DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION
 

Advisory Committee on 

Immunization Practices (ACIP) 

Summary Report
 

June 25-26, 2014 

Atlanta, Georgia 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Table of Contents Page 

Agenda 4-5 

Acronyms 6-7 

Wednesday: June 25, 2014 

Welcome and Introductions 8-15 

General Recommendations 

 Introduction 

 Vaccination of Persons with Altered Immunocompetence 

 Vaccination Programs 

16-23 

Child/Adolescent Immunization 

 Introduction 

 Healthcare Provider Review of 2014 Catch-Up Schedule and Supplementary Tables 

24-28 

Yellow Fever Vaccine 

 Introduction 

 GRADE and Workgroup Conclusions Regarding Yellow Fever Vaccine Booster Dose 

29-45 

Influenza 

 Introduction 

 Novel Influenza Vaccine Workgroup 

 Influenza Vaccine Safety Update 

 Assessing Fever Rates in Children Following LAIV and IIV 

 LAIV and IIV Vaccine Safety 

 Proposed Recommendations 

46-68 

Human Papillomavirus (HPV) Vaccines 

 Introduction 

 9-Valent HPV Vaccine Clinical Trial Data 

 9-Valent HPV Vaccine: Overview of Workgroup Considerations 

 2-Dose HPV Vaccine Schedules: Review of Data 

 HPV Workgroup Plans 

68-87 

Vaccine Safety 

 Introduction 

 Seizures Following Administration of Multiple Vaccines: A VSD Study 

 Febrile Seizures after Administration of Trivalent Influenza Vaccines: PRISM System, 2010-2011 Influenza Season 

 Summary 

87-99 

Adult Immunization 

 Introduction 

 Update on Adult Immunization Coverage 

 Update on CDC’s Adult Immunization Communication Activities 

100-111 

Public Comments Day 1 112 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Thursday: June 26, 2014 

Typhoid Vaccines 112-113 

Agency Updates 

 CDC 

 Center for Medicare and Medicaid Services (CMS) 

 Department of Defense (DoD) 

 Department of Veteran’s Affairs (DVA) 

 Food and Drug Administration (FDA) 

 Heath Resources and Services Administration (HRSA) 

 Indian Health Services (I HS) 

 National Institutes of Health (NIH) 

 National Vaccine Advisory Committee (NVAC) 

 National Vaccine Program Office (NVPO) 

113-118 

13-Valent Pneumococcal Conjugate Vaccines 

 Introduction & Update on 3-Dose Schedule for Infants 

 PCV13 Efficacy Among Adults: Results of CAPiTA Study 

 Potential Public Health Impact and Cost-Effectiveness of PCV13 Use in Adults 

 Considerations for PCV13 Use among Adults and Policy Options 

118-144 

Measles Update 

 Global Update 

 Domestic Update 

144-152 

Meningococcal Vaccine 

 Introduction 

 Epidemiology of Meningococcal Disease Outbreaks in the United States 

 Interim Guidance for the Use of Serogroup B Meningococcal Vaccines Under a CDC-Sponsored IND 

152-161 

Hepatitis Vaccines 

 Update: ACIP Hepatitis Workgroup 

161-163 

Vaccine Supply 163-164 

Public Comments Day 2 164-165 

Certification 166 

Membership Roster 167-175 

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 9:35	 Yellow Fever Vaccine 

 Introduction 

 GRADE and Work Group conclusions regarding yellow fever 

vaccine booster dose	 

10:35	 Break 

AGENDA ITEM	 PURPOSE PRESIDER/PRESENTER(s) 

5:00	 Adult Immunization 

 Introduction 

 Update on adult immunization coverage 

 Update on CDC’s adult immunization communication activities

Wednesday, June 25th 

8:00 Welcome & Introductions

 9:15	 Child/Adolescent Immunization 

 Introduction 

 Healthcare provider review of 2014 catch-up schedule and 

supplementary tables 

12:30	 Lunch 

1:45	 Human Papillomavirus (HPV) Vaccines 

 Introduction 

 9-valent HPV vaccine clinical trial data 

 9-valent HPV vaccine: overview of WG considerations 

 2-dose HPV vaccine schedules: review of data 

 HPV Vaccines Work Group plans 

	 Dr Jonathan Temte (Chair, ACIP) 

Dr Larry Pickering (Executive Secretary, ACIP, 

CDC) 

3:45	 Vaccine Safety 

 Introduction 

 Febrile seizures after administration of trivalent influenza vaccines 

– PRISM system, 2010-2011 influenza season	 

 Seizures following administration of multiple vaccines: a VSD study

 Summary
 

8:30	 General Recommendations 

 Introduction 

 Vaccination of persons with altered immunocompetence 

 Vaccination programs	 

Information 

Discussion 

Dr Jeff Duchin (ACIP, WG Chair) 

Dr Andrew Kroger (CDC/NCIRD) 

Dr Andrew Kroger (CDC/NCIRD) 

Information 

Discussion 

Dr Renée Jenkins (ACIP, WG Chair) 

Dr Andrew Kroger (CDC/NCIRD) 

Information 

Discussion 

Vote 

Dr Joseph Bocchini (ACIP, WG Chair) 

Dr Erin Staples (CDC.NCEZID) 

11:00	 Influenza 

 Introduction 

 Novel Influenza Vaccine Work Group 

 Influenza vaccine safety update 

 Assessing fever rates in children following LAIV and IIV 

 LAIV and IIV vaccine safety 

 Proposed recommendations 

Information 

Discussion 

Dr Ruth Karron (ACIP,WG Chair) 

Dr Doug Campos-Outcalt (ACIP, WG Chair) 

Dr Maria Cano (CDC/NCEZID) 

Dr Melissa Stockwell (Columbia University) 

Dr Lisa Grohskopf (CDC/NCIRD) 

Vote Dr Lisa Grohskopf (CDC/NCIRD) 

Dr Joseph Bocchini (ACIP, WG Chair) 

Dr Alain Luxembourg (Merck) 

Dr Eileen Dunne (CDC/NCHHSTP) 

Dr Lauri Markowitz (CDC/NCHHSTP) 

Dr Lauri Markowitz (CDC/NCHHSTP) 

Information 

Discussion 

3:15	 Break 

Dr Tom Shimabukuro (CDC/NCEZID) 

Dr Alison Kawai (Harvard Medical School, 

Harvard Pilgrim Health Care Institute) 

Information 

Discussion 

Dr Jonathan Duffy (CDC/NCEZID)
 

Dr Tom Shimabukuro (CDC/NCEZID)
 

Information 

Discussion 

Dr Tamera Coyne-Beasley (ACIP, WG Chair) 

Dr Walter Williams (CDC/NCIRD) 

Dr Kristine Sheedy (CDC/NCIRD) 		

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

MEETING OF THE ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES (ACIP) 

Centers for Disease Control and Prevention
 

1600 Clifton Road, NE, Tom Harkin Global Communications Center (Building 19), Atlanta, Georgia
 

June 25-26, 2014 

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6:00	 Adjourn 

Thursday, June 26th 

8:00	 Updates 

 Typhoid Vaccines 

 Agency Updates: CDC and ACIP Ex Officio Members 

 CMS, DoD, DVA FDA, HRSA, IHS, NVPO, NIH 

8:15	 13-Valent Pneumococcal Conjugate Vaccine 

 Introduction & update on 3-dose schedule for infants 

 PCV13 efficacy among adults: results of CAPiTA study 

 Potential public health impact and cost-effectiveness of PCV13 use 

in adults 

 Considerations for PCV13 use among adults and policy options 

 

Dr Nancy Bennett (ACIP, WG Chair) 

Dr Rosalind Hollingsworth, (Global Medical 

 Lead, Pfizer) 

Dr Charles Stoecker (Tulane University, School 

of Public Health) 

 

 10:45	 Break 

12:00	 Hepatitis Vaccines 

Update: ACIP Hepatitis Work Group 

1:15	 Public Comment 

1:30	 Adjourn 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

5:45	 Public Comment 

AGENDA ITEM PURPOSE PRESIDER/PRESENTER(s) 

Dr Brendan Jackson (CDC/NCEZID) 

Information 

Information 

Discussion 

Dr Tamara Pilishvili (CDC/NCIRD) 

9:55	 Vaccine Supply Information Dr Jeanne Santoli (CDC/NCIRD) 

10:00	 Measles Update 

 Global update 

 Domestic update

Information 

Discussion 

Mr Jim Goodson (CDC/CGH/GID) 

Dr Greg Wallace (CDC/NCIRD) 

11:00	 Meningococcal Vaccines 

 Introduction 

 Epidemiology of meningococcal disease outbreaks in the United 

States 

 Interim guidance for the use of serogroup B meningococcal 

vaccines under a CDC-sponsored IND 

Dr Lorry Rubin (ACIP, WG Chair) 

Dr Sarah Meyer (CDC/NCIRD) 

Ms Jessica MacNeil (CDC/NCIRD) 

Information 

Discussion 

 Information Dr Art Reingold (ACIP, WG Chair) 

Acronyms 

CDC Centers for Disease Control & Prevention
 

CMS Centers for Medicare and Medicaid Services
 

DOD Department of Defense
 

DVA Department of Veterans Affairs
 

FDA Food and Drug Administration
 

GRADE Grading of Recommendations Assessment, Development and Evaluation
 

HRSA Health Resources and Services Administration
 

IHS Indian Health Service
 

IIV Inactivated Influenza Vaccine
 

IND Investigational New Drug
 

IHS Indian Health Service
 

LAIV Live-Attenuated Influenza Vaccine
 

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

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

NCZVED National Center for Zoonotic, Vector-Borne, and Enteric Diseases [of CDC/OID]
 

NIH National Institutes of Health
 

NVPO National Vaccine Program Office
 

WG Work Group
 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Acronyms 

AAFP American Academy of Family Physicians 

AAP American Academy of Pediatrics 

ABCs Active Bacterial Core Surveillance 

ACA Affordable Care Act 

ACIP Advisory Committee on Immunization Practices 

ACNM American College of Nurse Midwives 

ACOG American College of Obstetricians and Gynecologists 

ACP American College of Physicians 

AE Adverse Events 

AFP American Family Physicians 

AHIP America’s Health Insurance Plans 

AIM Association of Immunization Managers 

AMA American Medical Association 

ANA American Nurses Association 

BLA Biologics License Application 

CBER Center for Biologics Evaluation and Research (FDA) 

CDC Centers for Disease Control and Prevention 

CGD Chronic Granulomatous Disease 

CHS Chediak-Higashi Syndrome 

CI Cochlear Implants 

CIN Cervical Intraepithelial Neoplasia 

CISA Clinical Immunization Safety Assessment 

CMS Centers for Medicare and Medicaid Services 

COI Conflict of Interest 

COID Committee on Infectious Disease 

COPD Chronic Obstructive Pulmonary Disease 

CSF Cerebrospinal Fluid 

CSTE Council of State and Territorial Epidemiologists 

CUMC Columbia University Medical Center 

DoD Department of Defense 

DSMB Data Safety Monitoring Board 

DTaP Diphtheria, Tetanus, and Pertussis 

DVA Department of Veterans Affairs 

ED Emergency Department 

EMA European Medicines Agency 

EMR Electronic Medical Record 

FACA Federal Advisory Committee Act 

FDA Food and Drug Administration 

GBS Guillain–Barré Syndrome 

GMTs Geometric Mean Titers 

GP General Practitioner 

GRADE Grading of Recommendation Assessment, Development and Evaluation 

GSK GlaxoSmithKline 

HR Hazard Ratio 

HCT Hematopoietic Cell Transplants 

HHS (Department of) Health and Human Services 

Hib Haemophilus influenzae Type b 

HPV Human Papillomavirus 

HRSA Health Resources and Services Administration 

IAC Immunization Action Coalition 

ICD International Classification of Diseases 

IDSA Infectious Disease Society of America 

IHR International Health Regulations 

IHS Indian Health Service 

IIS Immunization Information System 

IIV Inactivated Influenza Vaccine 

ILI Influenza-Like Illness 

ILINet Influenza-Like Illness Surveillance Network 

IND Investigational New Drug 

IOM Institute of Medicine 

IPD Invasive Pneumococcal Disease 

IRB Institutional Review Board 

IRR Incidence Rate Ratio 

ISO Immunization Safety Office 

JE Japanese Encephalitis 

LAD Leukocyte Adhesion Deficiency 

LAIV Live Attenuated Influenza Vaccine 

MAARI Medically Attended Acute Respiratory Illness 

MAW Medically-Attended Wheezing 

MCV4 Meningococcal Conjugate Vaccine 

MedDRA Medical Dictionary for Regulatory Activities 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

MMWR Morbidity and Mortality Weekly Report 

MSM Men Who Have Sex With Men 

NACCHO National Association of County and City Health Officials 

NCDPS North Carolina Department of Juvenile Justice and Delinquency Prevention 

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

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

NFID National Foundation for Infectious Diseases 

NHANES National Health and Nutrition Examination Survey 

NHIS National Health Interview Survey 

NIAID National Institute of Allergy and Infectious Diseases 

NICU Neonatal Intensive Care Unit 

NIH National Institutes of Health 

NIS National Immunization Survey 

NMA National Medical Association 

NNV Number Needed to Vaccinate 

NVAC National Vaccine Advisory Committee 

NVP National Vaccine Plan 

NVPO National Vaccine Program Office 

OM Otitis Media 

PCV Pneumococcal Conjugate Vaccine 

PhRMA Pharmaceutical Research and Manufacturers of America 

PICO Population, Intervention, Comparison, and Outcome 

PIDS Pediatric Infectious Diseases Society 

PRISM Post Licensure Rapid Immunization Safety Monitoring 

PRNT Plaque Reduction Neutralization Test 

QALYs Quality Adjusted Life Years 

RCA Rapid Cycle Analysis 

RCT Randomized Controlled Trial 

RIV Recombinant Influenza Vaccine 

SAEs Serious Adverse Events 

SAGE Strategic Advisory Group of Experts (WHO) 

SAHM Society for Adolescent Health and Medicine 

SCRI Self-Controlled Risk Interval 

SES Socioeconomic Status 

SME Subject Matter Expert 

SOS Serious Outcome Surveillance 

SSUAD Serotype-Specific Urinary Antigen Detection 

Td Tetanus-Diphtheria 

Tdap Tetanus and Reduced Diphtheria Toxoids 

TIV Trivalent Inactivated Vaccine 

TNF Tumor Necrosis Factor 

UK United Kingdom 

UNC University of North Carolina 

US United States 

VA Department of Veterans Affairs 

VAERS Vaccine Adverse Event Reporting System 

VE Vaccine Effectiveness 

VFC Vaccines for Children 

VICP National Vaccine Injury Compensation Program 

VIS Vaccine Information Statements 

VLP Virus-Like Particles 

VRBPAC Vaccine and Related Biologic Products Advisory Committee 

VRC Vaccination Report Card 

VSD Vaccine Safety Datalink 

WHA World Health Assembly 

WHO World Health Organization 

YF Yellow Fever 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Welcome and Introductions 

Welcome 

Dr. Jonathan Temte Dr. Larry Pickering 

Chair, ACIP / CDC Executive Secretary, ACIP / CDC 

Welcome 

Dr. Larry Pickering 

Executive Secretary, ACIP / CDC 

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

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

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

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

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

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

Chris Caraway. 

Emphasizing that there would be a full agenda for both days of the meeting, Dr. Pickering noted 

that handouts of the presentations were distributed to the ACIP members and were made 

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

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

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

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

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

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

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

Dr. Pickering expressed sincere appreciation to the three ACIP members for whom this would 

be their last ACIP meeting including Renee Jenkins, Tamera Coyne-Beasley, and Jeff Duchin 

who would be rotating off the committee at the end of June. He recognized them for their 

incredible contributions to ACIP over the past four years, stressing that they were members 

during a transformative time in this committee’s history. 

Dr. Temte acknowledged the passing of Ciro de Quadros who led efforts to successfully 

eradicate polio and measles in the Americas, as well as smallpox in Ethiopia. Dr. de Quadros 

died in May 2014 from pancreatic cancer. In an article for The Huffington Post in 2013, Dr. de 

Quadros wrote, “Medicine, sanitation, nutrition, education—all are necessary and interrelated 

components of preventing and curing sickness, but there is one tool that stands out as the most 

effective: vaccines. Every child—no matter where he or she is born—has a fundamental right 

to vaccines.” Dr. de Quadros was essential in efforts to eradicate smallpox, polio, and measles 

across the Americas. His work improved the lives of millions of people, and his commitment to 

country ownership of health programs helped fundamentally shape the current public health 

landscape. He served as Director of PAHO, Executive Vice President of the Sabin Vaccine 

Institute, and Director of Sabin’s Vaccine Advocacy and Education Program. Due to his work, a 

contingency of vaccine experts from Mexico was in attendance at the ACIP meeting through 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

sponsorship from PAHO and Sabin. Dr. Temte offered condolences to Dr. de Quadros’ wife 

Susan and his two daughters, and recognized his incredible body of work. 

Dr. Temte then recognized the following ACIP members who reached the end of their four-year 

terms and were rotating off of the committee, and presented each of them with a Certificate of 

Appreciation and a letter from Dr. Frieden, CDC’s Director: 

Dr. Tamera Coyne-Beasley 

Dr. Tamera Coyne-Beasley is an Associate Professor in the Department of Pediatrics and 

Department of Internal Medicine at the University of North Carolina (UNC), and is trained in both 

areas. She is also a Senior Fellow for the Center for Prevention of School Violence, and works 

with the North Carolina Department of Juvenile Justice and Delinquency Prevention (NCDPS). 

Dr. Coyne-Beasley has served as the Chair of the Adult Immunization Work Group, and has 

also been very active with the Measles, Mumps, and Rubella Work Group, Influenza Work 

Group, and HPV Work Group. She has also been very instrumental with the National Adult 

Immunization Summit. The first publication Dr. Temte could find for Dr. Coyne-Beasley was 

from 1999 titled, “Epidemiology of Adolescent Homicide in North Carolina from 1990-1995 in the 

Archives of Pediatric and Adolescent Medicine. In 2000, she published “The African American 

Church: A Potential Forum for Adolescent Comprehensive Sexuality Education.” In 2014, she 

published “Vaccine Intervention Effects from a Social Marketing Campaign to Promote HPV 

Vaccinations in Pre-Teen Boys.” In addition, Dr. Coyne-Beasley is a published poet and in 1995 

and 1997 she won the National Library of Poetry Excellence Award. 

Dr. Coyne-Beasley said that it had been one of life’s greatest pleasures and privileges to serve 

on and be a part of the ACIP. She expressed her gratitude for the opportunity, which included 

the opportunity to work with each and every one of her ACIP colleagues, CDC leaders and staff, 

liaison members, and audience members who share their wisdom and experiences such as Dr. 

Plotkin and Frankie Milley who has shared her pain and has turned that into a movement that 

supports vaccination. Dr. Coyne-Beasley said that she had never been so remorseful about 

rotating off of a committee, particularly one that requires so much work, time, and energy. She 

emphasized that what ACIP does is so important, as is the opportunity to deliberate extensively 

and make evidence-based recommendations that are translated into policy and practice within a 

matter of months or at least within a year. She expressed her hope that she had been able to 

contribute in some small way, and said that she looked forward to continuing to collaborate with 

ACIP. She expressed her sincere appreciation to her nominator who was a former ACIP Chair, 

was the Chair of Pediatrics at Duke when she was there, and also had something to do with the 

measles vaccine. She said she was eternally grateful for his support and his confidence in her. 

She also said that one of her greatest joys had been the opportunity to serve with one of her 

most invaluable and special mentors, Dr. Renée Jenkins. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Jeff Duchin 

Dr. Jeff Duchin is Chief of the Communicable Disease Epidemiology and Immunization Section 

for Public Health Seattle and King County in Washington State. He is also Associate Professor 

of Medicine in the Division of Allergy and Infectious Diseases at University of Washington 

School of Medicine. One of his quotes is, “The GRADE process makes me a low quality judge 

of the importance of my contributions.” Dr. Duchin has served as Chair of the Zoster, General 

Recommendations, and Febrile Seizure Work Groups and as a member of the Influenza and 

Pneumococcal Work Groups. He served as the ACIP liaison for the National Association of 

County and City Health Officials (NACCHO) from 2006 through 2010, as well as the Chair of the 

NACCHO Immunization Work Group. He was recently appointed as a member of the National 

Quality Forum, Adult Immunization Steering Committee, and the Public Health Committee for 

Infectious Disease Society of America (IDSA). Dr. Duchin has been very active with various 

efforts, including as an EIS Officer. Some of his publications include “Hantavirus Pulmonary 

Syndrome: A Clinical Description of 17 Patients with a Newly Recognized Disease” in 1994, 

“High Prevalence of Multidrug-Resistant Streptococcus pneumoniae among Children in a Rural 

Kentucky Community” in 1995, and “Evaluation of Electronic Ambulatory Care Data for Use in 

Influenza-Like Illness Surveillance Network (ILINet)” published in 2013. Dr. Temte noted that 

Dr. Duchin once became hypothermic in Hawaii when he got caught in a storm while biking at 

9,000 feet and had to seek aid at a ranger station. Dr. Duchin is an avid biker and often 

exercises at 3:00 am. 

Dr. Duchin said that it was a great honor and pleasure to serve with such a great group of 

colleagues, and that he had learned a lot from the experience. He looked at himself on the top 

of Haleakalā and asked himself the same question that he was asking now, “Where do you go 

from here?” Unfortunately, from Haleakalā one can only go down, so he was hoping the same 

was not true of his ACIP experience. He thanked his great colleagues on the CDC WGs who 

helped accomplish so much during his four years on the committee, particularly the Designated 

Federal Officers (DFO) Dr. Andrew Kroger from the General Recommendations WG, Craig 

Hales and Rafael Harpaz from the Zoster WG, and Lisa Grohskopf from the Influenza WG, and 

Tamara Pilishvili from the Pneumococcal WG. The DFOs make it possible for the WGs to 

accomplish what they do, and they are outstanding in their dedication, professionalism, and 

intelligence. It was a great pleasure to be able to work with those colleagues as well. Dr. 

Duchin also thanked everyone who participated in the WGs on which he served for their 

contributions, particularly some who were not present who joined them for the Febrile Seizure 

WG. He said it was a great honor to be an ACIP member during the time that Dr. Pickering 

characterized as transformative, making explicit the evidence base on which ACIP makes its 

recommendations. That is outstanding and is moving ACIP in a very good direction. He was 

also very impressed by the increasing sophistication and capacity of the vaccine safety 

program. It has been outstanding to have the contributions of the Immunization Safety Office 

(ISO), particularly with respect to issues pertaining to febrile seizures and other ongoing 

monitoring. He stressed that it had been a pleasure, and that he looked forward to continuing to 

contribute to the extent possible in the future. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Renée Jenkins 

Dr. Renée Jenkins is Professor and Chair Emeritus in the Department of Pediatrics and Child 

Health at Howard University College of Medicine in Washington, DC. She served as the Chair 

of the Childhood Schedule Harmonization Work Group and as a member of the HPV Work 

Group. She has also represented ACIP at National Vaccine Advisory Committee (NVAC) 

meetings. Looking at her resume, Dr. Jenkins has served on nearly every committee of the 

American Academy of Pediatrics (AAP) and the Society for Adolescent Health and Medicine 

(SAHM). Some of her publications include “Adolescent Hypertension” in 1975 and “Health 

Disparities across the Lifespan: Where are the Children?” in 2009. Dr. Jenkins has done 

virtually everything, including serving as the first African American President of SAHM in 1989, 

serving as the first African American President of the AAP in 2007, and being elected to the 

Institute of Medicine. ACIP stands in great honor of having Dr. Jenkins on the committee for the 

last four years. 

Dr. Jenkins said that it had been an awesome experience and responsibility in that when 

decisions are made at ACIP, they hold. That is a heavy weight to bring to the table, but it also 

reflects a sense of how important it is to get it done right. Many people contribute to that, of 

whom they are appreciative. She said she came along during a time when adolescents were 

given one vaccine, tetanus-diphtheria (Td), to now which is so complicated. During her 

experience with the AAP, she and Dr. Schuchat became more connected by incredible 

challenges such as the Jenny McCarthy movement. She had Dr. Bocchini on speed dial 

because so many questions needed to be answered. Dr. Jenkins said that while this has been 

quite a transition for her, she learned a lot and appreciated all of the people who contribute. 

She gave a “shout out” to Dr. Cody Meissner, who was her ACIP buddy who oriented her. 

Another issue that is evolving that she will be interested in following is cost, and how ACIP does 

now have to figure out how to address that. Resources are not endless, so consideration must 

be given to how to best use them. At one point, it was just the science, safety, and such issues. 

But now, cost is also part of the equation. She congratulated Dr. Temte for being such a 

fearless leader, and said she would miss him and would see him in Wisconsin. 

Dr. Temte then shared an image of the agenda from the first ACIP meeting convened 50 years 

ago on May 25, 1964, noting that the start time was 9:30 am. One of the agenda items was the 

simplification of the vaccine schedule, and another was the following statement pertaining to the 

formation of WGs: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

In terms of the simplification of the schedule, in 1964 there were seven vaccines in use (polio, 

smallpox, measles, diphtheria, tetanus, pertussis, and influenza). Going back 77 years, in 

particular with a nod to the March of Dimes, Dr. Temte shared a link to a YouTube video 

showing Franklin Delano Roosevelt (FDR) going to the All Star game in 1937 and reflecting the 

logistics needed to get someone with polio from the vehicle to the stands. The link for the video 

is http://youtube/CvKDwBMEycw. This counters the myth that FDR tried to avoid being seen in 

public with his polio, and it also underscores the important need across the world to eliminate 

polio. Also shown in the video are Lou Gehrig, Jimmie Foxx, Hank Greenberg, and Dizzy Dean. 

Dr. Temte concluded with a passage from Dr. William Carlos Williams, who was a family 

practitioner in New Jersey who dealt primarily with very poor immigrant families. He was 

posthumously awarded the Pulitzer Prize in May 1963 for his writing, and was one of the first 

American physician authors who was both a poet and an essayist. The following is an excerpt 

from his first published piece, which deals with an infant with meningitis: 

The baby is in a smother of sheets and crumpled blankets, its head on a pillow. The child’s left eye closed, its 

right partly opened. It emits a soft whining cry continuously at every breath. It can’t be more than a few weeks old. 

Do you think it is unconscious, doctor? 

Yes. 

Will it live? 

It is the mother. A grit tender-eyed blonde. Great full breasts. A soft gentle-minded woman of no mean beauty. 

A blue cotton house wrapper, shoulder to ankle. 

If it lives it will be an idiot perhaps. Or it will be paralysed—or both. It is better for it to die. 

There it goes now! The whining has stopped. The lips are blue. The mouth puckers as for some diabolic kiss. It 

twitches, twitches faster and faster, up and down. The body slowly grows rigid and begins to fold itself like a flower 

folding again. The left eye opens slowly, the eyeball is turned so the pupil is lost in the angle of the nose. The right 

eye remains open and fixed staring forward. Meningitis. Acute. The arms are slowly raised more and more from the 

sides as if in the deliberate attitude before a mad dance, hands clenched, wrists flexed. The arms now lie upon each 

other crossed at the wrists. The knees are drawn up as if the 

child were squatting. The body holds this posture, the child’s belly rumbling with a huge contortion. Breath has 

stopped. The body is stiff, blue. Slowly it relaxes, the whimpering cry begins again. The left eye falls closed. 

It began with that eye. It was a lovely baby. Normal in every way. Breast fed. I have not taken it anywhere. It is only 

six weeks old. How can he get it? 

The pointed beard approaches. It is infection, is it not, doctor? 

Yes. 

But I took him nowhere. How could he get it? 

He must have gotten it from someone who carries it, maybe from one of you. 

Will he die? 

Yes. I think so. 

Oh, I pray God to take him. 

Have you any other children? 

One girl five, and this boy. 

Well, one must wait. 

Again the night. The beard has followed me to the door. He closes the door carefully. We are alone in the night. 

It is an infection? 

Yes. 

My wife is Catholic—not I. She had him for baptism. They pour water from a can on his head, so. It runs down in 

front of him, there where they baptize all kinds of babies, into his eye perhaps. It is a funny thing. 

William Carlos Williams – Danse Pseudomacabre, 1920 

The Little Review VII. 1 46-49. 

Dr. Temte pointed out that the striking thing about this writing from 1920 is that it was so matter 

of fact. Infants and young people dying of meningitis was so commonplace. This is horrific and 

something rarely seen anymore due to the benefit of all of the things that Ciro de Quadros 

talked about (e.g., sanitation, education, good medical care, and especially vaccines). 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Pickering said he thought that for many of those in the room who lived through an era before 

vaccines were available, this was a very sad memory. Times are better now that most of these 

diseases can be prevented. 

He noted that at nearly every meeting, delegations from the World Health Organization (WHO) 

Pan-American Health Organization (PAHO) are in attendance. During this meeting, he 

welcomed the following delegates from Mexico’s Ministry of Health: 

 Dr. Jose de Jesus Mendez, Infant Health Subdirector for Mexico’s National Center for Child 

and Adolescent Health 

 Dr. Emilia Cain, Medical Supervisor, Mexico’s National Center for Child and Adolescent 

Health 

 Dr. Paulina Saldana, Medical Supervisor, Mexico’s National Center for Child and Adolescent 

Health 

 Dr. Armando Gonzalez, Division Director of Prevention and Disease Detection for the 

Mexican Institute of Social Security 

Dr. Pickering also welcomed Marla Dalton, Executive Director of the National Foundation for 

Infectious Diseases (NFID). 

With regard to information for future international visitors to ACIP meetings, due to changes in 

Department of Homeland Security (DHS) Policy, additional forms will be required for each 

meeting at the time an international guest registers. It is critical that international visitors 

complete and submit these forms as soon as possible following registration. Stephanie 

Thomas, Committee Management Specialist, will be able to help with any questions and 

concerns about the process. The next ACIP meeting will take place at CDC on Wednesday and 

Thursday, October 29-30, 2014. The registration deadline for U.S. citizens is Monday, 

October 13, and for non-U.S. citizens is Monday, October 6. Registration is not required for 

webcast viewing. Stephanie Thomas can assist anyone who experiences difficulties with this 

process. 

Dr. Pickering offered the following notes regarding liaison representatives: 

 David Johnson joined this meeting as liaison representative for Pharmaceutical Research 

and Manufacturers of America (PhRMA) in place of Damian Braga 

 Margot Savoy served as liaison representative during this meeting for the American 

Academy of Family Physicians (AAFP) in place of Jamie Loehr 

To avoid disruptions during the meeting, Dr. Pickering instructed those present to turn off all cell 

phones. He explained that topics presented during the ACIP meeting include open discussion 

with time reserved for public comment. During this meeting, a time for public comment was 

scheduled following the afternoon sessions during both meeting days. Time for public 

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

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

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

visit the registration desk in the rear of the auditorium to have Stephanie Thomas record their 

name and provide information about the process. Those who registered to make public 

comments were instructed to state their name, organization if applicable, and any conflicts of 

interest (COIs) prior to making their comments. 

He then announced several initiatives that are underway in an attempt to improve and 

accelerate communication and information delivery, including the following: 

 CDC has developed vaccine schedule apps for the child, adolescent, catch-up, and adult 

schedules-with a contraindications and precautions table. 

 Version 1.1 of the app is available in the app store for iPhone and iPad, and there is an 

Android version in the works. 

 This is the 50-year anniversary of ACIP, which held its first meeting in May of 1964. More 

information about this will be provided during the October meeting. 

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

safety presentation was planned for the first afternoon of this meeting. 

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

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

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

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

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

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

present to the committee on matters related to those specific vaccines. However, they are 

prohibited from participating in committee votes on issues related to those specific vaccines. 

Regarding other vaccines of the affected company, a member may participate in a discussion 

with a proviso that he or she abstains on all votes related to the vaccines of that company. It is 

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

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

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

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

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

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

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

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

Dr. Jean Clare Smith at jsmith2@cdc.gov 

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

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

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

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

published since the February 2014 ACIP meeting follows: 

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Dr. Pickering shared the following resource information pertaining to ACIP: 

 

 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Vaccine Safety: 

www.cdc.gov/vaccinesafety/index.html 

Immunization Schedules (2014): 

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

Vaccine Toolkit: 

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

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

www.immunizationforwomen.org 

You Are the Key to HPV Cancer Prevention: 

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

Vaccines for Preteens and Teens: 

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

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

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

 Coyne-Beasley: Research support is allocated to the University of North Carolina (UNC) 

by Merck Pharmaceuticals for clinical trials. 

 Bennett, Bocchini, Campos-Outcalt, Coyne-Beasley, Duchin, Harriman, Harrison, Karron, 

Jenkins, Kempe, Pellegrini, Reingold, Rubin, Temte, and Vazquez: No conflicts. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

General Recommendations 

Introduction 

Jeffrey Duchin, MD 

Chair, General Recommendations Work Group 

Dr. Duchin reminded everyone that the General Recommendations document is published in 

the Morbidity and Mortality Weekly Report (MMWR) every 3 to 5 years, and addresses a broad 

range of clinical practice issues that are relevant to all vaccines as opposed to the vaccinespecific publications. The General Recommendations are intended to address topics that 

cannot be attributed to a single vaccine, but that are germane to the practice of immunization in 

general. A number of topics have been or are being revised, including the following: 

 Timing and Spacing of Immunobiologics 

 Contraindications and Precautions 

 Preventing and Managing Adverse Reactions 

 Reporting Adverse Events After Vaccination 

 Vaccine Administration 

 Storage and Handling of Immunobiologics 

 Altered Immunocompetence 

 Special Situations 

 Vaccination Records 

 Vaccination Programs 

 Vaccine Information Sources 

The topics addressed during this session included: 

 Altered Immunocompetence 

 Vaccination Programs 

The updating process has basically been completed, with only a small amount of information 

that needs to be revised before the updated recommendations can be published. 

Dr. Duchin thanked Dr. Rubin and colleagues at the IDSA, because much of what was done 

was integrating the IDSA’s new guidelines for vaccination in persons with altered 

immunocompetence with the existing ACIP recommendations on vaccination of persons with 

altered immunocompetence. This is an increasingly complex area, so the collaboration with 

IDSA is very much appreciated. 

Vaccination In Persons with Altered Immunocompetence & Vaccination Programs 

Dr. Andrew Kroger 

CDC/NCIRD 

Dr. Kroger provided an update on the proposed changes to the Altered Immunocompetence 

section of the General Recommendations. He noted that all ACIP members should have four 

documents, including a clean copy and a version with tracked changes for each section. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

In terms of background, the following reflects the various components that are currently included 

in this section: 

 General Principles: 

 Defines “altered immunocompetence” 

 Refers to a table that describes broad categories of altered immunocompetence 

 Includes a statement that says that when there is deliberation to occur, providers are 

always welcomed and encouraged to refer to another treating provider who may be 

an expert in infectious disease or immunology 

 Altered Immunocompetence as an Indication to Receive a Vaccine: Describes 

situations in which a vaccine may be recommended outside of a routine age group, 

because altered immunocompetence is part of the patient’s profile 

 Vaccination of Contacts of Persons with Altered Immunocompetence: Emphasizes the need 

to provide community immunity 

 Vaccination with Inactivated Vaccines: Highlights, by way of general principles, that the 

concern is primarily with efficacy issues 

 Vaccination with Live Attenuated Viral and Bacterial Vaccines: Highlights, by way of general 

principles, that the concern is primarily with efficacy and safety issues 

 Recipients of Hematopoietic Cell Transplants (HCT) 

 Conditions or Drugs that Might Cause Immunodeficiencies: Highlights topics like asplenia 

for which it is difficult to apply general principles, such as withholding all live vaccines in all 

cases 

As noted by Dr. Duchin, IDSA published clinical practice guidelines in 2013 for vaccination of 

immunocompromised hosts. As far back as November 2011, CDC was involved with crosswalking topics in the draft of this document with vaccine-specific and general recommendations 

ACIP guidance. The IDSA document was published December 4, 2013. The authors include 

Dr. Lorry Rubin, who is a former member of the General Recommendations WG and current 

ACIP member, Dr. Harry Keyserling, who is a former member of the General Recommendations 

WG and a current member while these deliberations were ongoing. This is a very important 

source document for changes to the General Recommendations. There will be some 

differences between the two groups, which are primarily at the level of vaccine-specific 

recommendations and are not a part of the General Recommendations WG process. The 

primary differences are as follows: 

 IDSA: Recommendation for Gardasil® (HPV) for immunocompromised persons compared to 

ACIP recommendations .... 

 ACIP: No preference for Gardasil® or Cervarix® in immunocompromised females 

 IDSA: Recommendation for varicella vaccine for immunocompromised persons (within 

certain parameters) compared to ACIP recommendations.... 

 ACIP: Consideration for varicella vaccine for immunocompromised persons (within certain 

parameters) 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

In terms of what has changed in the General Recommendations document, there was 

information in the 2011 version that needed to be updated. Also, there is important resource 

information in the IDSA document as well as other source materials. For example, most of the 

primary source materials for changes to altered immunocompetence as an indication to receive 

a vaccine do not come from IDSA. These come from the vaccine-specific ACIP statements. 

This section addresses recommendations for use of pneumococcal, meningococcal, and HiB 

vaccines in patients who have conditions such as asplenia, anatomic barrier defects, 

cerebrospinal fluid (CSF) leaks, and Cochlear implants (CI). The WG has tried to harmonize the 

language in the General Recommendations document with the new information in the vaccinespecific documents for these vaccines. 

IDSA information is added into the sections on inactivated vaccines and vaccination with live 

attenuated viral and bacterial vaccines, so Dr. Kroger focused on these two sections. In terms 

of the background principles, the general statement is made that inactivated vaccines are safe 

in patients with altered immunocompetence, but that there are efficacy issues with both live and 

inactivated vaccines with certain diseases. Some specific diseases are listed in the IDSA 

document that the WG would like to incorporate into the General Recommendations. This is in 

the section where inactivated vaccine efficacy issues are discussed (Page 4, Line 26). 

Information is included from the IDSA document about B-lymphocyte deficiency and receipt of 

immunoglobulin therapy, with a recommendation to withhold both inactivated and by extension 

live vaccines. This is an efficacy issue. Patients receiving immunoglobulin therapy are thought 

to have reduced response even to inactivated vaccines. This is new to the General 

Recommendations. Likewise, cancer therapy and receipt of anti-B lymphocyte therapy (e.g., 

rituximab) will be addressed here. From the IDSA, the WG hopes to incorporate a 

recommendation to delay inactivated vaccines 6 months as opposed to 3 months. Again, this 

would be an efficacy issue. 

Safety and efficacy apply to the section on vaccination with live viral and bacterial vaccines. 

Clarification is included in this section about specific diseases (Page 5, Line 4). This will have 

relevance to the categories that were split out in the table as well. For instance, Chronic 

Granulomatous Disease (CGD) is described as a condition for which live bacterial vaccines 

should be withheld. However, with other phagocyte deficiency diseases such as Leukocyte 

Adhesion Deficiency (LAD) and Chediak-Higashi Syndrome (CHS), a recommendation is made 

to withhold both live bacterial and live viral vaccines. The 2011 General Recommendations are 

simplified in that they only recommend to withhold live bacterial vaccines, so this is new 

information from IDSA. The WG does not want to get into the specifics in the print of the 

General Recommendations document, but this has to do with the risk of these particular types 

of infections. With CGD and the lack of oxidative bursts associated with intercellular killing, 

patients have increased risk of bacterial infections. However, with LAD and CHS, there are 

adherence issues with the defects in natural killer cells that generate a risk for viruses and 

bacteria. A recommendation is included to withhold live bacterial vaccines with conditions such 

as defects of interferon-gamma/interleukin-12 axis, as well as a recommendation to withhold live 

bacterial and live viral vaccines with conditions such as defects of interferon-alpha or interferongamma. Again, that is a risk issue for those two conditions. 

Table 13 currently appears as follows; however, it will be updated to include the information just 

provided: 

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TABLE 13. Vaccination of persons with primary and secondary immunodeficiencies

Primary Specific 

immunodeficiency 

Contraindicated 

vaccines* 

Risk-specific 

recommended 

vaccines* 

Effectiveness and 

comments 

B-lymphocyte 

(humoral) 

Severe antibody 

deficiencies (e.g., X-linked 

agammaglobulinemia and 

common variable 

immunodeficiency) 

OPV†Smallpox

LAIV 

BCG 

Ty21a (live typhoid) 

Yellow fever 

Consider varicella 

vaccination in isolated 

humoral 

immunodeficiency 

The effectiveness of 

any vaccine is 

uncertain if it 

depends only on the 

humoral response 

(e.g., PPSV or 

MPSV4). 

IGIV interferes with 

the immune respons

to measles vaccine 

and possibly varicella

vaccine. 

e 

Less severe antibody 

deficiencies (e.g., selective 

IgA deficiency and IgG 

subclass deficiency 

OPV†

BCG 

Yellow fever 

Other live vaccines appear to 

be safe. 

Pneumococcal 

Hib 

All vaccines likely 

effective; immune 

response might be 

attenuated. 

T-lymphocyte 

(cell-mediated 

and humoral) 

Complete defects (e.g., 

severe combined 

immunodeficiency [SCID] 

disease, complete DiGeorge

syndrome) 

Partial defects (e.g., most 

patients with DiGeorge 

syndrome, Wiskott-Aldrich

syndrome, ataxiatelangiectasia) 

Interferongamma/Interleukin 12 axis 

deficiencies 

All live vaccines§,¶,** 

All live vaccines§,¶,** 

All live bacterial vaccines 

(All live vaccines 

contraindicated in 

Interferon-gamma or 

interferon-alpha 

deficiencies) 

Pneumococcal 

Pneumococcal 

Meningococcal 

Hib (if not administered 

in infancy) 

Vaccines might be 

ineffective. 

Effectiveness of any 

vaccine depends on 

degree of immune 

suppression. 

Complement Persistent complement,

properdin, or factor B 

deficiency 

 None Pneumococcal 

Meningococcal 

Hib 

All routine vaccines

likely effective. 

Phagocytic 

function 

Chronic granulomatous 

disease 

Leukocyte adhesion defect

and myeloperoxidase 

deficiency. 

Live bacterial vaccines§ 

Live viral and bacterial 

vaccines§¶ 

, Pneumococcal All inactivated 

vaccines safe and 

likely effective. 

