dose, much like this patient. His data 

show that the patient’s anti-FHbp and anti-NhbA levels were much higher than levels observed 

in vaccinated healthy individuals; whereas, the patient’s anti-NadA levels were comparable to 

those in unvaccinated individuals. These data show that at the time the patient died, she had 

very high antibody levels to the FHbp and NhbA present in the infecting strain, suggestive of a 

memory antibody response to these antigens [Data courtesy of Dr. Granoff]. 

To summarize the data from this case report, this was a fatal meningococcal disease case in an 

adolescent who had been treated with eculizumab and who had been vaccinated with both 

MenACWY and MenB vaccines about 6 months prior to disease onset. The strain was found to 

be NG both phenotypically by slide agglutination and genotypically by PCR and WGS. MenB4C vaccine was expected to provide protection against this strain based on antigen typing, but 

in fact serum from normal healthy adults, both pre- and post-immunization with MenB-4C, easily 

killed this strain. The patient furthermore died despite what appeared to be a strong memory 

antibody response to this strain. Together, these data demonstrate that this case was caused 

by a meningococcal strain that would normally be expected to be nonpathogenic, but that in this 

patient caused fatal illness in spite of appropriate meningococcal vaccination. 

After hearing about this case report, CDC put out an Epidemic Information Exchange (Epi-X) 

call for cases to try to learn about additional meningococcal disease cases in eculizumab 

recipients in the US. For those who are not familiar with Epi-X, this is CDC’s web-based 

communications platform to share and request preliminary health surveillance information, and it 

includes users from CDC and state health departments. In this call for cases, CDC requested 

that state and large local health departments review existing case investigation records to 

identify meningococcal disease cases in eculizumab recipients from 2007 to the present. CDC 

posted the Epi-X on February 3, 2017 and has been following up directly with sites via email. 

Please note that CDC did not ask sites to obtain new information on cases or review medical 

records, although some sites chose to do so. This was just an initial attempt to find out what 

information the sites already had on cases in eculizumab recipients. 

So far, CDC has received responses from 46 jurisdictions1 and has identified a total of 16 cases, 

including the one just described in detail. Please note that these are not the same 16 cases 

mentioned in the introduction, which were reported by the manufacturer back in 2014, although 

the cases do likely overlap. For the 16 cases identified through the Epi-X, median patient age 

was 30 years, with a range of 16 through 83. Of the patients, 10 were taking eculizumab for 

treatment of PNH, 5 for aHUS, and one for Devic’s disease through a clinical trial. All 16 of the 

cases presented with a BSI while only 6 had evidence of meningitis. All of the patients were 

hospitalized for an average of 6.6 days, with a range of 1 to 14 days. The only fatality was the 

case report just reviewed [

1Information pending from: ID, MD, MS, NE, NM, WV]. 

CDC wanted to know the serogroup causing each of these cases. This table shows the 

serogroup of each case by SASG, which again is looking at capsule expression, and by PCR, 

which looks at whether the capsule gene is present: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

Serogroup 

(SASG) 

Serogroup 

(PCR) 

N cases 

NG NG 4 

Unknown NG 1 

NG B 2 

NG C 1 

NG Y 3 

Y Y 4 

Unknown Unknown 1 

Five of these cases were NG by PCR, showing that they do not have the gene to produce a 

capsule, and 6 more were NG by SASG, but did have a capsule gene detected by PCR. CDC 

is currently working on WGS of these strains to better understand whether these are strains that 

can readily turn capsule on and off or if there are other genetic defects preventing capsule 

expression. This work is still in progress, but CDC has completed sequencing for a few of these 

strains already, so it is possible to report that at least 3 of these 6 strains do have clear, nonreversible defects in the capsule operon that are expected to prevent capsule expression. That 

is a total of at least 8 of 16 cases (50%) caused by strains CDC considers to be truly NG. 

CDC also collected information on case vaccination status, and found that of the 15 patients 

with known vaccination status, only 9 (60%) had documented receipt of MenACWY1 vaccine 

prior to meningococcal disease onset. [Post meeting note 8/24/17: We have since gained more 

information and updated this to 14/16 with documented receipt of MenACWY vaccine. Please 

see recently published MMWR: www.cdc.gov/mmwr/volumes/66/wr/mm6627e1.htm?s_cid=mm6627e1_w]. Of the 

cases with disease onset in 2015-2016, after licensure of the MenB vaccines, only 3 of 7 (43%) 

had received one or more doses of MenB vaccine. Complete vaccination data are always 

challenging to obtain, particularly for adults, and thus these data may not be complete. 

However, they suggest that not all eculizumab recipients are receiving the ACIP-recommended 

meningococcal vaccines [1Vaccine type not specified for one patient, but received prior to MenB 

vaccine licensure]. 