Live viral vaccines 

likely safe and 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

For HCT patients, the 2011 General Recommendations document refers to the source Tomblyn 

M, Chiller T, Eisele H, et. Al. Biol Blood Marrow Transplant 15:1143-1238;2009. When this was 

discussed in February 2009 for the last iteration of the General Recommendations, there was a 

recommendation to specifically reference this document, which was followed. The document 

was readily available for those using CDC’s website, and the WG tried to incorporate as much 

as possible in the document. IDSA now publishes recommendations for HCT in 

Rubin, LG, Levin MJ, Ljungman P., et. al. 2013 IDSA Clinical Practice Guidelines for 

Vaccination of the Immunocompromised Host. Clin. Infect. Dis. 2014; 58: e-44-100. HCT is a 

special category of altered immunocompetence because the patient is not only immunodeficient 

as a result of either underlying disease or treatment, but also is considered to be 

immunoablated (e.g., their entire immune history is completely removed). This raises concerns 

not only about which vaccines to give and contraindications or precautions, but also about 

revaccinating patients who have had vaccines administered prior to HCT. 

The IDSA document is remarkably similar to the 2009 document. They are basically identical 

for pneumococcal conjugate vaccine (PCV) vaccines for which a specific series is 

recommended post-HCT. Zoster and rotavirus vaccine are not recommended post-HCT, so that 

remains the same. The IDSA document is remarkably flexible with respect to different 

strategies for these patients. Often, multiple options are presented, specifically with the use of 

pertussis-containing vaccines. This is a unique issue with respect to HCT, because in this 

circumstance, patients who receive pertussis-containing vaccines will have waning of immunity 

anyway, so these two issues have to be reconciled. That is to say, the schedule for post-HCT 

should take into account that routine scheduling of pertussis vaccine already accounts for lack 

of residual immunity. The IDSA document does a good job of providing multiple options for 

patients with respect to use of pertussis-containing vaccines post-HCT. There are some 

changes from the 2009 document. HPV vaccine is recommended post-HCT in the IDSA 

document. Varicella vaccine is recommended in the IDSA document as long as the patient is 

immunocompetent, does not have graft versus host disease, and is 24 months post-HCT. That 

would be a new addition to the General Recommendations. 

In terms of conditions or drugs that might cause immunodeficiency, IDSA classifies its 

categories somewhat differently than ACIP traditionally has done. It defines different levels of 

immunosuppression as high- or mid-level. In IDSA, high-level includes the following: 

 Three-months withholding of live vaccines following completion of cancer chemotherapy 

 Two-month withholding of live vaccines following completion of solid organ transplant 

rejection therapy 

 Daily corticosteroid therapy with dose 20 mg or higher prednisone equivalent (or 2 mg/kg or 

greater) for 14 days or more 

 Receiving immune modulators such as tumor necrosis factor (TNF)-alpha inhibitors or anti-B 

cell agents (rituximab) 

IDSA low-level immunosuppression includes the following, which ACIP previously considered 

not immunosuppressed at all for the purposes of some drugs: 

 Alternate dose corticosteroid therapy 

 Methotrexate, azathioprine or 6-mercaptopurine in doses as stated in ACIP Zoster Vaccinespecific statement 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

IDSA defines the interval following the use of a medication in terms of low-dose (1 month 

interval), high-dose (3 month interval unless otherwise stated), solid organ transplant antirejection (2 month interval), and anti-B lymphocyte (6 month interval) for administration of both 

live and inactivated vaccines. There is a bidirectional nature to this recommendation in terms of 

what to do if the vaccine is given first. The IDSA document has made some changes here as 

well. The document recommends withholding live vaccines unless 4 weeks before the 

beginning of therapy, and a full recommendation to withhold 2 weeks before beginning of 

therapy. The provider would use this recommendation to determine the threshold by which they 

would need to wait if the vaccine is given first before starting therapy. For inactivated vaccines, 

IDSA recommends withholding 2 weeks before beginning of therapy. 

The 2011 General Recommendations divides the discussion into the following categories: 

 Vaccination of Children and Adolescents 

 Adult Vaccination 

 Evidence-Based Interventions to Increase Vaccination Coverage 

 Other General Programmatic Issues 

Changes by the WG have been to include the adult vaccination standards, which are discussed 

in the introduction to the entire Vaccination Program section. Clear language has been included 

to discuss the Affordable Care Act (ACA) that states, “Effective for all health-plans drafted or 

updated after September 2010, the ACA requires plans to cover ACIP recommended vaccines 

without deductibles or copayments when delivered by an in-network provider.” There is a 

discussion of barriers to vaccination in the General Recommendations adult component of this 

section, which is where this language was inserted. ACA applies to childhood and adult 

vaccination, though it could be argued that the impact may be greater with adult compared to 

childhood vaccinations. The 2011 General Recommendations included of information on costeffectiveness, which the WG decided to remove. One reason was because it caused an 

imbalance in the document. While there was cost-effectiveness information in the adult section, 

there was really no cost-effectiveness or cost-savings data described in the child section. When 

this section was first built in the General Recommendations, ACIP-specific documents were 

incorporated about adult immunization and VFC. To balance this, the cost-effectiveness 

discussion was removed. Cost-effectiveness is best discussed in vaccine-specific statements 

rather than the General Recommendations. 

The last change by the WG is the Strategies Table, which was updated based on the Task 

Force for Community Preventive Services (Task Force) with current updates from The 

Community Guide.org/vaccine/index.html. The Task Force has removed the word “strongly” and 

now states “recommended.” They have made a change to certain recommendations as well. 

For instance, “patient or family incentives or sanctions” previously was listed as having 

“insufficient evidence.” In the interim, the Task Force has divided that out as “patient or family 

incentives” are recommended and “sanctions” are not recommended. This appears in Table 15 

as follows: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

TABLE 15. Recommendations regarding interventions to improve coverage of 

vaccines recommended for routine use among children, adolescents, and adults

Intervention Recommendation

Increase community demand for vaccination

Client reminder or recall systems Recommended 

Requirements for entry to schools, child-care facilities, 

and colleges 

Recommended

Community education alone Insufficient evidence

Community-based interventions implemented in 

combination

Recommended

Clinic-based education Insufficient evidence

Patient or family incentives Recommended

Patient or family monetary sanctions Insufficient evidence

Client-held medical records Insufficient evidence

Enhance access to vaccination services

Reducing out-of-pocket costs Recommended

Enhancing access through the U.S. Department of 

Agriculture's Women, Infants, and Children program

Recommended 

Home visits, outreach, and case management targeted 

to particularly hard to reach populations to increase 

vaccination rates

Recommended 

Enhancing access at schools Recommended

Expanding access in health care settings Recommended as part of 

multicomponent interventions only

Enhancing access at organized child care centers Recommended

In conclusion, Dr. Kroger indicated that the next steps would be to invite discussion during this 

session, and an anticipated vote on the entire updated General Recommendations document 

during the October 2014 ACIP meeting. All of the important sections have been discussed by 

ACIP, with the exception of the introductory paragraph and the vaccine information sources. He 

will update those two sections. Areas that need some editing include vaccination of the 

hospitalized patient and all of the interventions such as anesthesia or surgery that may occur, 

alternate routes and whether doses are counted when given at alternate routes, and febrile 

seizures with respect to simultaneous vaccination. 

Dr. Kroger expressed gratitude to outgoing Chair, Dr. Duchin. The WG went through a great 

deal of very complicated subject material over the last four years, which Dr. Duchin’s 

meticulous but easy going style made very pleasurable. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Discussion Points 

Dr. Riley (ACOG) is involved with high-risk obstetrics, and is commonly asked about women 

who are on rituximab. They have not been delaying their vaccination because there may be 

only six months of pregnancy. If there is a suggestion, it should be incorporated someplace 

because the natural reflex is going to be not to give it. She was concerned that inactivated 

influenza vaccine and tetanus and reduced diphtheria toxoids (Tdap) that should be given might 

be delayed because of the six-month concern, which will miss the ability to protect the infant. 

Dr. Kroger responded that this is being discussed by CDC, less so the issue of vaccination of 

the pregnant woman herself, although that is an important topic, but the WG is also discussing 

the issue of whether immunodeficiency can be transferred to the infant. That has relevance with 

rotavirus vaccine, which is given in early infancy. He did not know how much movement there 

would be on those recommendations. It might be in the rotavirus vaccine-specific statement as 

opposed to the General Recommendations, but perhaps they can get it into the General 

Recommendations as well. The issue of vaccinating the pregnant woman herself, there is a 

general recommendation regarding live vaccination during pregnancy. Live vaccines generally 

are contraindicated in pregnancy, so the pregnancy itself might contraindicate the use of these 

medications as well if they are defined as immunosuppressive. This may need to be discussed 

further during review of the Special Situations section of the General Recommendations, which 

includes a discussion of pregnancy. 

Dr. Rubin noted that in studies conducted in which people are vaccinated who have received 

rituximab, since it is essentially a B lymphocyte poison, they just do not make antibody. In 

terms of relying on humoral immunity, the likelihood of significant effectiveness is extremely low. 

Dr. Riley (ACOG) inquired as to whether his suggestion would be not to bother in those patients. 

Dr. Rubin replied that his personal suggestion would be that there is very little risk, but the 

likelihood of a positive effect is virtually zero so he would not give it. 

Dr. Harrison inquired as to whether ACIP was going to attempt to harmonize with IDSA or 

remain divergent. 

Dr. Kroger responded that the goal was to harmonize the General Recommendations with 

IDSA, but this does involve a degree of “cherry picking” from the IDSA document. That is what 

the WG attempted to do in the draft as opposed to not putting content in the draft and just 

including a citation. There will be ongoing attempts through discussion with vaccine subject 

matter experts (SMEs) on specific issues that may appear in vaccine-specific statements that 

may not harmonize precisely with what is in IDSA’s document. That is outside of the purview of 

the General Recommendations WG. The work is ongoing. The recommendations for use of 

zoster vaccine are not harmonized with ACIP specific recommendations, but the vaccine SMEs 

are aware of these issues. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Child/Adolescent Immunization 

Introduction 

Renée Jenkins, MD 

Chair, Child/Adolescent Immunization Work Group 

Dr. Jenkins indicated that this session would include a review of the status of the 

childhood/adolescent immunization schedule; a review of a provider interview project to assess 

the usability of the catch-up schedule; and a presentation of the draft supplementary table (job 

aid) for diphtheria, tetanus, and pertussis (DTaP) vaccine for ACIP review. She indicated that 

Dr. Kroger would present on behalf of Dr. Strikas, CDC Work Group Lead, who was unable to 

attend due to a scheduling conflict. 

Healthcare Provider Review of 2014 Catch-Up Schedule and Supplementary Tables 

Dr. Andrew Kroger 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Kroger indicated that CDC has the following two schedules currently being used for 

childhood immunizations: 

 A schedule of recommended vaccines for children ages birth through 18 years 

 A catch-up schedule for when vaccines have been missed or children are behind in the 

schedule 

There has been an ongoing effort since 1964 to clarify the schedule as it has become 

increasingly complicated, and even more so recently. As follows is Figure 2, the 2014 

childhood/adolescent immunization catchup schedule. There is abundant, dense text for some 

of the vaccines, particularly Hib and pneumococcal conjugate, and to a lesser extent 

DTaP/Tdap: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

In an effort to improve childhood and adolescent immunization schedules, CDC and partner 

organizations have developed job aids to be used with the current catch-up schedule. 

In addition to testing the job aids, CDC wanted to learn from practicing providers their current 

usage of the catch-up schedule, ease of use, and how it might be improved so that a catch-up 

schedule can be more user friendly. 

CDC created job aids for two vaccines: 

 Haemophilus influenzae type b (Hib) 

 Diphtheria, tetanus, and acellular pertussis (DTaP); tetanus, diphtheria, and acellular 

pertussis (Tdap); tetanus and diphtheria (Td) 

Two job aids were borrowed from the Immunization Action Coalition (IAC): 

 Pneumococcal conjugate (PCV13: http://www.immunize.org/catg.d/p2016.pdf) 

 Meningococcal conjugate (MCV: http://www.immunize.org/catg.d/p2018.pdf 

The job aids were tested in variable formats with healthcare providers. Formats were 

sometimes shown in algorithm forms as opposed to table form, and the table was broken up in 

different ways as well. Eight groups of healthcare providers were interviewed, including the 

following: 

 Family Practitioners 

 Pediatricians 

 Public Health Nurses 

 Nurse Practitioners 

 Nurses in Private Settings 

 Physician Assistants 

 Medical Assistants 

 Immunization Information System or Registry Staff 

These target audiences were chosen because of their role in vaccinating children. Physician 

participants were identified who are board-certified in either pediatrics or family practice. All 

participants had to report spending at least 50% of their time in direct patient contact; deciding 

what childhood or adolescent immunizations they will recommend for at least five patients per 

week; and that they work primarily in a private practice or a public health clinic that provides 

immunizations to children. These qualifications did not apply to participants who worked at 

state registries. 

CDC contacted several professional organizations in mid-February to recruit potential 

participants, including the following: 

 American Academy of Pediatrics (AAP) 

 American Association of Family Practitioners (AAFP) 

 American Nurses Association (ANA) 

 American Association of Physician Assistants (AAPA) 

 National Association of Pediatric Nurse Practitioners (NAPNAP) 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

State health departments and state immunization registries were also contacted. The original 

goal was to contact 10 to 15 people from each of 8 providers groups, anticipating an 

approximately 46% response rate to result in 48 records. Contact information was received for 

55 individuals, all of whom were contacted. The following table reflects the make-up of 

practices contacted and interviewed: 

Type of Practice Contacted Scheduled Interviewed Target % Completed 

Family Practice 

Physicians 

11 7 7 10 70 

Public Health Nurses 9 4 4 5 80 

Private Setting Nurses 6 3 1 5 20 

Registry 3 2 2 3 66 

Pediatricians 9 6 6 10 60 

Nurse Practitioners 7 5 5 5 100 

Physicians Assistants 4 1 1 5 20 

Medical Assistants 6 4 4 5 80 

Totals 55 32 30 48 62 

The Survey Monkey internet-based survey tool was used to create a questionnaire for this 

project and to collect data. Survey Monkey collected demographic information, information 

about how the participants were using the current catch up schedule, and their initial 

impressions of the job aids. Respondents’ answers from Survey Monkey were reviewed on the 

day of the phone interview, and they were then asked about three case studies of children with 

lapsed vaccinations. The case studies were for the pneumococcal, Hib, and meningococcal job 

aids. Participants were asked to review the case study, and answer using the catch up 

schedule and then the job aid. The interviews were conducted from March 20, 2014 through 

May 1, 2014. Over 50% of the target number was reached for 6 of the 8 groups, and 30 people 

were interviewed. By this point, there was enough similarity of responses to analyze the results. 

The following example is one of the 4 pages of the DTaP job aid, which was one of the products 

given to the respondents: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

The job aid table is intended for instantaneous use by providers when they see a patient to 

make a decision about what immunizations are needed. The last column provides information 

about when the next dose is due, and is important for discussions with patients. This is a 

prospective tool. It is not meant to be used to validate doses that have already been given, but 

instead is to support use of the childhood schedule moving forward. This is an easier way to 

see the information. 

This is the IAC pneumococcal job aid, which is useful and was included in the interview and 

focus group: 

The IAC combines catchup vaccination with high risk recommendations, which is quite an effort 

and accomplishment. However, the Child/Adolescent Immunization WG’s goal is to focus on 

the healthy child for CDC’s tools. 

In terms of the survey results, participants felt that the current catch-up schedule has very useful 

information but that it is difficult to read or understand. Specifically, the footnotes were brought 

up often as too dense, confusing, and that people can either miss them or not reference them. 

For the Hib job aid, a table and an algorithm were given to participants. Two-thirds of 

participants preferred tables over algorithms. Two participants had no preference. The 

preference was evenly split for the DTaP tables, but there was a slight preference for Version 2 

that is a single table. Some participants felt that Version 1 was easier to read and provides a lot 

of information, but there was a slight preference to have a separate table for the tetanus toxoidcontaining vaccines. 

The meningococcal and pneumococcal job aids created by the IAC were provided to 

participants. Each table was on only one page. Participants liked these, and thought the tables 

were clear and easy to read. There were some comments about highlighting or bolding certain 

sections or moving footnotes directly into the table. 

Overall people liked the job aids and think that they would be a helpful resource. Participants 

were very appreciative that CDC is creating something to help them with reading the current 

catch up schedule. The best summary of what the job aids should do came from a participant 

who said, “It should be clear, concise, and correct.” 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Regarding next steps, the job aids will be refined as necessary by CDC staff to appear the same 

as the DTaP example shown earlier. ACIP members were asked to review the DTaP format 

and offer any input in the next several weeks. The job aids will be CDC documents, and will be 

clearly noted as adjuncts to the published Recommended Immunization Schedule for persons 0 

through 18 years of age to assist with schedule interpretation. 

Discussion Points 

Dr. Temte commented that 90% of the questions he gets in his clinic deal with just this question,
 

particularly from medical assistants. He thinks having a flow-through table will be very
 

beneficial as compared to the current tool, and he thanked the WG for this effort.
 

Dr. Harriman inquired as to whether there was a goal to work with manufacturers of electronic
 

medical records (EMRs) to have these programmed in, which would be optimal.
 

Dr. Kroger replied that there has been an ongoing project with the registry branch of his division 

to ensure that the information in the CDC childhood schedule and the General
 

Recommendations are incorporated into EMRs. The childhood schedule has the tool for
 

moving forward for someone with a lagged schedule. The General Recommendations has the
 

table that is useful for back-validating, which is known as evaluation in the registry and 

forecasting for forward thinking. CDC is working with the registry group to ensure that ACIP 

recommendations are programmed in. The registry group has stated repeatedly that they want 

to program in what ACIP recommends. The job aids will be harmonized with the childhood 

schedule, so it will not matter whether the job aid or the schedule is used to interact with the 

registry. 

Beyond the registry, Dr. Harriman said she was thinking of EMR systems such that reminders
 

and pop-ups would be programmed in.
 

Dr. Kroger said he thought there was a process to harmonize the way the registry functions with
 

medical records as part of Meaningful Use as well. That is an ongoing concern and 

consideration.
 

Dr. Schuchat added that there is ongoing work with EMR vendors. The ideal circumstance is 

bidirectional information flow between the EMR and registries so that in a single application, a
 

practitioner opens the EMR, it queries the registry for all relevant doses, and indicates what 

needs to be done at that point. This is a major priority for CDC in the Office of the National
 

Coordinator.
 

Dr. Groom (IHS) said she was happy to see the job aids, but requested to follow-up with Dr. 

Kroger, because she was still seeing a contradiction in the catch-up schedule about whether 

one of the children in the case IHS presented to him would need the booster dose of Hib. As 

she read through the current language and tried to unpack it, she could come to two different
 

conclusions.
 

Dr. Kroger acknowledged that SME follow-up is needed on that point, and indicated that the 

issue was one of beginning vaccination at 7 months or older and getting three doses in, and
 

whether the dose at 12 months or older was needed.
 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Yellow Fever Vaccine 

Introduction 

Joseph A. Bocchini, Jr, MD 

ACIP, Workgroup Chair 

Japanese Encephalitis (JE) and Yellow Fever (YF) Vaccines Work Group 

Professor and Chairman, Department of Pediatrics 

Louisiana State University Health Sciences Center 

Dr. Bocchini reminded everyone that this WG has been tasked with evaluating the World Health 

Organization (WHO) decision for continuation of a booster dose for Yellow Fever (YF) vaccine. 

The Japanese Encephalitis (JE) Work Group became the JE and YF Vaccines Work Group. 

The membership of the WG was modified to add the expertise needed to evaluate the question 

they were asked to solve. He indicated that during this session, Dr. Staples would provide the 

GRADE evaluation of the available evidence pertaining to the use of YF vaccine booster doses, 

as well as the WG conclusions and recommendations for consideration, which would lead to a 

vote. He then highlighted some of the key issues. 

Since 1965, the International Health Regulations (IHR) allowed countries to require a YF 

vaccine dose within past 10 years for entry. In April 2013, the WHO Strategic Advisory Group of 

Experts (SAGE) concluded single dose of YF vaccine is sufficient to confer sustained immunity 

and lifelong protection. Therefore, booster doses were no longer considered to be needed. 

However, SAGE did identify that there are specific risk groups who might benefit from a second 

dose or booster dose in its recommendations. YF vaccine is the only vaccine covered by IHR. 

IHR does stipulate that YF vaccine provides protection against infection for 10 years. Requiring 

proof of vaccination (i.e., certificates) from travelers is at the discretion of each country; 

therefore, the certificate of vaccination provided at the time of vaccination is valid for 10 years. 

In May 2014, the WHO World Health Assembly (WHA) adopted an amendment to the IHR that 

extends YF vaccine protection to the life of the person vaccinated. Therefore, they will no 

longer recommend booster doses, and the change to the IHR will be official in June 2016. 

ACIP recommendations for YF vaccine were last updated in 2009 and were published in 2010. 

Currently, YF vaccination is recommended for the following: 

 Persons aged ≥9 months traveling to or living in areas at risk for YF virus transmission in 

South America or Africa 

 Laboratory workers exposed to virulent virus strains in their routine work 

 Per IHR, YF vaccine may be required by a country for entry at intervals of 10 years 

Also in the ACIP recommendations are the following statements: 

 Because of risk of serious adverse events (SAEs), health-care providers should vaccinate 

only persons who are at risk for exposure to YF virus or require proof of vaccination for 

country entry. 

 IHRs require revaccination at intervals of 10 years to boost antibody titer. Evidence from 

multiple studies demonstrates that YF vaccine immunity persists for many decades and 

might provide life-long protection. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

In essence, ACIP has followed IHR recommendations, but has not specifically made 

recommendations about use of the vaccine. 

Live attenuated YF vaccine was developed initially in the 1930s. The only YF vaccine available 

in the United States (US) is the 17D-204 strain vaccine (YF-VAX®) manufactured by Sanofi 

Pasteur. Over 540 million doses of YF vaccine have been administered worldwide. No human 

studies have been conducted to determine the efficacy or identify a correlate of protection for 

YF vaccine. One study established a minimal level of neutralizing antibodies needed to protect 

monkeys against virulent YF virus as log10 neutralization index (LNI) ≥0.7. This is not used for 

diagnostic evaluation of antibody response in humans given the vaccine. Humans are typically 

tested with a plaque reduction neutralization test (PRNT), but no correlate has been determined 

for this more commonly used test of protection. It is also not known whether the lack of 

detectable antibody in previously immunized person indicates susceptibility to YF after 

exposure. 

As noted, the JE Vaccine WG was reformed to include YF vaccine in October 2013. The WG 

has met 12 times to discuss YF vaccine booster doses. During these teleconference, the WG 

has reviewed the duration of immunity following YF vaccine and the safety of YF vaccine 

booster doses. The WG completed the GRADE analysis, reviewed the epidemiology of YF 

vaccine in travelers, and developed proposed recommendations. There have been two 

previous presentations to ACIP on this topic, including one in October 2013 focused on the WG 

charge and plans and one in February 2014 focused on YF and YF vaccine background 

information. 

The WG has 21 members who attended calls regularly and includes subject matter experts in 

YF and other live viral vaccines, travel medicine physicians, and representatives from several 

liaison groups as well as the Food and Drug Administration (FDA), National Institutes of Health 

(NIH), Department of Defense (DoD), and CDC. 

Background of YF Disease, YF Vaccine, and Recent Vaccine Developments 

J. Erin Staples, MD, PhD 

Arboviral Diseases Branch 

Division of Vector-Borne Diseases 

Centers for Disease Control and Prevention 

Fort Collins, Colorado 

The WG used GRADE to review data related to YF vaccine booster doses. The nine steps of 

GRADE are as follows: 

 Develop policy question 

 Identified and ranked importance of outcomes 

 Searched and reviewed of published and unpublished data 

 Summarized evidence for critical outcomes 

 Evaluated quality of evidence for outcomes 

 Assessed values related to options and outcomes 

 Reviewed health economic data 

 Considerations for formulating recommendations 

 ACIP recommendations and GRADE category 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

During her presentation, Dr. Staples went through each of these steps as they relate to the WG 

considerations for YF vaccine booster doses. The first step was to develop a policy question. 

The primary policy question developed by the WG was as follows: 

“Should booster doses of YF vaccine every 10 years continue to be recommended for 

healthy travelers and laboratory workers?” 

This included healthy travelers and laboratory workers of the population. The intervention was 

to remove the current recommendation for booster doses versus the current option, which is to 

continue the current recommendation for booster doses of YF vaccine. 

Next, the WG identified and ranked the importance of outcomes related to this policy question. 

Four benefits were assessed by the WG, including vaccine efficacy, vaccine effectiveness as 

measured by vaccine failures, seroprotection, and seropositivity. Although efficacy and 

seroprotection were considered critical, there are no data available for these areas. Given this, 

seroposivitity, which was originally assessed by the WG to be important, was changed to 

critical. Vaccine effectiveness and seropositivity were considered critical by the WG and were 

included in the evidence profile. Five harms were assessed by the WG, including SAEs, two 

known YF vaccine-associated SAEs (viscerotropic disease and neurologic disease), 

anaphylaxis, and systemic adverse events. SAEs, viscerotropic disease, and neurologic 

disease were considered critical by the WG and were included in the evidence profile. 

The WG next searched and reviewed published and unpublished data. To do this, the WG 

performed a systematic search and review of published literature. The WG identified 32 studies 

that reported primary data relevant to critical outcomes. In addition, the WG reviewed 

unpublished data from three sources as follows: 

 Data from Brazil Ministry of Health (MOH) on duration of immunity and vaccine failures 

 Vaccine Adverse Event Reporting System (VAERS) reports for YF vaccine administered 

from January 2007 through December 2013 

 CDC Arboviral Diseases Laboratory data on antibody titers in vaccine recipients ≥10 years 

post-vaccination 

Of the studies, five included data on vaccine effectiveness as measured by vaccine failures 

reported following YF vaccination from 1940 through 2013. The non-endemic population 

included travelers, laboratory workers, and military personnel from areas without YF virus 

transmission. The endemic population included persons who live in areas at risk for YF virus 

transmission. Few vaccine failures have been documented following YF vaccination over the 

last 70+ years. All but two cases where the data are known occurred in persons who reported 

receiving YF vaccine within the last 10 years. There was one vaccine failure noted 20 years 

and one at 27 years post-vaccination. To summarize the vaccine effectiveness data, 18 vaccine 

failures have been noted among over 540 million doses of YF vaccine delivered. There are 

limited data on the majority of cases that support the diagnosis of YF. Of the vaccine failures, 

16 (89%) occurred in persons receiving a YF vaccine dose in last 10 years. Two vaccine 

failures occurred ≥10 years from last YF vaccine dose (20 and 27 years). 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Seven studies contained seropositivity data 10 or more years following YF vaccination. Among 

those, two primary assays were noted. The mouse protection study which are no longer being 

used, and the more modern assay, the PRNT. For the PRNT, different cutoffs were used for 

virus inhibition, and different titers were used to define seropositivity. These seven studies 

contained data starting at 10 years post-vaccination and ranged from 77% to 100% of the 

subjects being seropositive. Six more studies contained seropositivity data up to 69 years postYF vaccination. The range for those that were seropositive among these studies was 75% to 

97%. 

To summarize, there have been 13 observational studies with immunogenicity data for 1,137 

persons vaccinated 10 or more years previously. There were 1,002 (88%) persons who were 

seropositive 10 or more years post-vaccination. However, when study size differences and 

variability between the studies were accounted for in a meta-analysis, the estimated 

seropositivity is 92% with a 95% confidence interval of 85% to 96%. The proportion decreases 

to 80% (131/164) by 20 years post-vaccination, but there are only 164 persons for whom there 

are data. The estimated seropositivity from the meta-analysis is also 80%, with a 95% 

confidence interval of 74% to 86%. 

For all harms, studies were included that had denominator data or more specifically, the number 

of adverse events for the total number of doses distributed or administered. There were 9 

studies with data on SAEs, which included data from 1990 through 2013. All of these studies 

were observational. To summarize the SAEs, there were 9 observational studies from 

manufacturers and national surveillance data that accounted for 333 million doses of vaccine 

administered. However, it is unknown how many of these doses were administered as primary 

versus booster doses, so rates could not be determined. There were 1,255 subjects who 

reported an SAE following YF vaccination. For 84% (1,054) of the subjects experiencing an 

SAE following YF vaccine, the vast majority, the dose type was unknown. Of the subjects 

experiencing an SAE following YF vaccine for whom the dose type was known, 7% (14/201) 

received a YF booster dose. 

In terms of viscerotropic disease data, a number of cases could have been included in the SAE 

table. The studies include data from 1990 through 2010 and range from studies that have 

42,000 up to 276 million doses administered. One viscerotropic disease case was noted 

following a booster dose of YF vaccine. To summarize, there were 8 observational studies from 

manufacturers and national surveillance data that included 437 million doses of vaccine 

administered. Again, it is unknown how many of those doses were administered as primary 

versus booster doses. Overall, 72 subjects reported viscerotropic disease following YF 

vaccination. The vaccination type was unknown for 57% (41) of subjects. For 3% (1/31) of 

subjects whose vaccination type was known, SAEs occurred following the booster dose. 

Similar to the viscerotropic disease cases, the neurologic disease cases may have been 

included on the SAE table. The studies pertaining to neurologic disease included data from 

1990 through 2010, and 3 neurologic disease cases were reported following booster doses of 

the vaccine. To summarize, there were 8 observational studies from manufacturers and 

national surveillance data that accounted for 462 million doses of vaccine administered. 

However, the number of doses administered as booster doses is unknown other than for one 

study. There were 218 subjects who reported neurologic disease following YF vaccination. For 

50% (108) of these subjects, the vaccine type was unknown. For 3% (3/110) of subjects for 

whom the dose type was known, neurologic disease was reported following the YF booster 

dose. 

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For vaccine effectiveness, there were 5 observational studies that had a risk of bias as there 

was incomplete case capture and no comparison group. These were also further downgraded 

due to the indirectness as the majority of data were from endemic areas, and it is unknown how 

many persons at risk for YF would not have received a booster dose of the vaccine. The final 

evidence type is 4 for vaccine effectiveness. For seropositivity, there were 13 observational 

studies. They had the same limitations, with the risk of bias coming from those who might have 

been tested for their long-term seropositivity, indirectness due to differences in the population, 

the fact that no vaccine efficacy or seroprotection data are available, and different assays and 

different cutoffs were used to assess seropositivity. The final evidence type for seropositivity is 

4. There were 8 to 9 observational studies related to the harms (SAEs, viscerotropic disease, 

neurologic disease). All harms were downgraded due to indirectness, as it was unknown for all 

but one study the number of doses that were administered as booster doses versus primary 

doses. Thus, the rate of SAEs could not be calculated. The evidence type was 4 for any SAE, 

viscerotropic disease, and neurologic disease. The overall quality of evidence for critical 

outcomes used to assess YF vaccine booster dose was Type 4—the lowest evidence type. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Regarding evaluation of the quality of evidence for the outcomes, the following evidence types 

are used for GRADE: 

 1 = Randomized control 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, observational studies with important limitations, or RCTs with 

several major limitations 

Before moving into the value assessment, Dr. Staples discussed an additional policy question 

considered by the WG. While the primary policy question focused on healthy travelers and 

laboratory workers, the additional policy question was created for special populations whose 

initial immune response to YF vaccine may be suboptimal. The question was: 

“Should booster doses of YF vaccine every 10 years continue to be recommended for 

travelers and laboratory workers who had a precaution to vaccination that might have 

negatively impacted their immune response to their primary dose of YF vaccine (e.g., 

pregnancy, asymptomatic HIV infection, or age 6-8 months)?” 

There were very limited data related to the special populations whose immune response to YF 

vaccine may be suboptimal. Therefore, the WG decided not to perform GRADE. However, the 

immunogenicity data were reviewed for pregnant women, HIV-infected persons, and young 

children for whom Dr. Staples presented data. 

Regarding the immunogenicity of YF vaccine in pregnant women, the two studies that have 

been published on cohorts of pregnant women show that the proportion of pregnant women who 

develop antibody titers after YF vaccination is variable. One study found that 39% (40/101) of 

pregnant women vaccinated during their third trimester seroconverted compared to 92% of the 

general population. In the second study, 98% (425/433) of pregnant women vaccinated 

primarily during their first trimester developed YF-virus specific antibodies. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Two studies have been published with immunogenicity data for YF vaccine in HIV-infected 

persons that had a comparator group and were beyond the first one to two months postvaccination. In the first study performed retrospectively among HIV-infected travelers, 83% 

(65/78) of HIV-infected persons had YF virus-specific antibodies one year post YF vaccination 

compared to 97% (64/66) of uninfected controls. This difference was significant (p=0.01). The 

second study found that only 17% (3/18) of HIV-infected children in an endemic area of Africa 

had YF virus-specific antibodies 10 months post vaccination compared to 74% (42/57) age and 

nutritionally matched children. 

There were 9 studies with seroconversion rates following the primary dose of YF vaccine in 

children from endemic areas aged 6 through 36 months. The studies included those that have 

been published since 1980 and thus would use vaccine formulations that are currently in use 

today. Some of the studies were RCTs and others were observational. All but one of the 

studies was designed to assess the potential immune response when YF vaccine was coadministered with another vaccine. Again, the assays used were variable between the studies 

and each study had at least 100 children and up to 900 children in one of them. The 

seroconversion rates ranged from 78% to 96%. To summarize, there were 9 studies that 

included data on children 6 through 36 months of age in endemic areas. From these studies, 

98% (2,433/2,754) of children seroconverted one to two months post-YF vaccination. There 

were very limited long-term immunogenicity data available for children beyond the first one to 

two months post-vaccination to know if their antibody decay rates would be different than adults. 

Regarding the assessed values related to the options and outcomes, from 1970 through 2013, 

there have been 10 YF cases reported in travelers from the US (3) and Europe (7). Of the 10 

cases, 9 were in unvaccinated travelers of whom 8 (89%) died. One traveler reported receiving 

YF vaccine 5 years before traveling to West Africa where she developed YF. She survived. YF 

vaccine has been available since the late 1930s. It is currently unknown how many cases of 

disease have been prevented due to vaccination. Overall, vaccination coverage rates reported 

from airport or clinic surveys for persons traveling to YF endemic areas is high at 91% to 93%. 

The risk of YF disease and death in an unvaccinated traveler for a 2-week stay in West Africa is 

estimated to be about 50 disease cases and 10 deaths per 100,000 population. In South 

America, the risk is estimated to be 5 disease cases and 1 death per 100,000 population. The 

risk of YF varies based on location, duration, season, and activities. The WG agreed that the 

risk of YF will be lower in persons receiving at least one dose of YF vaccine 10 or more years 

previously, but it is not quantifiable given the lack of available data. 

The WG discussed some additional considerations regarding disease risk in the US population. 

Overall, the WG considered persons who might be at higher risk of exposure to YF virus based 

on a number of factors, including: 1) location, with the YF disease risk in West Africa estimated 

to be 10 times higher than South America; 2) duration of travel, with longer travel (e.g., months 

to years) likely to increase risk of disease; and 3) the type of exposure, such as a more 

consistent exposure to virulent virus among laboratory workers. For each of these, there are 

minimal to no data to support these considerations of increased disease risk. 

In the end, the values considered by the WG during the GRADE process were that YF is a 

severe disease with substantial mortality. There is no specific treatment for the disease. A safe 

and effective vaccine is available to prevent the disease. Furthermore, there is a low probability 

of SAEs with revaccination. The vaccine prevents importation and spread of YF virus. Finally, 

the vaccine is expensive. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

In terms of the review of the health economic data, there are no data on the cost-effectiveness 

of vaccinating travelers with either primary or booster doses of YF vaccine. Providing YF 

vaccines to all travelers going to endemic areas would not be cost-effective, given the large 

number of travelers to endemic areas (~3 million/year). The risk of YF disease for vaccinated 

travelers is less than 5 to 50 cases per 100,000 population. The cost of YF vaccine varies from 

$150 to $350. Travel vaccines are usually paid for by travelers. These vaccines are not 

covered by most private insurance and are not included in the Vaccine for Children (VFC) 

program. Given this information, the WG decided not to perform cost-effectiveness study of YF 

vaccine booster doses. 

Three potential recommendations were considered by the WG to begin with, including the 

following: 

 A booster doses of YF vaccine every 10 years is recommended for travelers and laboratory 

workers. 

 A single dose of YF vaccine is sufficient to confer sustained life-long protective immunity 

against YF disease, and a booster dose is not necessary [WHO SAGE recommendation]. 

 Booster doses are no longer recommended for most travelers or laboratory workers. 

However, booster doses are recommended for certain persons at risk for exposure to YF 

virus. 

When formulating the recommendations to present to ACIP, the WG considered that there have 

been very few vaccine failures noted following YF vaccination. Most (92%) vaccine recipients 

are seropositive 10 or more years post-vaccination. SAEs are uncommon following booster 

doses of YF vaccine. High value is placed on preventing a serious disease with no treatment 

and poor outcome. Finally, the current statement in the ACIP recommendations regarding 

booster doses will soon be antiquated as IHR will remove the language of YF booster doses in 

June 2016. As a reminder, the language currently used in the ACIP recommendations that has 

been in place since 1969 states, “IHRs require revaccination at intervals of 10 years to boost 

antibody titers.” 

Based on the GRADE process, review of additional data, and SME, the WG reached the 

following conclusions. A single dose of YF vaccine provides long-lasting protection in most 

travelers. The WG proposes to no longer recommend a booster dose of YF vaccine for most 

travelers. Based on limited data, the WG would recommend YF vaccine booster doses for 

certain persons, including those who are at increased risk of exposure to YF virus and those 

whose immune response to their previous dose might have been compromised due to an 

existing condition at time of vaccination. 

The WG proposed the following wording and recommendation categories for ACIP’s 

consideration: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Option for ACIP Consideration (1 of 4) 

“Booster doses are no longer recommended for most travelers or laboratory workers 

(Recommendation category A).” 

Option for ACIP Consideration (2 of 4) 

“However, based on limited data, a YF vaccine booster dose is recommended for certain 

persons either at increased risk of exposure to YF virus or whose immune response to their 

previous dose might have been compromised due to an existing condition at the time of 

vaccination (Recommendation category A).” 

OR 

“However, based on limited data, a YF vaccine booster dose may be considered for certain 

persons either at increased risk of exposure to YF virus or whose immune response to their 

previous dose might have been compromised due to an existing condition at the time of 

vaccination (Recommendation category B).” 

Option for ACIP Consideration (3 of 4) 

Booster doses for: 

“Travelers who received their last dose of YF vaccine ≥10 years previously and plan to stay in 

an endemic area for a prolonged period (e.g., months or longer) or plan to travel to a highly 

endemic area (e.g., rural West Africa)” Alternative: remove examples in parenthesis as they are 

based on limited data 

“Laboratory workers who routinely handle infectious YF virus and who have no detectable YF 

virus-specific neutralizing antibody titers or who received their last dose of YF vaccine ≥10 years 

previously and for whom YF virus-specific neutralizing antibody titers are unavailable.” 

Option for ACIP Consideration (4 of 4) 

Booster doses for: 

“Persons who received their last dose of YF vaccine ≥10 years previously and who had, at the 

time of their last vaccination, a condition that might have compromised their immune response 

to that dose (e.g., age <1 year, pregnancy, or HIV infection).” 

“Persons who had an intervening condition, since their last dose of YF vaccine, that might have 

a substantial impact on their memory immune response (e.g., bone marrow transplantation).” 

Based on the review of data and gaps that exist, the WG had the following recommendations for 

areas of further study: 

 Assess neutralizing antibody levels ≥10 years post-initial vaccination in travelers 

 Evaluate amnestic immune response to re-vaccination in persons without detectable 

antibodies 

 Determine seroprotective level of antibodies using a PRNT by correlating it to LNI ≥0.7 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

 Establish role of vaccine-induced cell-mediated immunity in long-term protection against YF 

 Assess neutralizing antibody levels among persons with suboptimal immune response to YF 

vaccine 

Dr. Staples invited questions and discussion, as well as a vote on no longer recommending a 

booster dose for most travelers and a vote on whether to recommend or consider YF vaccine 

booster doses in certain persons. She noted that a VFC vote would not be necessary. 

Discussion Points 

Dr. Temte pointed out that this was an example of a category A or strong recommendation 

based on level 4 data and evidence, which is perfectly acceptable. The nice thing is that this 

lays out all of the evidence in a transparent manner for everyone to see. 

Dr. Harrison inquired as to whether there was anything to be learned from the vaccine failures 

themselves in terms of whether there was something different about them immunologically or 

otherwise. 

Dr. Staples responded that the vast majority of the vaccine failure data came from endemic 

areas, and some of the data are from the 1940s for military personnel. So, the non-endemic 

data are for people who were stationed in Africa during World War II. The data on those cases 

are old case reports. Very few recent vaccine failures have been documented. The most 

recent ones were documented in Brazil. Testing has been performed on those cases, but 

actually understanding what it was about those original persons is not clear. As a reminder, in 

clinical trials, when normal healthy adults or children are given the vaccine, in general there is a 

good seroconversion rate of greater than 99%. But, a small proportion of persons might not 

respond to the initial dose. There is nothing in common from the few vaccine failures noted that 

could denote who might be at risk. 

Regarding the lumping together of all persons 10 or greater years post-vaccination, Dr. Duchin 

thought it was likely that immunity probably wanes with duration from vaccination. Those 

vaccinated at 11 years would be more likely to retain some endurance evidence of protection 

versus those vaccinated 30, 40, or 50 years ago. He wondered whether any of the data 

presented in slides 11 or 12 could be further analyzed to assess whether the seropositivity rates 

are lower the further out from vaccination. It appeared that some of the studies that assessed 

years post-vaccination, the greater number of years post-vaccination have slightly lower rates of 

seropositivity. He wondered whether someone who was vaccinated in their teens or early 20s 

who wanted to return to an endemic area at age 50, 60, or 70 should be subject to the same 

recommendations as someone who was vaccinated 11 years ago. 

Dr. Staples replied that the WG discussed this. She tried to present the meta-analysis for 10 

years or more versus 20 years or more, and there is at least a decrease though it is not 

significantly different between those two groups. The problem, going further out, is there are 

insufficient data. Minimal numbers of subjects have been followed throughout that period. 

There are current plans to conduct a study working with the military to assess people who may 

have been vaccinated at longer terms. But even then, the numbers would probably limit the WG 

from making firm conclusions. The WG discussed this option and did not feel that there were 

enough data to firmly establish a 20-year cutoff, and this might further complicate the already 

complicated proposed recommendations in terms of subcategories to consider a booster dose. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Plotkin (Vaccine Consultant) pointed out that revaccination of populations subject to 

endemic yellow fever is a major public health issue so he could understand why they would not 

recommend boosters. Here, the focus is essentially on US travelers who will want the 

maximum protection possible. Another point relates to the correlate of protection. He did not 

agree that there is no correlate of protection. Studies have been conducted in monkeys and 

other animals suggesting that a neutralizing titer of 1:40 is equivalent to protection, which 

means that titers lower than that may not protect. Assessing the geometric mean titers (GMTs) 

of a population is fine, but it is also important to assess those who fall below the GMT. There 

are studies showing falling titers with duration from the initial vaccination, which also has to be 

taken into account. In relation to Dr. Duchin’s question, there is waning of antibody with time. 

Regardless of the study, there are data showing that antibody falls such that some percentage 

is below the likely protective titer long after vaccination. The issue with children is also 

important, because children do not respond to yellow fever vaccine as do older individuals. If he 

were writing the recommendation, he would recommend one booster dose for children at 10 

years. He emphasized that he was not saying everyone needs to be vaccinated every 10 years, 

but he thinks there is a need in certain populations such as children for a booster dose. In 

Brazil where mass vaccination is used against yellow fever, 2% of individuals who have had 

yellow fever have been vaccinated. So, there are primary as well as secondary failures and 

these often occur in children. In relation to laboratory workers, the vaccine is expensive. 

However, if he were a laboratory worker, he would certainly want to at least have a high 

neutralizing titer. If not, he would definitely want to be boosted. There are data regarding the 

anamnestic responses to YF and, indeed, those who have low titers do respond. Though Dr. 

Plotkin noted that while it was difficult to speak to specifics without having the papers in front of 

him, he thought this recommendation went too far for travelers. He believes that travelers going 

to a YF endemic area should have at least one booster after 10 years. 

Referring to slide 46 pertaining to booster doses, Dr. Orenstein (NVAC) thought the implication 

was that someone vaccinate at age less than one year, during pregnancy, or who had HIV 

infection, that individual would have to wait at least 10 years to have another dose. Slide 27 

showed that only 39% of women in the first trimester seroconverted, and only 17% of HIVinfected children seroconverted at 10 months. It seemed to him that the 10-year timeframe is 

not appropriate, and that if someone is making another trip, they should be vaccinated 

regardless of the interval. The way it reads is that the interval should be 10 years before giving 

another dose. 

Dr. Staples replied that the phrasing was discussed extensively in the WG regarding the same 

principle that, in fact, some of these population may have more rapid waning immunity and may 

be thought to require boosting sooner. It would be easy to boost them before their next travel, 

but what about an HIV-infected person who travels three or four times a year on a regular basis 

to an endemic area? Are they going to be boosted every time they travel? The WG did not feel 

that they had enough evidence to determine when they should be boosted, but they did favor 

including 10 years. However, she agreed that it would probably be wise to boost them before 

they travel again. 

Dr. Bocchini added that while that was discussed in detail, there has never been a 

recommendation to administer this vaccine earlier due to a low seroconversion rate. Therefore, 

the WG tried to maintain the primary recommendation for booster doses in no less than 10 

years. However, the WG also raised the issue that this needs to be studied and is one of the 

questions that is unanswered because there are no data. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Schmader (AGS) pointed out that another factor to consider with regard to adverse events is 

age, given that it is well known that older adults are at increased risk for SAEs from YF 

vaccines. He wondered whether the WG included this in their considerations. 

Dr. Staples replied that the risk of SAEs with older age has been shown in a recently published 

study to be relative to the primary dose, because the low level of viral replication occurs after 

the primary dose. The study showed older adults’ levels of viremia were higher in comparison 

to younger adults, and it took them longer to develop antibodies. In the current ACIP 

recommendation, age greater than 60 years is a precaution to the primary dose of vaccination. 

In terms of the booster dose, ideally there should be some sort of anamnestic response. In 

general, most people who receive a booster dose do not have actively replicating virus and the 

risk of SAEs due to YF vaccines is thought to be negligible. However, in general, a number of 

studies have shown that older persons are at risk for SAEs following any vaccination as they get 

older. 

Dr. Temte said he was curious to know whether within the “Baby Boom” cohort more first-time 

vaccinees were being observed in individuals 60 years of age and older receiving YF vaccine 

due to retirement and international travel. 

Dr. Schmader (AGS) responded that this is occurring. Many people are aging well and 

successfully into their 60s, 70s, and 80s who are traveling around the world. Therefore, this is a 

very important issue. 

Dr. Fryhofer (AMA/ACP) inquired as to whether there is a list of countries that currently require 

the vaccination, which could help practitioners determine who would need a booster dose if they 

plan to enter a particular country. 

Dr. Staples responded that this information is readily available on the CDC Traveler’s Health 

website. People in the travel health group are devoted to contacting every country to check 

regulations every other year, and as regulations change. That is also published in the “Yellow 

Book,” which is the travel health recommendation book. She recommends going on line, 

because if there are updates between when the book is published every two years, the 

information about which country requires proof of YF vaccination can be found on the CDC site. 

Additional language will be incorporated regarding which countries decide to administer booster 

doses or not. Some feedback has been received that some countries may continue to require 

booster doses, and that information will be available in real-time on the CDC website. 

Dr. Fryhofer (AMA/ACP) said she understood to always check the website when she has a 

patient who will be traveling. She wondered whether any specific updating had been done yet 

to show which countries require just one dose, a dose every 10 years, et cetera based on the 

new international policy. 

Dr. Staples indicated that the WGA met in May to propose that the change be made to the IHR. 

It will not go into effect until 2016. While WHO SAGE removed booster dose requirements, IHR 

are still in place, so countries can still allow a booster dose every 10 years. CDC will be 

incorporating this information as they learn which countries plan to still require it or not. This is 

a process that will have to be live, and on which CDC will have to continue to work. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Regarding the suggested booster dose for travelers who would be traveling for longer periods 

and in more highly endemic areas, Dr. Moore (AIM) said she would like to see more operational 

specificity. She agreed with the idea of leaving out particular locations, but if that were to be 

approved, she thinks more specific language will be essential for travel clinics to really 

understand what is meant by “highly endemic” in terms of rates. Rates and demographics may 

change as there are newly endemic areas. 

Dr. Staples replied that a lot of these data already exist. The current ACIP recommendations 

have a section that notes when rates would be highest in Africa and South America, as well as 

the rates in those countries. 

Dr. Englund (PIDS) expressed concerned about including the age of less than one year. 

Incredible data are available to show that children less than two or three years of age do not 

respond well. 

Dr. Karron wondered if any data were available on duration of protection after a single booster 

dose. 

Dr. Staples responded that there are limited data pertaining to duration of protection in persons 

who receive vaccine booster doses, and most of the data are short-term to assess their 

response. There is little to draw from, given that the published literature includes less than 10 

people. 

Dr. Bennett said she continued to be concerned about the people who did not respond when 

they received their first dose. She requested further information about this, and why a booster 

would not be considered for them at potentially less than 10 years. 

Dr. Bocchini replied that the WG discussed this, but felt that there were no data or studies to 

support moving forward. Some of the data are very limited in terms of number of people 

studied, so the WG felt that further study would be needed before decisions could be made 

about an earlier dose or second dose. There has been some discussion about having a twodose series for younger children, rather than calling it a booster dose, but there are really no 

data upon which to base that recommendation. 

Dr. Staples added that the Brazil Ministry of Health is proposing to conduct a study to assess a 

two-dose series, but the study has not yet been conducted. 

Dr. Harrison said he was struggling because he was getting the sense that if the data were 

being reviewed routinely, ACIP would not be making this change, except for the change 

recommended by WHO. 

Dr. Staples said the first recommendation published in 1969 used IHR requirements of 10 years 

to note that the booster doses should be given. ACIP has never recommended booster doses 

of YF vaccine. Beginning in April 2016, IHR will no longer require booster doses every 10 

years, so ACIP will have to deal with some wording or recommendation. Many WG members 

did not feel that the data were strong enough to firmly state that booster doses need to be given 

every 10 years for everybody. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Kempe noted that the issue of whether patients are in an endemic area appeared to be 

crucial. She inquired as to where the studies were conducted that showed longer duration and 

how relevant they are to the US population. 

Dr. Staples responded that the meta-analysis was done on the 13 observational studies to 

assess the 10-year cut, and it was also broken out to assess differences between endemic and 

non-endemic populations. Essentially, endemic and non-endemic were identical in terms of the 

proportion who were seropositive at 10 years. 

Dr. Reingold said that as an “elderly” member of the ACIP who has now had his fifth YF 

vaccine, he supports the recommendations of the WG. 

Dr. Temte asked Dr. Reingold whether he was involved in the SAGE discussions. 

Dr. Reingold indicated that he was present for the SAGE discussions, but was not a member of 

SAGE at that time. 

Dr. Staples added that she was on the SAGE committee that made these recommendations, 

and there were heated discussions pertaining to endemic versus non-endemic populations. 

There are many other consideration at the WHO level that are not taken into account at a US 

traveler level about the cost, coverage, and availability of the vaccine. It is important to point out 

that while SAGE used basically the same data, they had a slightly different policy question, 

which was: Is there evidence that a booster dose is required in immunocompetent individuals to 

ensure long-term protection? Based on the same data, SAGE reached the conclusion that 

there are not enough data to support requiring a booster dose. 

Dr. Moore (AIM) said what struck her was the very definitive slide 10 that basically said that 18 

vaccine failures occurred over 540 million doses and only 2 of those occurred beyond 10 years 

at 20 or more years after the last dose. On its face, that seems quite striking. But, the 

additional conversation suggests that perhaps that is an absence of all of the information rather 

than evidence of very strong protection. 

Dr. Staples responded that the lack of vaccine failures was one of the considerations that SAGE 

took highly as one of the reasons to move forward with their recommendations. That needs to 

be caveated by pointing out that a lot of YF disease is occurring in areas where there may not 

be good surveillance to detect YF vaccine failure cases that occur. Another issue pertains to 

knowing vaccination status for some people. The other problem is that since 1965, WHO has 

recommended booster doses under IHR, so it is uncertain how many people have not received 

booster doses. This makes it difficult to put the 540 million doses into context in terms of how 

many are primary versus how many people have received routine booster doses. Few people 

have probably received booster doses in endemic areas in Africa, given that there have been 

large preventive campaigns. Booster doses are administered to the populations of South 

America and Brazil every 10 years. They are delivering 13 million doses of the 30 million that 

they have over a certain time period as booster doses. It depends on information, location, and 

the certainty behind it. Unfortunately, there is a lot of uncertainty. 

With the thought of the vote looming over them, Dr. Jenkins questioned timing. There have 

been a number of responses that there are no data. She inquired as to whether there was 

anticipation that in another year, there would be better data. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Staples responded that there is unlikely to be sufficient data provided in the next few years. 

Small studies are planned that CDC is conducting to try to answer these questions, but nothing 

is going to be Earth-shattering or change. This vaccine has been available since the 1930s, 

and the data have not existed up to this point. There is not enough impetus to study this. Brazil 

is conducting the most research, and CDC has had conversations with the Brazil Ministry of 

Health about what they are planning to do. It is unclear whether the planned studies will provide 

enough certainty to make firmer recommendations. In general, the WG felt that this would not 

be the case. 

Dr. Temte said he thought they had a situation in which the WG correctly identified the low 

quality evidence with which to work, and is to be commended for setting up a number of 

potential areas to be investigated as time goes on should someone be willing to fund such 

studies. Until then, he thought they were stuck with what is available in terms of making a 

recommendation. He inquired as to whether they needed to vote on two separate 

recommendations, or if it would be a package vote. 

Dr. Staples responded that they were thinking that the vote should be a package deal. 

Dr. Reingold made a motion to accept the recommendation as proposed. 

Dr. Rubin said he remained unclear about the recommendation. 

Dr. Staples indicated that this would be an option for consideration in terms of whether ACIP 

wanted to state that booster doses are recommended or considered for certain persons, and 

agreeing with the statement of removing parentheses or not. 

Dr. Coyne-Beasley requested further clarification regarding whether they would not be voting for 

recommendation 1 of 4 if they were interested in recommendations 2 and 3. The first slide 

states “most” travelers, and it was not clear to her whether 2 of 4 was to explain which travelers 

would need it. 

Dr. Staples responded that 1 of 4 would be the first statement written to indicate that booster 

doses are no longer recommended. That would be followed up with one of the statements on 

recommendation 2 of 4. That would be followed by recommendation 3 of 4 stating the specific 

persons for whom it is recommended. 

Dr. Temte inquired as to whether there was a preference for “is recommended” versus “may be 

considered.” 

Dr. Bocchini said the WG leaned more toward “is recommended” versus “may be considered” 

because it was a category A recommendation and provided additional guidance for travel 

medicine clinics. 

It seemed to Dr. Bennett that the first statement and the statement on 3 or 4 may be somewhat 

contradictory in terms of the broadness of the first statement compared to specificity of the 

second. The first recommends for persons “whose immune response to their previous dose 

might have been compromised due to their existing condition at the time of vaccination” and the 

next states “≥10 years.” 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Harriman agreed that the first statement was very broad, so perhaps it would be preferable 

to state, “these are the people for whom revaccination is recommended” rather than say “most 

people.” 

Dr. Harrison wondered whether this could be a feedback providing session and that a more 

definitive recommendation could be brought back to the committee during the next ACIP 

meeting. 

Dr. Bocchini replied that this would be up to ACIP. If they had additional feedback they would 

like to provide the WG and postpone the vote, that would be acceptable. But if there was 

general agreement that most travelers do not need a booster dose, these could all be linked 

together to solve the problem. 

Dr. Temte indicated that one option would be to condense the recommendation and bring it 

back later in the day or during the next morning. 

Dr. Staples shared the following example that was put forth for a more condensed version of the 

recommendation: 

A single dose of YF vaccine may provide long-lasting protection and booster doses are 

not routinely recommended for all travelers or laboratory workers. 

However, a YF vaccine booster dose is recommended for certain persons at risk for 

exposure to YF virus, particularly those with long stays or travel to highly endemic areas, 

and persons that were pregnant, age <1 year, or had HIV infection at the time of their 

initial vaccination. 

Dr. Kempe indicated that one of her concerns was addressed with the condensed version; 

however, she requested further discussion regarding the age of <1 year for children. 

Dr. Staples replied that in general, there are not enough data to make a more definitive 

statement. The data usually encompass a period up to 3 years of age. While this could be 

changed, there are sparse data upon which to base any other recommendation. Currently, age 

6 to 8 months is a precaution to vaccination due to the potential for increased adverse events 

and potentially no seroconverting or having a good immune response. 

Dr. Karron inquired as to whether there were any data in children under 5 years of age to show 

that both their initial response and duration of protection are comparable to older children and 

adults. 

Dr. Staples indicated that there are no data on the duration of protection. 

Given the dearth of data, Dr. Kempe thought they would have to rely on expert opinion in order 

to make a recommendation. She thought expert opinion would probably state that <1 year is 

not the right cutoff. 

Referring to Dr. Englund’s comment and slide 29, “Seroconversion rates following primary dose 

of YF vaccine in children aged 6 through 36 months,” Dr. Pickering said he assumed that YF 

was given with measles vaccine which was a precedent. The seroconversion rates for YF 

seemed higher than what would be expected for measles vaccine at 6 through 9 months of age. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Indeed, when the measles vaccine is given at less than a year, it is not counted toward the twodose measles vaccine schedule because of the potential lack of response. He wondered 

whether there was any correlation that could be made, whether measles vaccine titers are also 

available for that group to make some comparisons, and whether the measles vaccine was a 

consideration in using 6 months, 9 months, or 1 year. 

Dr. Staples indicated that while she did not have the data in front of her to know what the 

measles responses rates were, she can look at those individual studies. 

Ms. Pellegrini noted that one of the other issues raised was the length of duration not only for 

children receiving the vaccine, but also for people who receive it later in life. For example, 

someone who receives the vaccine in his or her 20s and then travels at age 70. She 

recognized the serious lack of data, but wondered whether they wanted to include anything 

about extreme amounts of time since initial vaccines. 

Dr. Temte pointed out that one of the realities in clinical practice is that patients do not ask him 

for this vaccine because of their perceived risk. They ask for the vaccine because they are 

going to be traveling to a country that requires it. Once that requirement goes away, he 

believes they will observe a great decline in anyone requesting revaccination. As noted, there is 

a severe dearth of data, and the evidence is basically in the realm of expert opinion for the 

entire recommendation. With absolutely no evidence, he wondered how much more work would 

need to be done to get the recommendation to a level at which ACIP would be comfortable. 

Acknowledging the complete lack of evidence, Dr. Karron suggested that the age be <5 years 

rather than <1 year. 

Dr. Netoskie (AHIP) asked whether there was any evidence or information that would be helpful 

regarding the minimal interval from the first vaccine. 

Dr. Staples replied that the only data available about the immune response regarded giving the 

vaccine sooner. The scenario presented in the very small study that was conducted had to do 

with administering vaccine to someone who loses their card in terms of what time of response is 

observed and whether any harm is being done. That study had less than 20 subjects total. All 

of those who received the vaccine at an interval less than 10 years already had antibodies. 

When they were given the dose and were all boosted, their antibody titers did not go as high as 

a primary vaccine recipient. Their kinetics were such that they returned to the state of where 

they were prior to receiving the vaccine in a short time period, versus a sharp immune peak and 

much more of a decay rate with the primary dose. 

Dr. Neuzil (IDSA) indicated that this was discussed at SAGE, and there is at least one good 

study that evaluates MMR and YF vaccine. MMR does affect the response to YF vaccine if 

given concomitantly and not 30 days apart. That may be worth discussing in terms of age 

selection, and whether this was influenced in any way by the concomitant administration with a 

measles-containing vaccine. 

Dr. Staples replied that the WG is aware of the concomitant administration and was not 

specifically dealing with interference from live viral vaccine administered at the same visit. In 

that study, the seroconversion rates with the separation of vaccine were lower than what would 

be anticipated. A study is planned in Argentina to reproduce those data to try to understand 

whether there is truly interference occurring when MMR is added in combination with YF 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

vaccine. Previous studies have shown that when YF and measles vaccines are given together 

they do not cause a problem in terms of immune response. 

Dr. Kempe said she felt that the age cutoff for children remained unclear, and she wondered 

whether they should seek further input from other groups such as the Red Book committee and 

Pediatric Infectious Diseases Society (PIDS) rather than making a hasty decision. 

Dr. Temte requested Dr. Bocchini’s thought on that. Regardless, Dr. Temte felt that an age 

cutoff would be fairly arbitrary. Given that a recommendation will be made based on expert 

opinion, having a full level of expert opinion may be beneficial. 

Dr. Bocchini indicated that the WG had representation from COID. However, he thought it 

would be very reasonable to seek additional feedback from representative organizations about 

an age cutoff and provide them with the data that the WG has before making a final decision. 

Dr. Temte asked whether the decision was to table the vote until the next ACIP meeting, 

understanding that three of the ACIP members are rotating off. On the plus side, two of the new 

members were present during this meeting and heard the GRADE discussion. 

Dr. Bocchini suggested that another possibility if everything else in the recommendation was 

acceptable would be to accept these recommendations except for the age cutoff for children, 

and have that come back to the committee after receipt of input from other organizations. 

Dr. Bennett said her concern about that was that there were two sets of wording that were quite 

different. She thought the committee would probably want an opportunity to weigh in on the 

wording. 

Dr. Harrison commented that it is difficult to bring highly complex issues to the full committee for 

the first time and expect a vote. He thought in the future, highly complex issues should be 

vetted for feedback. 

Dr. Jenkins inquired as to what the issue was regarding seniors who travel, and whether there 

was enough evidence to be concerned about that at this point. 

Dr. Staples replied that the concern with older individuals is the risk of adverse events that occur 

with the primary dose of vaccine. Given the considerations about booster doses, that should 

not apply. 

Dr. Temte asked whether there was consensus to ask for thoughtful revision taking into account 

the comments during this discussion period, with the recommendation to be presented for a 

vote during the October 2014 meeting. 

Dr. Bocchini said the WG would appreciate very specific comments related to options presented 

for category A versus category B and other options provided for ACIP’s consideration. 

Dr. Temte said he did not believe there would be a need for representation of the GRADE 

evaluation, and indicated that efforts will be made to directly inform the third new committee 

member. He thanked Dr. Stapes for her patience with the deliberations, emphasizing that this is 

what ACIP is meant to be doing in terms of making complex decisions. 

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Dr. Karron reminded everyone that the Influenza WG’s primary activity has been to review the 

relative efficacy and safety of live attenuated influenza vaccine (LAIV) and inactivated influenza 

vaccine (IIV) for use in children. There has been additional consideration of the language for 

use of LAIV and IIV when both are available. The WG has also reviewed data on children with 

high-risk conditions, including children with a history of asthma or wheezing and other high-risk 

conditions. In addition, the WG has discussed the dose algorithm for children aged 6 months 

through 8 years, particularly for this year when there is not a strain change. The WG has also 

finalized the draft 2014-2015 ACIP Influenza Statement. 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Influenza 

Introduction 

Ruth Karron, MD 

Chair, Influenza Work Group 

Novel Influenza Vaccines Work Group 

Dr. Doug Campos-Outcalt 

Chair, Novel Influenza Vaccines Work Group 

Dr. Campos-Outcalt reported that the Novel Influenza Vaccines WG had been meeting regularly 

for a couple of months, and that the limited charge of this WG is to develop recommendations 

for use of influenza A (H5N1) vaccine during an inter-pandemic period. There are currently four 

H5N1 vaccines in the national stockpile; however, only two of those have been licensed for 

general use and only one will be available for inter-pandemic use (e.g., the GSK vaccine): 

Virus Clade FDA Licensure 

A/Vietnam/1203/2004 1 Yes (Sanofi) 

A/Indonesia/5/2005 2.1.3.2 Yes (GSK) 

A/bar-headed goose/Qinghai/1A/2005 2.2 No

A/Anhui/1/2005 2.3.4 No 

Use of vaccine in the national stockpile is limited to a pandemic, and inter-pandemic use is not 

possible. The GSK vaccine, Q-Pan, will be produced in a small volume of approximately 

100,000 doses and will be stored in part at the National Institutes of Health (NIH) and in part at 

the manufacturer’s facility. These doses will be available to high-risk investigators and other 

high-risk groups. The WG will focus on making recommendations for this vaccine’s use in a 

very limited group of people, and will be working to identify the target audience. The WG plans 

to conduct a GRADE analysis on the evidence for use of the Q-Pan vaccine, and to identify 

high-risk groups during inter-pandemic period. The WG planned to present recommendations 

to the full ACIP committee in October 2015. However, given the yellow fever discussion, it is 

more likely that language will be presented for discussion in October 2015 and a vote will be 

planned for February 2015. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Influenza Vaccine Safety Update 

Maria Cano, MD, MPH 

Immunization Safety Office 

Centers for Disease Control and Prevention (CDC) 

During this session, Dr. Cano presented the end-of-season influenza vaccine safety update for 

the 2013-2014 season. As a reminder, the strengths of VAERS are that it includes national 

data; accepts reports from anyone; has rapid signal detection; captures rare adverse events; 

collects information about vaccine, characteristics of vaccinees, and adverse events; and data 

are available to the public. VAERS also has limitations, including reporting bias, inconsistent 

data quality and completeness, general inability to assess whether a vaccine caused an 

adverse event, lack of an unvaccinated comparison group, and lack of inclusion of pregnancy 

status. Another limitation of VAERS is illustrated by the following graphic: 

Of the total population, only individuals who were vaccinated and had adverse events that were 

reported to VAERS are included and are shown in the pink cell. VAERS data do not include 

those in the white cells, which include those who were vaccinated but who had no adverse 

event or who had not reported to VAERS. Given this limitation, VAERS is not able to calculate 

rates of occurrence of adverse events, determine increased risk, or calculate vaccination 

coverage. 

The following table summarizes the licensed influenza vaccines that became available during 

the current season. There was a complete switch to quadrivalent LAIV this season, so 

comparison between trivalent and quadrivalent forms will be between seasons. For IIV, both 

trivalent and quadrivalent vaccines are available and comparison can also be made within the 

current season. The second column shows the abbreviations that Dr. Cano referred to during 

this presentation. The last column shows the recommended age groups for the vaccines listed: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Vaccine Abbreviation Brand name 

(Manufacturer) 

Year 

licensed 

Recommended age 

group 

Quadrivalent 

inactivated 

influenza vaccine 

IIV4 Fluarix 

® 

Quadrivalent 

(GlaxoSmithKline) 

2012 >3 yrs 

Fluzone 

® 

Quadrivalent 

(Sanofi Pasteur) 

2012 >6 mos 

Flulaval 

® 

Quadrivalent 

(GlaxoSmithKline) 

2013 >3 yrs 

Cell culture-based 

trivalent inactivated 

influenza vaccine 

ccIIV3 Flucelvax 

® 

(Novartis) 2012 >18 yrs 

Recombinant 

trivalent inactivated 

influenza vaccine 

RIV3 FluBlok 

® 

(Protein 

Sciences) 

2013 18-49 yrs 

Quadrivalent live 

attenuated 

influenza vaccine 

LAIV4 FluMist ® 

Quadrivalent 

(MedImmune) 

2013 2-49 yrs 

VAERS surveillance includes US reports after IIV and LAIV received by VAERS for those 

vaccinated between 7/1/2013 and 5/2/2014. Signs and symptoms or diagnoses are coded into 

the VAERS database using the international Medical Dictionary for Regulatory Activities 

(MedDRA) terms. MedDRA terms are not mutually exclusive, and a report may have several 

different MedDRA. Medical records were reviewed for all serious reports after the newly 

licensed influenza vaccines listed in the above table and Fluzone Intradermal®. Pregnancy 

reports were also reviewed for spontaneous abortion, stillbirths, congenital anomalies, serious 

reports; as well as all reports of anaphylaxis with history of egg allergy. The Food and Drug 

Administration (FDA) conducted empirical Bayesian data mining to detect disproportional 

reporting in the VAERS database. 

Between 7/1/2013 and 5/2/2014, there were 493 US reports to VAERS following IIV4 and 

approximately 7000 reports for IIV3. Most of the reports were classified as non-serious. It is 

important to look at the percentages rather than the actual numbers when comparing the 

results. Guillain–Barré Syndrome (GBS) was comparable for IIV3 and IIV4, and anaphylaxis 

was higher for IIV4 compared to IIV3 for the previous and current seasons. However, there was 

no disproportional reporting in data mining for GBS or anaphylaxis for the last season and the 

current season. 

In a comparison for LAIV4 from this season to LAIV3 from last season, there were 486 total 

reports for LAIV3 compared to 657 for LAIV4. The percentages of serious reports and 

anaphylaxis were higher for LAIV3. GBS was comparable for both LAIV3 and LAIV4. There 

was no disproportionate reporting in data mining for GBS and anaphylaxis. 

To summarize results for Fluzone Intradermal® (IIV3-ID) reports in VAERS from 7/1/2013 

through 5/2/2014, there were 243 reports with 3% classified as serious. Of these, 20% were in 

males. The median age was 44 years, with a median onset interval of one day. The top five 

MedDRA terms included injection site erythema 62 (26), injection site swelling 55 (23), injection 

site pain 40 (16), erythema 39 (16), and injection site pruritus 34 (14). There were no new data 

mining findings for IIV3-ID this season. 

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-

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

In terms of the results for Flucelvax® reports in VAERS from 7/1/2013 through 5/2/2014, there 

were a total of 167 reports of which 3% were serious and 46% were in males. The median age 

was 36 years, with a median onset interval on the day of vaccination. The most common 

MedDRA term was drug administered to patient of inappropriate age 49 (31). The 

recommended age is 18 or older. However, 37% of the reports were in those less than 18 years 

of age. Other common adverse events included pain in extremity 18 (11), injection site pain 13 

(8), rash 13 (8), and nausea 11 (7). 

There were 20 FluBlok® reports in VAERS between 7/1/2013 and 5/2/2014, all of which were in 

females. None of the reports was considered to be serious. The most common MedDRA terms 

included pruritus 6 (35), dyspnoea 3 (18), headache 3 (18), erythema 3 (18), and rash 3 (18). 

The median age was 47, with a median onset interval on the day of injection. 

There were 61 pregnancy reports in VAERS following IIV3 or IIV4 vaccination for the time 

period 7/1/2013 through 5/2/2014. The median age was 30 years, with a median gestational 

age at vaccination of 18 weeks. The pregnancy-specific outcomes included spontaneous 

abortions (5), stillbirth (1), fetal death, pre-term delivery (1), cleft lip and palate (1), Trisomy 18 

(1), and increased fetal movement (1). Of the reports, 31 (~51%) were non-specific and 19 had 

no adverse events. There were 22 reports without any adverse events after LAIV4 and 1 

serious report, which was a case of pulmonary hypertension in an infant whose mother received 

LAIV4. 

There was one anaphylaxis report in VAERS following influenza vaccination in a person with a 

history of egg allergy. A 4-year-old male developed diffuse hives, watery eyes, sneezing, and 

vomiting within 15 minutes after IIV3. He had allergy testing after the reaction, which showed a 

positive skin prick test for commercial egg extract and gelatin and a positive serum test for egg 

white and bovine gelatin. His past medical history included perioral rash after ingestion of 

meringue icing, which has egg whites; and increased salivation, abdominal pain, and weakness 

after ingestion of gummy candies and marshmallows, which have gelatin. This case was 

reported in the literature and the authors concluded that the reaction was most likely related to 

gelatin rather than egg protein in the vaccine. 

With regard to the findings from Vaccine Safety Datalink (VSD) surveillance for 2013-2014 

influenza season, this is the sixth season that real-time Rapid Cycle Analyses (RCA) have been 

conducted within the VSD. The RCA for specific age groups is performed for the pre-specified 

outcomes using International Classification of Diseases (ICD)-9 codes as shown on the 

following table: 

Pre specified outcomes* IIV LAIV 

Anaphylaxis >6 months 2-49 years 

Acute disseminated encephalomyelitis >6 months 2-49 years 

Encephalitis >6 months 2-49 years 

Transverse myelitis >6 months 2-49 years 

Guillain-Barré syndrome >6 months 2-49 years 

Bell’s palsy >6 months† 2-49 years 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

With the exception of anaphylaxis, the outcomes are neurologic adverse events. For the 2013­

2014 influenza vaccine, RCA used automated data from approximately 9.3 million patient 

records. As of April 11, 2014, approximately 3,811,478 doses of IIV3 (dose 1) and 218,875 

doses of LAIV4 (dose 1) were administered. This total does not include Fluzone® high dose and 

interdermal, but does include cell culture-based and recombinant IIV3. There has been very 

limited uptake of IIV4 and cell culture-based and recombinant IIV3. There have been no signals 

in the VSD RCAs during the 2013-2014 influenza season for any pre-specified outcomes. 

In summary, no new safety concerns were detected for IIV or LAIV during the 2013-2014 

influenza season. Surveillance for the 2014-2015 influenza season will include enhanced safety 

monitoring for the following: 

 Quadrivalent IIV and LAIV vaccines 

 Cell culture-based IIV 

 Recombinant IIV 

 Pregnancy reports 

 Reports of anaphylaxis in persons with history of egg allergy after IIV and LAIV 

 Reports with history of asthma/wheezing after LAIV4 

Assessing Fever Rates in Children Following LAIV and IIV 

Melissa Stockwell, MD MPH 

Columbia University 

Clinical Immunization Safety Assessment Center (CISA) 

Dr. Stockwell reported on a study conducted to assess fever rates in children ages 24 through 

59 months of age after receiving LAIV or IIV during the 2013-2014 influenza season. The study 

was conducted by Columbia University’s Clinical Immunization Safety Assessment Center 

(CISA) investigators through a contract from CDC. 

LAIV is potentially more effective than IIV in children. Therefore, characterizing fever rates after 

LAIV and IIV with or without simultaneous vaccination may help inform national policies for 

pediatric influenza vaccination. That includes evaluation of quadrivalent influenza vaccines as 

they are introduced. One previous study in children suggested higher fever rates in the day 0­

10 after LAIV versus IIV, particularly on day 2 when fever rates were 5.4% versus 2.0%) [Belshe 

et al N Engl J Med. 2007]. Therefore, the risk interval for fever LAIV was thought to be from the 

day 0-2 period. In contrast, the at risk interval for IIV in a previous study was show to be 

vaccination day or the day after vaccination, or the day 0-1 period [Rowhani-Rahbar et al 

Vaccine. 2012]. 

Text messaging can be used for public health surveillance and prevention efforts, such as 

reminder recalls for vaccination. Dr. Stockwell and colleagues successfully used text 

messaging to assess rates of fever after simultaneous vaccination with IIV3 and 13-valent 

pneumococcal conjugate vaccine (PCV-13) [Stockwell, Broder et al JAMA Pediatr. 2014] and 

decided to employ this method in this study as well. The primary objective of this study was to 

assess the rates of fever in children 24 through 59 months of age receiving LAIV compared to 

those receiving IIV. The primary hypothesis was that fever rates in risk window day 0-2 postvaccination would be higher in those receiving LAIV versus IIV, with the day 0-2 being defined 

as the vaccination day and the first 2 days post-vaccination. That risk window was selected 

based on the two previous studies mentioned. The secondary hypothesis was that fever rates 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

in the non-risk window of days 3-10 post-vaccination would not be significantly different in those 

receiving LAIV versus IIV. 

There were a number of secondary objectives in the Fever LAIV/IIV Study, which were to: 

 Assess whether fever rates in the day 0-2 post-vaccination are higher in those children 

receiving IIV4 versus IIV3 

 Characterize the clinical importance of the reported fevers with respect to height of the 

fever, occurrences of medically attended fever, and associated medically attended health 

outcomes 

 Explore whether fever rates after vaccination are different in children who receive LAIV 

simultaneously with other childhood vaccines versus LAIV alone 

The Fever LAIV/IIV Study was an observational prospective cohort study that was conducted 

between September 13, 2013 and April 13, 2014. Patients were recruited from Columbia 

University Medical Center (CUMC) / New York-Presbyterian Hospital clinical sites at the time of 

vaccination. Vaccination decisions were made solely by the healthcare provider caring for 

particular patients. The investigators did not randomize patients to which vaccine to receive, 

and receipt of other vaccines was not an exclusion criterion. The study was approved by the 

CUMC Institutional Review Board (IRB), and the CDC relied on the determination by the CUMC 

IRB. Families who were recruited were consented and completed an intake form, enrolled via 

text message, and were trained in the use of temporal artery scanner thermometer. 

The eligibility and exclusion criteria for participants to be enrolled in the Fever LAIV/IIV Study 

included the following: 

Eligibility Criteria 

 Age 24 through 59 months 

 Had a visit at a study site anytime during the study period 

 Received a first dose of LAIV or IIV in the season 

 Parent had a cell phone with text messaging capabilities 

 Parent spoke English or Spanish, which are the primary languages at the clinical sites 

Exclusion Criteria 

 Had a chronic medical condition considered a contraindication or precaution to LAIV (except 

for asthma/wheezing history) 

 Were currently on oral or other systemic steroids or used in past month 

 Were currently on inhaled steroids or used in the past 2 weeks 

 Had the presence of fever ≥100.4 ̊F at time of vaccination 

 Had administration of any antipyretic in the 6-hour period prior to vaccination 

 Stated intent, at time of vaccination, to use prophylactic antipyretics before the development 

of a fever 

 Parent spoke only a language other than English or Spanish 

 Parent was unable to read text messages 

 The child was receiving the second dose of influenza vaccine in the current season 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Parents were sent a text message on Day 0, the day of enrollment, and subsequently for the 

next 10 days at 8:00 pm. The information collected included the following: 

 Temperature range, actual temperature, time taken 

 Antipyretic medicine given, name and time 

 Care sought (i.e., clinic and emergency department) 

The following is the first text message that was sent: 

FeverFLU. Reply 1-5. Child’s highest temperature since last text? 

1 = 95.0 to 100.3 

2 = 100.4 to 102.2 

3 = 102.3 to 104.0 

4 = above 104 

5 = Did not take temp today 

Text responses were reviewed each morning to identify non-responders, initiate phone contact, 

troubleshoot problems, and collect unreported temperatures. Families also used a paper diary 

and were asked to send these back at the end of 10 days. A chart abstraction was conducted 

for medically attended visits during the Day 0-10 period post-vaccination for any ambulatory 

care, emergency department (ED), or hospital visits to the NYP/CUMC system. The following 

were abstracted: 

 Chief complaint, final diagnosis 

 Review of symptoms 

 Documented temperatures 

 Verify other vaccines (single and combination) given at time of enrollment using New YorkPresbyterian Hospital’s electronic health record, which includes an immunization registry 

(EzVac) 

In terms of analyses and case definitions, Day 0 was defined as the time period immediately 

after vaccination to the response to the text sent at 8:00 pm on vaccination day. Days 1-10 

were defined as being from response to the text sent at 8:00 pm the night before to the 

response to the text sent that night at 8:00 pm. Fever was defined as any temperature of 

>100.4 ̊F and moderate temperature of >102.2 ̊F. The two time periods of Days 0-2 and Days 

3-10 were assessed. 

There were 991 patients approached of whom 642 patients were eligible, 102 patients refused, 

5 patients had inadequate information, and 535 (83.1%) patients were enrolled and analyzed. 

Of the 535 patients enrolled, 309 (57.8%) received IIV and 226 (42.2%) received LAIV4. Of 

those who received IIV, 211 (68.3%) received IIV3 and 98 (31.7%) received IIV4. All LAIV was 

LAIV4. Of the children who received IIV3, almost two-thirds were 2 to 3 years old. Of those 

who received IIV4, about 60% were 4 to 5 years old. The quadrivalent product was not 

available for children under 3 years of age at the study sites. IIV4 was evenly divided between 

the three age groups. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Information received came primarily from the text messages. There was a good response rate, 

particularly during the Day 0-2 period. In terms of assessing the fever rates during the risk 

window of Days 0-2 for temperatures of ≥100.4 ̊F, of the children who received IIV, 5.8% had a 

fever at 0-2 days post-vaccination compared to 3.8% of those receiving LAIV. That is a nonsignificant difference. Breaking down those receiving IIV3 versus IIV4, 5.2% of those receiving 

IIV3 and 7.1% receiving IIV4 had a fever. Again, that was a non-significant difference. Of note, 

4 of the 22 had a temperature of T ≥102.2 ̊F and none of those were in the LAIV group. Looking 

at the rates during the non-risk window of Days 3-10 and a temperature of ≥100.4 ̊F, 9.9% of 

children who received IIV compared to 10.4% of children receiving LAIV had a fever and that 

was non-significant. Further breaking down those receiving IIV3, 11.8% had a fever compared 

to 6.3% receiving IIV4 and 10.3% receiving LAIV4 and that was non-significant. Of note, only 

10 of 33 fevers included temperatures ≥102.2 ̊F and 6 of those were in the LAIV4 group. With 

regard to co-administered vaccines in all of the groups, the majority of children received 

influenza vaccine alone. Of those who received co-administered vaccines, 82.6% received 

DTaP-IPV and/or Hep A. 

A regression model was conducted assessing the risk window of Day 0-2 with a temperature of 

≥100.4 ̊F. The log binomial regression was adjusted first a priori for Hepatitis A vaccine and 

Kinrix® (DTaP-IPV) since those are the most commonly co-administered inactivated vaccines. 

Concurrent PCV13 vaccination was also adjusted for, given the historical association with fever 

following PCV13 and influenza vaccine co-administration. Also adjusted for were age group 

(12-23, 24-35, 36-48 months) and previous receipt of influenza vaccination. Other variables 

were considered but were not included based on a non-significant p-value >0.1 for the bivariate 

association with a temperature ≥100.4 ̊F. These included ethnicity, gender, enrollment month, 

and high risk for influenza. Looking at the risk window of Day 0-2 with a temperature of 

≥100.4 ̊F, the adjusted relative risk of LAIV versus IIV was 0.60 and that was non-significant. 

Sensitivity analyses were also conducted for the risk window of Day 0-2 with a temperature of 

≥100.4 ̊F, assessing just those children who received influenza vaccine alone. Those children 

who received any antipyretic medicine within 8 hours before the temperature that was taken for 

the report were removed. Only the data reported via text message were assessed, and the 

analyses were limited to children ≥ 3 year of age. The adjusted relative risk remained the same 

in all of these analyses at 0.60. 

In the medical record review assessing all participants (n=535) from day 0-10, no febrile 

seizures or hospitalizations were documented. There were 9 ED visits and 17 ambulatory care 

visits. Assessing participants with fever in the Day 0-2 (n=22), 1 child who received IIV4 had an 

ED ambulatory care visit and 1 child who received IIV3 had an ED visit. 

In summary, there was no significant difference in fever rates of ≥100.4 ̊F on vaccination day or 

in first 2 days post-vaccination with LAIV4 (3.8%) versus IIV3 or IIV4 (5.8%). That nonsignificance continued even after adjusting in the regression models. There were few fevers 

≥102.2 ̊F in any study group, with 4 being in the IIV group and none in the LAIV4 group. There 

were also no significant differences in fever rates in the 3-10 days post-vaccination after LAIV4 

versus IIV, and there were no hospitalizations or febrile seizures in the 0-10 days postvaccination with any influenza vaccine. Data analyses are ongoing. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Discussion Points 

Dr. Harrison requested that Dr. Stockwell comment on the statistical power of the study to find 

differences. 

Dr. Stockwell replied that the study was powered to find about a two-fold difference between the 

studies. They would not have been powered to find a 2% difference considering that the rates 

are so small. 

Dr. Kempe noted that the analyses were broken down by high fever for the first two days, but 

not for Days 3-10 for which it appeared to be a third versus a half. The issue regards whether 

there is enough statistical power. 

Dr. Stockwell responded that LAIV groups would have been 6 out of 14 versus 4 out of 19 for 

Days 3-10. In terms of fever ≥102.2 ̊F, there were not enough cells to assess this. Therefore, 

the raw crude data were reported for fevers of ≥102.2 ̊F rather than showing that statistical 

change for the moderate. 