Of the 4 patients with disease caused by meningococci that were both phenotypically and 

genotypically serogroup Y, and so theoretically preventable with MenACWY vaccine, 2 (50%) 

had documented prior MenACWY vaccination. This is consistent with the data the 

manufacturer1 shared with FDA and prior reports2 showing that serogroup C, W, and Y disease 

could all occur in eculizumab recipients in spite of prior MenACWY vaccination. Finally, one 

patient was noted to be receiving prophylactic penicillin at the time of disease onset; however, 

this patient reported poor compliance [1http://www.fda.gov/downloads/AdvisoryCommittees/ 

CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM4 

23031.pdf 2Cullinan et al. 2015; Pediatrics 135(6):e1506-9]. 

To summarize the Epi-X data, among these reports CDC is seeing a high frequency of cases 

due to NG meningococci, with at least 8 of 16 total cases (50%) due to NG strains. Of the 

cases, 5 were due to meningococci that are NG by PCR and 3 more were phenotypically NG by 

SASG; had a gene for serogroup B, C, or Y capsule detected by PCR; but had a capsule operon 

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defect that would prevent capsule expression that was identified by whole genome sequencing. 

Further characterization of additional isolates is ongoing. Of the cases, 40% with known 

MenACWY vaccination status and 57% of cases with known MenB vaccination status and with 

disease onset in 2015-2016 had not been vaccinated with the respective vaccine prior to 

disease onset, although again routine case investigations may not always capture a patient’s full 

vaccination history. Finally, 2 of 4 (50%) of the cases caused by meningococci that were 

phenotypically serogroup Y occurred in people who did have prior MenACWY vaccination 

documented. Together, these data suggest that vaccination provides incomplete protection to 

eculizumab recipients, both because of breakthrough cases of the serogroups that should be 

covered by the vaccines and because of the fairly high incidence of cases due to NG 

meningococcal bacteria, for which MenACWY vaccine provides no protection and for which the 

potential for cross-protection with MenB vaccines has not been assessed. 

Dr. McNamara briefly shared some in vitro data that may shed some light on why patients on 

eculizumab therapy are so susceptible to meningococcal disease. As mentioned earlier, 

eculizumab binds to complement component C5 and blocks cleavage of this component into 

C5a and C5b. C5b is needed for the membrane attack complex, which underlies serum 

bactericidal activity, so based on this SBA would be expected to be heavily impaired in 

eculizumab recipients. In the absence of SBA, meningococcal killing hopefully would be 

accomplished through opsonophagocytosis (OPA). However, C5a, the other product of C5, 

promotes inflammation and phagocytosis. Therefore, an open question is whether eculizumab 

might inhibit OPA as well as SBA. 

To answer this question, Dr. Granoff’s laboratory has been performing some studies looking at 

the effects of eculizumab on whole blood killing of meningococci, which should encompass both 

SBA and OPA. These graphs summarize the results: 

These graphs show geometric mean colony forming units (CFU) per ml of two different 

meningococcal strains, a serogroup B strain on the left and a serogroup C strain in the middle, 

following a 3-hour incubation with whole blood from 12 subjects who all received both 

MenACWY conjugate and MenB vaccines. In each graph, the first bar shows the CFU detected 

at time 0. In the second, blue, bar, it can be seen that after a 3-hour incubation with no inhibitor, 

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both strains of bacteria are consistently killed. The orange bars show what happens when a 

physiologically relevant concentration of eculizumab is added. Instead of being killed, the 

bacteria are able to rapidly replicate. Dr. Granoff performed a similar assay using the NG strain 

from the fatal case described earlier in this presentation, shown on the right. In this case, the 

assay was performed with whole blood from just one donor, a healthy adult who had received 2 

doses of MenB-4C. Even this unencapsulated strain, which is easily killed by serum from most 

healthy unvaccinated adults, cannot be killed by whole blood from a vaccinated donor in the 

presence of eculizumab. Together, these data suggest that either eculizumab does inhibit 

opsonophagocytic activity, or that OPA in the absence of SBA is not able to inhibit growth of 

these strains even in whole blood from vaccinated subjects. 

To summarize, eculizumab is associated with a 1- to 2000-fold increased incidence of 

meningococcal disease, and the case report and Epi-X data CDC collected suggest that a high 

proportion of the meningococcal disease cases in eculizumab recipients in the US are due to 

NG Neisseria meningitidis. These meningococci do not normally cause disease and since they 

lack a capsule, no protection against them is offered by MenACWY vaccine. The MenB 

vaccines may theoretically provide protection against these strains, but the proportion of NG 

strains for which MenB vaccines might offer cross-protection has not been assessed. 

Furthermore, both in the data CDC collected through the Epi-X and in prior reports from the 

manufacturer and literature, they have seen that breakthrough serogroup C, W, and Y cases 

can occur in eculizumab recipients in spite of MenACWY vaccination. CDC also heard of a few 

case reports from other countries of serogroup B meningococcal disease in eculizumab 

recipients who have received a MenB vaccine. Finally, in vitro data from Dr. Granoff’s 

laboratory show that eculizumab not only blocks SBA, but also impairs whole blood killing of 

meningococci, showing that OPA is either inhibited by eculizumab or is inadequate for 

meningococcal killing in the absence of SBA. 