Dr. Rubin requested clarification from Dr. Cano regarding the cell culture-based vaccine in 

terms of whether those under 18 years of age were reported because they were given vaccine 

at an incorrect age rather than because they had an excess of adverse events. 

Dr. Cano responded that they did have some adverse events. When the demographics were 

reviewed on the VAERS form, they were less than 18 years of age. 

Dr. Moro added that those who received Flucelvax® but should not have were 11 to 18 years of 

age. The majority of them did not have an adverse event. Those who did have an adverse 

event mainly experienced local injection sites reactions. The reason for reporting was because 

the vaccine was administered at an incorrect age. 

LAIV and IIV Vaccine Safety 

Dr. Lisa Grohskopf 

Influenza Division 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Grohskopf reported on LAIV and IIV vaccine safety in children with high-risk conditions that 

confer higher risk of poor outcomes or severe disease from influenza. As a reminder, there 

were a number of presentations during the February 2014 ACIP meeting related to GRADE 

analyses of LAIV and IIV for healthy children (e.g., children who do not have chronic medical 

conditions that confer a higher risk for severe outcomes due to influenza infection). Data were 

presented on several age groups, though the focus was primarily on children 2 through 8 years 

of age. The rationale for the selected age group was that LAIV is not licensed for children under 

2 years of age, and 8 years is the upper limit of the age range for consideration of whether 1 

versus 2 doses are needed. That was selected for programmatic consistency and simplicity of 

the recommendations to be formulated. During the discussion period after the GRADE 

assessment that was presented for healthy children during the February 2014 ACIP meeting, 

questions were raised regarding the use of LAIV for children with chronic medical conditions. 

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



Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

When the WG initially planned its work, they decided to tackle the literature on healthy children 

first. However, since the questions were raised, a review was done for high-risk children. 

In terms of background, ACIP currently does not recommend the use of LAIV for children with 

asthma or other chronic medical conditions conferring high-risk of complications or severe 

illness due to influenza. The 2013-2014 package insert for LAIV, FluMist® quadrivalent licensed 

a couple of years ago and on the market for the first time during the 2013-2014 season, 

includes the following bullets in the Warnings and Precautions section that state the following: 

“Children younger than 5 years of age with recurrent wheezing and persons of 

any age with asthma may be at increased risk of wheezing following 

administration of FluMist® Quadrivalent. FluMist® Quadrivalent has not been 

studied in persons with severe asthma or active wheezing.” 

“The safety of FluMist® Quadrivalent in individuals with underlying medical 

conditions that may predispose them to complications following wild-type 

influenza infection has not been established” 

In a review of comparative studies, similar to the review conducted for healthy children, the WG 

sought to evaluate studies that compared the two vaccines—not one or the other versus 

placebo, but studies that had an LAIV arm and an IIV arm. They may or may not have had 

placebo in addition. The following were considered for the comparative studies of LAIV and IIV: 

Author Season Population Design Outcomes 

­

. 

Open-label, randomized 

­

­

The Ashkenazi and Belshe studies did not have an inclusion criterion that the child had to have 

asthma or wheezing, but there were children who had an asthma or wheezing history or asthma 

diagnosis in both of those studies. The Fleming study was specifically of children with an 

asthma diagnosis that included older children 6 through 17 years of age. Given the focus on the 

younger age group, data were not presented for the Fleming trial. However, the WG will likely 

return to this later. 

55 

Ashkenazi 

et al. 

PIDJ, 2006 

2002

2003 

6-71 months 

2 RTIs in previous 12 mos

Medically documented 

wheezing 

Any Wheezing 

Fleming et 

al. 

PIDJ, 2006 

2002

2003 

6-17 years 

clinical diagnosis of asthma 

plus ≥1 prescription for 

asthma medication within 

the past 12 months 

Open-label, 

randomized 

Medically attended 

wheezing 

Asthma 

exacerbation 

Asthma symptoms 

Belshe et 

al. 

NEJM, 

2007 

2004

2005 

6-59 months 

included children with mild 

or moderate asthma or 

wheezing history more 

than 42 days before 

enrollment. 

Double-blind, placebo 

controlled 

Medically significant 

Wheezing 

Any wheeze 

Hospitalization 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

The Ashkenazi and Belshe studies compared LAIV and IIV. Askhenazi was an open label study 

and Bleshe was a placebo-controlled blinded study that had placebo for LAIV and IIV. Belshe 

was a somewhat larger study than Ashkenzi. The data for these two studies subsetted out for 

the children who were between 24 and 59 months of age, and who had a history of asthma 

and/or wheezing. This was nicely broken down in a paper by Ambrose et al in 2012, which is 

where the data presented during this session was obtained. 

The primary efficacy endpoint for the GRADE evaluation was laboratory-confirmed influenza, 

which was a crticial outcome. This was not downgraded for any of the parameters (e.g., risk of 

bias, inconsistency, indirectness, or imprecision). There was a relative risk of 0.53, which was 

significant with a 95% confidence interval of 0.38-0.73, and an estimated risk difference of 47 

fewer cases/1000 with LAIV. The 0.53 risk ratio corresponds nicely with the one obtained last 

February when these data were presented for the entire group of children, not just those with 

asthma and wheezing, which was 0.47. The overall evidence quality was high. 

The definitions for the wheezing outcomes differed somewhat between Belshe and Ashkenazi, 

and for reasons of being consistent, Belshe was used for the evaluation of wheezing outcomes. 

For the Belshe paper, medically significant and medically attended wheezing outcomes were 

both reported and both were similar. For protocol-defined “medically significant wheezing” in 

children aged 24 through 59 months with a follow-up period of 42 days (6 weeks after 

vaccination), the WG downgraded on the basis of imprecision on the basis of the confidence 

interval including 1 and also being fairly wide. The risk ratio was 0.69, with a confidence interval 

that was not significant at the 95% level. The overall evidence quality assigned was 2, or 

moderate, due to downgrading for imprecision. 

The protocol-defined “medically significant wheezing” in children aged 24 through 59 months 

with a follow-up period of 42 days, children with asthma and/or wheezing were included but 

there was a further subdivision of children who had no wheezing in the last 12 months. Of 

course, the N was smaller so the confidence interval was wider and again included 1. 

Therefore, the WG downgraded this for imprecision and assigned an overall evidence quality of 

2, or moderate. For the children who wheezed in the last 12 months, there was an insignificant 

risk ratio and confidence interval. The WG downgraded for imprecision and assigned this an 

overall evidence quality 2, or moderate. For children who had an asthma diagnosis, the subset 

was only 120 to 130 children per arm. This is the one instance where the point estimate is on 

the other side of 1, but it is still fairly wide at 0.29-1.88. Because of that downgrade, this was 

estimated as 2, or moderate quality evidence. 

An effort also was made to find studies involving head-to-head comparisons of the two vaccines 

for children with other chronic medical conditions, but few were found. However, this is 

preliminary and the WG will continue to search for these studies. The following four studies 

have been located thus far: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

HR 

Condition 

Study Seasons Subjects N Outcomes 

Cancer Carr 

2011 

2008-09 

1 season 

Children 

2–21Y 

28 LAIV / 27 TIV SAFETY (SAEs): 

(a) 11Y old LAIV required hospitalization for fever, 

cough, rhinorrhea, myalgia, mild hypertension and 

positive Flu A test 

(b) 2Y old TIV developed afebrile seizure-like 

activity within 30 minute of TIV injection. 

Cystic 

fibrosis 

Gruber 

1994 

1989­

1992 

3 

seasons 

Children 

6M–23Y 

44 LAIV / 42 TIV 

subject years 

SAFETY: fever = no difference 

EFFICACY: LCI = 6 LAIV and 3 TIV 

King 

1987 

1984-85 

1 season 

Children & 

young 

adults 

27 LAIV, then 

MIV 

1 week later 

SAFETY: Reactions such as fever at Day 3 and Day 

6 post-vaccination. Results not analyzed statistically. 

HIV Levin 

2008 

2004-05 

1 season 

Children 

5–17Y 

122 LAIV / 121 

TIV 

SAFETY: SAEs based on dairy cards, phone calls & 

scheduled study visits on different days for each arm. 

“Pulmonary signs” included asthma & wheezing ≤28 

days = no difference between arms. 

These are studies with small numbers of subjects, and at this point, the WG did not feel that 

there was sufficient evidence to move forward on children with high-risk medical conditions or 

asthma. 

Dr. Grohskopf pointed out that there were some limitations to the evidence profiles she 

presented. The studies were not powered to detect differences in wheezing/asthma outcomes 

among the subgroup of children with a history of these conditions, and the confidence intervals 

were wide. The data do not clearly indicate the degree of asthma or wheezing severity for 

which LAIV benefits would outweigh risks. This becomes important when trying to formulate a 

recommendation, because it is important to clearly indicate the context in which the vaccine 

should be used. The data presented had a relatively long follow-up time of 42 days, and there 

are no data on earlier outcomes. At this point, there are few comparative data for other chronic 

medical conditions. No significant language changes were proposed for the upcoming season 

for high-risk medical conditions. 

In terms of the evidence profile for healthy children 2 through 8 years of age, the outcomes 

considered are shown in the following table: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Due to an inability to find any evidence from the studies on influenza-associated mortality, this 

was not included in the results. Though considered to be critical, it was not possible to assess 

immediate hypersensitivity/anaphylaxis, febrile seizure, and GBS given that these are 

sufficiently rare outcomes. Though considered to be important, an evidence profile was not 

included for respiratory symptoms or other neurologic outcomes because these were not 

defined specifically enough to make them feasible to assess. Because there were a couple of 

serious outcomes that were rated critical that could not be assessed, any related SAE was 

included. However, a value was not included for this because of the disparate types of events 

that occurred. Given that the evidence profiles for healthy children were presented during the 

February 2014 meeting, Dr. Grohskopf reviewed only those that had a significant result or were 

critical safety outcomes. 

For laboratory-confirmed influenza, data were assessed from Ashkenazi and Belshe. The 

Ashkenazi was open-label, while the Belshe study was blinded. Data from both studies were 

restricted to children aged ≥24 months, so children 6 through 23 months of age are not 

included. The evidence profile for laboratory-confirmed influenza was not downgraded for any 

serious concerns. The risk ratio was 0.47 with a confidence interval of 0.38 – 0.58. The overall 

evidence quality assigned was 1, or high. The risk difference was estimated to be 46 fewer 

cases/1000. 

The other outcome that showed a significant difference in favor of LAIV was influenzaassociated otitis media, and this was not downgraded. The same two studies were used for this 

profile, Ashkenazi and Belshe. The risk ratio was 0.47 with a confidence interval of 0.30 – 0.73. 

This was rated overall as a 1, or high quality evidence. The other critical outcomes (medicallyattended acute respiratory illness, hospitalization, and ILI did not show significant differences. 

For medically significant wheezing, only the Belshe study was included in order to keep the 

definitions of the wheezing outcomes consistent. This assessment included children 24 through 

49 months of age, with a follow-up time of 42 days. Although there was a slightly larger group 

of children for this profile, the confidence interval was fairly wide and the evidence was 

downgraded for imprecision. The overall quality of evidence was 2, or moderate. Children in 

the Belshe study could have been vaccine-naïve or not, so data were reported after dose 1 for 

both previously vaccinated children and vaccine-naïve children. The overall quality of evidence 

for vaccine-naïve children also was rated as 2, or moderate. 

In summary of the outcomes for which there was information, there was a significant difference 

for laboratory-confirmed influenza and otitis media in favor of LAIV and there was no difference 

for the other outcomes. The lowest quality of evidence for the critical outcomes was 

hospitalization with an evidence quality of 3. The WG elected to count the lowest quality as 

MARRI rather than hospitalization, because the hospitalization data was not influenzaassociated hospitalizations, so it was downgraded for indirectness. Because there is another 

critical outcome, laboratory-confirmed influenza, for which there is a specific outcome, 

hospitalization was not used as the lowest evidence quality. The overall quality of evidence for 

the benefits outcomes was 2, or moderate. All of the harms had a moderate quality of evidence. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Given that Medimmune presented on supply issues during the February 2014 ACIP meeting, 

Dr. Grohskopf did not address this. Another issue pertains to cost. A formal cost-effectiveness 

analysis has not been conducted on the relative cost of LAIV and IIV. It is likely that this would 

be a very complex undertaking at this point due to the very large number of products and 

presentations available. It will probably take a couple of years to conduct this type of analysis 

when there is a better sense of what is being used, and what the ratio is of IIV3 to IIV4 use is 

and whether it reaches some type of equilibrium. The WG decided that they did not feel it was 

necessary to have a formal cost-effectiveness analysis to move forward. The comparative 

prices per dose are from the VFC tables and are as follows: 

Vaccine product 

LAIV LAIV4: 

Price/dose 

$22.70 

IIV (with indication for ≤8 years) 

IIV3: 

IIV4: 

 $7.65 –$14.81 

 $14.90 – $21.09 

A 2008 cost-effectiveness model estimated a cost savings of $45.80 per child with LAIV as 

compared with IIV, but it is unclear what the applicability of this particular model would be given 

the current range of products, including quadrivalents which were not in use in 2008 [Luce BR et 

al, Vaccine (2008),;26:2841-2848]. 

In summary of considerations for formulating recommendations, the overall evidence type was 2 

or moderate for efficacy and safety. Evidence is lacking for some critical outcomes, such as 

influenza-related mortality, febrile seizure, GBS, and immediate hypersensitivity. The studies 

might not be powered to detect some rare but serious events. In terms of the balance between 

benefits and harms, benefits appear to outweigh harms, there is modestly better efficacy of 

LAIV at an estimated 47 fewer cases of lab-confirmed influenza per 1000, and no significant 

differences were observed in the rates of wheezing and fever. The Influenza WG placed a high 

value on the prevention of lab-confirmed influenza. There is uncertainty at present regarding 

the relative cost-benefit given the currently available range of vaccines. 

There are some limitations. All of the published studies used trivalent vaccines instead of 

quadrivalent vaccines, which were not yet available. All LAIV is now quadrivalent, but there is 

still a mixture of IIV3 and IIV4. The quadrivalent vaccines were licensed on the basis of being 

immunogenically non-inferior. There is no reason to expect that efficacy would be any less from 

a safety standpoint, given that across the board the safety profiles seem similar. However, it is 

possible that there could be rare but SAEs that could be identified over the years of postmarketing for which there would not have been adequate power to determine in the premarketing period. It is unclear whether the greater relative efficacy of LAIV is sustained with 

repeated vaccination over sequential years or with increasing age. Studies in adults generally 

have noted similar efficacy between the two vaccines, or slightly greater efficacy of IIV. It does 

seem that there is a point at which something changes, but exactly where that is remains 

unclear. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Proposed Recommendations 

Dr. Lisa Grohskopf 

Influenza Division 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Grohskopf reviewed the proposed recommendations for the 2014-2015 season. The 

MMWR will be in the Policy Note format again for 2014-2015. The core recommendations have 

not changed. Annual influenza vaccination is recommended for all persons aged 6 months and 

older. New and/or revised information includes the following: 

 Influenza vaccine virus composition for 2014-2015 

 A minor change to the egg allergy language 

 A minor change in the pediatric dosing algorithm 

 New recommendations regarding the use of LAIV and IIV for young children where either is 

available and appropriate 

Given the information just presented and that has been discussed within the WG over the last 

several months, the following new language is proposed for the use of LAIV and IIV for health 

children aged 2 through 8 years: 

Use of LAIV and IIV for Healthy Children Aged 2 through 8 Years 

 All individuals ≥6 months of age should receive influenza vaccine. Influenza vaccination 

should not be delayed to procure a specific vaccine preparation if an appropriate one is 

already available. 

 When both LAIV and IIV are available, LAIV should be used for healthy children aged 2 

through 8 years who have no contraindications or precautions (Category A). 

 If LAIV it is not immediately available, IIV should be used. Vaccination should not be 

delayed in order to procure LAIV. 

Discussion Points 

Dr. Reingold requested that Dr. Grohskopf explain the difference between the first and third 

bullets for this recommendation. 

Dr. Grohskopf replied that there is not a lot of difference, but the WG felt that it was important to 

emphasize this point. 

Dr. Bocchini inquired as to how this would impact the second dose if the first dose is one 

vaccine and that same vaccine is not available in a timely fashion for the second dose, and 

whether a separate statement should be made about this. 

Dr. Grohskopf indicated that this could be clarified in the recommendations if necessary, but the 

WG was not proposing a change in the current recommendation that each dose can be either. 

It is not necessary to have both LAIV or both IIV. It could be one or the other. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Brady (AAP) reported that one of COID’s concerns is the fact that providers already placed 

their orders in February for the doses. If the preferential language “should be used” is included 

in the recommendation, there could be issues related to how families might respond if 

pediatricians run out of the vaccine that should be used. The other situation is that a much 

larger proportion of infants is being vaccinated, and the additional children who need multiple 

doses in the older age group may be problematic in that LAIV may not necessarily be a more 

effective vaccine in that age group. The draft recommendations being sent to the AAP board 

will state that LAIV “should be considered” rather than “should be used” for healthy children to 

make it less preferential. 

Dr. Hahn (CSTE) commented that the second bullet could simply state, “When LAIV is 

available, it should be used . . .” because as written it sounded as though it was saying, “do not 

use LAIV unless you have both on hand.” 

Dr. Englund (PIDS) pointed out that the first bullet might be applicable this year and next year, 

given that some trivalent vaccines are still available. There has been confusion over the past 

year about withholding trivalent until quadrivalent is available. It is about more than just LAIV 

and IIV, so she liked the first bullet and thought it would be helpful. 

Ms. Pellegrini raised the issue of families who would be sensitive to the price point. While the 

ACA language requiring insurance coverage of these vaccines is very helpful, a significant 

number of families are still not covered by those protections for one reason or another. While 

she did not have a specific proposal, she wanted to make sure they were thinking about the 

strength of this recommendation in terms of guiding families toward LAIV when for some of 

them the approximately $10 price difference may play a role in their decision. 

Dr. Bennett thought all of those families would be covered by the VFC. 

Ms. Pellegrini clarified that she was thinking about families with private coverage who are not 

covered by ACA protection. 

Dr. Duchin noted that ACIP has tried to emphasize that both of these vaccines are excellent and 

effective, and that when possible, LAIV is preferential. However, not receiving LAIV is not a 

major disadvantage. 

Dr. Grohskopf indicated that there was some additional language related to LAIV regarding 

some conditions for which ACIP has recommended LAIV not be used to clarify that per the 

package insert, those are precautions. The additional language is as follows: 

Persons Who Should Not Receive LAIV 

 LAIV Should not be administered to: 

 Those aged <2 years or >49 years; 

 Those with contraindications as per the package insert: 

 Children aged 2 through 17 years who are receiving aspirin 

 Persons who have had severe allergic reactions to the vaccine or its 

components; 

 Pregnant women; 

 Immunosuppressed persons; 

 Persons with egg allergy; 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

 Children aged 2-through 4 years who have had a wheezing episode noted in the 

medical record within the past 12 months, or for whom parents report that a healthcare provider stated that they wheezing or asthma within the last 12 months; and 

 Persons who have taken influenza antiviral medications within the previous 48 hours. 

 Other chronic medical conditions conferring higher risk of complications due to influenza are 

precautions to use of LAIV 

 Per package insert, safety has not been established 

Vaccine Strain Selection for 2014-2015 

The FDA Vaccine and Related Biologic Products Advisory Committee (VRBPAC) convened on 

February 28, 2014 at which time they recommended the same composition for the 2014-2015 

season as for the 2013-204 Northern Hemisphere vaccine, including the following: 

 An A/California/7/2009 (H1N1)pdm09-like virus; 

 An A/Texas/50/2012 (H3N2)-like virus; 

 A B/Massachusetts/2/2012-like virus. 

 A B/Brisbane/60/2008-like virus for quadrivalent vaccines in addition to the first three 

Strain selection information was presented primarily for information, given that this is what the 

composition of the vaccine will be for the 2014-2015 influenza season. 

The next two topics have relatively minor changes. One of these pertains to the algorithm for 

determining the number of doses for children 6 months through 8 years of age. According to a 

couple of studies, children in this age range seem to need two doses of vaccine instead of one 

the first time they are vaccinated in order to achieve an optimal immune response. This was a 

relatively uncomplicated situation until the 2009 pandemic during which the doses received of 

the 2009 H1N1 antigen had to be counted. For 2012-2013, the approach was the same and 

consisted of two approaches, both of which were acceptable. There was a simplified approach 

which considered only doses since July 2010, and a more complicated approach that was good 

for those in settings with good registry data that considered all vaccination history, including the 

pre-pandemic period. For 2014-2015, the WG proposes to keep both the simplified and 

complicated approaches, but with the additional information that children in this age group who 

received at least one dose of the 2013-2014 seasonal vaccine need only one dose in 2014­

2015. This is being done because the vaccine viruses will remain unchanged for the 2014-2015 

season, and it is analogous to a change that was made for 2011-2012, which was the last time 

that the strains were unchanged from the previous seasons. These are as follows: 

Determining Doses for Children Aged 6 Months through 8 Years 

 Children age 6 months through 8 years receiving vaccine for the first time require 2 doses 

 Need to consider doses of pandemic 2009 H1N1 

 For 2012-13 and 2013-14 two accepted approaches 

 Simplified approach considering only doses since July 2010 

 Second approach considering all vaccination history 

 For 2014-15, both approaches retained, with additional information that children in this age 

group who received at least 1 dose of 2013-14 seasonal vaccine need only one dose in 

2014-15 

 Vaccine viruses unchanged this season 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

 Analogous to 2011-12 recommendations (strains also unchanged) 

Discussion Points 

Dr. Groom (IHS) commented that for those trying to program this into their EHRs and registries, 

to have this decision come in June is very challenging. They definitely want to incorporate it 

because it will dramatically reduce the number of children who need two doses, but she 

suggested in the future including something in the recommendation so that if there is not a 

strain change, it can be assumed that only one dose for these children would be needed. Then 

moving forward, everyone could anticipate this a lot sooner. 

Dr. Grohskopf replied that while she appreciate this, unfortunately VRBPAC and WHO meetings 

tend to occur in February, it is sometimes difficult to know what will occur with the strains. This 

may or may not be an issue going forward, because one thing that is under discussion is that 

this will become less of an issue the further out from the pandemic year. At some point, the WG 

is likely to discuss returning to the simplest approach that was last applicable in 2009, which 

was two doses should be administered the first time. This required only a sentence rather than 

an algorithm. The WG had some discussion regarding the change and the difficulties that 

poses to programming. 

Referring to Slide 6, it seemed to Dr. Gorman (NIH) that changes had been made to the list that 

the FDA lists as precautions or warnings to contraindications. He said he would like for those to 

be separated out. 

Dr. Grohskopf replied that an effort was made in the 2013-2014 statement to make a distinction 

between those conditions that are package insert specified contraindications, of which there are 

only two, and those conditions for which ACIP recommends against use of LAIV. There has 

long been a dichotomy of those conditions. For example, probably the largest one is against 

use in persons who have chronic medical conditions conferring a higher risk of complications 

from influenza. An attempt was made to make that same distinction in the proposed 

recommendation by reflecting the age indication in the first bullet, while the second bullet 

reflects the pathogen groups that are package insert-defined contraindications. The remaining 

bullets under the first main bullet should not be administered to those with conditions for which 

ACIP does not recommend use. 

Dr. Gorman (NIH) recommended that the language state “persons who the ACIP does not 

recommend receive LAIV” as opposed to “should not.” 

Dr. Middleman (SAHM) thought that the bullet regarding 2 through 4 year olds who have had a 

wheezing episode made it seem like adolescents who have a diagnosis of asthma are included 

in that. It implies that vaccine could be administered to those who are 5 years of age and older 

who do have asthma or who have had wheezing. 

Dr. Grohskopf indicated that there was an additional bullet that should have been included, and 

that the draft guidance provided to ACIP members included a bullet on persons of any age with 

asthma. 

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Dr. Grohskopf clarified that any preferential language pertained strictly to healthy children and 

not those with chronic medical conditions. Regarding the action step for precautions or 

conditions that would be deemed a precaution that are not listed under the “should not be 

administered to” section, precautions are situations that generally require clinical judgment and 

for which the benefits and harms have to be weighed. It is difficult to make a statement about 

the relative benefits and harms in this particular case simply because there are insufficient data 

for a lot of groups. At this point, it is difficult to have a recommendation in a document that is 

intended to cover every possible scenario in the absence of those data. By the definition of 

“precaution,” that would involve clinical judgment. 

Dr. Kimberlin (AAP) inquired as to whether the language “should be used for healthy children” 

would go into the immunization schedule footnote as such. The AAP Board of Directors 

approves language of “should be considered” and ACIP states “should be used,” there will be a 

divergence of schedules after many years of trying to harmonize them. 

Ms. Pellegrini inquired as to whether the AAP recommendation was based on the fact that ACIP 

was out of sync with pediatricians’ ordering schedules for vaccine, such that the AAP and ACIP 

language would be out of sync only for one year. 

Dr. Harrison said his greatest concern was that for a clinician trying to figure out what to do, it 

was not clear what “should be considered” meant. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Ms. Stinchfield (NAPNAP) pointed out that the Vaccine Information Statements (VIS) are 

sometimes the only documents that clinicians look at. Now that this is separated out into 

precautions, she wanted to ensure that the VIS writers carried that over and not overstate it 

there. 

Dr. Moore (AIM) asked what the intent of the WG was related to the use of LAIV when there is a 

precaution and it is truly not a contraindication, in terms of whether they were saying that if there 

is a precaution for LAIV and IIV is on hand, LAIV should not be used. However, if only LAIV is 

on hand, it should be used. 

Dr. Schuchat emphasized that this would be reflected in the schedule. 

Dr. Brady (AAP) entered a plea for the language approved by AAP and ACIP to be identical, 

given the number of years it has taken to be harmonious. 

Dr. Kimberlin (AAP) responded that this was part of the discussion, and that they would 

potentially be discordant for only one year if there were no additional information to suggest that 

there may be a need to reconsider that. 

Dr. Schuchat reminded everyone that ACIP moved away from using the term “should be 

considered” based on the AAP’s strong recommendation that this be done. 

Dr. Brady (AAP) responded that that was based on whether a vaccine was permissive. The 

recommendation under consideration was based on not placing someone in a situation in which 

families might think that the practitioner was not doing what was best for their child. 

Dr. Temte pointed out that in February practices have already ordered influenza vaccine for the 

upcoming season, in June practices have already ordered and the influenza vaccination season 

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is underway, and in October the vaccination season is well underway. There really is not a 

good time to make changes in influenza vaccine recommendations. As part of the discussion 

regarding recommendations and codifying language, ACIP tried to strongly move away from 

“should be considered,” which is confusing to clinicians. 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Hosbach (Sanofi Pasteur) said that from the manufacturer perspective, a mid-season 

recommendation such as this is disruptive. Not only have clinicians ordered, but when this 

recommendation is published, they could cancel their orders. Manufacturers are already well 

into and nearly finished with the major manufacturing process. It is not without precedent that 

ACIP has given forewarning that something is coming in an outgoing year. This is disruptive to 

a number of stakeholders, including EHR systems. This will complicate things for 

manufacturers, and will have a financial impact for manufacturers and perhaps health care 

practitioners. 

Ms. Stinchfield (NAPNAP) said she was experiencing déjà vu from the conversation when 

universal influenza vaccine was recommended for everyone 6 months of age and older, and she 

thought it was this same time of year. At that time, the term “as feasible” was added. 

Regarding Dr. Hosbach’s comments, if vaccine rates were in the 80% to 90% she would worry 

about the disruption. However, the US has a long way to go to vaccinate people who are 

eligible and for whom IIV is available. Therefore, she did not see a need to hold. 

Dr. Temte added that in his own state, especially for children 5 through 17 years of age, uptake 

is about 30% to 32%. 

Dr. Decker (Sanofi Pasteur) stressed that the AAP participants noted that the studies comparing 

LAIV and TIV were sufficiently old, and practice has changed sufficiently since then. Therefore, 

it is not entirely clear that whether the benefit observed in those studies still pertains. In that 

regard, the manufacturer of LAIV has an obligation to the FDA obligation to conduct and efficacy 

trial in the group for whom the proposed recommendation is being made (2 through 8 years of 

age). He inquired as to when the results of that study would be available. 

Dr. Grohskopf replied that she did not know when the results would be available. 

Dr. Friedland (GSK) indicated that GSK certainly supports the use of evidenced-based 

recommendations. He thought the language providers would like to see would be for clarity and 

understanding of the recommendation, so he thought there would be value in the language to 

say that when IIV vaccines are used, they are safe and effective in this patient population. The 

proposed language did not necessarily state that. 

Dr. Duchin noted that the annotated text describes both vaccines as safe, effective, and 

desirable. He reminded everyone that the issue of timing had been discussed during a number 

of ACIP meetings, and the WG attempted to signal its intent about this during multiple meetings. 

This meeting marked at least the third one during which this was discussed and an indication 

was given that the WG was moving in this direction. 

Dr. Grohskopf indicated that there was a minor change to the recommendation for vaccination 

of persons with severe egg allergy. Since 2011-2012, there has been a dichotomy between 

what to do with persons who have mild allergy defined as hives in response to egg exposure 

versus severe allergy defined as any symptoms other than hives following egg exposure. For 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

the most recent round of the recommendations discussed a year ago, recombinant influenza 

vaccine (RIV) came into existence. The language as it currently reads is as follows: 

Vaccination of Persons with Severe Egg Allergy 

 Persons with symptoms other than hives are recommended to 

 Receive recombinant influenza vaccine (RIV3) if age 18 through 49 years, or 

 Be referred to a “physician with expertise in the management of allergic conditions.” 

 Joint Task Force on Practice Parameters (ACAAI/AAAAI), 2013: 

 Cites 2012 review of 4,172 patients, including 513 with history of severe allergic 

reaction—no occurrences of anaphylaxis; some milder reactions 

 Recommends that “special precautions regarding medical setting and waiting periods 

after administration of IIV to egg-allergic recipients beyond those recommended for 

any vaccine are not warranted” 

 However, 

 Occasional cases of anaphylaxis possibly due to egg in VAERs 

 Concern that not all settings may have required equipment and personnel 

 New language seeks to 

 Clarify that referral is not strictly necessary, assuming that the person who is going to 

be administering it is a physician with expertise in allergic conditions 

 Maintains 30 minute wait period: reiterates need for resuscitative resources 

Vaccination of Persons with Severe Egg Allergy 

Proposed change from: 

“Persons who report having had reactions to egg involving such symptoms as angioedema, 

respiratory distress, lightheadedness, or recurrent emesis; or who required epinephrine or 

another emergency medical intervention, particularly those that occurred immediately or within a

short time (minutes to hours) after egg exposure...may receive RIV3, if aged 18 through 49 

years and there are no other contraindications. If RIV3 is not available or the recipient is not 

within the indicated age range, such persons should be referred to a physician with 

expertise in the management of allergic conditions for further risk assessment before 

receipt of vaccine”. 

To: 

“...may receive RIV3, if aged 18 through 49 years, and there are no other contraindications. If 

RIV3 is not available or the recipient is not within the indicated age range, IIV should be 

administered a physician with experience in the recognition and management of severe 

allergic conditions.” 

Discussion Points 

Dr. Jenkins noted that the change should read, “administered by a physician . . .” 

Referring to the slide regarding LAIV, Dr. Rubin suggested changing the first phrase to say 

“When feasible, LAIV should be used . . .” to address some of the concerns with price, 

availability, et cetera. 

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Dr. Kempe agreed and said she could think of a lot of children who for some strange reason 

prefer the injection. As a physician, she is never going to say “no” because she wants them to 

receive the vaccine. It may help to word the recommendations in terms of the data. Both LAIV 

and IIV are efficacious and safe. Data suggest that LAIV may be more effective in healthy 

children; therefore, that should be a preference. Stick with the facts. “Should be used” is too 

encompassing and does not really incorporate what ACIP is trying to do, which is make 

recommendations based on what the evidence shows. 

Dr. Karron commented that the additional language in the recommendations actually goes 

through the evidence and discusses the data. She thought it would be rather cumbersome to 

actually include that in the proposed recommendation. From the WG’s perspective, this has 

been a long time coming and there has been a lot of discussion. The WG specifically chose the 

language “should be used” after deliberation and review of the data. 

Dr. Temte reminded everyone that that was based on moderate to high quality evidence. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Kempe agreed that this wording would be helpful in light of the fact that people might find 

themselves in a bind for the next year or so. 

Instead of including this in the final recommendations, Dr. Duchin suggested annotating the 

guidance with that type of information as is frequently done when a recommendation is 

published. This type of statement would put it into some context that would explain the timing, 

ordering issues, and the fact that this might be challenging the first year, but people should not 

feel bad about that. 

Dr. Bennett clarified that the objection to the first bullet stating “When both LAIV and IIV are 

available” was that it implied that practitioners must have both in the office. 

Dr. Karron thought the phrasing suggested for that was “when LAIV is available,” which she 

agreed with because this made is much cleaner and simpler. However, it did not address the 

feasibility issue. She agreed with Dr. Duchin that perhaps this could be annotated rather than 

being included in the primary language. 

Ms. Pellegrini emphasized that there are multiple aspects to feasibility, and she wondered how 

strong this preferential recommendation would be in terms of whether it was limited to a small 

universe of feasibility issues, or if it was broad enough to include family preference, economic 

consideration, et cetera. That is, there is a large philosophical question. 

Dr. Savoy (AAFP) inquired as to whether people would feel better if there were job aids similar 

to those shown earlier in the day that were more specific. If she just read the text as written, 

she would have assumed that if she had LAIV and IIV, she should give the live vaccine. 

However, if she did not have both she should give whichever one she had. A job aid could 

clarify this without having to change the actual recommendation. 

Dr. Coyne-Beasley emphasized that the session was running about 25 minutes overtime, and 

she wanted to ensure that the Adult Immunization WG did not get bumped again. 

Dr. Temte said to let the record show that during the last meeting, he promised Dr. CoyneBeasley that would not happen and the Adult Immunization WG would have its time in the 

afternoon. 

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 0 Opposed: 

 0 Abstained: N/A 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Brady (AAP) agreed that probably from the perspective of what he mentioned previously, if 

the second bullet was changed to “if LAIV was available” and did not include both. Then if a 

pediatrician did not have any LAIV, that would give them an easier out. 

Dr. Bocchini agreed, but stressed that this would be a one year statement, so it would be 

suitable to make an interim change with the language mentioned and then change it again next 

year based on the fact that people would be ready to order in a different way. 

Dr. Temte clarified that the proposed language for the use of LAIV and IIV for healthy children 

aged 2 through 8 years was suggested to read as follows: 

 All individuals ≥6 months of age should receive influenza vaccine. Influenza vaccination 

should not be delayed to procure a specific vaccine preparation if an appropriate one is 

already available. 

 When available, LAIV should be used for healthy children aged 2 through 8 years who 

have no contraindications or precautions (Category A). 

 If LAIV is not immediately available, IIV should be used. Vaccination should not be 

delayed in order to procure LAIV. 

Vote 

Dr. Duchin made a motion to accept the recommendations as a package as proposed, with the 

clarifications and changes suggested. Dr. Harrison seconded the motion. The motion carried 

with 15 affirmative votes, 0 negative votes, and 0 abstentions. The disposition of the vote was 

as follows: 

15 Favored: Bennett, Bocchini, Campos-Outcalt, Coyne-Beasley, Duchin, Harriman, 

Harrison, Karron, Jenkins, Kempe, Pellegrini, Reingold, Rubin, Temte, and 

Vazquez 

N/A 

Human Papillomavirus (HPV) Vaccines 

Introduction 

Joseph A. Bocchini, Jr, MD 

Chair, ACIP HPV Vaccine Working Group 

Dr. Bocchini indicated that this human papillomavirus (HPV) vaccine session would include the 

following topics: 

 9-valent HPV vaccine clinical trial data 

 Policy considerations and approach to GRADE for 9-valent vaccine 

 2-dose schedules for bivalent and quadrivalent HPV vaccines 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

The HPV vaccine WG is working to prepare for the expected licensure of the 9-valent HPV 

vaccine in late 2014, and is continuing to review the data on 2-dose schedules. In 2013, the 

WG heard a GSK presentation on the GSK 2-dose development program, and recently 

reviewed available data on 2-dose schedules. 

The overall proposed timeline for consideration of the investigational 9-valent vaccine is 

reflected in the following table: 

ACIP Date Topic 

October 2013 Overview of 9-valent vaccine clinical program 

February 2014 Attribution of types in HPV-associated disease 

Clinical trial data 

June 2014 Clinical trial data 

GRADE Policy Questions 

October 2014 Health Economics 

GRADE 

Recommendation options and discussion 

February 2015 Earliest potential vote 

To review, during the October 2103 ACIP meeting HPV session, an update was presented on 

HPV vaccination coverage in the US; review of 9-valent HPV vaccine was begun, with a 

presentation from Merck on the clinical development program. Since the October 2013 ACIP 

meeting, the WG has had regular conference calls to review and discuss a variety of data, 

including the 9-valent HPV vaccine clinical trials and HPV type attribution in HPV-associated 

disease, and to initiate discussion of GRADE considerations. 

9-Valent HPV Vaccine Clinical Trial Data 

Alain Luxembourg, MD, PhD 

Director, Clinical Research 

Merck & Company, Inc. 

Dr. Luxembourg reminded everyone that last time, there was a presentation of the three pivotal 

studies in the program: 

 Protocol 001: Efficacy study in young women 

 Protocols 002 and 009: Immunobridging studies in adolescents 

These studies have been completed and are continuing as longer-term effectiveness and 

immunogenicity studies. 

The following Phase III studies are ongoing: 

 Protocol 003: Immunobridging study in young men 

 Protocol 010: Two-dose regimen 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

During this session, Dr. Luxembourg presented information on the following supportive studies 

that have been completed: 

 Protocols 005 and 007: Concomitant use studies 

 Protocol 006: Study in prior quadrivalent HPV vaccine recipients 

 Integrated summary of safety for Protocols 001, 002, 005, 006, 007, and 009 

To summarize the presentations during the February 2014 meeting on Protocols 001, 002, and 

009, all efficacy and immunogenicity objectives were met. Non-inferiority was demonstrated 

with respect to the 4 original types in the quadrivalent vaccine. Approximately 97% protection 

was documented against HPV 31-, 33-, 45-, 52-, and 58-related disease. Non-inferior 

immunogenicity was demonstrated in boys and girls versus young women. The AE profile was 

similar to that of the quadrivalent HPV vaccine, except that there were more injection site AEs 

that were mostly mild to moderate in intensity. 

The immunogenicity objective of Protocol 005 was to demonstrate that concomitant 

administration of 9vHPV vaccine with Menactra® and Adacel® does not interfere with the 

antibody response to any of the vaccine antigens. The safety objective was to evaluate the 

safety and tolerability of the 9vHPV vaccine when concomitantly administered with Menactra® 

and Adacel®. On Day 1 in the concomitant cohort, subjects received 9vHPV vaccine 

concomitantly with Menactra® and Adacel®. Subjects in the non-concomitant group received 9­

valent alone. The non-concomitant group received Menactra® and Adacel® one month later. All 

subjects received a second and third dose of 9vHPV at Months 2 and 6, respectively. 

With respect to the 9vHPV vaccine antigens, the non-inferiority criterion was met for all 9 HPV 

types (all p<0.001). The seroconversion rates in the concomitant group were the same as in the 

non-concomitant group after vaccination with 9vHPV vaccine. Menactra® contains 4 N. 

meningitidis serogroups, and the non-inferiority criterion was met for all 4 of these serogroups. 

This means that there is no substantial difference between the concomitant and nonconcomitant cohorts. In terms of the Adacel®, the non-inferiority criterion was met for diphtheria, 

tetanus, and all 4 pertussis antigens. 

To summarize the findings for Protocol 005, 9vHPV vaccine can be administered concomitantly 

with Menactra® and Adacel®. There is no interference with the antibody response to any of the 

vaccine antigens, and 9vHPV vaccine is generally well-tolerated. 

Repevax® is used in Europe, so it is not directly relevant to the US. To be complete, Dr. 

Luxembourg summarized the findings for Protocol 007, indicating that concomitant 

administration of 9vHPV vaccine and Repevax® does not interfere with the antibody response to 

any of the vaccine antigens. Concomitant administration of 9vHPV vaccine with Repevax® is 

generally well-tolerated in young adolescents. These are very consistent with the findings of 

Protocol 005. 

Protocol 006 was primarily a safety study to help healthcare professionals advise their patients 

about 9vHPV vaccination (e.g., individuals seeking follow-up vaccination or with unknown 

history of HPV vaccination). The safety objective of Protocol 006 was to evaluate the safety and 

tolerability of the 9vHPV vaccine in prior Gardasil® recipients. The immunogenicity objective of 

Protocol 006 was to demonstrate that the 9vHPV vaccine is immunogenic with respect to HPV 

31, 33, 45, 52, 58 in prior Gardasil® recipients. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

The study population was comprised of 900 girls and young women. There were approximately 

180 subjects aged 12 through 15 years and approximately 720 subjects aged 16 through 26 

years. All subjects were prior recipients of a 3-dose regimen of Gardasil®. Subjects were 

randomized 2:1 to 9vHPV vaccine or saline placebo in order to allow safety profile of the 

vaccine to be more completely defined. The key immunogenicity endpoints included anti-HPV 

6, 11, 16, 18, 31, 33, 45, 52, and 58 titers and seropositivity rates for Day 1, Month 2, and 

Month 7. The key safety endpoints included injection-site and systemic AEs Day 1 to 15 

following any vaccination through Vaccination Report Card (VRC)-aided surveillance, and SAEs 

for Day 1 through Month 7. Subjects received 3 doses of Gardasil® before entering the study, 

and their doses had to be administered within a period of 12 months and documented by 

medical records. A time interval was requested of 12 months between the last dose of 

Gardasil® and the first dose of whatever they were receiving in the trial, so that the antibody 

response to Gardasil® had decreased for all subjects to a immunogenicity plateau and so that 

the study would contain a homogeneous population in terms of antibody titers. 