Together, these points lead to two key concerns. First, patients on eculizumab are at risk of 

meningococcal disease due to both typical disease-causing strains and strains that do not 

normally cause disease, but that are frequently carried asymptomatically in the nasopharynx. 

Second, vaccination offers limited or possibly no protection against meningococcal disease for 

patients on eculizumab. In reviewing these data, CDC has been discussing whether there 

should be a role for antibiotic chemoprophylaxis for patients taking eculizumab. Some countries 

recommend antibiotic prophylaxis for the duration of eculizumab treatment. UK guidance states 

that patients are advised to take daily prophylactic antibiotics, either penicillin or erythromycin 

for those with penicillin allergies1. Similarly, guidance in France is to take continuous antibiotic 

chemoprophylaxis until 60 days after stopping eculizumab treatment2. In the US, CDC is aware 

that some individual providers also choose to recommend antibiotic prophylaxis for the duration 

of eculizumab treatment for some or all of their patients; however, there is no official guidance 

on this topic in the US [

1http://www.pnhleeds.co.uk/professionals/meningococcal-infection-andeculizumab/; 2Zuber et al. 2012 Nat Rev Nephrol 8(11):643-57, http://www.hcsp.fr/Explore.cgi/ 

avisrapportsdomaine?clefr=447]. 

Based on the literature and recommendations in other countries, penicillin appears to be the 

most commonly used antibiotic for long-term prophylaxis for eculizumab recipients. However, 

there are limited data available on the efficacy of this prophylaxis. Meningococcal strains with 

both intermediate susceptibility to penicillin and penicillin-resistance have been identified, and 

there are a few published reports of breakthrough cases in eculizumab recipients on penicillin 

that are due to meningococcal strains with intermediate penicillin susceptibility or resistance1,2. 

Recent studies of invasive meningococcal isolates from the US showed that between 10% and 

37% had intermediate susceptibility to penicillin3,4. However, penicillin resistance remains rare 

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and has been identified in only about 1% of US strains. Several studies in Europe have found 

similar or greater prevalence of intermediate susceptibility and resistance to penicillin among 

invasive isolates, but again, the majority of these isolates have intermediate susceptibility rather 

than full resistance5-7. The clinical implications of intermediate penicillin susceptibility are 

unclear [1Cullinan et al. 2015; Pediatrics 135(6):e1506-9; 2Parikh et al. IPNC 2016 abstract, 

available at: http://www.ipnc2016.org/;

3Harcourt et al. 2015, OFID 2(3):ofv117, 4Blain et al. 

2016, OFID 3(3):ofw152 5Canica et al. 2004 EID 10(3):526-9 6Bijlsma et al. 2014 Lancet ID 

14(9):805-12 7Bertrand et al. 2012 Antimicrob Agents Chemother 56(5):2268-72]. 

Although there are also limited data specifically assessing the safety of long-term penicillin 

therapy1, it is generally considered to be safe and is routinely used for prophylaxis for rheumatic 

fever, as well as prevention of Streptococcus pneumoniae (S. pneumoniae) infection in asplenic 

children2 [

1https://www.fda.gov/drugs/emergencypreparedness/bioterrorismanddrug 

preparedness/ucm072755.htm 2Enzler et al. 2011, Mayo Clin Proc86(7):686-701]. 

This raises a key discussion question, which regards whether antibiotic chemoprophylaxis for 

meningococcal disease should be recommended for eculizumab recipients in the US in addition 

to vaccination. If so, should this be penicillin or are there other good options for long-term 

antibiotic prophylaxis? Should antibiotics be recommended for all eculizumab recipients or for a 

subset, for instance, those expected to have a shorter course of treatment? Some aHUS 

patients may have a shorter course of treatment than PNH patients, for example, for whom 

treatment is typically expected to be life-long. Or should prophylaxis be limited to those in 

higher risk age groups? CDC does not really have data on which age groups of eculizumab 

recipients are at highest risk, but in the general population it is known that infants, adolescents, 

and older adults are at higher risk for meningococcal disease. If the concern is about disease 

due to strains more commonly associated with asymptomatic carriage, it is also known that 

asymptomatic carriage typically peaks among young adults. CDC does not anticipate an ACIP 

vote on this topic, but wanted to open it up for discussion with ACIP to acquire insight and ideas. 

CDC also hopes that ACIP can help identify additional stakeholders to engage on this issue. 

Discussion Points 

Dr. Romero emphasized that biologics are very important, but as they are being used, more is 

being learned about their unintended side-effects. His opinion is that antibiotics and 

chemoprophylaxis should be considered for these patients. However, it is not clear that there is 

enough information in these populations using this drug to break it out into saying it is infants, 

adolescents, or young adults who require this. Without looking at the data closer, he would 

probably recommend that all persons receiving eculizumab, short- or long-term, receive 

antimicrobial prophylaxis. They probably would need to discuss further whether that prophylaxis 

should be penicillin or some other drug. Certainly, one of the patients reported poor compliance 

to the regimen, which brings to mind whether other options are necessary. It is also important 

to consider whether these patients need a salvage protocol. Many patients have cell-mediated 

effects or congenital neutropenia, so their parents are given a dose of X and are told to give it if 

the child becomes sick and proceed immediately to the ED. 

Dr. Walter concurred with Dr. Romero with regard to recommending the use of prophylaxis in 

this case. 

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Dr. Bennett inquired as to whether there were any comparable data on the 16 cases reported to 

the manufacturers that differ from the other 16 cases. 

Dr. McNamara replied that the 16 cases reported from the manufacturer occurred from 2007 to 

the first quarter of 2014; whereas, the 16 she reported on occurred from 2008 and 2016. They 

know that there are different cases, but some are likely to be the same. CDC does not have 

access to very much information on the cases that have been reported to the manufacturer 

apart from what she presented, but is working to obtain that information. 

Dr. Romero asked where they were observing higher incidences of other bacterial infections in 

these patients. 

Dr. McNamara replied that there was some documentation of other infections that have 

occurred in eculizumab recipients. There is nothing else that looks like it has as dramatic an 

increase in incidence as meningococcal disease. The REMS program and black box warning 

are specifically focused on meningococcal disease. 

Dr. Hunter inquired about the denominator of prevalence of the disease for which eculizumab is 

used. In his role as the sexually transmitted disease (STD) consultant for the City of Milwaukee 

Health Department, he argued against using benzathine penicillin as a prophylaxis so that it is 

available for syphilis. 

Dr. McNamara replied that they do not have information specifically on the denominator aside 

from the information shared with the manufacturer and FDA of the 5207 person years of 

exposure in the US from 2007 to 2014. It is important to note that not all people with PNH or 

aHUS would be on eculizumab therapy at any given time. 

Ms. Pellegrini was very troubled by the reports of under-vaccination in this population and 

whether that is due to providers not being diligent or patients not complying. There seems to be 

a role for CDC and FDA to work together to address compliance with the REMS requirements. 

If the REMS requirements are not being abided by appropriately, that is a tremendous problem. 

If the vaccines are not being administered, perhaps the education is also not occurring and 

parents, caregivers, and patients are not being appropriately sensitized to what they need to 

look for and how to care for themselves. 

Dr. Sun (FDA) indicated that the REMS requirements are detailed and comprehensive. The 

data are reviewed periodically, including compliance data. He understood the point being made 

about the need for vaccination, but stressed the importance of also recognizing that in this 

particular case, vaccination may provide a false sense of security that it is actually doing 

something that it may not be. 

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Before weighing in on antimicrobial prophylaxis, Dr. Atmar would like to understand more about 

the minimal inhibitory concentration (MIC) for meningococci compared to group A strep or 

Streptococcus pneumoniae where it has been used effectively. If the MICs are similar, there is 

a chance it will be beneficial, but if they are a log higher on average, this may lead to a false 

sense of security in relying on antimicrobial prophylaxis. Failures have been observed. 

Dr. Stephens noted that most strains in this country remain susceptible to penicillin at 

reasonable MICs. There are intermediate strains on the order of 20% or so. One option for Dr. 

Romero’s suggestion to consider a salvage protocol could be ceftriaxone. It is used in other 

countries in settings where meningococcal disease is suspected, and that point could be made 

about providing families with ceftriaxone as an IM injection in cases like this. Ceftriaxone 

potentially could be used as a longer-term prevention methodology. 

Dr. Friedand (GSK) acknowledged that is a very challenging area. He brought to the attention 

of ACIP that an international workshop will be convened in September 2017 in Prague on 

meningococcal disease and complement deficiency to continue to understand the knowledge in 

this very important area. The data remain limited and are technically challenging. He reminded 

everyone that during the last ACIP meeting in February 2017, GSK presented the results of a 

clinical study of response to MenB-4C among individuals with immunodeficiencies, including 7 

patients who were treated with eculizumab. In that study, those patients receiving eculizumab 

did have the lowest response to the vaccines compared to people with other complement 

deficiencies, although there was evidence of SBA? activity in some individuals taking 

eculizumab. In addition, during the September 2016 International Pathogenic Neisseria 

Conference in Manchester, there was a presentation from Public Health England on the results 

of 23 individuals who have received eculizumab. There they found that while eculizumab blocks 

SBA, it was not blocked in all subjects. Interestingly, they found that OPA activity was 

maintained and was not blocked in their subjects. These results suggest that completing 

vaccination can still be beneficial for these patients. 