In terms of the safety data for 9vHPV vaccine versus placebo, the vaccine appeared welltolerated. There were very few discontinuations due to vaccine-related AEs and very few 

vaccine-related AEs as well. It was important to assess injection site AEs because the subjects 

in the 9vHPV vaccine cohort will have received 6 doses of HPV vaccine in their lifetimes. The 

frequency of injection site reactions was consistent with that observed in Protocol 001, with 

pain, swelling, and erythema were by far the most common. Injection site AEs were of mild to 

moderate intensity, so tolerability appears to be acceptable. 

Regarding immunogenicity in prior Gardasil® recipients, a primary endpoint was to assess 

seroconversion rates. In the girls and young women subsets, seroconversion rates were high. 

This means the vaccine is very immunogenic in both populations. With respect to 

immunogenicity in prior Gardasil® recipients aged 12 to 15 years following Dose 1 and Dose 3, 

substantial GMTs were observed for types 6, 11, 16, and 18. . After 1 dose at Month 2, there 

was a substantial increase. After Month 3, there was not much of a change. This means that 

most of the increase occurs after the first dose. This is not a surprise, given that they were all 

prior Gardasil® recipients. It is a memory response. For the additional types, in general there 

was no or very little antibody at Day 1. There was a substantial increase following the first dose, 

with further increase after the third dose. With some of the types, there was more than a 3-fold 

difference. These results suggest that there is benefit in receiving more than one dose for the 

additional types. In young women 16 to 26 years of age, memory response for the original 

types and the new types was essentially the same. The girls and young women are analyzed 

separately because immunogenicity is age-dependent. 

To summarize the key findings for Protocol 006, 9vHPV vaccine has an acceptable safety 

profile in prior Gardasil® recipients. Most injection-site reactions are of mild or moderate 

intensity. 9vHPV vaccine is highly immunogenic with respect to the new types in prior Gardasil® 

recipients. Of the subjects, greater than 98% became seropositive after 3 doses of 9vHPV 

vaccine. Important considerations for Protocol 006 are that the study investigated subjects who 

received 3 doses of Gardasil® followed with 3 doses of 9vHPV vaccine. The study did not 

investigate mixed regimens of the 2 vaccines. This was primarily a safety, placebo-controlled 

study. No subjects who were naïve to HPV vaccination were enrolled in this study. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

An exploratory immunogenicity analysis was conducted which compared Protocol 006 to the 

other 9vHPV vaccine studies. The goal was to assess the immunogenicity of 9vHPV vaccine 

after qHPV vaccine versus 9vHPV vaccine alone. There are a number of caveats. Since no 

subjects received 9vHPV vaccine only in this study, this was a cross-study comparison. Studies 

of other vaccines have shown that previous antigenic encounter may result in a lower 

subsequent response to a related antigen. The explanation may be that memory response was 

favored over primary response. Protocol 006 may represent a similar situation. Because there 

is strong L1 homology among HPV types (example HPV 16 vs. HPV 31: 83% homology), the 

HPV antigens in Gardasil® and the additional antigens in 9vHPV vaccine are related antigens. 

This means that it cannot be said that subjects who were prior recipients of Gardasil®, strictly 

speaking, are totally naïve to the additional types. It is of interest to assess what is occurring. 

In the cross-study immunogenicity comparison of 9vHPV in prior Gardasil® recipients compared 

to subjects naïve to HPV vaccination, the two groups were not distinguishable in terms of 

seroconversion rates. In young women 16 through 26 years of age, the GMTs for types 6, 11, 

16,18 in subjects who received 9vHPV vaccine following 4-valent vaccine were higher than that 

observed in the combined studies where subjects received 9vHPV vaccine alone. This is 

consistent with memory response once again. Looking at the new types, the picture is reversed 

and immunogenicity is lower with respect to the new types. The GMTs in subjects who received 

9vHPV vaccine following 4-valent vaccine are lower for the new types but still higher than with 

natural HPV infection. Looking at the GMTs in girls 12 through 15 years of age who received 

9vHPV following 4-valent vaccine compared to women who received 9vHPV only, the difference 

was less in respect to the additional types. For some types, the GMTs are comparable, but for 

some the GMTs are slightly lower. For the original types, GMTs are higher. 

The results of the cross-study immunogenicity comparison should be interpreted with caution, 

given that this was an exploratory analysis comparing across different studies. The findings 

were consistent with previous observations of lower response to antigenic variants following 

initial exposure to a given antigen. The practical consequences of these findings are likely 

limited for several reasons. Seroconversion rates are high in all subjects. The clinical 

significance of differences in GMTs between vaccination groups is unknown, given that there is 

no known threshold of antibody protection. In Protocol 001, lower Month 7 anti-HPV 31, 33, 45, 

52, and 58 titers are not correlated with lower efficacy. The impact of “Original Antigenic Sin” is 

considered limited in the context of influenza vaccination. Revaccination is associated with 

reduced mortality risk compared with first time vaccination (Voordouw AC., JAMA 292:2089-95, 

2004). 

Turning to safety results, Dr. Luxembourg reminded everyone that in Protocol 001, the safety 

profile was generally comparable for the 9-valent and 4-valent vaccines, but there was a higher 

frequency of injection site AEs with the 9-valent vaccine. There were approximately 7000 

subjects in each cohort in Protocol 001. With respect to the integrated safety data for all six 

studies (001, 002, 005, 006, 007, and 009), the integrated database includes over 13,000 

subjects, and the safety profile is comparable to what has been observed so far in Protocol 001. 

The vaccine is well-tolerated and most of the AEs are injection site-related, and there are very 

few SAEs that are vaccine-related. Pain, swelling, and erythema are the most common 

injection site AEs and the numbers and frequency are consistent with what has been observed 

in Protocol 001. In the integrated database, most injection site reactions are mild to moderate in 

intensity. Systemic vaccine-related AEs with an incidence of more than 1% included headache, 

pyrexia, nausea, dizziness, and fatigue. These are everyday life events, and are common in 

any vaccine trial. There were 5 vaccine-related SAEs, 2 of which required hospitalization. All 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

were resolved, and there was nothing unusual that has not previously been observed in the 4­

valent program. 

To summarize the safety conclusions, 9vHPV vaccine was found to be generally well-tolerated 

in over 13,000 subjects. There were few discontinuations, few vaccine-related SAEs, and no 

vaccine-related deaths. The adverse experience profile is generally comparable to that of the 4­

valent HPV vaccine. There were more 9vHPV vaccine injection-site AEs, but most were mild to 

moderate in intensity. The adverse experience profile is comparable across age groups, 

gender, race, ethnicity, and HPV status at baseline. 

In terms of the overall summary, a non-inferior antibody response was demonstrated with 

respect to the original types compared to the 4-valent vaccine. Approximately 97% protection 

was demonstrated against HPV 31, 33, 45, 52, and 58-related disease. Non-inferior 

immunogenicity was demonstrated in boys and girls versus young women. 9vHPV vaccine is 

generally well-tolerated, and the AE profile is similar to that of the 4-valent vaccine. There were 

more injection-site AEs with the 9vHPV vaccine, but most were mild to moderate in intensity. 

9vHPV vaccine can be co-administered with Menactra® and Adacel®, is generally well-tolerated, 

and is highly immunogenic in prior 4-valent HPV vaccine recipients. As a reminder, the 9vHPV 

vaccine is still an investigational product under review by the FDA. 

9-Valent HPV Vaccine: Overview of WG Considerations 

Eileen F. Dunne MD, MPH 

HPV Vaccine Working Group 

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

Centers for Disease Control and Prevention 

Dr. Dunne pointed out that this presentation would set the stage for a GRADE review of the 

evidence for 9-valent HPV vaccine in October 2014. In order to frame the policy questions, she 

reviewed the attribution of HPV types to cervical precancers and cancers. This was presented 

to ACIP in February 2014. She then discussed the 9-valent HPV vaccine policy questions for 

consideration; the available 9-valent HPV studies; the conclusions from the WG on critical 

outcomes to consider for GRADE; the population, intervention, comparison, and outcomes 

(PICO) for the primary policy questions; cost-effectiveness considerations; and next steps for 

GRADE. 

With regard to HPV type attribution by cancer site in the US, most cancers are attributable to 

HPV16/18. The 5 additional types are associated with 14% to 18% of cervical, vulvar, and 

vaginal cancers, and 6% to 9% of anal, penile, and oropharyngeal cancers. 

To provide an overview of attribution of the 9 HPV types to cervical intraepithelial neoplasia 

(CIN)2+ and HPV associated invasive cancers, about 50% of CIN2+ are attributable to 

HPV16/18 and about 25% to the 5 additional types in 9-valent HPV vaccine. Of invasive 

cancers, 62% are attributed to HPV16/18 and this is similar for males and females. Of cancers, 

11% are attributed to the 5 additional types in the 9-valent HPV vaccine, and this is different for 

females and males with 14% in females and 5% in males. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

To summarize the 9-valent HPV vaccine policy questions for GRADE, the primary questions 

are: 1) Should 9vHPV vaccine be recommended routinely for 11 or 12 year olds?; and 2) Should 

9vHPV vaccine be recommended for females aged 13 through 26 years and males aged 13 

through 21 years who have not initiated or completed the vaccine series? The ACIP HPV WG 

was strongly interested in considering these policy questions for males and females at the same 

time for programmatic reasons, although because the outcomes are different for males and 

females as well as the attributable fraction of 9 types to cancer, the PICO would be considered 

separately for males and females. The workgroup would like to consider a recommendation for 

adult males with available data in October 2014, even though there would likely not be an adult 

male indication for 9-valent HPV vaccine at the time of first licensure. The additional policy 

questions included: 1) Should girls/women who received 3 doses of quadrivalent HPV vaccine 

be revaccinated with 9vHPV vaccine?; and 2) Should 9vHPV vaccine be recommended for men 

who have sex with men (MSM) through age 26 years? 

The available data for the initial filing of 9-valent HPV vaccine are shown in the following table: 

Dr. Dunne highlighted some features of the data available for policy considerations. As a 

reminder, the main trial was a comparison of HPV4 and 9-valent HPV and there was no placebo 

arm. For adult females, there will be efficacy and immunogenicity data, and for adult males 

there will be immunogenicity data. The data on revaccination with 9vHPV are available for 

females only, and the immunization schedule in the trials was 0, 2, 6 months. 

In order to address the critical outcomes to consider for GRADE, the ACIP HPV WG was 

surveyed in May 2014 on the key outcomes; 21 responses were received. This included 

outcomes in females and males, and benefits and harms. The Association of Immunization 

Managers (AIM) members were also surveyed, and 26 responses were received. AIM feedback 

was consistent with that of the ACIP HPV WG. 

Critical outcomes for females included cervical cancer, cervical precancer, anal cancer, 

vaginal/vulvar cancer, CIN, definitive therapies and oropharyngeal cancer, as well as SAEs and 

anaphylaxis. As a reminder, for many of the outcomes there is no direct data from the clinical 

trials, so outcomes were listed for which there are direct data including cervical precancer, CIN, 

definitive therapies, SAE, and anaphylaxis. For some outcomes, there will not be direct data but 

there may be indirect data such as data on cervical precancer, vaginal/vulvar precancer, or 

immunogenicity. For males, the critical outcomes included anal cancer, oropharyngeal cancer, 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

SAEs, and anaphylaxis. There will be no direct data on these outcomes in males; however, 

there will be indirect immunogenicity data. 

Regarding the PICO comparison and outcomes for the primary policy questions, for the 

question of routine vaccination at 11 or 12 years, the population is females immunized at age 11 

or 12, the intervention is of 9vHPV and comparison of HPV4, and the critical outcomes were as 

highlighted earlier. The primary objective is an evaluation of HPV6, 11, 16, 18 equivalence, and 

evaluation of HPV 31, 33, 45, 52, 58 superiority. For males, the population is males immunized 

at 11 or 12, with the same intervention, comparison, and the critical outcomes highlighted 

earlier. The primary objective is the evaluation of HPV 6, 11, 16, and 18 equivalence. 

Superiority of 5 types of HPV outcomes will not be evaluated in males, given that the attribution 

of 5 types to males’ critical outcomes such as anal and oropharyngeal cancers is limited. 

The PICO for the question pertaining to older females and males includes the population of 

females immunized at ages 13 through 26 years; intervention of 9vHPV vaccine; comparison of 

HPV4; critical outcomes as highlighted earlier; and the objective of evaluation of HPV6, 11, 16, 

18 equivalence and HPV 31, 33, 45, 52, 58 superiority. For males, the population includes 

males immunized at ages 13 through 21 years, intervention of 9vHPV vaccine, and HPV4 as the 

comparison. The objective for males is evaluation of HPV 6,11, 16, 18 equivalence. 

As highlighted earlier, the data available for the primary policy questions include efficacy and 

immunogenicity in adult females, immunogenicity in boys and girls, and immunogenicity in adult 

males. Data in adult males are expected to be available in October of 2014 for GRADE 

consideration, but will be pending FDA approval for an adult male indication at the time of 

primary licensure. 

Cost-effectiveness is also considered for GRADE. For 9vHPV vaccine, cost-effectiveness data 

will be presented for males and females separately and combined in October 2014. Also, the 

cost-effectiveness of revaccination with 9vHPV after receipt of 3 doses of HPV 4 will be 

presented. A variety of CDC and external models will presented that use US data. 

In summary, this purpose of this presentation was to provide the foundation for the next 

presentation to ACIP on GRADE. Policy question and PICO have been developed, and tables 

of evidence will be developed on 9vHPV vaccine and presented to the ACIP HPV WG. Costeffectiveness and GRADE data will be presented to ACIP during the October 2014 meeting in 

order to be prepared for possible recommendations in early 2015. 

Discussion Points 

Dr. Karron remembered that in a previous presentation, Dr. Dunne spoke about ethnic and 

racial disparities in terms of the 5-valent and she was not clear whether that was for carriage, 

CIN2+, or for cancer. 

Dr. Dunne responded that during the February 2014 ACIP meeting data were presented by Dr. 

Hariri and Dr. Saraiya; there was discussion regarding attribution of 5 and 9 types to CIN2+ and 

cancers. There were race/ethnicity differences for the cervical precancers in particular. 

However, the largest percentage of precancers are due to HPV16/18 regardless of race. For 

the invasive cancers, the attributions of 16/18 are the same across race/ethnicity. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Karron inquired of Dr. Luxembourg as to when data would be available on the 2-dose 

regimen for the 9-valent vaccine. 

Dr. Luxembourg responded that the study is ongoing and data are expected before the end of 

2015. 

While the change in antibody titer between Doses 1 and 3 was shown, Dr. Harrison wondered 

about the change between Doses 2 and 3. 

Dr. Luxembourg responded that in Protocol 001, post-dose 2 and post-dose 3 antibody titers 

were analyzed. There is an increase, but it is relatively small at about 30% (Post-minutes note: 

The increase between post-dose 2 and post-dose 3 varies by HPV type, ranging from 

approximately 20% to 70%). 

Dr. Vazquez inquired as to whether there was information on what occurs with one or two doses 

in the cross-study. 

Dr. Luxembourg replied that this type of information is not available for the cross-study 

comparison. In Protocol 006, only post-dose 1 was studied. In Protocol 001, only post-dose 2 

was studied. 

Dr. Reingold requested that Dr. Dunne elaborate on the decision not to assess the critical 

outcome in males for HPV 31, 33, 45, 52, and 58. 

Dr. Dunne replied that it would be possible to assess these outcomes, but the focus of the WG 

was that the attribution to these specific 5 types is less for males than for females. The 

attribution for penile is 9% and the overall attribution for males is 5%. Cost-effectiveness data 

have not yet been presented, but that will be presented in October 2014. This will provide 

additional information regarding the cost-effectiveness of 9-valent for males versus females. 

Dr. Karron said she was aware that there is a formal study assessing two doses, but she 

wondered whether there are existing data for naïve individuals getting two doses of 9-valent 

vaccine. Perhaps they received three, but there are immunogenicity data after two doses. She 

wondered whether those data already existed, or if they did not exist and Merck anticipates 

getting these data with the upcoming study. 

Dr. Luxembourg responded that the only data Merck has for two doses are in the context of 

Protocol 001 in young women 16 through 26 years of age. It is not completely relevant to what 

the ACIP would be interested in for two reasons. One is that it is not the group where a 2-dose 

regimen would be considered. The other is that the schedule is different from what will be 

considered, because the subjects received doses at Day 1, Month 2, and Month 6. Any 2-dose 

schedule would be with longer intervals. That is to say that Merck does not have relevant data 

at this time. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

2-Dose HPV Vaccine Schedules: Review of Data / HPV Vaccine WG Plans 

Lauri Markowitz, MD 

HPV Vaccine Working Group 

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

Centers for Disease Control and Prevention 

Dr. Markowitz indicated that the purpose of this presentation was to inform and update the 

committee on the accumulating data on 2-dose HPV vaccination schedules. As background, 

there are two licensed HPV vaccines in the US, quadrivalent vaccine (Gardasil®) and bivalent 

vaccine (Cervarix®). Both are virus-like particle (VLP) vaccines using L1 surface protein. The 

vaccines contain different adjuvants. The licensed schedule for both is a 3-dose schedule with 

the second dose given 1 to 2 months after first, and the third dose 6 months after the first. 

For licensure of the currently available HPV vaccines, large efficacy trials were performed in 16 

through 26 year old females. The endpoints were precancer lesions. Bridging immunogenicity 

trials were conducted in 9 through 15 year olds—an age group in which efficacy trials are not 

possible. Licensure in this age group was based on the non-inferior antibody response in this 

age group compared with women in the efficacy trials. For both vaccines, over 99% of 

vaccinees developed antibody after vaccination, and the antibody titers in the younger age 

group were higher than those aged 16 through 26 years. 

GMTs for HPV 6, 11, 16, and 18 one month after the third dose of quadrivalent vaccine, were 

highest in the youngest age group for all four types and decreased with increasing age at 

vaccination. [Giuliano, et al. JID 2007]. Similar findings by age were found for HPV 16 and 18 

GMTs for the bivalent vaccine 

The main basis of protection is thought to be neutralizing antibody, but the minimum protective 

antibody threshold is not known. The high efficacy found in vaccine trials has precluded 

identification of a protective titer, but vaccination induces antibody titers that are much higher 

than natural infection. In clinical trials of the quadrivalent HPV vaccine, some vaccinees lost 

detectable HPV 18 antibody, but there was no loss of protection against study endpoints. 

There is global interest in simplified schedules for HPV vaccine. These would be more 

convenient for providers, parents, and vaccines; and might facilitate implementation by reducing 

logistical challenges for vaccine delivery and decrease resource needs. The high efficacy found 

in the initial clinical trial prompted investigation of reduced dose schedules. 

Before reviewing the data, Dr. Markowitz mentioned what is considered to be the immunologic 

basis of the HPV vaccination schedule. The 3-dose schedule (0, 1-2, 6 months) can be 

considered a “prime-prime-boost,” with the first two doses being priming doses and the third 

dose being the boost. Two-dose schedules that have been studied with at least 6 months 

between the doses can be considered a “prime boost” schedule without the second priming 

dose. Memory B cells require at least 4 to 6 months to mature and differentiate into high-affinity 

B cells. Six months between the first and last dose allows the last dose to efficiently reactivate 

memory B cells. 

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WHO’s SAGE considered 2-dose schedules during their meeting in April 2014. At that time, 

they recommended a 2-dose HPV vaccination schedule for girls, if vaccination is initiated prior 

to 15 years of age. The minimal interval between 2 doses is 6 months, and the interval may be 

extended to 12 months if this facilitates administration. A 3-dose schedule remains necessary if 

immunization is initiated after the 15th birthday. A 3-dose schedule (i.e., at 0, 1-2, 6 months) 

remains recommended for immunocompromised individuals, including those known to be HIVinfected. SAGE reviewed a variety of data on 2-dose schedules for this decision, some of which 

Dr. Markowitz reviewed during this session. This included a systematic review of the literature 

and the European Medicines Agency (EMA) assessment report for Cervarix®. These are 

available on the WHO website: 

http://www.who.int/immunization/sage/meetings/2014/april/report_summary_april_2014/en/ 

http://www.who.int/immunization/sage/meetings/2014/april/presentations_background_docs/en 

Manufacturers have submitted data for regulatory approval in a variety of countries. Bivalent 

vaccine has regulatory approval for use as a 2-dose schedule in Europe from the EU and 5 

other countries, as well as countries in Africa, Latin America, and Asia. HPV4 also has 

regulatory approval for use as a 2-dose schedule by the EU and a variety of other countries. 

Regarding the current status of regulatory issues in the US, for the bivalent vaccine, there has 

not been a submission to FDA and the manufacturer has no plans to submit. For the 

quadrivalent vaccine, Merck has no plans for submission to FDA as they are focusing on their 9­

valent vaccine which is under consideration now as a 3-dose schedule. For the 9-valent 

vaccine, there are no data on 2 doses included in the BLA under consideration by FDA, but a 2- 

versus 3-dose trial has been initiated [Clinicaltrials.gov NCT01984697]. 

With that background in mind, Dr. Markowitz then reviewed the available data on 2-dose 

schedules. Most of the data are from immunogenicity studies. There are limited efficacy data 

from post-hoc analyses, and there are post-licensure effectiveness data which are challenging 

to interpret. 

Regarding the immunogenicity studies comparing 2- versus 3-dose schedules, there are 3 

studies of the bivalent vaccine and 2 studies of the quadrivalent vaccine. The Romanowski 

(Protocol 048) study was a GSK study that was also a dose ranging study. There are two 

publications from this study, with the most recent having data from a 48 month follow-up [Hum 

Vaccin 2011 and Hum Vaccin 2014]. The Puthanakit (Protocol 070) is considered by GSK to be 

their confirmatory study of 2 doses. These data were presented during two international 

meetings in the last 8 months, but have not been published [EUROGIN 2013; ESPID 2014]. 

The Lazcano-Ponce study was conducted by independent researchers in Mexico [Vaccine 

2014]. There are two studies with a direct comparison of 2- and 3-dose schedules for the 

quadrivalent vaccine. Neither of these was industry sponsored. The Dobson study was 

conducted in Canada and is the only published study for quadrivalent vaccine [JAMA 2013]. 

The Sankaranarayanan is being conducted in India. This study was originally planned as an 

efficacy RTC of quadrivalent vaccine with over 20,000 girls 10 through 18 years of age who 

were randomized to receive 2 or 3 doses. The original design was going to evaluate CIN 

outcomes, but this study was not completed as planned due to the study being halted by the 

government. At the present time, data are only available on a subset for immunogenicity and 

for incident infection, and the randomized design has been compromised [EUROGIN 2013]. 

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Four of the five studies (Romanowski, Puthanakit, Lazcano-Ponce, and Dobson) had a group 

which included the standard 3-dose schedule at age 15 through 26 years, the age group of the 

women in the efficacy trials. The main comparisons were between antibody response in this 

group, and the experimental 2-dose schedules in the young adolescents. Four studies 

(Romanowski, Lazcano-Ponce, Dobson, and Sankaranarayanan) also were designed to allow 

direct comparison of the 2- and the standard 3-dose schedules within the same age group. One 

study (Romanowski) of the bivalent vaccine compared two different intervals 2-dose schedules: 

a 0,6 months schedule and a 0,2 month schedule. This comparison was made in several age 

groups. 

Four studies contributed to the analysis of girls who received 2 doses and the women who 

received 3 doses in the systematic review used for the SAGE review by D’Addario, et al . For 

HPV16 for all comparisons, there was no difference in seroconversion or seropositivity between 

the girls who received 2 doses and the women who received 3. For HPV 18 in the one study of 

quadrivalent vaccine, seropositivity was higher at 24 and 36 months in the girls who received 2 

doses compared with the women who received 3 doses, but this was not statistically significant. 

The same four studies contributed to the analysis comparing GMCs in girls receiving 2 doses 

and women receiving 3 doses one month after their last dose—three of the bivalent and one of 

the quadrivalent vaccine. Studies were stratified by high and middle income countries. Results 

were considered separately for types 16 and 18. All trials met the criteria for non-inferiority. For 

most comparisons, data favored girls receiving the 2-dose schedules. 

Two studies contributed to the analysis of differences in the proportions of girls of the same age 

seroconverting or seropositive who received 2 doses compared with those who received 3 

doses. For HPV 16, for all comparisons there was no difference in seroconversion or 

seropositivity between the girls who received 2 doses or 3 doses. For HPV 18, in the Canada 1 

study of quadrivalent vaccine (Dobson), seropositivity was higher at 24 and 36 months in the 

girls who received 3 doses compared to the girls who received 2 doses, but the lower 

confidence intervals include the non-inferiority margin. 

In terms of the comparison of differences in GMC among girls of the same age group who 

received 2 or 3 doses at one month after the last dose, there are three studies—two of 

quadrivalent and one of bivalent. For HPV 16 in the bivalent trial, the GMC was lower after 2 

doses compared with 3 doses, but not significantly. For the quadrivalent trial (Dobson), the 

estimates were not different between the two schedules one month after the last does. For HPV 

18, both for the bivalent and quadrivalent vaccines, the GMCs after the 2-dose schedule were 

lower, but were non-inferior to 3 doses. For the limited data presented from the India trial, the 2­

dose GMCs were non-inferior to the 3 doses GMC, and the data favored two doses. 

All of the data for the comparison of 2 different interval 2-dose schedules were from one study of 

the bivalent vaccine. Intervals compared were a 0,6 months schedule compared with a 0,2 

month schedule. The 0,6 month interval resulted in higher titers in all age groups for both HPV 

16 and 18. 

Dr. Markowitz then separately and in more detail reviewed the available data for the bivalent 

and quadrivalent vaccines, and focused on some data submitted for regulatory approval to the 

EMA and for other countries. For the bivalent vaccine, this included immunogenicity data and 

efficacy data. The main immunogenicity data came from 2 studies that were included in the 

meta-analysis mentioned earlier: Romanowski et al, Hum Vaccin 2011 and 2014; and 

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Puthanakit et al, EUROGIN 2013. The efficacy data were from two post-hoc analyses: Kreimer 

et al, JNCI 2011 and the unpublished post-hoc analysis of the GSK pivotal efficacy trial. 

The bivalent HPV study in the SAGE review (Protocol 048) was a dose ranging trial as well as a 

2- versus 3-dose trial. A 48-month follow-up was recently published that followed 2 groups who 

received the licensed formulation: 2 doses in 9 through 14 year olds and 3 doses in 15 through 

26 year olds. All subjects remained seropositive for HPV 16 and 18 by ELISA at month 48, 

GMTs were non-inferior for the 2-dose group compared with the 3-dose group, and antibody 

kinetics were similar in both groups. 

In Protocol 070, the GSK confirmatory trial of 2 versus 3 doses, 9 through 14 year old females 

were randomized to receive 2 doses at 0,6 months or 0,12 months. There was a concurrent 

group of 15 through 25 year olds who received 3 doses in the standard schedule. Data from the 

0,12 month group were just presented in June 2014 and were not included in the SAGE review. 

In this trial, GMTs were non-inferior in the 2-dose group compared with the 15 through 25 year 

old women who received 3 doses. The longest follow-up to date is 6 months after the last dose. 

Data are only available for the 0,1, 6 month schedule and 0,6 month schedule groups. GMTs 

were slightly lower in the girls who received 2 doses, but non-inferiority criteria were met and 

titers were remained substantially higher than those after natural infection [Puthanakit, et al. 

ESPID 2014]. 

Efficacy date are available from two post-hoc analyses. It is important to note that these studies 

were not designed to evaluate the number of doses. Among women enrolled in the Costa Rica 

RCT, about 20% received less than 3 doses. In a post-hoc analysis, the endpoint was incident 

infection that lasted at least 10 months. The numbers are small, but it shows high efficacy 

among those who received 1, 2, or 3 doses, with an efficacy of 84% for those who received 2 

doses; this was not different from the efficacy in those who received 3 doses [Kreimer A, et al. 

JNCI 2011]. 

In the second post-hoc analysis is from the pivotal RCT trial conducted by the manufacturer 

(Patricia Trial). In this large trial in 15-25 year old females, compliance with the 3 dose schedule 

was high and only 5% received 2 doses. Regarding the 2-dose and 3-dose efficacy against 6­

month persistent HPV16/18 infection and incident infection, there was 100% efficacy against 6­

month HPV16/18 persistent infection and 84.5% efficacy against 16/18 incident infection. 

Efficacy was 93.7 for 3 doses [GlaxoSmithKline. GSKBio_WWMA_DoF068_1_2011, Data on 

file. 2011; Assessment report, EMA/789820/2013]. 

The main data available on 2 doses for the quadrivalent vaccine are the immunogenicity data 

from a study conducted in Canada [Dobson, et al. JAMA 2013]. Some data available from a 

RCT of different 3-dose schedules of quadrivalent HPV vaccine also provide information on 2 

doses [Neuzil, et al. JAMA 2011 and LaMontagne, et al. JID 2014]. 

In terms of the design of the quadrivalent 2- versus 3-dose study in the Dobson study, 9 through 

13 year old females were randomized to receive 2 doses at 0,6 months or the standard 3 doses 

and there was a concurrent group of 16 through 26 year olds who received 3 doses by the 

standard schedule. The main analysis was comparing the 2-dose girls with the 3-dose women. 

For the 36-month results, non-inferiority criteria were met for all types and antibody response 

was generally higher in the 9 through 13 year olds who received 2 doses, with GMTs ratios 

greater than 1. In the comparison of the 2 and 3 dose schedules in 9 through 13 year olds, the 

GMT ratios were less than one, and non-inferiority was lost for HPV18 by 18 months and for 

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HPV 6 by 36 months. For the GMTS through 36 months for HPV 16 and 18 for the three groups 

in the 2- vs 3-dose trial, the antibodies followed the same kinetics for all schedules. Antibody 

reached a peak 1 month after the last dose and then declined between 7 and 18 months and 

reached plateau. Both 3- and 2-dose girls maintained at plateau levels higher than the young 

adult women. There are greater differences between groups for HPV 18 than HPV 16 [Dobson, 

et al, JAMA 2013]. 

The trial of quadrivalent vaccine was conducted in Vietnam, which evaluated different 3-dose 

schedules provides some data on response to 2 doses. As noted earlier, 11 through 13 year 

olds girls were randomized to the standard 0,2,6 month schedule or one of three experimental 

schedules: 0,3,9 month, 0,6,12 month and 0,12, 24 month schedules. The main end point was 

GMTs 1 month post dose 3. For the 0,3,9 and 0,6,12 schedules, non-inferiority criteria were 

met for all types. For the 0,12, 24 schedule, non-inferiority was not met for HPV 6 and 16. In a 

follow-up study, for GMTs 29 through 32 months post dose 3, non-inferiority criteria met were 

for all schedules [Neuzil, et al. JAMA 2011; LaMontagne, et al. JID 2013]. 

In the RTC in Vietnam, a serology sample was obtained pre- and post-dose three. The predose 3 blood draw can be considered a post-dose 2. In terms of the GMTs after dose 2 in this 

study, there was a trend for higher antibody levels prior to dose 3 with increasing intervals 

between the first and second doses. Of note, because the schedules were different, the time 

between vaccination and blood draw after dose 2 also varied. For example, in the 0,2,6 month 

schedule, the time between vaccination and the post-dose 2 blood draw was 4 months while in 

the 0,6,12 month schedule it was 6 months [Neuzil, et al. JAMA 2011]. 

Data are now available from post-licensure monitoring studies; population impact on some early 

outcomes has been demonstrated in countries with high as well as moderate and low coverage 

(e.g., Australia, Denmark, Germany, New Zealand, Scotland, Sweden, UK, US). Four studies 

provide information on post-licensure effectiveness by number of doses, 3 of which are for 

HPV4 and 1 of which is for HPV2. Three were data linkage studies that use the registry data 

available in three countries and one was a serial cross-sectional study of prevalence. Two 

studies evaluated cervical abnormalities, one condyloma, and one type-specific prevalence. 

There are a variety of other ongoing studies, including one in the US looking at effectiveness 

against condyloma. There are a variety of challenges and limitation of these studies. First, 

there may be differences between 2- and 3-dose recipients. In these effectiveness studies early 

in the programs, outcomes being detected were in the catchup populations, not those who were 

vaccinated at the target age groups, so many people could have been infected before 

vaccination. Second, there are differences between 2- and 3-dose recipients. Third, the 

evaluations do not examine the 0,6 month 2-dose schedule. Instead, they examine persons 

who started the 0,2,6 month schedule but did not receive the third dose. 

In regard to the Getlig data from Australia, the outcome was cervical abnormalities (CIN3/AIS or 

CIN2). As noted earlier, the hazard ratio (HR) for those who received 3 doses was 0.53, while 

for those who received 2 doses was 0.87 and that was not significantly different from the 

unvaccinated. For CIN2, the HR was 0.70 for 3 doses and 0.99 for those who received only 2 

doses. The authors point out the main limitations of the study. While they controlled for 

differences between women who received 3 doses and those who received less than 3 doses, 

they note that women who had only 1 or 2 doses were younger age at first screening (indicating 

earlier sexual debut), older at vaccination, and had lower socioeconomic status (SES). 

The Crowe study from Australia had a difference study design, but also looked at cervical 

abnormalities. For the entire age range of 11 through 27 years, a difference was found between 

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2- and 3-dose recipients, with the adjusted odds ration being 0.54 for 3 doses and 0.79 for 

2doses, which was significant. For the 15 through 18 year olds, the adjusted odds ratio was 

0.43 for 3 doses and 0.77 for 2 doses. This study had some of the same limitation as the other 

study in Australia. 

In the Herweijer quadrivalent HPV vaccine effectiveness study for prevention of condyloma in 

Sweden, an open cohort of females aged 10 through 24 was followed using population-based 

registers. This evaluation included over 1 million women and 20,000 cases of genital warts. 

Incidence was significantly reduced for 1, 2, and 3 dose vaccinees compared with those who 

were unvaccinated. The incidence ratio for 1, 2, and 3 dose vaccinees compared with the 

unvaccinated differed, with the incidence ratio being 0.18 for 3 doses and 0.29 for 2 doses. This 

study clearly demonstrated an impact from less than a complete 3 dose series; however, there 

were differences by number of doses. The authors point out that the main analysis was done 

with an interval of 3 months between vaccination and case counting. With a longer period 

between vaccination and case counting, more genital warts can be excluded that might be due 

to infection prior to vaccination. With a buffer period of 5 months or longer, a statistically 

significant difference in the risk of condyloma between 2 and 3 doses recipients was no longer 

observed. 

The Kavanagh study in Scotland was a cross-sectional study of bivalent vaccine effectiveness 

in women aged 20 through 21 presenting for cervical cancer screening, which assessed HPV 

prevalence. Over 4700 specimens were tested between 2009 through 2012. Data were linked 

to immunization registries. The adjusted odds ratio differed for 2 and 3 doses: 0.43 for 3 doses 

and 0.68 for 2 doses. 

In summary of the immunogenicity and effectiveness data, the GMTs for bivalent and 

quadrivalent vaccines were non-inferior after 2 doses given 6 months apart in young adolescent 

girls compared with 3 doses in a routine schedule in women 15 through 26 years of age. The 

GMTs were lower but non-inferior after 2 doses compared with 3 doses in adolescents of the 

same age group one month after the third dose. Some quadrivalent vaccines lost non-inferiority 

for two types at later time points. For both vaccines, GMTs are higher for 2 doses with longer 

intervals between doses in a 2-dose schedule. For efficacy, there were two small post-hoc 

analyses for the bivalent vaccine that found high efficacy. For the quadrivalent vaccine, more 

data may be available in the future from the study in India. For effectiveness, 4 post-licensure 

effectiveness evaluations assessed number of doses, 3 for the quadrivalent and 1 for the 

bivalent. These found lower effectiveness for 2 versus 3 doses. However, there are many 

limitations and challenges with post-licensure effectiveness evaluations at this point in the 

vaccination programs. 

One of the main questions remaining is: Will there be differences in duration of protection for 2­

and 3-dose schedules? Longer follow-up will be available from some studies. Some 

information is available from modeling studies that have assessed this issue [Jit et al. Vaccine 

2014: 32]. Two studies suggest that if 2-dose schedules protect for at least 20 years, then the 

benefits of the 3rd dose are small. If 2 doses protect for 10 years, then the 3rd dose may prevent 

as many cancers as the first 2 doses. The WG intends to further evaluate this question for the 

US for later presentation to the full ACIP. 

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As mentioned earlier, SAGE has recommended a 2-dose schedule for HPV vaccination. 

However, before that time, several countries had changed to 2-dose schedules or to the socalled “extended 3-dose” schedules. The purpose of the extended 3-dose schedule is to allow 

implementation of the first 2 doses on a schedule that would essentially be the 2-dose schedule 

if it is decided later that the 3rd dose is not needed, (0, 6, 60 month schedule). The following are 

the countries with these extended schedules or with 2-dose schedules: 

 Quebec, Canada 

 Implemented extended HPV4 3-dose schedule in 2008 

 Changed to HPV4 2-dose schedule in 2013 

 British Columbia, Canada 

 Changed from HPV4 3-dose schedule to extended HPV4 3-dose schedule in 2010 

 Mexico 

 Using extended 3-dose schedule (since national program 2012) 

 Switzerland 

 Changed from 3-dose to 2-dose schedule for 11-14 year olds in 2012 

 England 

 Will change from HPV4 3-dose to HPV4 2-dose schedule in fall of 2014 

Just to review again the status of regulatory approval for 2 dose schedules in the US; for the 

bivalent vaccine, there has been no submission to FDA. For the quadrivalent vaccine, Merck 

has no plans for submission to FDA as they are focusing on their 9-valent vaccine, which is 

under consideration now as a 3-dose schedule. For the 9-valent vaccine, there are no data on 

2 doses included in the BLA under consideration by FDA, but a 2 versus 3 dose trial has been 

initiated. 

The 9-valent HPV vaccine 2- versus 3-dose trial is a Phase III immunogenicity study that started 

in December 2013. According to the website, the last visit for the last patient enrolled will be 

July 2015, and it is assumed that it would then take several months to analyze the data. There 

are 5 arms and a total of 1500 subjects to be enrolled. There are 3 experimental groups: 1) 2­

dose groups at 0,6 in 9 through 14 year old girls; 2) 2-dose group at 0,6 months in 9 through 14 

year old boys; and 3) 2-dose group at 0, 12 months in 9 through 14 year old boys and girls. 

There are 2 control groups: 1) 3-dose group in 9 through 14 year olds; and 2) 3-dose group in 

15 through 26 year old women [Clinicaltrials.gov identifier NCT01984697]. 

The WG’s plans are to review and consider 9vHPV as a 3-dose schedule, and to consider 2­

dose schedules when data from 2- versus 3-dose trial of 9vHPV are available. However, the 

WG has had discussions about other options. The primary option is to consider a 2-dose 

schedule now for HPV2 and HPV4 in 9 through 14 year olds. For older individuals, a 3-dose 

schedule would be recommended. Because of the intersection of consideration of the 9-valent 

and 2-dose, the options are complicated. If a 2-dose schedule is recommended, the WG 

discussed the potential options when 9vHPV licensed. The options include waiting until there 

are data for a 2-dose schedule before considering recommendations for 9vHPV, recommending 

9vHPV as a 3-dose schedule, or recommending the 9vHPV as 2-dose schedule with no data. 

Most of the WG members felt that the WG should continue to review and consider the 9-valent 

vaccine as a 3-dose schedule, and to consider 2-dose schedules when data from the 2 versus 3 

dose trial are available. 

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To end this presentation, Dr. Markowitz reviewed data on coverage for the US from the NISTeen. Based on national vaccination coverage data among adolescents from 2006 through 

2012, as of 2012, 85% of adolescents had received a Tdap vaccine and 74% had received the 

meningococcal conjugate vaccine. In contrast, only 54% of girls had received 1 or more doses 

of HPV and only 33% of girls had received all 3 doses of the HPV series. For the past 3 years, 

there has been very little increase in HPV vaccine for girls. Between 2011 and 2012, no change 

in coverage was observed. Among adolescent boys, 21% received 1 or more doses of HPV 

and 7% received all 3 doses of the HPV series. This increase reflects the routine 

recommendation for male vaccination made in 2011. 2012 was the first year of data since the 

routine recommendation. One of the reasons for the interest in 2-dose schedules is because of 

the potential to facilitate implementation by simplifying the schedules, although there are no 

data to demonstrate that simplifying the schedules themselves would increase vaccine initiation. 

Coverage for at least one dose, at least 2 doses, and at least 3 doses all follow the same 

trajectory with drop-off similar between dose 1 and 2 and 2 and 3. Of persons who started the 

vaccination series, 67% completed all 3 doses based on NIS-Teen 2012. Overall, 33% received 

all 3 doses, about 10% received only 1 dose, and about 10% received only 2 doses [MMWR. 

2013;62;685-93]. 

In terms of the estimated timeline for future plans, in October 2014 there will be a GRADE 

presentation and discussion of the recommendation options and economic analysis 

presentation. If data are available from the immunogenicity trial in males 15 through 26 years of 

age, those data will be reviewed during the ACIP meeting. Based on timeline for FDA review, 

the estimated earliest possible vote on the 9vHPV vaccine would be February 2015. Data from 

the 9vHPV 2-dose trial may be available by the October 2015 meeting. 

Dr. Markowitz particularly expressed appreciation for Dr. Eileen Dunne, who will be moving to 

Thailand. 

Discussion Points 

Dr. Harriman inquired as to whether any of the countries that have switched to the 2-dose 

schedule signaled what they might do with the 9-valent vaccine. 

Dr. Markowitz indicated that she has had some informal discussions with people about that, and 

believes that everyone is grappling with the same issues. 

Dr. Duchin asked why a 2-dose regulatory approval was sought in so many other countries and 

not the US. 

Dr. Markowitz called upon the manufacturers to address this inquiry. 

Dr. Feinberg (Merck) indicated that in developing their products and contributing the evidence 

base that informs policy decisions, Merck engaged with policy-makers and regulators 

throughout the world. The level of interest for the 2-dose regimen has varied from country-tocountry. In Europe, there was significant interest in this, so Merck provided the data that were 

used by regulators and policy-makers to lead to that discussion. That being said, as seen in the 

presentations by Dr. Markowitz and others, the manufacturers have been involved in generating 

data that are relevant to the deliberations that ACIP will be carrying out. There has been a 

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focus on the development of the 9-valent vaccine, which is a very complicated program in and 

of itself, and in wanting to make sure that the transition from the quadrivalent to the 9-valent 

vaccine is smooth and effective from a medical and public health perspective. Thus, Merck felt 

that its efforts were best focused on delivering the 9-valent vaccine with the strongest dataset to 

support it. In the meantime, they are generating data on 2 doses of the 9-valent vaccine. 