Vaccine Adverse Event Reporting (VAERS) 2.0 Form 

Tom Shimabukuro, MD, MPH, MBA 

Immunization Safety Office

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention 

Dr. Shimabukuro indicated that this presentation would serve as the announcement of the new 

VAERS 2.0 form. As a reminder, VAERS is the national spontaneous reporting system for 

monitoring the safety of US-licensed vaccines that is co-managed by CDC and FDA. The 

current VAERS form, which is called the VAERS-1 form, has been in use since 1990. The 

paper version of this form must be filled out by hand and mailed or faxed in. An online reporting 

tool allows for web-based reporting of the VAERS-1 data. The following is the VAERS-1 form: 

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VAERS 2.0 consists of two major initiatives. One is a new VAERS form with revised data 

elements, which is called the VAERS 2.0 reporting form. The other is an updated process for 

submitting VAERS reports that includes two options: 1) updated online reporting tool; and 2) 

writable PDF form combined with electronic document upload capability. 

Proposed changes to the current VAERS form were first presented to ACIP, NVAC, and the 

Advisory Commission on Childhood Vaccines (ACCV) in September and October 2014. 

Proposed changes also were posted in the Federal Register for public comment in November 

2014 (https://www.federalregister.gov/documents/2014/11/24/2014-27678/request-for-commenton-draft-vaccines-adverse-event-reporting-system-vaers-20-form). CDC conducted extensive 

user testing during the development and revision process. Changes to the VAERS form were 

finalized in 2016. The new VAERS 2.0 form has updated data elements, such as pregnancy 

status, race, and ethnicity. New features include writable and savable options, and some smart 

features like logic checks to prevent users from entering non-logical answers. Information 

technology (IT) upgrades to the VAERS website were completed in 2017 to incorporate new 

data elements into a reconfigured online reporting tool, and to accommodate a new electronic 

document upload process. 

Starting on June 30, 2017 and extending through the end of December 2017, CDC and FDA will 

implement the VAERS 2.0 form and phase out the VAERS-1 form. VAERS 2.0 is for reporting 

by HCP, patients, parents, guardians, caregivers, and other non-manufacturer reporters. 

Reporters will be able to use the VAERS 2.0 online reporting tool to submit reports through 

direct online reporting, or download and complete the writable and savable VAERS 2.0 form and 

submit using an electronic document upload feature. Vaccine manufacturers report through a 

different process using the FDA Electronic Submissions Gateway (ESG). 

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Here are the online and writable/uploadable samples of the new VAERS 2.0 form: 

“Essential” items, or high value data elements, are highlighted with asterisks in the online 

reporting tool and with yellow boxes in the writable PDF form. 

Instructions for reporting to VAERS will be available at https://vaers.hhs.gov/reportevent.html. 

The URL will be activated June 30, 2017. Additional assistance is available via email at 

info@vaers.org or by phone at 1-800-822-7967. Transition to the VAERS 2.0 form is expected 

to be completed by the end of December 2017. Accommodations will be made for individuals 

unable to submit reports electronically. 

Day 2: Public Comment 

Ms. Patsy Stinchfield 

Director, Infection Prevention and Control at Children’s Minnesota 

ACIP Liaison Member for the National Association of Pediatric Nurse Practitioners 

Given that many people had asked about the Minnesota measles outbreak, she provided a brief 

update. She reported that Minnesota is still in the midst of this outbreak that began April 11, 

2017. At the time of this report, there were 78 cases. Children’s Minnesota has taken care of 

53 of those 78, with 21 admissions mostly for dehydration. There have been no cases requiring 

intensive care, and there have been no deaths. Of the 78 cases, 71 were completely 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

unvaccinated. The age group is primarily pre-school children between 1 and 4 years of age. Of 

the cases, 83% were Somali Minnesotans. There has been a lot of activity from anti-vaccine 

groups talking with Somali families about MMR and autism. A lot of work is underway in the 

community, including efforts by Lynn Bahta from the Minnesota Department of Health (MDH) 

who was in attendance at this ACIP meeting, to work with Somali religious leaders to try to 

break that link. The last positive rash onset occurred on the 13th. If there are no more cases by 

the end of July, the outbreak will be over. Notably, there have been over 8880 exposures. 

Given that many exposures in 6 schools, 12 child care centers, and many clinics and EDs and a 

high immunization rate, there have been only the 78 cases. This surpassed all 70 US 2016 

cases within 7 weeks. The MMR vaccine rates, particularly in the Somali community and 

typically in Hennepin County, would be about 500 Somali individuals getting vaccinated per 

week. After the outbreak began, there were 3 straight weeks of over 3000 MMR vaccines 

delivered. Outbreaks do change minds and Minnesota has seen this happen. The hope is that 

this will come to an end, and she will be happy to present more data during the October 2017 

ACIP meeting. 

Dr. Amy Middleman

ACIP Liaison Member 

Society for Adolescent Health and Medicine 

Dr. Middleman announced that the Society for Adolescent Health and Medicine (SAHM) 

published a position statement in the April 2017 issue of the Journal of Adolescent Health (JAH) 

supporting the establishment of a 16-year-old immunization platform. The platform would create 

an expectation among providers, parents, and patients to address immunizations that are due or 

overdue by 16 years of age and also would provide the opportunity to address other 

comprehensive and preventive healthcare needs. SAHM also recognizes with great 

appreciation the gray shading emphasizing this age group on the 2017 Immunization Schedule 

published by CDC, American Academy of Pediatrics (AAP), American Academy of Family 

Physicians (AAFP), and American Congress of Obstetricians and Gynecologists (ACOG). 