Generating data on the 2 doses of the quadrivalent vaccine beyond what is already available did 

not seem like the best investment of resources and time. 

Dr. Friedland (GSK) indicated that GSK has submitted and has had approved 2-dose Cervarix® 

in over 71 countries. It is recommended as part of the immunization recommendations in a 

number of countries to use the 2-dose schedule in their programs. In the US, the story with 

Cervarix® is slightly different. Because of the low uptake of the use of Cervarix® in the US, GSK 

is devoting its efforts to the 2-dose Cervarix® program in other countries around the world, 

particularly in developing countries where there is a greater opportunity for the use of the 

product, particularly around helping with adherence to and compliance with the schedule. 

Dr. Karron wondered what 2-dose schedule Merck is studying for the 9-valent vaccine. 

Dr. Markowitz responded that Merck is studying the 0,6 and 0,12 month schedules. 

Ms. Pellegrini pointed out that attention had been devoted to the 3-dose versus 2-dose 

schedules. She encouraged the WG and ACIP to pay equal attention to the intervals. The 

current interval of 0, 2, 6 is incredibly challenging for families. If a change could be made to a 0, 

12, 24 schedule that aligns with an annual well teen visit, she believes uptake would increase 

dramatically. 

In terms of targeting previously fully immunized individuals with 3 doses of HPV4, Dr. Temte 

asked whether there were considerations for revaccination. He was thinking about the switch 

over from PCV7 to PCV13 when there was an algorithm in which not everyone would receive 

the full complement. 

Dr. Markowitz said that for PCV13, the consideration was giving a single dose to people who 

had previously been vaccinated with PCV7 the WG will be considering data that are available 

regarding revaccination. 

Dr. Schuchat pointed out that the timeline for the WG presenting data to the full committee 

referred to the 9-valent vaccine. She thought it would be helpful to hear committee input 

regarding what else they would like to consider regarding changing the intervals or a 2-dose 

schedule in advance of other formulations potentially being available. If heading toward a 

fewer-dose schedule, changing the interval sooner would be better. 

Dr. Kempe thought the data were strong to support a 0,6 or 0,12 interval. She wondered 

whether they would be willing to do this without those data when the 9-valent vaccine is 

approved. It seemed as if the 9-valent vaccine were approved, they would recommend 

changing the intervals. Yet, everyone recognized the problem with having to make rapid 

adjustments in primary care. She said she would like to hear from the other committee 

members whether there would be any chance of what essentially would be an off-label 

recommendation for that interval. 

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Dr. Temte reflected on Ms. Pellegrini’s comments that in a primary care setting, the US is doing 

atrociously in terms of increasing HPV coverage\ over the past 8 years. Part of the problem 

arises from dealing with adolescents in primary care, given that adolescents do not present for 

follow-up in 1 to 2 months. As the parent of a 2-dose son who was immunized on a 0, 12 

interval, he said he was guilty as charged and could attest to how difficult it is to get a teen in. 

The realities of medical practices are incredibly important in terms of implementing a very good 

vaccine. 

Reflecting on the discussion of changing from 4 doses to 3 for pneumococcal conjugate vaccine 

and the standard of evidence the committee seemed to want, Dr. Reingold said he was dubious. 

It was not clear to him that there would be any more convincing evidence to support changing 

from a 2-dose to 3-dose schedule for HPV than there were for changing from a 4-dose to 3­

dose schedule for pneumococcal conjugate vaccine. Based on the pneumococcal conjugate 

vaccine discussion, he was not convinced that the committee was ready to do that. 

Dr. Bennett said she thought the HPV data were better than the pneumococcal conjugate data, 

because there are actually comparative trials for HPV. 

Dr. Reingold agreed that this was true for immunogenicity. However, in terms of the data for the 

clinical outcomes, the relative risks for the 2-dose schedule are not very impressive and they 

certainly do not look comparable to the 3-dose schedule. 

Dr. Bennett stressed that those were all 0,2 and did not compare 0,6 or 0,12 so there really are 

no data on that. 

Dr. Markowitz said she wanted to show the effectiveness data because she thought there was a 

feeling that there would be a lot of effectiveness data to possibly inform the 2-dose schedule. 

But, the effectiveness data are difficult to interpret at this point post-licensure not only because 

of the different intervals between doses, but also because of the catch-up population being 

evaluated in these studies and the differences between 2- and 3-dose vaccinees. It is 

interesting to see the data, but she was not sure how informative it would be for ACIP’s 

deliberations. 

Dr. Temte indicated that he has a screening test in his clinical practice for cervical cancer, but 

does not have one for invasive pneumococcal disease. 

Dr. Bocchini pointed out that the opportunity for considering a 2-dose schedule would be very 

different if they were not also faced with the 9-valent vaccine that may be licensed within the 

next 6 months. That would create a situation in which ACIP would be making multiple changes 

in vaccine recommendations within a very short period of time, which could make it very difficult 

for primary care practitioners to follow the recommendations or trust them as they evolve. 

Dr. Schuchat requested a reminder about what type of application is expected for males for the 

9-valent vaccine in terms of age groups, et cetera. There was some discussion regarding offlabel intervals and so forth. 

Dr. Markowitz indicated that the first licensure expected at the end of 2014 will be for females 9 

through 26 years of age and males 9 through 15 years of age. The data on 15 through 26 year 

olds will be available for the October 2014 ACIP meeting, even though they will not yet have 

been submitted to the FDA. The feeling of the WG is that it would be very difficult 

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Dr. Shimabukuro reintroduced the topic of the febrile seizure (FS) signal in 2010-2011 following 

trivalent inactivated influenza vaccine (TIV) and 13-valent pneumococcal conjugate vaccine as a 

lead-in to the two main presentations for this session. As a reminder, “A FS is a seizure 

accompanied by fever ... without central nervous system infection, that occurs in infants and 

children 6 through 60 months of age”* Febrile seizures are fairly common during childhood; 

about 2% to 5% of young children will have at least one febrile seizure.* FSs can happen with 

any condition that causes a fever, including typical childhood illnesses, many of which can be 

prevented by vaccination. Rarely, FSs can occur after vaccination. Nearly all children who 

have a FS recover quickly and are healthy afterward with no lasting effects. However, FSs 

often result in a visit to an emergency room and can be very frightening for parents and 

caregivers [ * Subcommittee on Febrile Seizures; American Academy of Pediatrics. 

Neurodiagnostic evaluation of the child with a simple febrile seizure. Pediatrics. 

2011;127(2):389-94]. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

programmatically to have the quadrivalent vaccine recommended for the older males, but the 9­

valent vaccine recommended for females 9 through 26 and males 9 through 15 years of age. 

Therefore, the proposal is to move forward with the recommendation for the full age group of 

females and males, even though technically this would be off-label for the 15 through 26 year 

old males. 

Dr. Pickering inquired as to what type of data would be available from Merck at the end of 2015. 

He also wondered whether the antibody levels and kinetics of the 5 strains in the new vaccine 

are similar to 16/18. 

Dr. Luxembourg responded that the available data would be immunobridging data comparing 

the immunogenicity data at the peak, which means 1 month after the last dose. The kinetics of 

between the additional and original types are similar based on the 3-dose immunobridging 

studies. 

Vaccine Safety 

Introduction 

Tom Shimabukuro, MD, MPH, MBA 

Immunization Safety Office 

Centers for Disease Control and Prevention (CDC) 

The post-licensure vaccine safety monitoring infrastructures are shown in the following table: 

System Collaboration Description 

Vaccine Adverse Event Reporting 

System (VAERS) 

CDC and FDA US frontline spontaneous reporting system to 

detect potential vaccine safety problems 

Vaccine Safety Datalink (VSD) CDC and health 

plans 

Large linked database system used for active 

surveillance and research 

Clinical Immunization Safety 

Assessment (CISA) Project 

CDC and 

academic centers 

Expert collaboration which conducts 

individual clinical vaccine safety assessments 

and clinical research 

Post-Licensure Rapid Immunization 

Safety Monitoring (PRISM) 

FDA and health 

plans 

Large linked database system used for active 

surveillance and research 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Definition of a signal in pharmacovigilance is, “Reported information on a possible causal 

relationship between an adverse event and a drug, the relationship being unknown or 

incompletely documented previously. Usually more than a single report is required to generate 

a signal, depending upon the seriousness of the event and the quality of the information” [Safety 

of Medicines - A Guide to Detecting and Reporting Adverse Drug Reactions - Why Health 

Professionals Need to Take Action. Geneva, WHO, 2002 

(http://apps.who.int/medicinedocs/en/d/Jh2992e/2.html)]. 

To recap background and key events, 2010-2011 there was a VAERS data mining signal for 

Fluzone® and febrile seizures. The clinical relevant age group was children 6 through 23 

months of age.* It is important to note that Fluzone® is the only TIV that is approved for use in 

children 6 through 23 months of age. At the same time, a signal was detected through VSD 

RCA for TIV in children 6 through 59 months of age.** As a reminder, RCA is weekly near realtime surveillance conducted during the influenza season and for other vaccines in the VSD. At 

the same time, surveillance was being conducted for PCV13, so it was possible to conduct an 

epidemiological study to assess TIV and PCV13 FSs. The key finding from that study was that 

the attributable risk (AR) for concomitant TIV+PCV13 peaked at 16 months, with 45 additional 

FSs per 100,000 children vaccinated. In the following season, 2011-2012, the TIV formulation 

did not change. The VSD RCA signal for TIV persisted. During that season, a CISA TIVPCV13 fever study was conducted.*** The key finding from that study was that children 6 

through 23 months of age who received TIV and PCV13 together at the same visit were about 3 

times as likely to have a fever on days 0-1 compared with children who received TIV or PCV13 

without the other product. In 2012-2013, there was a change in the TIV formulation and the 

2013-2014 TIV was also a different formulation from 2010-2011. No VSD RCA signal was 

detected for TIV [*Leroy et al. Vaccine. 2012;30(11):2020-3; **Tse et al. Vaccine. 2012 Mar 

2;30(11):2024-31; ***Stockwell et al. JAMA Pediatr. 2014;168(3):211-9]. 

There was a signal for FSs following CSL TIV in Australia during the 2010 Southern 

Hemisphere influenza season, which precedes and informs the US influenza season. Because 

of the finding in Australia, CDC and FDA conducted enhanced monitoring for FSs following TIV 

in 2010-2011 [http://www.tga.gov.au/pdf/alerts-medicine-seasonal-flu-100702.pdf; ** Vaccine 

Safety Datalink; ***Clinical Immunization Safety Assessment Project]. CDC routinely conducts 

monitoring for FSs every year during the influenza season, but because of what had been 

observed in Australia that season, every seizure report that came into VAERS was reviewed 

and 0-1 day and 0-7 day risk intervals were assessed in the VSD RCA. In terms of AR 

estimates for FSs following the first TIV, a small increased risk was observed for FSs peaking 

around 16 months of age. However, when TIV and PCV13 were administered together, a 

noticeable large peak of FSs occurred at 16 months of age with an AR of 45 additional FSs per 

100,000 children vaccinated with TIV+PCV13 together [Adapted from Tse et al. Signal 

identification and evaluation for risk of FSs in children following trivalent inactivated influenza 

vaccine in the Vaccine Safety Datalink Project, 2010-2011. Vaccine. 2012;30(11):2024-31. 

*Vaccines may have been received concomitantly with non-TIV, non-PCV13 vaccines]. 

CDC, FDA, and ACIP reviewed the data during the 2010-2011 season. After evaluating all the 

information, CDC determined that no changes in the childhood immunization schedule were 

necessary and posted this information on the CDC website. Language was also added to the 

inactivated influenza Vaccine Information Statement (VIS) for the next season to include the 

following: 

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*http://www.cdc.gov/vaccines/hcp/vis/vis-statements/flu.html 

Additional questions following the 2010-2011 FS signal included the following: 

 Did other vaccines besides TIV and PCV13 play any role? 

 Was there something unusual about the 2010-11 influenza vaccine that resulted in the 

increased risk for FSs in young children? 

 What do the data prior to the 2010-11 influenza season show? 

Seizures Following Administration of Multiple Vaccines: A VSD Study 

Jonathan Duffy, MD, MPH 

Immunization Safety Office 

Centers for Disease Control and Prevention 

Dr. Duffy reminded everyone that AAP defines FSs as, “seizures that occur in febrile children 

between the ages of 6 and 60 months who do not have an intracranial infection, metabolic 

disturbance, or history of afebrile seizures.” Prior to the 2010-2011 influenza season, other 

vaccines had been associated with an increased risk of FS, which are shown in the following 

table: 

Vaccine 

Diphtheria-Tetanus-whole cell Pertussis (DTP) 0 – 3 

Measles-Mumps-Rubella (MMR) 6 – 11 

Measles-Mumps-Rubella-Varicella (MMRV) 7 – 10 

Inactivated Influenza (TIV) 2010-2011 season formulation 0 – 1 

Pneumococcal conjugate vaccine-13 valent (PCV13) 0 – 1 

As reflected in the above table, the risk interval associated with each vaccine differed. A 

transient risk occurs over a several day period post-vaccination. Given that MMR and MMRV 

are live vaccines, the risk interval is related to the incubation period of the live virus. In 2010­

2011, the new finding for TIV and PCV13 were signaled. 

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Post -vaccination 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

A study was conducted in response to the 2010-2011 findings. The interest in PCV13 in 2010 

was due to the fact that the vaccine was new in that year. Subsequent to then, the VSD PCV13 

RCA for 2010-2011 did not find an increased risk of FS when comparing PCV13 to PCV7. The 

objective of Dr. Duffy’s current study is to assess whether vaccines other than PCV13 given 

concomitantly with TIV affect the risk of FS following receipt of TIV. This is a VSD study. The 

VSD is a collaboration between CDC and several integrated healthcare organizations, and has 

a combined annual population of over 9 million people (approximately 3% of the US population). 

For this study, 10 VSD sites geographically dispersed across the US contributed data: Group 

Health Cooperative, Kaiser Permanente Northwest, Kaiser Permanente Northern California, 

Kaiser Permanente Southern California, Kaiser Permanente Hawaii, Kaiser Permanente 

Colorado, Health Partners, Marshfield Clinic, Harvard Pilgrim, and Kaiser Permanente Georgia. 

These tend to represent more closed-model health plans that have good data capture and welldefined populations. 

Case-finding included searching for any medical visits with an ICD-9 diagnosis code of 780.3x 

(convulsion) occurring in the emergency department (ED) or inpatient settings. The first 

occurrence of the code had to be within 42 days to find incident events and exclude any followup. Medical records were abstracted to confirm the diagnosis and the time of onset in relation 

to vaccination. The study period included July 1, 2006 to July 1, 2011. The study focused on 

the 6- through 23-month age group, because they are at highest risk for FS at baseline and this 

is the age during which vaccines are recommended in the schedule. The FS case definition for 

this study was, “Clinician diagnosis of seizure; and fever measured or reported; and exclusion of 

patients with intracranial infection, metabolic disturbance, or history of afebrile seizures. A SelfControlled Risk Interval (SCRI) method was used for the analysis, and a Conditional Poisson 

Regression Model was used to model the incidence rate ratio (IRR). Only cases that occurred 

post-vaccination were used. The risk interval was Days 0-1 and the comparison interval was 

Days 14-20, with the thought being that Days 0-1 are the biologically plausible risk period for 

FSs following inactivated vaccines and the 14- to 20-day period represents a baseline risk in 

which vaccination plays no role in the incidence of FS. Attributable Risk (AR) was determined 

by multiplying the relative risk (RR) by the background incidence rate in the VSD population per 

person day, and taking into account a 2-day risk interval. 

In terms of the background rate of seizures in the VSD population regardless of vaccination, the 

peak incidence is at about 16 months of age. At the peak incidence, there are almost 5 

seizures per 100,000 persons per day. Also of interest in this study is vaccine combinations. 

The number of unique vaccine combinations received by children in practice in the VSD is large, 

with over 2,000 different combinations when unique products and formulations are considered. 

The percentage of vaccines given alone to children at 6 to 23 months is very low for most 

vaccines as expected, because vaccines are often co-administered. One exception to this is 

the inactivated influenza vaccine, which is given by itself in the VSD population about 50% of 

the time. This has been fairly consistent over the years examined. 

The SCRI analysis of TIV by influenza season using non-chart-confirmed data offers an initial 

sense of whether there were differences in influenza vaccine across seasons. For years prior to 

2010-2011 when just influenza vaccine doses given alone were stratified, there was no 

indication of increased risk of FS. This appeared to be different in the 2010-2011 season, and 

higher RRs were observed for those who received TIV simultaneously with another vaccine. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Regarding the chart-confirmed analysis, case-finding began with over 1.9 million vaccination 

visits within the study period for children in the target age group. Among these, 596 children 

were identified who had a medical visit for a convulsion during the pre-specified postvaccination intervals. A random sample was selected of 468 charts, of which 428 charts were 

available for review. In reviewing the charts, 18 of the cases did not represent a new seizure 

event. In 14 cases, the clinician was not sure whether there was a seizure. Of the events, 21 

were non-febrile seizures. In 27 cases, the fever status was not documented so those cases 

had to be excluded. Several cases had to be excluded for reasons related to timing of 

vaccination. For example, 2 people were vaccinated after they had a seizure, and 11 people 

had a time of onset that differed from what was recorded in the administrative data. 

Ultimately, 333 chart-confirmed FSs were included in the study (103 in the risk group and 230 in 

the comparison group). More seizures occurred in the 12- through 23-month age group 

compared to the 6- through 11-month age group as would be expected from the baseline rates. 

There were no significant differences by sex, race, or ethnicity although this is a diverse 

population. Further assessing these patients and their medical histories, for about half of the 

patients this event represented their first seizure in their lifetime. This means that half had a 

previous history of seizure. No differences were observed between the groups in family history 

of FS, premature birth, neonatal intensive care unit (NICU) admission, or developmental delay. 

Children who had their seizure in the risk interval were slightly more likely to have received an 

antipyretic in the 7 days before their seizure, but were not more likely to have received 

antibiotics in the previous 7 days. Some children had a possible non-vaccine cause of fever 

documented at the time of their evaluation. The most common of these other causes included 

otitis media, upper respiratory infection, or viral syndrome. Of children in the risk interval, 37% 

had some other cause documented compared to 77% of children in the comparison group. As 

expected, this suggests that some of these seizures were influenced by the recent vaccination. 

Only 10% of children in the comparison group and 13% in the risk group were admitted for their 

seizure. There was no significant difference. The following chart shows the vaccine exposures 

these patients had in descending order of frequency: 

PCV7, Hib, TIV, HepA, and DTaP were the most common vaccines. The crude RR shown in 

the far right column did not take into account any confounding or interaction between different 

vaccines. This just illustrates that if any vaccine is assessed without taking into account 

confounding of other vaccines, there will not be a true estimate of the risk. 

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Looking at the issue of combinations of different vaccinations received on the same day, there 

were 129 unique vaccine combinations received among the 333 cases. Among these 

combinations, only 21 were received by four or more patients. This is to say that risk for each 

combination cannot be assessed separately, so these are examined through regression 

modeling. First, the two time periods were examined separately: 2006-2007 through 2009­

2010 influenza seasons and the 2010-2011 influenza season to determine whether there were 

differences. Based on those results, it seemed valid to pool all of the study time together. The 

approach was then to perform multivariate modeling to identify vaccines associated with an 

increased risk of FS, while accounting for confounding and effect modification between multiple 

vaccines received on the same day. The process was to begin by considering all of the 

vaccines shown on the above table, and conduct a manual backward elimination process to 

look for those that had some effect on FS using TIV as the main effect of interest. The vaccines 

retained in the final multivariate model included TIV, PCV7 or 13, and DTaP-containing vaccines 

considered as a group. Once these vaccines were identified using that process, separate 

models were also examined for each strata defined by the mutually exclusive combinations of 

these three vaccines. 

In the assessment of TIV when given without the other two vaccines, there was no suggestion 

of an increased risk of FS. When PCV7 was given without the other vaccines, the RR was 2, 

which was borderline significant. This is consistent with previous findings. When DTaP was 

given without the other two vaccines, there was not a suggestion of increased RR. When PCV 

was given at the same time as DTaP, the risk was similar to when PCV was given alone. When 

TIV was given with DTaP, there was an increased RR of FS of 3.5, which was statistically 

significant. When TIV was given on the same day as PCV7, similar results were observed. The 

highest RR, 6.6 (2.8 – 15) occurred on days when children received all three vaccines together. 

The same approach was used to assess the 2010-2011 influenza season, the difference being 

that the sample size was smaller and none of the RRs were statistically significant when 

restricted to the single influenza season. However, a similar pattern is observed. 

The investigators believed that comparing the results for the two time periods offered the best 

estimate of risk for the different vaccine combinations. The RRs were then extrapolated into 

attributable risks. The differences between the AR estimates for each age group reflected the 

difference in background incidence of FS in the population rather than a difference in RR due to 

vaccination. The highest estimate of AR was for the combination of the three vaccines given at 

15 months of age, which results in an estimate of 38 FS cases per 100,000 children vaccinated 

with that combination of vaccines compared to the background rate. 

In conclusion, the concomitant administration of TIV + PCV and TIV + DTaP-containing 

vaccines had higher risks of FS than when the vaccines were given independently. The 

concomitant administration of TIV + PCV + DTaP-containing vaccines had the highest RR. 

These increased risks with concomitant vaccination were observed in all influenza seasons 

studied, not just during the 2010-2011 season. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Febrile Seizures After TIV: PRISM System, 2010-2011 Influenza Season 

Alison Tse Kawai, ScD 

Harvard Medical School 

Harvard Pilgrim Healthcare Institute 

On Behalf of the Mini-Sentinel PRISM Team 

Dr. Kawai noted that for the 2010-2011 influenza season, VSD investigators found a 2.4-fold 

increased risk of FSs following TIV when adjusting for concomitant PCV13 [Tse et al., 2011]. 

Similarly, VSD investigators found a 2.5-fold increased risk of FSs following PCV13 when 

adjusting for concomitant TIV. Furthermore, risk difference calculations suggested a greater 

risk of FS with same day TIV and PCV13 vaccination when compared to separate day 

vaccination. However, a formal test of significance was not available at that time. Also relevant 

were the VAERS findings in which there was disproportional reporting of FS following 2010­

2011 FluZone®. As a result of the VAERS findings, the FDA posted a notice on its website 

telling the public about the findings, and also stating that further investigation was underway. As 

part of that investigation, the FDA Center for Biologics Evaluation and Research (CBER) 

provided funding to conduct the Post-Licensure Rapid Immunization Safety Monitoring (PRISM) 

study. The study questions for this assessment of children 6 through 59 months of age in the 

2010-2011 influenza season included the following: 

1)	 Was exposure to TIV or PCV13 associated with a greater risk for FS when compared to 

unexposed periods? 

2)	 Assuming children received both TIV and PCV13, did administering them on the same day 

lead to a greater risk for FS when compared to separate days? 

These questions were examined in the PRISM system, which is the vaccine safety component 

of the FDA-sponsored Mini-Sentinel Pilot Program developed to conduct active surveillance for 

medical product safety. PRISM Data Partners currently include five health insurers. For this 

study, data were included from three PRISM Data Partners participating at the time: Aetna, 

HealthCore, and Humana. Children 6 through 59 months of age who were vaccinated between 

July 1, 2010 through June 30, 2011 were included in the study. Information was also collected 

on DTaP-containing vaccines to adjust for the potential confounding influence on relative risk 

estimates for TIV or PCV13. A self-controlled risk interval study design was used. A 0-1 day 

risk interval was used, with 14-20 days used for the control interval. Exposures to TIV, PCV13, 

and DTaP or DTaP combination vaccines were identified in claims and immunization registry 

data. TIV, PCV13, and DTaP administration was validated in medical records if available. 

Cases were excluded if they were later determined to have LAIV or PCV7 exposures based on 

medical record review. Outcomes were identified in claims data using ICD-9 codes for seizures, 

simple FSs, complex FSs, or other seizures (780.3, 780.31, 780.32, or 780.39). Codes were 

included for inpatient and ED settings only. FS status was validated using medical record 

reviews. Each case was independently reviewed by two pediatrician adjudicators blinded to 

vaccination status, and FS were considered confirmed if there was a seizure and fever within 24 

hours or a diagnosis of FS. Also excluded were those with conditions stated in AAP treatment 

guidelines for FS, as well as those with focal seizures unless they were associated with a 

diagnosis of complex FS. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Approximately 1.9 million children were identified as potentially eligible for this study. Of those, 

approximately 840,000 children received 1 of 3 vaccines of interest in the study. Of those, 252 

were identified to have had a potential FS event in the risk or control interval according to 

electronic data. As mentioned earlier, medical record review was conducted of potential FS 

cases identified in electronic data. Of the 252, 86% had charts available to confirm FS status. 

Of those, 152 were confirmed for a positive predictive value (PPV) of 70%. Of the 64 not 

confirmed, 19 were excluded because seizures were ruled out, 7 were deemed possible 

seizures without sufficient documentation, 8 were seizures without sufficient documentation of 

fever, 22 were afebrile seizures, and 8 were excluded due to other reasons. 

Medical record review was also conducted of vaccinations identified in claims or immunization 

registry data. For the vast majority of vaccinations identified in electronic data, medical records 

were available. Of the charts, 79% were available for TIV exposure, 91% were available for 

PCV13 exposure, and 91% were available for DTaP exposure. Vaccine confirmation rates were 

high when charts were available. TIV or influenza vaccine was chart-confirmed in 98% of 

cases. PCV13 or PCV was chart-confirmed in 94% of cases. DTaP was chart-confirmed in 

100% of cases. Because the chart-confirmed rate of vaccination rates was so high, the analysis 

included vaccines identified in electronic data or in medical records. Following medical record 

review, 5 cases were excluded because medical records indicated that seizures occurred 

outside of the risk or control intervals following vaccination. A further 5 were excluded because 

LAIV or PCV7 was identified in the medical record. 

In terms of the descriptive characteristics of the confirmed febrile seizure cases, the vast 

majority occurred before 2 years of age as expected. Most occurred in the ED setting without 

requiring hospitalization. About a third experienced more than one vaccine of interest on the 

index date of vaccination, demonstrating the high rate of concomitant vaccination in the study. 

Of note, the rate of concomitant vaccination is much lower than what was seen in the VSD. 

Next, the first research question was analyzed: In the 2010-2011 influenza season, was 

exposure to TIV or PCV13 associated with a greater risk for FS, when compared to unexposed 

periods? This was done by calculating RR and AR estimates comparing exposed to unexposed 

periods. RR was estimated using a series of conditional Poisson models. The first models 

were bivariate or unadjusted models. Then adjustments were made for age and calendar time. 

The primary analytic model was adjusted for age, calendar time, and the three vaccines of 

interest. The shape of the age- and calendar time-based risk curves were determined prior to 

including them in the age and calendar time adjusted models. To do this, person time was 

included from the underlying PRISM cohort regardless of vaccination. Specifically, quadratic 

splines were used to adjust for age and calendar time. 

In the unadjusted analysis, each of the IRRs were above 1.0. PCV13 was statistically 

significantly associated with risk of FSs. When further adjusted for age and calendar time, the 

results were similar and PCV13 was significantly associated with the risk for FSs. When further 

adjusted for concomitant vaccines, the IRRs for TIV and PCV13 attenuated slightly and PCV13 

was no longer statistically significantly associated with risk of FSs. Furthermore, the IRR for 

DTaP attenuated greatly to 1. 

Each of the ARs, regardless of vaccine type or age, was below 4 per 100,000 doses. The 

highest AR was seen for PCV13 followed by TIV. The AR for DTaP was negligible. The highest 

ARs were seen at 16 months of age, and the lowest AR were seen at 59 months of age. AR 

was also calculated based on the worst case scenario, which was done by calculating the ARs 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

that corresponded to the upper limit of the 95% confidence interval for the IRRs. Under these 

assumptions, the AR for TIV ranged from 0.93 to 7.1 per 100,000 doses. For PCV13, the AR 

ranged from 1.2 to 9.2 per 100,000 doses. These AR estimates for TIV and PCV13 based on 

the worst case scenario were quite modest in size considering that the baseline risk of FS is 

approximately 2700 per 100,000 children across a child’s lifetime. 

The second research question was then assessed: Assuming children received both TIV & 

PCV13 in the 2010-2011 influenza season, did administering them on the same day lead to a 

greater risk for FS when compared to separate days? This was done by calculating the 

difference in AR for same day vaccination versus that for separate day vaccination. Specifically, 

the ARs were translated from the IRR estimates from the self-controlled risk interval design data 

described earlier. The AR for same day vaccination was calculated based on the IRR estimates 

from the Conditional Poisson Model described earlier. The AR for separate day vaccination was 

calculated by summing the AR for TIV without concomitant PCV13 plus the attributable risk for 

PCV13 without concomitant TIV. An assessment was then made of whether the AR for same 

day vaccination was equal to the AR for separate day vaccination. To test whether there were 

meaningful differences between the ARs for same day and for separate day vaccination, the two 

ARs were then subtracted. Using Monte Carlo simulations, 95% CIs were constructed. No 

evidence was found to suggest that same day TIV and PCV13 was associated with an excess 

risk of FS when compared to separate day vaccination. In fact, the point estimate itself 

suggested 1.1 fewer FS per 100,000 children with same day TIV and PCV13 vaccination, when 

compared to separate day vaccination. However, it is important to note that the result was not 

statistically significant and the CI was quite wide. 

The investigators also thought it was important to quantify any potential increase in risk 

following vaccination on the absolute scale. This was done by calculating AR by age in weeks 

since the baseline rate of FSs is known to vary dramatically by age. The AR was calculated as a 

function of the IRRs from the primary model, as well as the baseline rate of claims-identified 

seizures in PRISM population. The baseline rate was adjusted downward using the PPV of 

claims codes from this current evaluation. That quantity was then multiplied by 2, the length of 

the risk interval in days in order to get the AR per dose rather than per person day. The 

assumptions made when calculating AR were that the IRR was assumed to be constant across 

all ages, the baseline rate was based on quadratic spline for age, and the PPV was based on 

chart review of control interval cases. 

Before making her conclusions, Dr. Kawai thought it would be important to lay the PRISM 

results in the context of the Tse et al., VSD review results from the 2010-2011 season. Of note, 

the IRR were statistically significant in the VSD study but were not in the PRISM study. 

However, the results between the two studies were considered to be consistent for two reasons. 

First, the IRRs were above 1.0 for both studies. Secondly, the CI overlapped widely. However, 

the CI in the PRISM study was much narrower and the point estimates lower. It is therefore 

thought that if present, any increased risk associated with TIV or PCV13 would likely be lower 

than previously thought. Next, same day versus separate day vaccination of TIV plus PCV13 

was compared for the PRISM and VSD studies. For the PRISM study, the point estimate 

suggested that same day vaccination was associated with approximately 1.1 fewer FS per 

100,000 children. However, the result was not statistically significant. The VSD study 

suggested that there were 7.3 excess cases per 100,000 children vaccinated with same day TIV 

+ PCV13 vaccination. However, no statistical test was done. 

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The study had many strengths. The first strength was that a self-controlled risk interval design 

was used. A rigorous adjudication process of febrile seizure cases was implemented by 2 

pediatricians blinded to vaccination status. Age, calendar time, and DTaP vaccine adjustments 

were also made in the analytic models. Perhaps the greatest strength was that there was 80% 

power to detect IRRs of a size of 2 or above. Like any other observational study, this study was 

subject to limitations including the inability to validate all vaccine exposures and the limited 

power to detect IRRs less than 2. However, vaccinations were confirmed in the vast majority of 

instances when medical records were available. Also, this was the largest study to date on the 

associations of TIV, PCV13, and risk of FSs in the 2010-11 influenza season in the United 

States. 

In conclusion, in the 2010-2011 season, the IRR point estimates for TIV and PCV13 were above 

1.0. However, TIV, DTaP, and PCV13 were not significantly associated with FS in the primary 

analytic models. The presence of increased risk cannot be ruled out for TIV or for PCV13. 

However, if they existed, the magnitude of IRRs is lower than originally thought and any 

potential increase on the absolute scale would be quite modest in size because the ARs based 

on the upper bound of the 95% CI for IRRs suggest this. Assuming children received both TIV 

and PCV13 in the 2010-2011 season, administering both vaccines on the same day was not 

significantly associated with risk of FS when compared to separate day vaccination. 

Summary 

Tom Shimabukuro, MD, MPH, MBA 

Immunization Safety Office 

Centers for Disease Control and Prevention (CDC) 

Dr. Shimabukuro thanked all of the CDC and FDA staff and staff at CDC’s partner organizations 

who have been investigating who have investigated this issue over the past four years. 

Regarding whether the overall risk of FS increased with the 2010-2011 formulation of TIV, 

evidence from published studies includes the following: 

 VAERS signal in 2010-11 for Fluzone®* 

 VSD Rapid Cycle Analysis (RCA) signal in 2010-2011 

 Further analysis found a peak AR for concomitant TIV+PCV13 at 16 months of age 

with 45 additional FSs per 100,000 children vaccinated ** 

 Persistence of the VSD RCA signal for TIV during 2011-2012 (same TIV formulation as 

2010-2011) 

 CISA study that found a 3-fold higher rate of fever on days 0-1 when TIV and PCV13 were 

given together as opposed to separately (2011-2012 influenza season, adjusted for other 

concomitant vaccines including DTaP) *** 

The above studies could not adequately distinguish the independent risk of FS associated with 

TIV alone versus risk with concomitant vaccinations [*Leroy et al. Vaccine. 2012;30(11):2020-3; **Tse et al. Vaccine. 2012;30(11):2024-31; *** Stockwell et al. JAMA Pediatr. 2014;168(3):211-9]. 

In terms of the independent effect of TIV on risk of FSs, the PRISM analysis * found no 

statistically significant independent increased risk of FS associated with TIV during the 2010­

2011 influenza season. The RR was 1.4 (95% CI 0.8, 2.4) in the adjusted analysis when TIV 

was adjusted for PCV13 and DTaP. The updated VSD analysis ** found no statistically 

significant independent increased risk of FS associated with TIV during the 2010-2011 influenza 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

season, with a RR 1.2 (95% CI 0.2, 5.8) in the stratified analysis of TIV given without PCV13 or 

DTaP. The updated VSD analysis ** found no independent increased risk of FS for TIV given 

without PCV13 or DTaP during the 2006 through 2009 influenza seasons. In terms of whether 

the risk of FS was greater when TIV was given with PCV and/or DTaP, the updated VSD 

analysis for the 2010-2011 season suggested that the RR increased about 3-fold when TIV was 

given with PCV and/or DTaP compared with unexposed periods. * Similar results were seen for 

the 2006-2009 influenza seasons. * The PRISM analysis did not find any greater risk of FSs for 

same day versus separate day vaccination with TIV and PCV13 during the 2010-11 influenza 

season ** [ * Duffy et al. Seizures Following Multiple Vaccines: A Vaccine Safety Datalink (VSD) 

study. June 2014 ACIP meeting; ** Kawai. Assessment of FSs after Trivalent Influenza Vaccines 

during the 2010-2011 influenza season in the PRISM system. June 2014 ACIP meeting]. 

The weight of the evidence and the consistency of the findings from the VSD analysis over 

several seasons suggest that when TIV is given alone, risk of FS is not increased. When TIV is 

given with PCV and/or DTaP, however, risk of FS is increased. The highest risk is when TIV + 

PCV + DTaP are given together at 15 months of age. The AR was 38 additional febrile seizures 

per 100,000 children vaccinated with that combination, which is similar to FS risk seen with 

measles-mumps-rubella (MMR) vaccine* [ * Barlow et al. The risk of seizures after receipt of 

whole-cell pertussis or measles, mumps, and rubella vaccine. N Engl J Med. 2001;345(9):656­

61]. 

In conclusion, simultaneous administration of TIV with PCV and/or DTaP vaccines appears to 

be associated with an increased risk for FS in young children. This increased risk is transient 

from the day of to the day after vaccination (days 0-1). Although frightening for parents and 

caregivers, FSs do not have lasting effects. Getting recommended childhood vaccines during a 

single healthcare visit has important benefits. On-time vaccinations keep children protected 

against many infectious diseases, and providing multiple vaccinations in a healthcare visit 

minimizes the number of healthcare visits that parents, caregivers, and children must make. 

Discussion Points 

Dr. Reingold found it interesting that the control interval chosen was after the risk interval rather 

than before. He wondered whether the same analyses had been done using the comparison 

interval before and after the risk interval, and if it made any difference. 

Dr. Duffy indicated that the control interval was chosen specifically to exclude the risk period for 

MMR and MMRV vaccines. The goal was to replicate the original findings so that it would be 

closely comparable to the surveillance conducted in 2010-2011, which used the same risk 

intervals. 

Dr. Reingold said he was not sure that was the answer to his question. He clarified that his 

question was, “If you choose the controlled interval before rather than after, does it make any 

difference?” 

Dr. Duffy replied that they did not believe it should, but this has not been assessed. 

Dr. Reingold said he was just curious because it seemed to him that if something touched off a 

seizure, perhaps during the several weeks after that, there would be a lower risk of seizure. 

The PRISM analysis showed that there is basically no greater risk of giving vaccines together 

on the same day with respect to the AR, which would be expected. But, this seemed to be at 

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odds with the conclusion that the RR of giving the vaccines together on the same day is 

increased. He wondered how the possibility could be excluded that each of the individual 

vaccines given separately has perhaps a 50% increase in RR, an RR of 1.5, which these 

studies do not have the power to exclude. In fact, the overall risk is no different giving them 

combined on the same day as opposed to giving them separately on individual days. 

Dr. Kawai said she was not entirely sure she understood the question. In this study, the 

investigators did examine whether same day TIV + PCV13 was associated with a greater risk 

for FS and did not find any difference. For the RR estimates, they wanted to isolate the 

independent effect of each of the vaccines, which was why the joint effects of TIV + PCV13 

were not presented in RR format. 

Dr. Reingold referred to the slide that stated, “Simultaneous administration of TIV with PCV 

and/or DTaP vaccines appears to be associated with an increased risk for febrile seizures in 

young children.” He emphasized that his point was that if giving one vaccine on one day has an 

RR of 1.5, which cannot be excluded with the CIs, then perhaps the risk of giving the vaccines 

individually on separate days, overall there is no greater RR than giving them all together on 

one day. 

Dr. Duffy indicated that this was tested in the multivariate model. Using a multivariate model 

that included all three vaccines in the same model, tests were conducted for effect modification. 

In terms of the P results, the TIV/PCV interaction was 0.0494. The TIV/DTaP interaction was 

statistically significant at 0.0031, and the 3-way interaction was 0.0735, so it was tending toward 

significance but was not significant. He would argue that this suggests that there is a difference 

in RRs for the 2-way combinations at least, and a suggested interaction for the 3-way 

combinations that are different than giving them on separate days. 

Regarding Dr. Reingold’s question pertaining to why not a pre-control interval versus a postpost interval, Dr. Lee (MS/PRISM Team) said this had always traditionally been done because 

of the healthy vaccinee effect. One could argue that in this instance, it probably would have 

been okay because of the short time interval, and it probably would have made no difference 

either way. This was not done in this instance. In terms of the second question raised, both 

interpretations are correct but answer slightly different questions—one being the 2 vaccines and 

exposed period compared to an unexposed period. If two vaccines are given, then there is 

more risk of fever and potentially that puts the recipient at a higher risk of FSs. But regarding 

the assumption that children will receive vaccines and whether there is a greater risk for same 

day versus separate day, at least in the PRISM study, it is believed that there is no greater risk 

of giving them on the same day, assuming that children are going to be vaccinated anyway. 

The method was not available in the prior VSD study to be able to provide CIs. It looked 

elevated. It may have been that the CIs were wide in the first place, and the investigators could 

not say either way. 

Dr. Gorman (NIH) inquired as to whether Dr. Kawai was talking about a Poisson distribution 

around the lambda as the model. He also said that in terms of quadratic smoothing or quadratic 

splining, his understanding was that Poisson is a logarithmic function and not a quadratic 

function. He asked whether that was just a terminology change in the 30 years since he looked 

this last, or if it is a difference in interpretation of how the math is done. 

Dr. Kawai responded that she used a Conditioning Poisson Model, and that she used the 

quadratic spline for the age and calendar week effects, not the effects of vaccination. 

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Regarding Dr. Gorman’s question about quadratic splining, Dr. Lee (MS/PRISM Team) said this 

was specifically used because there was so much time varying confounding by week of age that 

the investigators felt the need to adjust for that in the offset term. 

Dr. Plotkin (Vaccine Consultant) asked about the recommendation concerning use of 

antipyretics for TIV. 

Dr. Kimberlin (AAP) replied that the recent recommendation is that the AAP is not supportive of 

using prophylactic antipyretics, but is very comfortable with using antipyretics for children who 

have developed fever. 

Dr. Plotkin (Vaccine Consultant) wondered whether there was any possibility of reexamining 

that in light of the data suggesting that TIV together with other vaccines increases the risk. 

Dr. Kimberlin (AAP) said he thought that because of the concerns of the safety of the 

antipyretics in that age group, the risks of the antipyretics would have to be balanced with the 

risks of the FSs. His guess was that this would be a wash. Given the data suggesting that 

there is only a slight increase in the risk for an FS, a lot of children would be given antipyretics 

to prevent very few FSs. Also, there is not a lot of good data to suggest that using antipyretics 

prophylactically actually does reduce FSs. Therefore, he thought the AAP currently probably 

would stand on the recommendation that antipyretics should not be administered 

prophylactically but would have no problem with treating a fever. 

Dr. Temte asked Dr. Broder whether she had a response. 

Karen Broder (ISO) indicated that there is some pilot work underway with the CISA project 

through Duke University and CDC, which is exploring the effects of using prophylactic 

antipyretics versus placebo on immune responses after inactivated influenza vaccine. The work 

is just beginning, but over the next year or two these data might be informative—at least to 

speak to the issue of whether antipyretics blunt immune responses. That is the concern of 

previous literature. 

Dr. Englund (PIDS) asked whether the investigators took rotavirus vaccination into account in 

their analyses. A recent paper in 2013 showed protective association of rotavirus vaccine and a 

decrease in FS. In other words, rotavirus is not very likely to cause a substantial amount of FS 

in children under 2 years of age and with the increasing use of rotavirus vaccine, the overall 

incidence of FS has gone down. 