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Certification 

Upon reviewing the foregoing version of the June 21-22, 2017 ACIP meeting minutes, Dr. 

Nancy Bennett, ACIP Chair, certified that to the best of her knowledge, they are accurate and 

complete. Her original, signed certification is on file with the Management Analysis and 

Services Office (MASO) of CDC. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

ACIP Membership Roster 

September 26, 2016

Department of Health and Human Services 

Centers for Disease Control and Prevention 

Advisory Committee on Immunization Practices

July 1, 2016 through June 30, 2017 

CHAIR 

BENNETT, Nancy, MD, MS 

Professor of Medicine and Public Health Sciences 

Director, Center for Community Health 

Co-director, Clinical and Translational Science Institute 

University of Rochester School of Medicine and Dentistry 

Rochester, NY 

Term: 07/01/2015-06/30/2018 

EXECUTIVE SECRETARY 

COHN, Amanda, MD 

Senior Advisor for Vaccines 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Atlanta, GA 

MEMBERS 

ATMAR, Robert L., MD 

John S. Dunn Clinical Research Professor in Infectious Diseases 

Interim Chief, Section of Infectious Diseases 

Departments of Medicine and Molecular Virology & Microbiology 

Baylor College of Medicine 

Chief, Infectious Diseases Service 

Ben Taub General Hospital, Harris Health System 

Houston, TX 

Term: 7/1/2016 – 6/30/2020 

BELONGIA, Edward, MD 

Director 

Center for Clinical Epidemiology & Population Health 

Marshfield Clinic Research Foundation 

Marshfield, WI 

Term: 07/01/2014-06/30/2018 

EZEANOLUE, Echezona, MD, MPH 

Professor of Pediatrics and Public Health 

Department of Epidemiology and Biostatistics 

Director, Global Health and Implementation Research Initiatives 

University of Nevada 

Las Vegas, NV 

Term: 07/01/2015-06/30/2019 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

HUNTER, Paul, MD 

Associate Professor of Family Medicine and Community Health 

University of Wisconsin School of Medicine and Public Health 

Associate Medical Director 

City of Milwaukee Health Department 

Milwaukee, WI 

Term: 7/1/2016 – 6/30/2020 

KEMPE, Allison, MD, MPH 

Professor of Pediatrics 

Director of Primary Care Fellowship 

University of Colorado School of Medicine 

Director of Research 

Division of General Academic Pediatrics 

Director of Children’s Outcomes Research Program 

The Children’s Hospital of Denver 

Denver, CO 

Term: 07/01/2013 - 06/30/2017 

LEE, Grace M., MD, MPH 

Associate Professor of Population Medicine & Pediatrics 

Director, Center for Healthcare Research in Pediatrics (CHeRP) 

Harvard Pilgrim Health Care Institute & Harvard Medical School 

Associate Medical Director of Infection Control, Boston Children's Hospital 

Boston, MA 

Term: 7/1/2016 – 6/30/2020 

MOORE, Kelly, MD, MPH, 

Director, Tennessee Immunization Program 

Tennessee Department of Health 

Assistant Clinical Professor, Department of Health Policy 

Vanderbilt University School of Medicine 

Nashville, TN 

Term: 07/01/2015-06/30/2019 

PELLEGRINI, Cynthia 

Senior Vice President 

Public Policy and Government Affairs 

March of Dimes 

Washington, DC 

Term: 07/01/2013-06/30/2017 

REINGOLD, Arthur L., MD 

Professor of Epidemiology 

Edward Penhoet Distinguished for Global Health and Infectious Disease 

Associate Dean for Research 

School of Public Health 

University of California 

Berkeley, CA 

Term: 07/01/2013-06/30/2017 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

RILEY, Laura E., MD 

Associate Professor, Obstetrics, Gynecology and Reproductive Medicine 

Harvard Medical School 

Maternal Fetal Medicine 

Massachusetts General Hospital 

Boston, MA 

Term: 07/01/2014-06/30/2018 

ROMERO, José R., MD, FAAP 

Professor of Pediatrics 

Horace C. Cabe Endowed Chair in Infectious Diseases 

Director, Pediatric Infectious Diseases Section 

University of Arkansas for Medical Sciences and Arkansas Children's Hospital 

Director, Clinical Trials Research 

Arkansas Children's Hospital Research Institute 

Little Rock, AR 

Term: 07/01/2014-06/30/2018 

STEPHENS, David, MD 

Professor of Medicine, Division of Infectious Diseases 

Chair, Department of Medicine 

Emory University School of Medicine 

Emory University 

Atlanta, GA 

Term: 07/01/2015-06/30/2019 

SZILAGYI, Peter MD, MPH 

Professor of Pediatrics 

Executive Vice-Chair and Vice-Chair for Research 

Department of Pediatrics 

University of California, Los Angeles (UCLA) Los 

Angeles, California 

Term: 7/1/2016 – 6/30-2020 

WALTER, Emmanuel (Chip), Jr., MD, MPH 

Professor of Pediatrics 

Duke University School of Medicine 

Durham, NC 

Term: 07/01/2015-06/30/2019 

EX OFFICIO MEMBERS 

Centers for Medicare and Medicaid Services (CMS)

HANCE, Mary Beth 

Senior Policy Advisor 

Division of Quality, Evaluations and Health Outcomes 

Children and Adults Health Programs Group 

Center for Medicaid, CHIP and Survey & Certification 

Centers for Medicare and Medicaid Services 

Baltimore, MD 

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Department of Defense (DoD)

DEUSSING, ERIC, MD, MPH 

Commander, Medical Corps, United States Navy 

Department of Defense Liaison 

Centers for Disease Control and Prevention 

Atlanta, GA 

Department of Veterans Affairs (DVA)

KIM, Jane A., MD, MPH 

Deputy Chief Consultant for Preventive Medicine 

Office of Patient Care Services 

National Center for Health Promotion and Disease Prevention 

Durham, North Carolina 

Food and Drug Administration (FDA)

SUN, Wellington, MD 

Director, Division of Vaccines and Related Product Applications 

Office of Vaccines Research and Review 

Food and Drug Administration 

Rockville, MD 

Health Resources and Services Administration (HRSA)

NAIR, Narayan, MD 

CAPT, USPHS 

Acting Division Director/Chief Medical Officer 

Division of Injury Compensation Programs 

Healthcare Systems Bureau 

Rockville, MD 

Indian Health Service (IHS)

GROOM, Amy, MPH 

Immunization Program Manager 

Indian Health Service 

Albuquerque, NM 

National Vaccine Program Office (NVPO)

GELLIN, Bruce, MD, MPH 

Director 

National Vaccine Program Office 

Department of HHS, Public Health and Science 

Washington, DC 

National Institutes of Health (NIH)

GORMAN, Richard L., MD 

Associate Director for Clinical Research 

Division of Microbiology and Infectious Diseases/NIAID 

National Institute of Health 

Bethesda, MD 

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American College of Nurse Midwives (ACNM) (alternate) 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

LIAISON REPRESENTATIVES 

American Academy of Family Physicians (AAFP)

SAVOY, Margot, MD, MPH 

Medical Director, Department of Family & Community Medicine 

Christiana Care Health System 

Wilmington, DE 

American Academy of Pediatrics (AAP)

BYINGTON, Carrie L., MD 

Chair, AAP Committee on Infectious Diseases 

H.A. and Edna Benning Presidential Professor of Pediatrics 

Associate Vice President for Faculty and Academic Affairs 

University of Utah Health Sciences Center 

Salt Lake City, UT 

American Academy of Pediatrics (AAP)

Red Book Editor 

KIMBERLIN, David, MD 

Professor of Pediatrics 

Division of Pediatric Infectious Diseases 

The University of Alabama at Birmingham School of Medicine 

Birmingham, AL 

American Academy of Physician Assistants (AAPA)

LÉGER, Marie-Michèle, MPH, PA-C 

Senior Director, Clinical and Health Affairs 

American Academy of Physician Assistants 

Alexandria, VA 

American College Health Association (ACHA)

EVEN, Susan, MD 

Executive Director 

Student Health Center 

University of Missouri 

Columbia, MO 

American College of Nurse Midwives (ACNM)

HAYES, Carol E., CNM, MN, MPH 

Atlanta Perinatal Associates 

Atlanta, GA 

MEHARRY, Pamela M., PHD, CNM 

Midwifery Educator, Human Resources for Health 

In partnership with University of Rwanda and University of Illinois, Chicago 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

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 

POLAND, Gregory A., MD 

Mary Lowell Professor of Medicine and Infectious Diseases 

Mayo Clinic 

Rochester, MN 

American Geriatrics Society (AGS)

SCHMADER, Kenneth, MD 

Professor of Medicine-Geriatrics 

Geriatrics Division Chief 

Duke University and Durham VA Medical Centers 

Durham, NC 

America’s Health Insurance Plans (AHIP)

NETOSKIE, Mark J., MD, MBA 

Market Medical Executive, CIGNA 

Houston, TX 

American Medical Association (AMA)

FRYHOFER, Sandra Adamson., MD 

Adjunct Associate Professor of Medicine 

Emory University School of Medicine 

Atlanta, GA 

American Nurses Association (ANA)

RITTLE, Charles (Chad), DNP, MPH, RN 

Assistant Professor, Nursing Faculty 

Chatham University, School of Health Sciences 

Pittsburgh, PA 

American Osteopathic Association (AOA)

GROGG, Stanley E., DO 

Associate Dean/Professor of Pediatrics 

Oklahoma State University-Center for Health Sciences 

Tulsa, OK 

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American Pharmacists Association (APhA)