Dr. Duffy responded that the VSD study addressed the transient risk during the post-vaccination 

period and would not address the more cumulative effect over a child’s lifetime in terms of how 

many febrile seizures they might have by being vaccinated versus unvaccinated with particular 

vaccines. Specifically regarding the 0-1 day risk interval post-vaccination, all other vaccines 

that the children in the VSD study received were assessed. No vaccines other than TIV, PCV, 

or DTaP seemed to have an independent effect once the effects of the others were controlled 

for. While they did not have data on monovalent rotavirus vaccine, there was no suggestion of 

an independent risk of FS with the pentavalent rotavirus vaccine in the 0-1 period. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Adult Immunization 

Introduction 

Dr. Tamera Coyne-Beasley, Chair 

Adult Immunization Work Group 

Since the Adult Immunization WG was not able to provide this update during the February ACIP 

meeting, Dr. Coyne-Beasley highlighted the work done in advance of the publication of the adult 

schedule. She thanked all of the collaborating organizations and CDC staff for their help in 

publishing the yearly update and associated materials on the CDC website and elsewhere. The 

updated schedule is also published along with the updated adult immunization coverage data. 

The ACIP recommendations were published in Annals of Internal Medicine on February 3, 2014 

and were approved by the following: 

 American College of Physicians 

 American Academy of Family Physicians 

 American College of Obstetricians and Gynecologists 

 American College of Nurse Midwives 

The recommendations also were published in the MMWR in an e-notice to readers on February 

3, 2014 and a print version on February 6, 2014. The differences between the Annals of 

Internal Medicine and MMWR publications is that the MMWR publication highlighted the 

changes from the previous years and did not include figures in the contraindications tables. 

Since that time, there have been many communications documents and the CDC adult and 

adolescent immunization quiz was also updated in February 2014. 

During this session, Dr. Walter Williams provided a summary of recently published noninfluenza vaccine coverage among adults. Dr. Kris Sheedy provided an update describing the 

CDC adult immunization campaign, including materials developed to promote adoption of NVAC 

updated Adult Immunization Practice Standards. Dr. Coyne-Beasley provided an update on 

other key adult immunization activities to address lagging coverage in adults. 

Update on Adult Immunization Coverage 

Walter W. Williams, MD, MPH 

Medical Epidemiologist 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

In this presentation, Dr. Williams summarized the results from the 2012 NHIS on non-influenza 

adult vaccination coverage published in the MMWR on February 7, 2014. He described the 

data source, provided a top-level summary of the key coverage findings, and provided sources 

for additional information. The NHIS is an annual in-home survey about the health and health 

status of non-institutionalized civilians in the US using nationally representative samples. 

Questions about receipt of recommended vaccinations for adults are asked of one randomly 

selected adult within each family in the household. Weighted data were used to produce 

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national coverage estimates. The final sample adult component response rate for the 2012 

NHIS was 61.2%. The sample size was 34,218. 

This report does not include influenza vaccination, but does include pneumococcal vaccination 

(overall, including the 23-valent pneumococcal polysaccharide vaccine and the 13-valent 

pneumococcal conjugate vaccine); tetanus toxoid–containing vaccines (including Td or Tdap); 

hepatitis A; hepatitis B; herpes zoster (shingles); and HPV vaccines. Analyses were conducted 

to estimate Tdap vaccination of adults aged 65 years of age and older being collected in the 

NHIS for the first time starting in 2012. Comprehensive information on high-risk status for 

hepatitis A or B was not collected in the 2012 NHIS. Information was collected on travel status 

and chronic liver disease for high-risk for HepA, and diabetes mellitus for HepB. HCP were 

identified, including those who provided direct patient care. 

Adults were considered to be at high risk for pneumococcal disease if they had been told by a 

doctor or other health care professional that they ever had diabetes mellitus; emphysema; 

coronary heart disease, angina, heart attack, or other heart condition; lymphoma, leukemia, or 

blood cancer. Adults were also considered to be at high risk for pneumococcal disease if during 

the preceding 12 months they had a cancer diagnosis (excluding non-melanoma skin cancer), 

asthma episode or attack, chronic bronchitis, weak or failing kidneys, or were current smokers. 

As a reminder, there are two types of pneumococcal vaccine: 23-valent polysaccharide vaccine 

(PPSV-23) which has been recommended for many years for adults, and the 13-valent 

conjugate vaccine (PCV-13) which was recommended in June 2012 for adults with weakened 

immune systems and other specific groups. Estimates reflect overall pneumococcal vaccination 

coverage for PPSV-23 and PCV13 vaccine uptake. The 2012 NHIS did not estimate the 

proportion of pneumococcal vaccinations by type. Coverage among high-risk adults aged 19 

through 64 years was 20.0%, and pneumococcal coverage among adults aged 65 years and 

older was 59.9%, similar to the estimates for 2011. Among adults aged 60 years and older, 

20.1% reported receiving herpes zoster vaccination, a 4.4 percentage point increase from the 

estimate for 2011 (15.8%). That was primarily due to increases among non-Hispanic whites. 

The proportion of adults who received a tetanus vaccination during the past 10 years was 

64.2% for those aged 19 through 49 years, 63.5% for those aged 50 through 64 years, and 

55.1% for those aged 65 years and older. Overall tetanus coverage did not increase from 2011. 

Reported Tdap coverage among persons aged 19 through 64 years was 15.6%, a 3.2 

percentage point increase compared with the 2011 estimate. Again, that increase was due 

primarily to increases among non-Hispanic whites. Tdap vaccination coverage of adults aged 

19 through 64 years among those with household contact with an infant aged less than 1 year 

was 25.9%, similar to the 2011 estimate. Tdap vaccination from 2005-2012 among HCP aged 

19 through 64 years was 32.6%, a 5.8 percentage point increase over 2011. Of the 

respondents for Tdap vaccination, 34% were excluded from estimations of Tdap coverage, 

creating a potential for bias. Tdap coverage was estimated after excluding from the 34,218 

respondents aged 19 years and over all those without a “yes” or “no” response for tetanus 

vaccination status in the past 10 years (5.4%); those without tetanus vaccination status during 

2005–2012 (3.7%); and those who reported tetanus vaccination during 2005–2012 but were not 

told (20.4%) or did not know the vaccine type (4.3%). This yielded a sample of 22,653 

respondents aged less than 19 years for whom Tdap vaccination status could be assessed. 

Sensitivity calculations were conducted to assess the magnitude of potential bias that might 

result from these exclusions. Depending on what proportion of excluded respondents actually 

received Tdap, actual Tdap coverage could fall within the range of 11.2% to 39.4% for adults 19 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

through 64 years and 6.0% to 31.0% for adults age 65 years of age and over. This sensitivity 

analysis assumed no errors in reporting when the responses were all “yes” or “no” 

combinations. 

With regards to the proportion of tetanus vaccine that was Tdap among those who received a 

tetanus vaccination, among 13,145 respondents 19 years of age and over who received a 

tetanus vaccination during 2005–2012, 52.6% reported that they were not informed of the 

vaccination type and 11.1% could not recall what type of tetanus vaccination they had received. 

Of the remaining 36.3% of respondents who reported they knew what type of tetanus vaccine 

they received, 65.4% reported receiving Tdap. Among 1,501 health-care personnel 19 years of 

age and over who received a tetanus vaccination, 33.1% reported they were not informed of the 

vaccination type, and 9.3% could not recall what type of tetanus vaccination they had received. 

Of the remaining HCP (57.6%) who reported they knew what type of tetanus vaccine they 

received, 76.3% reported receiving Tdap. Vaccination of HCP for Tdap was statistically higher 

than that among non-HCP. 

Hepatitis A coverage remained low among adults aged 19 through 49 years at 12.2%, and was 

similar to the estimate for 2011 (12.5%). HepA coverage was higher among those with travel 

outside the US to an endemic area (18.9%) compared with those without endemic area travel 

(8.6%). Vaccination coverage among adult travelers to highly endemic countries was similar to 

the estimate for 2011. Hepatitis B coverage among adults aged 19 through 49 years was 

35.3%, similar to the estimate for 2011. Among persons with diabetes, coverage was 28.6% for 

adults aged 19 through 59 years and 15.1% for adults aged 60 and older, similar to the 

estimates for 2011, highlighting the need to increase awareness of the higher risk for acute 

HepB in this population and the need for vaccination. 

Among women aged 19 through 26 years, 34.5% reported receiving at least one dose of HPV 

vaccine, an increase of 5.0 percentage points from the 29.5% reported for 2011. Again, this 

increase was due to increases primarily among non-Hispanic whites. Coverage among women 

aged 19 through 21 years was 44.3%, similar to the 2011 estimate. Coverage among women 

aged 22 through 26 years was 28.2%, a 6.7 percentage point increase compared with 2011. 

The increase among women aged 22 through 26 years indicated that some catch-up 

vaccination is occurring in this age group, primarily among white women. Data were not 

collected on age of HPV vaccination in 2012, so it was not possible to determine whether 

vaccination occurred as part of an adolescent program or when recipients were 19 years of age 

or older. Data on age of HPV vaccination was collected in the 2013 NHIS. Coverage among 

males has remained low since the ACIP recommendation to vaccinate males in October 2011. 

Receipt of at least one dose of HPV vaccine among males aged 19 through 26 years was 2.3%, 

similar to the estimate for 2011. Coverage was 2.4% for males aged 19 through 21 years and 

2.2% for those aged 22 through 26 years. 

To summarize, compared with estimates from the 2011 NHIS, modest statistically significant 

increases in 2012 were observed for three of the more recently recommended vaccinations for 

adults, HPV, herpes zoster, and Tdap. The increases ranged from 3 to 6 percentage points. 

The increases in HPV, Tdap, and zoster vaccination were due primarily to increases among 

non-Hispanic whites, indicating a widening gap in coverage compared with non-Hispanic blacks, 

Hispanics, and non-Hispanic Asians. The differences seen in HPV vaccination coverage of 

non-Hispanic white and Hispanic women is not observed in data from the NIS among teens. 

This is being assessed in greater detail by comparing cohorts reporting vaccination in NHIS 

versus NIS. There are similar overall results when comparing HPV coverage among persons 

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who are 17 years old in NIS teen data and 18 years olds in NHIS data, except that there were 

substantial differences for Hispanics that may actually indicate a large bias in the NHIS selfreported data for HPV vaccination among Hispanic women. 

For the vaccination groups for which the results were reported by race/ethnicity, the vaccination 

coverage among non-Hispanic whites and the difference in coverage for non-Hispanic blacks, 

Hispanics, and non-Hispanic Asians compared to whites, there were statistically significant 

disparities for 31 of the 42 comparisons by vaccine and age/target groups. These disparities 

ranged from -2 percentage points for Hispanics versus whites for HepA in 19 through 49 year 

old adults, to -27 percentage points for Asians versus whites for HPV in 19 through 26 year old 

women. There was only one instance with higher coverage than whites, with Asians having 

HepA coverage seven percentage points higher than whites aged 19 through 49 years. 

To summarize the racial/ethnic disparities, compared with 2011, racial/ethnic differences 

persisted for all six vaccines and widened for Tdap, herpes zoster, and HPV. Non-Hispanic 

blacks, Hispanics, and Non-Hispanic Asians generally had lower vaccination coverage than 

non-Hispanic whites for all vaccines routinely recommended for adults with several exceptions. 

For PPSV/PCV13 among those 19 through 64 years of age, blacks had coverage similar to 

whites. For Tdap among those 19 years of age and older, Asians had coverage similar to 

whites. For Tdap among those 65 years of age and older, blacks had coverage similar to 

whites. For HepA, blacks had coverage similar to and Asians had coverage higher than whites. 

For HepB, Asians had coverage similar to whites. Among HCP, non-Hispanic black and 

Hispanic HCP had lower coverage for Tdap, but coverage similar to whites for HepB. 

The findings in this report are subject to at least five limitations. First, the NHIS sample 

excludes persons in the military and those residing in institutions, so the results apply only to the 

civilian, non-institutionalized population. Second, the response rate was low at 61.2%. A low 

response rate can result in sampling bias if the nonresponse is unequal among the participants 

regarding vaccination. Third, the determination of vaccination status and identification of highrisk conditions in NHIS were not validated by medical records. Self-report of vaccination is 

subject to recall bias and overestimation of rates. However, adult self-reported vaccination 

status has been shown to be sensitive for pneumococcal, tetanus, hepatitis A, hepatitis B, HPV 

and herpes zoster vaccination and specific for vaccination with all these vaccines, except for 

tetanus vaccination [Rolnick et al. Self-report compared to electronic medical record across 

eight adult vaccines. Vaccine 2013;31:3928-3935]. It is important to note that the accuracy of 

recall by young adults of vaccinations routinely recommended during adolescence has not been 

studied. Fourth, the Tdap estimate is subject to considerable uncertainty since many 

respondents were excluded from estimations of Tdap coverage. Finally, age at vaccination was 

not known for vaccines adults reported having “ever” received, so it is not clear for younger 

adults whether vaccination occurred as an adult aged 19 or older or was given as part of a child 

or adolescent vaccination program. 

In conclusion, vaccination coverage estimates for the three vaccines in this report that are 

included in Healthy People 2020 (pneumococcal, herpes zoster, and hepB for HCP) are well 

below the respective target levels of 90% for persons aged ≥65 years and 60% for persons 

aged 18 through 64 years at high risk (pneumococcal vaccine), 30% (herpes zoster), and 90% 

(hepatitis vaccine for HCP). Despite some improvements in vaccination, coverage remains low 

for most vaccines routinely recommended for adults and racial and ethnic disparities remain. 

Much remains to be done to increase utilization. 

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Update on CDC’s Adult Immunization Communication Activities 

Kristine Sheedy, PhD 

Associate Director for Communication Science 

Office of the Director 

National Center for Immunization and Respiratory Disease 

Centers for Disease Control and Prevention 

Dr. Sheedy presented an update on CDC’s communication activities related to adult 

immunization. In the fall of 2012, CDC launched a 2-year adult immunization communication 

program. The broad goal was to develop a brand as well as messages and materials that could 

help raise awareness and promote immunization according to the recommended schedule by 

targeting adults and the physicians and other healthcare professionals who serve them. 

Knowing that making changes in social norms and behaviors related to adult immunization 

requires a long-term effort well beyond the 2-year project timeline, CDC set out to lay a strong 

foundation for this in future work through formative communication research. The research 

included a national survey, which Dr. Sheedy shared with ACIP in 2013; focus groups with 

adults; and a review of available published and gray literature related to adult immunization 

communication. In addition, 28 in-depth interviews were conducted with physicians and nurse 

practitioners and nurse practitioners. The topics discussed with them included vaccine 

administration, knowledge of immunization schedules, attitudes regarding VPDs, vaccine 

recommendations and conversations, and resources and support needed. Summaries of this 

research are available for those who are interested in more details. 

Based on CDC’s research, best practices, and a number of helpful behavioral change models 

and theories, the following framework was developed for how communication efforts can 

encourage adults to get vaccinated: 

The bottom line is that behavior change is complicated. On the left side of the framework are 

the different states that people may go through in terms of vaccine decision-making. On the 

right side are the various strategies that can be helpful in moving people through those 

changes. In the middle are some of the key factors that mediate those. It is known that it is 

important for all of these to be delivered by the most trusted sources (e.g., doctors and other 

health care professionals), which is the green arrow going through all of the stages. 

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There are some key drivers in CDC’s framework and approach to communicating with adults 

about immunization. These include stressing the relevance and importance of timely 

vaccination by highlighting susceptibility and explaining the severity and potential costs of 

getting vaccine-preventable diseases. However, this information has to be balanced with 

empowering messages that present vaccination as a doable step that can be taken to protect 

themselves and their loved ones. It is also necessary to provide plain language information that 

can help adults make informed decisions, and provide support in getting vaccinated. The 

information should be tailored as much as possible. For CDCs communication to the public, 

adults are encouraged to talk with their HCPs about vaccines that are right for them. 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Key principles of CDC’s communication with HCPs include reminding them why vaccination is 

an important preventive measure, and their role in making sure their patients are protected. The 

recently updated NVAC standards provide guidelines that call on all HCPs to take certain steps, 

including sharing a strong recommendation. It is important to share what has been learned from 

consumer research regarding what can make recommendations compelling, and how to best 

address patients’ questions and concerns. 

In CDC’s most recent research with HCPs, not all physicians responded positively to information 

about the standards, in some cases feeling that it is not realistic to ask them to assess 

vaccination status and discuss needed vaccines at every visit. For instance, when they are 

dealing with a patient who has an acute issue. 

A critical piece of CDC’s focus was the conversation between providers and their patients. For 

some patients, a clear and strong recommendation that a vaccine is needed may be sufficient. 

Others may want additional information. CDC summarized the five main best practices the 

agency identified for strengthening vaccination recommendations into an approach called 

SHARE, which includes the following: 

 Share the reasons why the recommended vaccines are right for the patient given age, 

health status, lifestyle, job, or other risk factors. 

 Highlight your own experiences with vaccination to reinforce benefits and strengthen 

confidence. 

 Address patient questions and any concerns about vaccines, including side effects, 

safety, and vaccine effectiveness, in plain and understandable language. 

 Remind patients that many vaccine-preventable diseases are common in the U.S. and 

can be serious for them. 

 Explain the potential costs of getting VPDs, including serious health effects, time lost 

(such as missing work or family obligations), and financial costs. 

While there is no magic message or script that can work across all adult vaccines and for all 

patients, CDC believes that these are important communication strategies that providers should 

keep in mind when helping patients make the decision to get recommended vaccines. 

CDC has developed a variety of communication resources that can be used with a broad 

general audience of adults, as well as those with chronic conditions. These include outreach 

products (e.g., posters, flyers, web buttons, banners, et cetera), materials that can be used for 

patient education such as fact sheets, and tools to assist adults such as the online vaccine quiz 

and the revamped adult immunization website. The following are a few samples of CDC’s 

media and outreach products: 

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Communication products, resources, and tools have also been developed to encourage and 

support HCPs in improving adult immunization practices, who are critical in getting adults 

vaccinated. CDC launched its vaccine schedule app in May 2014. In its first 20 days of being 

available, it was downloaded 3600 times. That includes the adult immunization schedule. 

Materials for HCPs includes a series of fact sheets on improving adult immunization practice, 

including vaccine assessment, recommendations, administration, referral, and documentation. 

Each sheet covers one of the steps and provides tips, resources, and tools to aid in 

implementation: 

The second sheet in the series includes the SHARE approach, as well as some tips on how to 

address common questions. 

CDC continues to look for opportunities to get the word out broadly about adult immunization, 

and had the opportunity to do that in February 2014 with the release of the 2014 adult 

immunization schedule and the NHIS 2012 adult vaccination coverage data. Some of the 

activities included the following: 

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 Coverage in national media of adult vaccination coverage rates 

 Social Media: CDC, Dr. Frieden, and Dr. Besser (ABC news) tweet about adult vaccination 

 Radio Media Tour with CDC and ACP vaccination experts reaching an estimated 

35,876,886 listeners from live and taped interviews, and a :60 packaged news segment 

 Distribution of a matte article for placement in print and electronic media 

The next major outreach effort will be during National Immunization Awareness Month in August 

2014. CDC looks forward to working with partners to try to get the word out about adult 

immunization during that month. 

The next steps for CDC are to continue to share key research findings with partners and health 

communication professionals; continue to test and develop patient education materials and 

other HCP resources, including Spanish language; and continue to disseminate messages, 

products, and resources through engagement of partners and media. Of course, with influenza 

season approaching, CDC will look for opportunities to promote adult immunizations and for 

encouraging people to get their annual influenza vaccinations. As always, CDC asks its 

partners to use the agency’s products in a number of ways, and to feel free to offer input and 

feedback. 

Key Adult Immunization Activities to Address Lagging Coverage In Adults 

Dr. Tamera Coyne-Beasley, Chair 

Adult Immunization Work Group 

Dr. Coyne-Beasley presented information about some of the key activities that are underway to 

address lagging coverage in adults. She highlighted one of the primary activities, the National 

Adult and Influenza Immunization Summit (NAIIS) (aka the Summit). This summit is a 

partnership of 300 organizations with goals to convene adult and influenza immunization key 

stakeholders, identify actions that can be taken by members to improve the uptake of ACIP 

adult-recommended vaccines, and improve uptake of adult immunizations recommended by 

ACIP and influenza vaccine among all ages. A meeting was last convened in May 2014 in 

Atlanta, Georgia. However, the Summit work groups meet year-round. There are five work 

groups that are dedicated to issues related to providers, patient education, access and 

collaboration, quality, and decision-makers. 

Highlights of the May 2014 NAIIS meeting included the following: 

 Presentations by Dr. Howard Koh, Dr. Tom Frieden, and Dr. Anne Schuchat, with Dr. Koh 

noting the forthcoming National Adult Immunization Plan 

 Preliminary data from the University of Colorado that pointed out limited knowledge among 

providers regarding issues of billing and payment for adult immunizations (e.g., which are 

covered by Medicare B versus by D) 

 Limited use of immunization information systems by adult medical providers 

 Additional evidence confirming willingness of patients to be vaccinated if strongly 

recommended by their providers 

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 Presentations and discussions of challenges of developing quality measures for adult 

immunizations 

 Many examples of success in raising coverage where practice standards for adult 

immunizations were applied 

 Influenza vaccine dose projection from manufacturers of 157 million doses for 2014-2015 

season 

Presentations from the May 2014 NAIIS can be found at www.izsummitpartners.org 

In terms of future key activities, the NAIIS members are committed to exploring a CPT code for 

vaccine counseling; promoting implementation of the updated standards of practice for adult 

immunizations; increasing awareness of adult immunizations through National Immunization 

Awareness Month; identifying and disseminating provider business tools to reduce practice 

costs as barrier for providers; continuing evaluation of adult immunization quality measures; and 

addressing barriers related to in-network provider status requirements for patients and 

providers. 

Discussion Points 

Dr. Duchin indicated that at the local public health level, he deals with HCPs who have 

immunization issues and finds that one barrier is the perception of the time investment that is 

needed by providers to engage in the activities they are being asked to do with respect to 

counseling and explaining the risks, benefits, and burden of disease. He inquired as to whether 

CDC has assessed how much time it takes a provider to implement recommendations in the 

practice setting. It is important for practitioners to have a realistic expectation of how much time 

this will take. Increasingly, patients are being managed by medical teams as opposed to 

individual providers. Those teams have specialists who deal with specific aspects of a patient’s 

health. He wondered whether CDC had explored the potential to have immunization be a part 

of the team medicine approach and how that might work. 

Dr. Coyne-Beasley indicated that she is a member of the Provider WG where many of these 

issues are being discussed. The amount of time it takes is one of the primary reasons the WG 

is looking into the development of a CPT code so that not only can the amount of time it takes 

be evaluated, but also so that physicians can be reimbursed for that time. Management by 

medical teams is also being discussed and considered by the Provider WG. 

Dr. Bennett emphasized how discouraging adult immunization uptake is. A lot of work has been 

done to look granularly at what it takes to immunize adults in practices. John Fontanesi at UC 

San Diego used to study this in great detail, and there is a lot of interesting information from his 

work. The point about medical teams is a critical one. Years ago it was established in her own 

community that using extenders of professionals was the best approach and was the most costeffective and most efficient. Much of this can be automated to a large extent, so it is important 

to look for solutions that make this part of the way providers do business (e.g., through 

automation, use of extended teams, and standing orders). 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Kempe indicated that based on national surveys of family medicine and internal medicine 

providers, one of the biggest time issues is figuring out what people need and not having the 

information to do that. Having spent her career in implementation of delivery in pediatric 

practices, she thought they could learn a lot from each other. Since a major part of pediatrics is 

delivering immunizations, she expressed her hope that they could learn lessons from one 

another. She put in a major plug for systems changes, because behavior change is very 

difficult. The “low hanging fruit” really is much easier. The majority of adults as parents of 

children are not vaccine-hesitant or resistant. They simply do not know they need vaccines, and 

are vaccines are not routinely mentioned. Immunization registries, which now exist in every 

state, can immediately start having adult records and many states already do. This can provide 

a forecasting function at the point of care, and automatically generate reminder/recalls for entire 

populations. The efficiency is huge. Getting from 20% to 60% could be pretty quick if systems 

like this were implemented. 

Dr. Temte noted that he went through his recertification process in 2014 for AAFP. 

Maintenance and certification are required every 7 to 10 years, and part of that is a quality 

improvement project. He selected immunization for his quality project. This gets somebody in 

the habit of doing an assessment of reminder/recall. AAFP has approximately 9000 family 

doctors every year who have to be recertified. CDC could partner with professional societies in 

terms of creating a “low hanging fruit” that would be easy to do. 

Ms. Hayes (ACNM) indicated that ANA was recently funded through CDC and ASTHO to work 

on a communications project, with which they had a lot of fun. One of the things that they 

developed was super women that have amazing graphics, with shields with bacteria and viruses 

coming at them. This is all downloadable for free from http://www.midwife.org/ImmunizationResources-for-Midwives because it was funded by CDC, for which she expressed gratitude. 

The posters are giant and gorgeous and are available at midwife.org for shipping costs only. 

Dr. Riley (ACOG) indicated that ACOG has known for a long time that getting obstetricians and 

gynecologists on board with immunization campaigns has been difficult, and that it is the 

business aspect of starting an immunization program within an office that is a stumbling block. 

ACOG teamed up with AAP and there is a webinar on Wednesday July 30, 2014 from 12:00 PM 

to 1:00 PM titled “The Immunization Business and Clinical Strategies for OBGYN Practices.” 

Basically it is obstetricians and gynecologists learning from what pediatricians have been doing 

for years, and doing very well. She referred everyone to the ACOG website 

immunizationforwomen.org for more information. The intended audience is OB/GYNs, but it 

could be any practitioner. 

Dr. Even (ACHA) indicated that ACHA has adopted the idea that an institution is a really good 

way to get college students up to date on their immunizations. ACHA has a document that 

includes all of the recommended adult immunization for college students, which is kept up to 

date based on ACIP recommendations. As a practitioner and a director of a health center, her 

challenge has been not the interest by providers but the complexity. This is where a registry 

would be helpful. If they get an immunization in their electronic record, it will get dumped it into 

the state registry in Missouri. Students come to them from all over the country and fax and send 

documentation records, and only a few immunizations are required, so they pay attention to 

those. They are trying to increase the familiarity of the nurses and providers to ask whether 

students have had their Tdap. Their providers are interested in trying to move this forward. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Jenkins inquired as to whether there was any analysis by income level. It seemed to her 

that if there were disparities by ethnicity, it may be linked to disparities by income. The issue of 

practices that serve low-income populations is another challenge for the business model. 

Pediatricians report that setting up to administer immunizations is incredibly expensive in terms 

of the equipment and type of monitoring to manage immunizations. She wondered whether 

anything was known about the income differentials and whether the Provider WG is assessing 

practices that may need some incentives in order to be able to set up for immunizations. 

Dr. Williams replied that for this particular report, they basically assessed the covariates that he 

referenced at the beginning of his presentation: age, high risk status, and vaccination target 

group criteria. They have performed specific analyses on individual vaccines that included 

assessment of other demographics and access to care characteristics such as education, 

whether a person had a regular doctor, and whether they had health insurance and types of 

insurance. Where those types of analyses have been done, consistently a risk is seen for lower 

vaccination uptake among those with lower education, no regular doctor, no health insurance, 

and who make less money. 

Dr. Coyne-Beasley added that the Provider WG has talked about immunization registries. It is 

known that adults completely underutilize immunization registries. A larger issue is that it is 

assumed that everyone will have an electronic health record. But looking at the diversity of 

providers and who they serve and the resources that people have within their offices, there is a 

wide range. To try to meet that need, it is important to the Provider WG to have a diversity of 

providers as members of the work groups to help them figure out needs. She said she also 

appreciated the conversation about teams, because that is how vaccination programs can be 

done most efficiently and successfully in offices. They did not mean to imply at all that the work 

is going to be easy. Getting a diversity of opinions from practices with a wide variety of 

resources will be important in trying to combat this issue. Immunization registries are very 

important and so are electronic health records and accessing them. There are practices without 

internet access. 

Dr. Kohn (Merck) said he did not see any data in the presentations about the rates of 

immunization among HCPs. He wondered if it was realistic to expect that providers would carry 

the desired messages if they were not getting vaccinated themselves. It is known that even in 

the setting of the H1N1 pandemic this was really a challenge. He wondered if anyone had any 

thoughts about that and the types of activities they might engage in that area to improve adult 

immunization rates. 

Dr. Williams replied that at least two data points were provided for HCP in the presentation on 

coverage, one for Tdap and one for HepB vaccination. The experience has been that when 

HCPs themselves serve as models as well as offering some recommendations in their practices 

for their clients, vaccination levels in those types of practices are much higher than when that 

circumstance is not the case. 

Dr. Fryhofer (AMA/ACP) said that the internists do have a quality improvement project for which 

MOC credits are available. ACP also has an ACPConnect. What they are trying to do is find 

joy in quality improvement so they can also share in the joy of knowing their patients are 

vaccinated. 

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Dr. Bob Hopkins (Emergent BioSolutions) said he had always wondered whether it is possible to 

implement a personal vaccine record or personal medical record specific to vaccines in order to 

empower patients that could be started from birth. Skirt the HCP all together and go right to the 

mom, and then carry that forward through teen years, college, and further. 

Dr. Coyne-Beasley responded that she saw this approach more in terms of pediatrics than 

adults. This happens quite frequently in non-industrialized countries. She does a lot of mission 

work, and one of the things that is interesting to her is that often-time there are no electronic 

medical records or immunization registries. But somehow built into some of the cultures and 

countries where she has worked that are non-industrialized, people carry a health record around 

with them in the way that people in the US carry around a purse or wallet. Some communities 

have high population-based immunization data for some of their communities, but do not have 

some of the advances the US has. She does believe there are opportunities to empower 

families, patients, and adults to keep their own records. This was done a lot in pediatrics many 

years ago where everyone had their AAP guide. That is a great alternative in addition to trying 

to do some of the automation. 

Dr. Sheedy said she thought the comment about an app was also worth thinking about. They 

might be hard-pressed to get adults to download an app that was only about immunization, but if 

it was wrapped up in the different things they need at the different stages of their lives and 

immunization was a part of that, they might be more likely to put that on their iPads or iPhones. 

Dr. Gellin (NVPO) noted that Dr. Koh has spoken many times at the summit as making adult 

immunizations is a priority for him. He asked for the development of an adult immunization 

strategic plan, which is in development. Also, HHS has been working with the National Quality 

Forum to develop performance measures. Those are out in drafts and comments are being 

taken. A webinar is also schedule. All of these are related to improving the systems for adult 

immunizations. 

Dr. William Schaffner (NFID) read the following comment into the record on behalf of the 

Gerontological Society of America (GSA): 

The Gerontological Society of America (GSA) is pleased to present this statement on 

behalf of this initiative, the National Adult Vaccination Program (NAVP), which is a multistakeholder industry-supported collaboration to improve adult vaccinations aligned with 

recommendations of the CDC’s Advisory Committee on Immunization Practices. The 

members of the Gerontological Society of America include researchers, practitioners, 

educators, economists, health policy experts, and others interested in expanding 

scientific knowledge across the lifespan, making it a natural home for the NAVP. The 

NAVP promotes that immunizations continue to be one of the greatest public health 

success stories. Additionally, NAVP along with this committee, clearly recognizes that 

vaccine-preventable diseases disproportionately affect older adults. With this in mind, 

on behalf of GSA’s NAVP, we look forward to joining with the ACIP as you continue to 

consider the need for strong vaccine recommendations that include the unique 

challenges of older adults and the need to protect them from preventable diseases 

through vaccines. Thank you. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Day 1: Public Comment 

No public comments were offered during this session. 

Typhoid Vaccines 

Brendan R. Jackson, MD, MPH 

Medical Epidemiologist 

Enteric Diseases Epidemiology Branch 

National Center for Emerging and Zoonotic Infectious Diseases 

Division of Foodborne, Waterborne, and Environmental Diseases 

Dr. Jackson indicated that the most recent ACIP recommendations for typhoid immunizations 

were issued about 20 years ago in 1994. Because some of the information in this document is 

now out of date, CDC proposes to update it with new information about typhoid epidemiology, 

vaccine safety, and vaccine availability. 

Because typhoid fever is uncommon in the US, Dr. Jackson provided some brief background 

information. The disease is caused by Salmonella enterica serotype Typhi. Contrary to most 

other Salmonella serotypes, humans are the only reservoir. Infection is usually acquired from 

food or water contaminated with human feces. The incubation period is relatively long, ranging 

from about 6 to 30 days. The disease usually has an insidious onset with gradually increasing 

fever, malaise, headache, and anorexia. Typhoid fever can be severe and deadly, particularly if 

untreated. For example, a US study from the 1940s reported a case fatality rate of over 10%. 

Life-threatening complications include septic shock and intestinal hemorrhage and perforation. 

The disease can now be treated with one of several antimicrobial agents, including the 

following: fluoroquinolone, beta-lactam, azithromycin, chloramphenicol, or trimethoprimsulfamethoxazole. However, antibiotic resistance is common and increasing in many parts of 

the world, placing greater importance on prevention tools like vaccines. 

Although typhoid fever is uncommon in the US, it remains a major problem on a global scale. In 

the US, about 400 cases are reported annually compared with an estimated worldwide burden 

of over 20 million cases per year. Of the US cases, 90% are associated with foreign travel and 

75% of these cases are associated with travel to South Asia. 

The following table shows the three typhoid fever vaccines included in the 1994 ACIP 

statement: 

Vaccine Vaccine Type Mode of 

Administration 

No. of Doses 

Ty21a vaccine Live, attenuated Oral 4 

Vi capsular polysaccharide vaccine Subunit Parenteral 1 

Heat-phenol-inactivated vaccine Inactivated whole-cell Parenteral 2 

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Dr. Schuchat reported that the International Health Regulations (IHR) and World Health 

Assembly (WHA) have updated guidance on polio vaccination given the state of the world’s 

polio eradication efforts. An MMWR was expected to be published soon to clarify what this 

means for Americans traveling or living abroad regarding their need to have documentation for a 

recent polio vaccination. The next National Immunization Conference will be held on 

September 29-30, 2014 at the Crowne Plaza Ravinia in Atlanta. This will be the first National 

Immunization Conference in three years. Between now and the next ACIP meeting, there will 

be several reports on immunization coverage that CDC hopes partners will promote and 

highlight. Teen immunization coverage will be reported In the July 25, 2014 MMWR, and HPV 

coverage will be reported in that same issue as a stand-alone report. Toddler coverage will be 

reported in an August MMWR, and kindergarten coverage and exemptions in a September 

MMWR. Given the key priority areas for the nation’s immunization in terms of modernizing the 

immunization information systems in light of changing health IT and addressing lagging HPV 

vaccine coverage in teens, a number of FOAs were due to be published over the next several 

weeks. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Currently, the oral Ty21a vaccine and the parenteral Vi capsular polysaccharide vaccine are still 

marketed in the US. The heat-phenol-inactivated vaccine, which was associated with high rates 

of fever and other systemic reactions, was discontinued in 2000. The two available vaccines 

have been estimated to have similar efficacy of about 50%, though individual reports range from 

45% to 80%. 

Because immunization offers only partial protection against typhoid fever, travelers and other 

persons at risk should follow recommended food and water practices. Additionally, these 

vaccines offer little or no protection against paratyphoid fever, which is an increasingly common 

disease that causes symptoms similar to typhoid fever. 

Regarding the choice of vaccine, the most recent ACIP recommendation states, “Either oral 

Ty21a or parenteral ViCPS is preferable” to the parenteral inactivated vaccine, because the now 

discontinued inactivated vaccine caused substantially more adverse reactions and was no more 

efficacious. Typhoid vaccine is indicated for travelers to endemic areas, household contacts of 

carriers, and laboratory workers who work frequently with Salmonella serotype Typhi cultures or 

specimens. Travelers and clinicians can now consult www.cdc.gov/travel to find the most 

updated recommendations for each country. As of 2011, CDC no longer recommends typhoid 

immunization for travelers to 26 countries, including Eastern Europe. 

In summary, CDC proposes no substantial changes to the existing typhoid recommendations. 

For this reason, there are no plans to convene a WG. However, ACIP will be asked to vote 

during a future meeting on the new ACIP document with updated information on typhoid fever 

epidemiology, vaccine safety studies, and vaccine availability. 

Agency Updates 

Centers for Disease Control and Prevention (CDC) 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Centers for Medicare and Medicaid Services (CMS) 

Ms. Hance reported that CMS has updated regulations to ensure consistency between 

immunization quality measures and regulations. 

Department of Defense (DoD) 

Dr. Geibe reported that there have been no known cases of Japanese encephalitis (JE) in the 

armed services in more than two decades, but the DoD continues to reinforce recommendations 

for use of the vaccine in high risk settings, the need for careful screening, and assessment of 

risk conditions. Additional implementation guidance should be coming out to educate the DoD 

community. The DoD is also working to inform its providers and beneficiaries about potential 

changes to polio immunization recommendations for certain countries. So far, there has been 

no problem with personnel in regard to this issue. With respect to adenovirus, live oral vaccine 

has been used since October 2011, which continues to be a very successful vaccine with 

probably over 100,000 lost training days saved and far fewer hospitalizations. Though there 

have been challenges, DoD also continues to work on the area of HPV vaccine. 

Department of Veterans Affairs (DVA) 

Dr. Kinsinger reported that DVA is continuing a number of information technology projects to 

update its electronic medical record (EMR) to ensure inter-operability with the DoD and with 

other agencies and providers. DVA participated in the Adult Immunization Summit in May and 

presented work that it is doing, in conjunction with the Indian Health Service, to determine the 

proportion of veterans receiving care within the Veterans Health Administration (VHA) who have 

received a set of recommended vaccinations, measured as a composite score. DVA is also 

working with a private retail pharmacy to record influenza immunizations in its EMR given at the 

pharmacy’s locations to veterans who receive care in VHA facilities. A pilot program done this 

past influenza season in Florida will be expanded to the entire VHA system. 

Health Resources and Services Administration (HRSA) 

Dr. Houston indicated that the Notice of Proposed Rulemaking to amend the Vaccine Injury 

Table to add intussusception as an adverse event associated with rotavirus vaccine in some 

circumstances was published in July 2013. The second public hearing was held on April 28, 

2014, and the Final Rule is in the process of being developed. On March 31, 2014, HRSA 

published a Notice of Proposed Rulemaking proposing a Pandemic Influenza Countermeasures 

Injury Table for certain covered countermeasures identified by the Secretary in several Public 

Readiness Emergency Preparedness Act Declarations. The public comment period ended in 

May, and the final rule is in the process of being developed. The Advisory Commission on 

Childhood Vaccines (ACCV) made several recommendations to amend the Vaccine Injury Table 

during several meetings. The last meeting was held on June 5, 2014. Those recommendations 

are being considered. Increasing numbers of petitions are being filed with the national Vaccine 

Injury Compensation Program (VICP) each year. In FY 2012, 400 petitions were filed. In FY 

2013, there were 501 petitions filed. It is projected that this year, 550 petitions will be filed with 

the program. 

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Dr. Gorman highlighted four NIAID programs and presented an update on one set of clinical 

trials. At a White House event on December 2, 2013, to mark the 25th annual World AIDS Day, 

President Obama announced that NIH plans to redirect AIDS research funds to expand support 

for research directed toward a cure of HIV. NIH plans to invest an additional $100 million over 

the next three fiscal years to this increasingly promising area of HIV/AIDS research. Dr. Fauci 

noted that at this meeting that “our growing understanding of the cellular hiding spaces or 

reservoirs of HIV the development of new strategies to minimize or deplete these reservoirs, 

and encouraging reports of a small number of patients who have little or no evidence of virus 

despite having halted antiretroviral therapy, all suggest that the time is ripe to pursue HIV cure 

research with vigor.” 

NIAID’s Concept Acceleration Program (CAP) is a team of individuals charged with identifying 

promising early findings and facilitating their translation into products suitable for advanced 

development. These individuals seek active engagement with entrepreneurs and scientists to 

nurture early programs and accelerate their progression to the clinic. These individuals offer 

strategic advice to help shepherd candidate products through the research and development 

process, including formulation and formation of product development teams with a broad base 

of experience. This team also can explain and facilitate access to NIH-provided core research 

services. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Indian Health Services (IHS) 

Ms. Groom shared information about the IHS’s adult immunization activities. The IHS electronic 

medical record system includes health reminders. Adult vaccine coverage is monitored on a 

quarterly basis. Tdap coverage for adults 19 years of age and older is 70%, zoster vaccine 

coverage for adults 60 and older is 39%, and pneumococcal polysaccharide vaccine coverage 

for adults 65 and older is 75%. This is attributed to the fact that reminders are in place. IHS is 

exploring implementation of a composite immunization measure as a performance measure. 

Rather than monitoring individual vaccines, consideration is being given to bundling ageappropriate vaccinations (Tdap, zoster, and pneumococcal polysaccharide) and implementing 

this across the agency this year. Also of interest to IHS is the concept of bundling vaccines with 

other preventive care measures (e.g., colorectal cancer screening, pap smears, et cetera) and 

bundling these measures as a preventive health measure. Along those lines, IHS is exploring 

conducting some FLU-FIT projects and is looking at an initiative Kaiser tried last year with FIT 

kits as a model. This involves bundling influenza vaccination with the provision of colorectal 

cancer screening FIT kits. 