FOSTER, Stephan L., PharmD 

Professor and Vice Chair, Department of Clinical Pharmacy 

University of Tennessee Health Sciences Center, College of Pharmacy 

Memphis, TN 

Association of Immunization Managers (AIM)

FINLEY, Christine, RN, MPH 

Immunization Program Manager 

Vermont Department of Health 

Burlington, VT 

Association for Prevention Teaching and Research (APTR)

McKINNEY, W. Paul, MD 

Professor and Associate Dean 

University of Louisville School of Public Health and Information Sciences 

Louisville, KY 

Association of State and Territorial Health Officials (ASTHO)

DWELLE, Terry L, MD, MPHTM 

State Health Officer 

North Dakota Department of Health 

Bismarck, ND 

Biotechnology Industry Organization (BIO)

ARTHUR, Phyllis A., MBA 

Senior Director, Vaccines, Immunotherapeutics and Diagnostics Policy 

Washington, DC 

Council of State and Territorial Epidemiologists (CSTE)

HAHN, Christine, MD 

State Epidemiologist 

Office of Epidemiology, Food Protection and Immunization 

Idaho Department of Health and Welfare 

Boise, ID 

Canadian National Advisory Committee on Immunization (NACI)

GEMMILL, Ian MacDonald, MD 

Medical Officer of Health 

Kingston, Frontenac and Lennox & Addington Public Health 

Kingston, Ontario, Canada 

Infectious Diseases Society of America (IDSA)

NEUZIL, Kathleen M., MD, MPH 

Professor of Medicine 

Director, Center for Vaccine Development 

University of Maryland School of Medicine 

Baltimore, MD 

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Infectious Diseases Society of America (IDSA) (alternate) 

National Association of County and City Health Officials (NACCHO) (alternate) 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

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 

DUCHIN, Jeffrey, MD 

Health Officer and Chief, Communicable Disease Epidemiology and Immunization Section 

Public Health - Seattle and King County 

Professor in Medicine 

Division of Allergy and Infectious Diseases 

University of Washington School of Medicine and School of Public Health 

Seattle, WA 

National Association of Pediatric Nurse Practitioners (NAPNAP)

STINCHFIELD, Patricia A., RN, MS, CPNP 

Director 

Infectious Disease/Immunology/Infection Control 

Children's Hospitals and Clinics of Minnesota 

St. Paul, MN 

National Foundation for Infectious Diseases (NFID)

SCHAFFNER, William, MD 

Chairman, Department of Preventive Medicine 

Vanderbilt University School of Medicine 

Nashville, TN 

National Immunization Council and Child Health Program, Mexico

VILLASEÑOR RUIZ, Ignacio, MD 

Directora del Programa de Atencion da la Salud de la Infancia y la Adolescencia / Director 

General, Child and Adolescent Health 

Centro Nacional Para la Salud de la Infancia Y La Adolescencia / National Center for Child and 

Adolescent Health 

Ministry of Health / Secretaría de Salud 

Mexico 

National Medical Association (NMA)

WHITLEY-WILLIAMS, Patricia, MD 

Professor and Chair 

University of Medicine and Dentistry of New Jersey 

Robert Wood Johnson Medical School 

New Brunswick, NJ 

175 

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https://www.cdc.gov/vaccines/acip/meetings/downloads/min-archive/min-2017-06.pdf
 

 

 

 

 

Pediatric Infectious Diseases Society (PIDS) (alternate) 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 21-22, 2017 

National Vaccine Advisory Committee (NVAC)

THOMPSON, Kimberly, ScD 

Chair, NVAC 

Professor of Preventive Medicine and Global Health 

University of Central Florida, College of Medicine Orlando, FL 

Pediatric Infectious Diseases Society (PIDS)

O’LEARY, Sean, MD, MPH 

Associate Professor of Pediatrics 

Pediatric Infectious Diseases 

General Academic Pediatrics 

Children’s Hospital Colorado 

University of Colorado School of Medicine 

SAWYER, Mark H, MD 

Professor of Clinical Pediatrics 

University of California, San Diego School of Medicine 

San Diego, CA 

Pharmaceutical Research and Manufacturers of America (PhRMA)

JOHNSON, David R, MD, MPH 

Associate Vice President, Global Medical Affairs, Sanofi Pasteur 

Swiftwater, PA 

Society for Adolescent Health and Medicine (SAHM)

MIDDLEMAN, Amy B., MD, MSEd, MPH 

Professor of Pediatrics 

Chief, Section of Adolescent Medicine 

University of Oklahoma Health Sciences Center 

Oklahoma City, OK 

Society for Healthcare Epidemiology of America (SHEA)

WEBER, David, MD, MPH 

Professor of Medicine, Pediatrics, and Epidemiology 

University of North Carolina Schools of Medicine and Public Health 

Medical Director, Hospital Epidemiology and Occupational Health, UNC Health Care 

University of North Carolina 

Chapel Hill, NC 

176 

This document has been archived for historical purposes. (7/1/2017) 

https://www.cdc.gov/vaccines/acip/meetings/downloads/min-archive/min-2017-06.pdf