National Institutes of Health (NIH) 

The NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) has recently 

been re-funded. CEIRS continues and expands the institute’s animal influenza surveillance 

program internationally and domestically, and focuses on several high priority areas in influenza 

research. The future direction of the CEIRS program includes continued surveillance research, 

determining mechanisms underlying transmission from animals to humans, and determining 

mechanisms for the duration of immunity. The CEIRS sites are as follows: 

Emory University 

Emory-UGA Center of Excellence for Influenza Research and Surveillance (CEIRS) 

Principal Investigator: Dr. Walter Orenstein 

Co-principal Investigator: Dr. Richard Compans 

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Dr. Orenstein reported that the NVAC last met on June 10-11, 2014. They heard presentations 

from ASTHO and AIM regarding challenges they were facing in supporting and improving upon 

the infrastructure for immunization programs. NVAC also heard about a potential $50 million cut 

in the President’s budget submission for FY 2015 compared to 2014 in the immunization 

funding line and passed a resolution asking for the rationale behind that budget cut, given the 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Icahn School of Medicine at Mount Sinai 

Center for Research on Influenza Pathogenesis (CRIP) 

Principal Investigator: Dr. Adolfo Garcia-Sastre 

Johns Hopkins University 

Principal Investigator: Dr. Richard Rothman 

Co-principal Investigator: Dr. Andrew Pekosz 

St. Jude Children’s Research Hospital 

St. Jude Center of Excellence for Influenza Research and Surveillance (CEIRS) 

Principal Investigator: Dr. Richard Webby 

Co-principal Investigator: Dr. Stacey Schultz-Cherry 

University of Rochester 

New York Influenza Center of Excellence (NYICE) 

Principal Investigator: Dr. John Treanor 

Co-principal Investigator: Dr. David Topham 

Despite the success of vaccine therapy, people do still become sick and are treated with 

antibiotics. Antimicrobial resistance is an increasingly troublesome problem that NIAID is 

addressing with the Antimicrobial Resistance Leadership Group (ARLG), which was launched in 

2013. The ARLG has developed a process for identifying the pressing clinical questions in 

antimicrobial resistance. The studies conducted by the ARLG may include clinical testing of 

new drugs to treat multi-drug resistant gram-negative bacteria, evaluating diagnostics devices in 

clinical settings, evaluating the effectiveness of new antibacterial stewardship programs, and 

optimizing treatment regimes to reduce the emergence of resistance. The ARLG is drawing on 

the creativity of the global research community by inviting concept submissions identify and 

address antimicrobial resistance priorities. At this time, the ARLG is conducting three studies, is 

in the start-up phase for six more, and is planning three more studies at this time. 

In response to the outbreak of H7N9 last year, NIAID conducted two clinical trials that enrolled 

healthy adults 19 through 60 years of age to evaluate an investigational H7N9 vaccine 

developed by Sanofi Pasteur. The candidate vaccine was made from inactivated H7N9 isolated 

in China. Two adjuvants, MF59 and AS03, are being tested with the investigational vaccine 

because previous research involving other H7 influenza viruses have suggested that two doses 

of vaccine without an adjuvant may not produce an immune response adequate to provide 

effective protection. In pandemic situations, adjuvants can be used as part of a dose-sparing 

strategy that will allow the production of more doses of vaccine from the available supply of viral 

antigen thereby allowing a greater number of people to be vaccinated more quickly. The two 

clinical trials have completed enrollment of approximately 1700 human volunteers. The data 

gathered from those trials is being analyzed and the manuscripts are being prepared. 

National Vaccine Advisory Committee (NVAC) 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

challenges being faced with infrastructure. NVAC has three major working groups: Maternal 

Immunization Working Group, Vaccine Confidence Working Group, and HPV Working Group. 

The Maternal Immunization Working Group initially focused on how to improve compliance with 

current ACIP recommendations. That report was finalized and focuses on recommendations in 

five main areas: 

1) Enhancing communication to address safety and effectiveness 

2) Maximizing obstetric provider recommendation and administration 

3) Focusing on efforts to improve financing for immunization services during pregnancy 

4) Supporting efforts to increase the use of electronic health records for immunization for 

obstetrical providers 

5) Overcoming issues with regard to vaccine liability laws that are barriers to vaccination of 

pregnant women 

The report includes a sentence that specifically states that the ACIP could consider developing 

a separate statement that consolidates all of the information for pregnant women into a single 

document, with updating as new information becomes available, to make it easier for obstetric 

providers to access all of the information in one resource. 

The HPV Working Group endorsed the report from the President’s Cancer Panel to improve 

immunization. NVAC will continue to monitor the status of implementation of the 

recommendations of that report. The HPV Working Group continues to work on addressing 

issues with regard to vaccine confidence or hesitancy. NVAC expects to receive a set of 

recommendations during its September 2014 meeting to be finalized. 

During the June 2014 meeting, NVAC also heard about the status vaccine innovation and 

research, specifically with regard to influenza. Over time, NVAC will deal more with the issue of 

incentivizing innovation and research to develop and improve vaccines. 

National Vaccine Program Office (NVPO) 

Dr. Gellin reported that NVPO supported the AHRQ to conduct a review of vaccine safety. Part 

of that report was scheduled to be published in Pediatrics the week following the June ACIP 

meeting, and other parts will be published online. NVPO hoped to have the IOM return to 

present an update on their SMART Vaccines tool (Strategic Multi-Attribute Ranking Tool for 

Vaccines). While IOM was unable to attend this ACIP meeting, hopefully they will be able to 

present during a future meeting. 

Discussion Points 

Dr. Fryhofer (AMA) reported that in November 2014, two reports of interest to ACIP will be 

presented to the AMA House of Delegates, one of which concerns immunization exemptions. 

This is a joint effort by AMA’s Council on Science and Public Health and Ethics Committee. The 

other is a joint council report on pharmacist administration of immunizations. Organizations with 

policies on these topics that they would like to share to be included in the discussion as these 

reports are written were invited to email Dr. Fryhofer or contact Barry Dickinson, the Secretary 

for the AMA Council on Science and Public Health. 

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The WG is still in the decision making process on these, with some having moved forward and 

others waiting to do so. ACIP will be updated during a future meeting on the WG’s deliberations 

related to a 3-dose schedule. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Plotkin (Vaccine Consultant) reported that he recently attended a meeting sponsored by NIH 

on the immunologic problems of vaccine development, such as waning immunity and how to 

address that problem. He expressed his hope that NIH would continue to fund additional 

research on this issue. The meeting addressed a large variety of problems, and was quite 

useful. Also, an article was recently published in Nature Immunology by Wayne Koff, Ian Gust 

from Australia, and Dr. Plotkin that discusses a human vaccines project focused on the 

immunologic problems of developing new vaccines. The idea is to create a project much like 

the genetics projects to advance vaccine research. 

Pneumococcal Conjugate Vaccine (PCV) Session 

Introduction 

Nancy M. Bennett, MD, MS 

Pneumococcal Vaccines Working Group Chair 

Advisory Committee on Immunization Practices 

Dr. Bennett introduced the pneumococcal conjugate vaccine (PCV) session, indicating that the 

primary focus of this session would be to review current data on efficacy, effectiveness, 

immunogenicity, and cost-effectiveness of pneumococcal vaccines. First, she offered a brief 

update on the work related to the 3-dose infant schedule. 

As a reminder, in February 2014 the WG presented a very laborious GRADE review, which 

essentially indicated that there were high quality evidence and Category A recommendations for 

both 3+0 and 2+1 versus no vaccine. However, there was limited evidence comparing 3-dose 

schedules to a 4-dose schedule. Although there is evidence from other countries using a 3­

dose schedule, it is not possible to compare the two schedules directly. Observance of direct 

effect and indirect impact of PCV13 continues in the US, which informs the WG’s deliberations 

about how to move forward. The WG has been working with AAP and AAFP. Some potential 

projects include the following: 

 Careful consideration of implementation issues and potential impact on non-adherence 

 Survey of pediatricians and family practitioners to understand issues around hesitancy and 

refusals as they relate to PCV13 

 Survey or focus groups of parents related to potential policy change 

 Define groups to be excluded from potential policy change 

Given the focus of this session on routine adult immunization with 13-valent pneumococcal 

conjugate vaccine (PCV13), Dr. Bennett offered a recap of the background regarding this issue. 

This vaccine was licensed for use in adults over the age of 50 in 2011. It was approved under 

an Accelerated Approval Pathway essentially based on non-inferior immunogenicity compared 

to PPSV23. The indications on the license included prevention of pneumonia and invasive 

disease in adults 50 years of age and older to prevent disease caused by Streptococcus 

pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. One condition of 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

approval was an RCT PCV13 against pneumococcal pneumonia among adults over the age of 

65. This trial, conducted in the Netherlands, is known as the Community-Acquired Pneumonia 

Immunization Trial in Adults >65 years old in the Netherlands (CAPiTA). 

The reason that the WG did not go forward with a recommendation in 2012 was two-fold. The 

GRADE review and immunogenicity results from the Phase III trials were presented to ACIP, 

and the cost-effectiveness and public health impact of different adult pneumococcal vaccination 

strategies were discussed at that time as well. The decision was made to defer a 

recommendation until more data were available, the most important of which were from 

CAPiTA. The second most important data regard the indirect effects of PCV13 use in children. 

The WG has been presenting those data to ACIP over the last couple of years. ACIP 

recommended a dose of PCV13 for adults with immunocompromising conditions in addition to 

PPSV23. Those recommendations have been in effect and vaccination is moving forward. 

Dr. Bennett concluded that the objective for this session was to review the information that was 

now available, and to present specific policy options for ACIP’s input. However, the committee 

would not be asked to vote during this meeting due to the many complications related to making 

a recommendation for this vaccine, including the impact of the indirect effects on the older 

population and implementation issues that must be addressed. 

PCV13 Efficacy Among Adults: Results of CAPiTA Study 

Dr. Rosalind Hollingsworth 

Global Medical Lead for Prevnar 13® 

Pfizer 

Dr. Hollingsworth emphasized that that pneumococcal pneumonia remains a significant public 

health problem for adults aged 65 years and older, as well as individuals younger than 65 years 

of age with underlying medical conditions that significantly increase their risk of pneumococcal 

disease. Given this unmet medical need, CAPiTA, one of the largest vaccine efficacy studies 

ever conducted in the adult population, had a key focus to demonstrate and confirm the efficacy 

of Prevnar 13® for the prevention of vaccine-type community-acquired pneumonia (CAP) in 

adults aged 65 years and older irrespective of whether that pneumonia was considered to be 

invasive or non-invasive. 

Indeed, the study met its primary and both secondary objectives, and with a safety profile that 

was consistent with that observed in previous studies of Prevnar 13® in the adult population. Dr. 

Hollingsworth presented an overview of CAPiTA, the regulatory foundation underpinning the 

rationale and the need for the CAPiTA study, an overview of the study design and results, and a 

short overview of the public health impact of Prevnar 13® serotypes of CAP among adults in the 

US. 

Despite current vaccination strategies in children and adults in the US, hospitalizations due to all 

cause pneumonia by 2009 in adults aged 65 years and older still remained in excess of 1200 

cases/100,000 population annually. It was this clear clinical need plus the uncertainty 

surrounding the effectiveness of pneumococcal polysaccharide vaccines for the prevention 

particularly of non-bacteremic CAP that supported the approval of Prevnar 13® for US adults 

aged 50 years and older via the FDA’s accelerated approval pathway. The key focus of 

CAPiTA was to confirm the efficacy under these regulations of Prevnar 13® to prevent a first 

episode of confirmed vaccine-type CAP in adults aged 65 years and older. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

CAPiTA was a double-blind, randomized, placebo-controlled trial conducted in the Netherlands 

that included 84,496 adults aged 65 years and older who were randomized between September 

2008 and January 2009 to receive a single dose of either Prevnar 13® or placebo. This study 

population was followed until a pre-specified number of vaccine-type CAP cases had accrued. 

This occurred in August 2013. 

Adults had to be 65 years and older at time of study entry, male or female, ambulatory, living in 

the community, and registered with a general practitioner (GP) who was referring subjects into 

the study. Subjects could not have received any prior pneumococcal vaccine, and they had to 

be considered immunocompetent at the time that they were vaccinated. The typical 

contraindications to immunization applied. However, subjects could have underlying medical 

conditions that are typically associated with an increased risk of pneumococcal infection (e.g., 

chronic disease of the lungs, heart, liver, and kidneys), concomitant conditions (diabetes 

mellitus), and/or a current or past history of smoking. 

The study included one primary efficacy objective and two secondary objectives. The primary 

objective was to demonstrate the efficacy of Prevnar 13® in the prevention of a first episode of 

vaccine-type CAP, including invasive and non-invasive cases. The secondary objectives were 

to confirm efficacy against a first-episode of vaccine-type non-bacteremic pneumonia (NBP), 

non-invasive pneumococcal CAP, or a first-episode of vaccine-type invasive pneumococcal 

disease (IPD) with or without pneumonia. 

Detection of vaccine serotypes within the CAPiTA study was improved through Pfizer’s 

development of a serotype-specific urinary antigen detection (SSUAD) assay. Before 

development of this assay, there was no effective or efficient way of detecting vaccine serotypes 

within cases of non-bacteremic, non-invasive pneumonia. To facilitate the successful 

conclusion of this study, a way to improve the identification of cases was needed. Simply, 

microspheres are coated with highly specific monoclonal antibodies that are able to bind to the 

vaccine serotype pneumococcal polysaccharides that are excreted in the urine of adults with Xray confirmed pneumonia. This assay has been fully validated, and the results of that validation 

have been published [Pride MW, et al. Clin. Vaccine Immunol. 2012; 19(8): 1131-1141]. This 

allows for the detection of any one of the Prevnar 13® serotypes with 97% sensitivity and 100% 

specificity among this patient population. 

There was a standardized approach for identifying study subjects presenting with a clinical 

suspicion of CAP at the emergency department (ED) of any of the 59 sentinel hospital sites 

located across the Netherlands that were responsible for capturing cases and suspected cases 

of CAP and invasive pneumococcal disease among the patient population. There was a good 

geographical spread of these locations to ensure capture of as many cases as possible. When 

study subjects presented at one of these senitnal sites, their diagnostic work-up included a 

chest X-ray, blood culture and urine sample for BinaxNOW® testing according to standard care 

practice, plus a protocol defined collection of urine for SSUAD testing. The definition of CAP 

was based on protocol defined clinical criteria, as well as X-ray findings that were consistent 

with pneumonia. This was adjudicated in every case by an independent adjudication committee 

who had to confirm that each X-ray, if it was truly a vaccine-type CAP case, was consistent with 

the appearance of CAP. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

To be counted as a case of confirmed vaccine-type pneumococcal CAP, the individual had to 

exhibit two or more pre-specified clinical findings that are consistent with CAP. Their chest Xray appearance also had to be consistent with CAP, and a culture was required of a vaccinetype CAP of pneumococcous from any sterile site and/or a positive result from and SSUAD test 

for one of the vaccine types. For the secondary endpoint of confirmed non-bacteremic, noninvasive vaccine type CAP, the investigators wanted to be truly certain that these were 

absolutely non-invasive cases of vaccine-type pneumococcal CAP. There had to be X-ray 

consistency, clinical signs and symptoms that were consistent with CAP, and identification of a 

vaccine type through the SSUAD. For this endpoint, all individuals had to have had blood taken 

for culture. The results of that culture had to be negative and if any other culture results were 

available for any other sterile sites, those also had to be negative. In terms of vaccine-type IPD, 

this simply required isolation of a vaccine-type pneumococcous from any normally sterile site, 

and included pneumonia and non-pneumonia cases. 

In terms of the baseline characteristics of the subject population at the time they presented for 

vaccination, the mean age was 72.8 years and was well-balanced between the two groups. 

Approximately 55% of the population was male and again was well-balanced. Other 

characteristics were also well-balanced between the two groups. At the time individuals 

presented for vaccination, they were asked about their medical history specifically for the 

underlying conditions of asthma, diabetes mellitus with insulin use, diabetes mellitus without 

insulin use, heart disease, liver disease, lung disease, and splenectomy. Approximately 40% of 

the immunocompetent subjects eligible for study inclusion had at least one co-morbidity that 

might be expected to increase their risk of pneumococcal disease. Overall, 12% of each study 

vaccine group were current smokers. In terms of how this compares with the US population, 

data from the National Health Interview Survey (NHIS), 37% of adults aged 65 years and older 

were considered immunocompetent and reported at least one chronic medical condition that 

would be considered to increase their risk of pneumococcal disease [Weycker et al. Vaccine 

2012. 30: 5437–44; National Health and Interview Survey. 2006 and 2011]. 

In terms of efficacy, as noted earlier, the study did meet the primary and both secondary 

endpoints. The results were highly statistically significant, with a confidence interval that was 

well above zero as pre-specified within the protocol. For the primary endpoint, there were 49 

confirmed first episodes of vaccine-type CAP among recipients of Prevnar 13® compared to 90 

in the placebo group for a point estimate of vaccine efficacy of 45.56%. For the secondary 

endpoint of non-bacteremic, non-invasive vaccine-type pneumococcal CAP, there were 33 

cases among the Prevnar 13® recipients compared to 60 cases among the placebo group for 

45% vaccine efficacy. As expected from the pediatric experience, there was higher vaccine 

efficacy for IPD compared to non-invasive disease, with a point estimate of vaccine efficacy of 

75%. 

A post-hoc analysis was conducted to stratify by age. It is important to note that this study was 

not powered to detect serotype specific vaccine efficacy. For those less than 75 years of age 

and those greater 75 to less than 85 years, the efficacy numbers were largely consistent with 

that observed in the overall study population for each endpoint. There were relatively small 

numbers of subjects for those aged 85 years and older of about 1500 subjects in each group. 

This accounted for only 3.5% of the overall study population. Thus, there were insufficient 

numbers in the oldest age group to be able to draw any conclusions about vaccine efficacy. 

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Another potential benefit based on conjugate vaccines’ mechanism of action is the durability of 

protection that one might expect, which was also assessed in an ad-hoc manner. The mean 

duration of follow-up of the study population was 3.97 years. These was a clear separation of 

the Prevnar 13® group from the placebo group, which was sustained throughout the duration of 

follow-up of the study, with no suggestion at the end of the follow-up period that efficacy may be 

beginning to wane. Also reassuring with regard to duration of protection were the results of the 

pre-specified interim analysis, to which the investigators did not have access until the date the 

study was completed and the data were unblinded. In September 2011, an interim analysis was 

conducted. Although at that time vaccine efficacy did not reach statistical significance, it was 

reported at 49%. This again supported the idea of durability of protection across the duration of 

the study. Results were similar for both secondary endpoints. 

 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

A post-hoc analysis was also conducted to assess serotype specific efficacy. Again, the study 

was not powered to look on an individual basis. However, this is of key interest. Despite the 

use of Prevnar® in the Netherlands from 2006 and the replacement of that vaccine with a 10­

valent pneumococcal conjugate vaccine in 2011 under a 3+1 schedule and a 95% vaccine 

uptake, for the primary endpoint, episodes due to all 13 vaccine serotypes were observed. For 

the first episode of vaccine-type CAP, the majority of events which contributed to the overall 

analysis were observed from serotypes 1, 3, 7F, and 19A. Of these, serotype 7F was the only 

serotype under this post-hoc analysis to demonstrate statistically significant efficacy of 

approximately 77%. A consistent finding was observed for both secondary endpoints as well. 

Regarding safety, within the study design there was an immunogenicity subset. While the 

immunogenicity data were not yet available, this study subset also reported local and systemic 

reactions through 7 days after vaccination via an e-diary. There were approximately 2000 

subjects in total in this subset. In terms of local reactions, as would be expected comparing 

Prevnar 13® to placebo, there was a statistically significant difference among individuals 

reporting any local reaction. However, reassuringly, there was no difference between the 

groups in the frequency or prevalence of reports of severe local reactions. This pattern of local 

reactions is entirely consistent with that observed in the regulatory trials that supported licensure 

of this product for adults. Similarly for systemic events, differences were observed between the 

Prevnar 13® and placebo groups in terms of the events reported in the 7-days following 

vaccination. Again, this is a very consistent profile with that which was observed in earlier 

studies of Prevnar 13® in the adult population. 

SAEs were reported for all study subjects through 28 days following vaccination. The two 

groups were well-balanced in terms of the number of reports of SAEs. Information on mortality 

was collected for all study subjects throughout the case accrual period. There were 3006 

deaths reported among individuals receiving Prevnar 13® versus 3005 in the placebo arm. 

None of these deaths or the SAEs were considered by the principal investigator to be related to 

the vaccine. In terms of deaths specifically due to all-cause CAP or IPD, among recipients of 

Prevnar 13® there were 62 deaths due to CAP of any cause versus 70 in the placebo group. 

For IPD, there were 4 cases among Prevnar 13® recipients versus 5 in the placebo group. 

With respect to how vaccine efficacy will translate into public health impact through use of this 

vaccine, a key component of the CAPiTA study was the development of the SSUAD. Although 

the SSUAD was developed for use in the CAPiTA study to help facilitate detection of vaccinetype CAP cases, it is now enjoying huge utility globally in terms of offering good epidemiological 

insight into the spectrum of the vaccine serotypes causing CAP among adults. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

A number of studies have now been conducted in North America and have been compared to 

the CAPiTA study to answer questions regarding serotype distribution and how much of CAP is 

due to the serotypes included in the vaccine primarily in settings where pediatric conjugate 

vaccines are used. Studies 4007 and 1147 were both Pfizer sponsored studies. Pfizer made 

the SSUAD available to CDC to enable testing of the urine samples collected from the EPIC 

study. Dr. Shelly McNeil and colleagues from Canada conducted a study using their PCIRN 

Serious Outcome Surveillance (SOS) Network Study. 

Studies 4007 and 1147 were conducted in the US to assess adults presenting to hospitals with 

X-ray confirmed CAP. Study 4007 was conducted between February 2010 and October 2011, 

which encompasses the time period when US infants made the switch from Prevnar® to Prevnar 

13®. Because of the exciting data observed from that study, Pfizer decided to resurrect that in 

the follow-on 1147 study. Study 1147 began in October 2013. An interim analysis was 

undertaken that included all cases of pneumonia that had accrued by January 2014. Based on 

the SSUAD assay, study 4007 reported a Prevnar 13® serotype prevalence rate of 11%; 

whereas, study 1147 conducted three to four years later reported a Prevnar 13® serotype 

prevalence rate of 13.6%. These studies were conducted well after the introduction of Prevnar® 

into the infant schedule in the US, and straddle the switch from Prevnar® to Prevnar 13®. Also 

interesting in both of these cases is that the original Prevnar 7® serotypes accounted for 25%, 

while the additional six serotypes accounted for the remaining 75%. Serotype prevalence rates 

in the EPIC study were about 9%, while Canada reported 16% prevalence rates. Within 

CAPiTA, the first episode for CAP was 14.2%. Based on SSUAD and/or culture results these 

contemporary studies suggest that the 13 serotypes in Prevnar 13® are responsible for 10% or 

more of CAP in North American adults. This information can be applied to rates of 

hospitalization in the US to estimate the burden of vaccine-serotype CAP. 

Referring back to the Griffin data published in the New England Journal of Medicine (NEJM) in 

2013, all cause pneumonia hospitalizations 10 years after introduction of 7-valent 

pneumococcal conjugate vaccine in the US pediatric population were still in excess of 1000 

case/100,000 in those over 65 years of age [Griffin MR, et al. N Engl J Med. 2013; 369: 155-16]. 

If a conservative 10% prevalence rate is applied to these numbers, hospitalizations due to 

Prevnar 13-type CAP range from 121 cases/100,000 among the youngest elderly to >400 

cases/100,000 in those aged 85 years and older. By applying US population statistics, exactly 

how many cases that translates to can be determined. Thus, in 2009 there were approximately 

29,000 hospitalizations due to the Prevnar 13® serotypes in CAP among those aged 65 to 74 

years; 31,000 in those aged 75 to 84; and 25,500 in those over 85 years of age. Adding those 

together represents approximately 86,500 hospitalizations due to Prevnar 13® type CAP in this 

age group. Crudely applying the vaccine efficacy numbers from CAPiTA, there are potentially 

about 40,000 hospitalizations each year in the US among those aged 65 years and older. 

In conclusion, pneumococcal pneumonia and vaccine-type pneumococcal pneumonia continue 

to place a significant burden on adults in the US aged 65 years and older, as well as younger 

adults with underlying medical conditions that increase their risk. CAPiTA was a significant 

study due to its size, its focus on the questions of interest pertaining to prevention of nonbacteremic pneumonia, and the technology that was developed to underpin and insure the 

success of this study. Prevnar 13® demonstrated clinically relevant efficacy within that study for 

the prevention of vaccine-type pneumococcal CAP, with a durability of protection of at least four 

years and with a safety profile that was consistent with that observed in previous studies of 

Prevnar 13® in adults. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Discussion Points 

Dr. Vazquez inquired as to whether subjects who were bacteremic or had a positive sterile site 

culture correlated with the urine positive or negative tests. 

Dr. Hollingsworth replied that because there was 97% sensitivity and 100% specificity within the 

validation study, there was good agreement between the blood culture results and the UAD 

results. The assay missed one case of serotype 3 and one case of 6A within the validation 

study, but it is always better to miss cases than to get false positives. Within CAPiTA itself, 

there were 29 bacteremic cases where that comparison could be made. Again, there was good 

correlation between the blood culture results and the serotypes in the urine. 

Dr. Vazquez asked whether the sensitivity and specificity within the CAPiTA study were similar 

to the pre-study. 

Dr. Hollingsworth responded that this has not been recalculated. The purpose of the validation 

study was to provide sensitivity and specificity. While this was not revalidated within the 

CAPiTA study itself, looking crudely at the numbers, the test performed as well in CAPiTA as it 

had done previously. 

Dr. Harrison wondered whether there was any evidence for vaccine serotype replacement, and 

about vaccine efficacy by underlying medical conditions. 

Dr. Hollingsworth indicated that they had vaccine serotype information for non-vaccine 

serotypes from the culture results. Small numbers of the other serotypes were identified 

through that route, so it is not really possible to determine from this study. Regarding underlying 

medical conditions, the investigators have not been able to assess efficacy by individual 

comorbid condition. One difficulty is that because most of the subjects within this study 

population are over 65, many had more than one underlying medical condition. 

Dr. Schuchat inquired as to whether vaccine efficacy was assessed against CAP with a 

negative urine result. 

Dr. Hollingsworth replied that Pfizer is conducting a considerable number of analyses, and that 

they had a raft of exploratory endpoints. All-cause pneumonia was assessed for a first episode 

of any pneumococcal CAP irrespective of whether it was a vaccine or non-vaccine serotype. 

Vaccine efficacy was 30% and reached statistical significance. Non-bacteremic, non-invasive 

pneumococcal CAP of any serotype was 24%, but did not reach statistical significance. First 

episodes of all-cause CAP had a 5% point estimate of efficacy, but did not reach statistical 

significance. 

Dr. Kempe requested that Dr. Hollingsworth comment on the SSUAD assay and carriage of 

pneumococcus. 

Dr. Hollingsworth indicated that the cutoffs were defined for the UAD assay, which is a positive 

or negative assay. The cutoffs for the UAD assay were determined for each individual serotype 

specifically. A group of 400 adult control urines were collected from individuals in the 

Netherlands and the US who were either considered completely healthy with no evidence of 

respiratory infection, or they were undergoing elective surgery with no evidence of respiratory 

infection, as well as from individuals with chronic obstructive pulmonary disease (COPD). It was 

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assumed within that control urine population that there would be about a 5% to 10% carriage 

rate within the healthy adults or those undergoing elective surgery, with potentially a higher 

carriage rate among those with COPD. Those urines were then run through the UAD assay and 

the signals that were generated were assessed. The cutoffs were set to be able to distinguish 

between the signals observed in healthy individuals versus those seen in individuals with X-ray 

confirmed pneumonia. 

Dr. Reingold inquired as to whether Dr. Hollingsworth could say something about the efficacy by 

age in the younger versus older people, recognizing that the study was not powered for this. He 

also noted that 10% is certainly an underestimate of the burden of disease because all 

outpatient pneumonias were not included; however, it is not an underestimate of the proportion 

of cases that are attributable to vaccine types. 

Dr. Hollingsworth indicated that age was assessed and that among those aged 75 years and 

under and between 75 and 85 years of age, the overall efficacy was consistent with the 

population overall. For the oldest age groups, there were very small numbers of subjects in 

totality and a relatively small number of cases, so conclusions really could not be drawn. 

Dr. Pickering noted that the previous day, there was a presentation on vaccine safety among 

children who receive combinations of vaccines versus vaccines singly. He wondered whether 

the CAPiTA study included a subset of people who received both PCV13 and influenza 

vaccines and, if so, whether there were differences in adverse events among them compared to 

individuals who received pneumococcal or influenza vaccine alone. 

Dr. Hollingsworth replied that at the beginning of the study, there was co-administration of 

Prevnar 13® with TIV, with approximately 30% of the study population receiving both vaccines 

together. However, those individuals could not be included in the immunogenicity subset, and 

that was the group in which local reactions and systemic events were measured. Unfortunately, 

they do not have that solicited information in terms of the adverse event reporting. She was not 

aware of whether the overall population had been assessed in terms of SAEs and whether there 

were any differences between those two groups. 

Dr. Schmader (AGS) inquired as to why nursing home residents were excluded, and whether 

there were any plans to conduct follow-up in that sizeable population that develops pneumonia 

at a rapid rate. 

Dr. Hollingsworth indicated that nursing homes were excluded because those were not 

considered to be true community-acquired pneumonia cases. Though there are no plans at 

present to conduct follow-up on that population, she said that they always welcome good ideas. 

Dr. Weber (SHEA) asked what percentage of the bacteremic diseases was caused by a vaccine 

serotype. 

Dr. Hollingsworth replied that she did not believe they had that information. The only serotype 

not seen in IPD was 23F. All other 12 serotypes were present within this study population. A 

similar observation was made for the primary endpoint in terms of 1, 3, 7, and 19A making the 

major contributions. 

Dr. Schuchat inquired as to whether the efficacy against CAP had been assessed in those who 

received both Prevnar 13® and influenza vaccines versus those who received only Prevnar 13®. 

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Ms. Pellegrini agreed with Dr. Reingold’s comment that it seemed surprising that such a small 

number of cases occurred in the oldest age group. She wondered whether that was because of 

the number recruited in the first place, and whether they were all in nursing homes. She also 

inquired as to whether there was something in the recruitment process or otherwise that 

resulted in the small numbers of subjects over 85 years of age. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

She pointed out that 30% of 85,000 people was larger than most studies that have been 

conducted against influenza. 

Dr. Hollingsworth responded that this had not been assessed. Given the small number of 

overall cases, and bearing in mind that only 30% of the study population received both vaccines 

together, it is not possible from the parent study to do this type of evaluation. The investigators 

were looking for a total number of cases overall of about 130. They ended up with 139, which 

was the major determinant. 

Dr. Hollingsworth replied that there were only about 1500 subjects in each vaccine group over 

85 years of age, and that the small numbers of subjects over 85 years of age probably just 

reflected the population demographics. 

Potential Public Health Impact and Cost-Effectiveness of PCV13 Use in Adults 

Dr. Charles Stoecker 

Tulane University 

School of Public Health and Tropical Medicine 

Dr. Stoecker reported that a cost-effectiveness model was used to assess either adding PCV for 

older adults or removing the risk-based recommendation for the pneumococcal polysaccharide 

vaccine (PPSV). For this study, the following items were evaluated: 

 Program cost/savings 

 Changes in disease, medical costs, and nonmedical costs 

 Societal perspective 

 Population 

 Adults age 50+ or age 65+ as appropriate for each strategy being analyzed 

 Immunocompromised persons were excluded, given that there is already a 

recommendation for this group 

The primary strategies assessed included the following: 

1.	 PCV13 at age 50, which exclude the risk-based recommendation for those aged 50 through 

64 

2.	 PCV13 at age 65 

3.	 PCV13 and PPSV23 at 50 

4.	 PCV13 and PPSV23 at 65, which preserves the risk-based recommendation 

5.	 Adding PCV13 at 50, which preserves the risk-based recommendation 

6.	 Adding PCV13 at 65, which preserves the risk-based recommendation 

7.	 Replacing PPSV23 at 65 with PCV13 at 65, which preserves the risk-based 

recommendation and replaces the polysaccharide dose at 65 with the conjugate dose at 65 

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Each of these seven strategies was compared to the current strategy, which is PPSV23 for high 

risk individuals aged 50 through 64 and PPSV23 for everyone at 65. The assessment tracked 

current 50 or 65 year olds through life expectancy, or until age 100. All assessed were current 

disease rates and herd impacts from the child immunization program ahead 6 years. All 

outcomes and costs were discounted by 3%, and all costs were expressed in 2013 dollars. 

A cohort model was utilized in which cost per quality adjusted life years (QALYs) gained and 

cost per life year gained were assessed. Two cohorts were used: 1) 50 year olds for strategies 

that changed vaccinations for 50 year olds, and 2) 65 year olds for strategies that did not 

deviate from current recommendations until age 65. Each recommendation was compared to 

the status quo, and the incremental cost-effectiveness ratio was calculated by dividing the 

changes in costs by the changes in QALYs. The health outcomes assessed included cases of 

IPD, cases of NBP, cases of outpatient NBP, deaths due to IPD, deaths due to NBP, QALYs, 

and life years. 

Regarding the inputs into the model, disease burden due to IPD was divided into two risk 

groups: healthy and high risk 50 through 64 years of age and healthy and high risk 65 years of 

age plus. The IPD rate was lower in those 50 through 64 years of age and higher in those 65 

years of age plus. The percent of cases resulting in fatality ranged from 6% to 15%. The 

distribution of IPD due to PCV13 serotypes ranged from 25% to 26%. The distribution of 

disease due to the serotypes in PCV23 that are not in PCV13 ranged from 38% to 48%, and for 

non-vaccine serotypes ranged from 25% to 40%. This was from 2013 ABCs data. 

Inputs for the NBP disease burden included the 1

inpatient NBP rate per 100,000; 2the percent of 

NBP cases resulting in fatality; 3

the outpatient NBP rate per 100,000; and 4the percent of 

PCV13 serotypes [1

Simonsen et al Lancet Respir Med 2014; 2Huang et al Vaccine 2011 

(National Inpatient Survey 2004 data); 3

Nelson et al Vaccine 2008; 4CAPiTA, EPIC study, Pfizer 

supported US study]. Vaccine effectiveness inputs included PCV vs VT IPD (75%) and PCV vs 

VT NBP (45%) from the CAPiTA study; PPSV vs VT IPD (74%) from Moberley [2008 Cochrane 

Review]; and PPSV vs VT NBP (0) from Fry et al. [2002 Vaccine]. 

Inputs for herd effects from PCV7 in children turned out to be very important in the model. 

Changes were included separately for 50 through 64 year olds and those 65+ for non-vaccine 

types, PCV7, and serotypes in PPSV23 not in PCV7. For 50 through 64 year olds, the percent 

changes increased 38.9% for non-vaccine types, decreased 78.6% for PCV7, and increased 

77.9% for serotypes in PPSV23 not in PCV7. For those 65+, the percent changes increased 

64.5% for non-vaccine types, decreased 86.6% for PCV7, and increased 17% for serotypes in 

PPSV23 not in PCV7. In the model, these changes were then projected forward on “PCV6” and 

“PPSV23 not in PCV13” types. 

Inputs for vaccine coverage rates included 20% for high risk 50 through 64 year olds from NHIS 

2012 (MMWR Feb 7, 2014); 37.1% for healthy 50 through 64 year olds adapted from office visit 

ratios (NHIS 2012); and 59.9% for those 65+ from NHIS 2012 (MMWR Feb 7, 2014). The 

coverage rate for healthy 50 through 64 year olds is found by averaging 1) the high risk 50 

through 64 coverage rate (20%) and 2) the ratio of the percent of 45 through 64 year olds who 

had seen a doctor in the last year (84%) to the percent of 65 through 75 year olds who had seen 

a doctor in the last year (92.5%) and multiplying that by the coverage rate for 65+ (59.9%). 

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Separate cost inputs were used for 50 through 64 year olds and those 65+ to represent different 

insurance statuses. The costs for PCV13 and PPSV23 vaccines were taken from the July 2013 

CDC price lists, while vaccine administration and travel time and costs were taken from 

Maciosek et al [2006 Am J Prev Med]. For PCV13 vaccine, $128 was used for 50 through 64 

year olds and $85 was used for those 65+. For PPSV23 vaccine, $63 was used for 50 through 

64 year olds and $23 was used for those 65+. For vaccine administration, $17 was used for 

both groups. For travel and time costs, $29 was used for both groups. 

Disease costs were taken from MarketScan (2010) as follows: 

Variable Base 

50-64, IPD $42,906 

50-64, IPT NBP $37,336 

50-64, OPT NBP $ 136 

65+, IPD $28,949 

65+, IPT NBP $24,888 

65+, OPT NBP $ 271 

Inputs for utility decrements came from Melagaro & Edmunds [2004 Vaccine]. A case of IPD 

will cost 0.008665 QALYs, 3.2 days of healthy life lost, and 21 days of implied average duration 

of illness. IPT NBP will cost 0.006 QALYs, 2.2 days of healthy life lost, and 15 days of implied 

average duration of illness. OPT NBP will cost 0.004 QALYs, 1.5 days of healthy life lost, and 

15 days of implied average duration of illness. The utility decrements turned out to be 

somewhat important, so alternate larger utility decrements were also used. Using the 

alternative decrements, a case of IPD will cost .075 QALYs, 27.2 days of healthy life lost, and 

181 days of implied average duration of illness [Sisk et al 2003 Ann Intern Med]. IPT NBP will 

cost .075 QALYs, 27.2 days of healthy life lost, and 181 days of implied average duration of 

illness [Smith et al 2012 JAMA]. OPT NBP will cost .050 QALYs, 18.1 days of healthy life lost, 

and 181 days of implied average duration of illness [taking the ratio of OPT to IPT in Melagaro 

and applying to Smith]. 

In terms of the waning profile for 50 year olds, the polysaccharide vaccine wanes to zero by 

about 15 years. The conjugate vaccine does not weight to zero. There is no waning until age 

65, and then at age 65 a 10% decline in efficacy is observed every five years. If vaccination is 

started at age 65, waning is the same except for the no waning between the ages of 50 to 65 

[PPSV duration adapted from Fry et al. Vaccine 2002; PCV duration adapted from CAPITA 

results]. 

Regarding the results, there were some dominated strategies that are generally the strategies 

that remove the risk-based polysaccharide recommendation. These included increases in IPD, 

decreases in NBP, and overall decrease in QALYs and Life Years, and increased cost. So, 

dominated strategies were worse for health and cost. Health improving strategies preserved the 

risk-based PPSV recommendation and resulted in increased QALYs, Life Years, and cost. The 

dominated strategies that remove the risk-based recommendations, which either decrease 

health or have very large increased cost include the following: 

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1. PCV13 at 50 

2. PCV13 at 65 

3. PCV13 and PPSV23 at 50 

4. PCV13 and PPSV23 at 65 

Instead, focus was placed on the health improving strategies, which include: 

5. Adding PCV13 at 50 

6. Adding PCV13 at 65 

7. Replacing PPSV23 at 65 with PCV13 at 65 

Adding PCV13 at 50 in this model decreased IPD cases by 227, adding it at 65 decreased 

cases by 226, and replacing PPSV23 at 65 with PCV13 at 65 increased cases by 1298. Each 

strategy decreased the number of NBP cases. The decrease here is smaller and is likely due to 

the lower coverage rates assumed for the age-based recommendations in the 50 year old age 

group. Approximately 5000 fewer cases of hospitalized NBP were observed with this strategy, 

and similarly for outpatient NBP. Declines in deaths were observed for IPD under the first two 

strategies, and an increase in deaths due to IPD in the third strategy. Declines in deaths due to 

NBP were observed for all three strategies. All three strategies resulted in an increase in 

QALYs. For the third strategy, the increase in IPD is more than outweighed by the decreases in 

NBP when QALYs are added up. Similarly, there were increases in Life Years due to each 

recommendation. 

Comparing the costs among the three strategies to the current strategy, adding PCV13 at age 

50 will increase total costs by $687 million in this model. The total costs are divided separately 

into medical costs, with declines observed in medical costs for each of the three strategies. The 

declines in medical costs reflect the lower amounts of disease due to increased vaccination. 

Increases were observed in vaccine total costs, which included travel and time costs as well. 

The total cost was then divided by the QALYs gain. Adding PCV13 at age 50 costs about 

$461,229 per QALY gained. Adding PCV14 at age 65 instead resulted in a much lower cost of 

$62,065 per QALY gained. Replacing PPSV23 at 65 with PCV13 at 65 resulted in a cost of 

$46,396 per QALY gained. 

Due to some uncertainties, sensitivity analyses were done. Due to lack of certainty about the 

QALY numbers used, the alternate source of higher QALYs was used. It is possible that the 

vaccine price could change with a large increase in PCV orders, so an analysis was run that 

assumed that PCV13 fell as low as the public price for PPSV223 at $23.31 in 2013 dollars. Also 

assessed was how herd effects from the childhood program might affect these strategies in six 

years, which was based on when the herd effects observed to date in the PCV7 program in 

children manifested to an equal amount in the additional types in PCV13. The sensitivity 

analysis focused on the two age 65 strategy changes. 

In terms of the sensitivity analyses for the strategy of adding PCV13 to the existing 

recommendations, the base case cost-effectiveness ratio was $62,000 per QALY. Using the 

higher decrements, a modest change was observed down to $54,000 per QALY. If the low 

price was used, assuming the price of the conjugate is as low as the polysaccharide, cost was 

$12,000 per QALY. When added together, a small change was observed. In 2019, after the 

herd effects from PCV13 use in children have been manifested in the six additional serotypes in 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

PCV13 by the same extent as herd effects have been seen in PCV7, there was an increase to 

$272,000 per QALY in the model. 

The same sensitivity analysis was done for the replacement strategy, which resulted in a base 

case cost of $46,000 per QALY in the base case and $36,000 per QALY for the higher QALY 

decrements. When the price was changed to be the lowest price seen for pneumococcal 

vaccines, this strategy would actually be cost saving. That is, health would improve and there 

would be less total costs—even after accounting for the cost of the vaccines themselves. Using 

the higher decrements, the results were cost saving. However, looking six years ahead to the 

2019 cohort, the results were dominated in this model. This means an increase in costs and 

decrease in health as measured either by QALY or Life Years. 

The following table puts these QALY decrements into context in terms of where they fit with 

other interventions: 

27

Context Cost / QALY of Selected Other Interventions

Intervention

2013 

Cost/QALY Source

Childhood HiB cost saving Zhou et al 2002 Pediatrics

AHCPR Smoking Cessation Guidelines $4,000 Cromwell et al 1997 JAMA

Sigmoidoscopy followed by 

colonoscopy if high-risk polyp 

diagnosed every 10 years $28,000 Frazier et al. 2000 JAMA

Herpes Zoster Vaccination at 60 $80,000 Ortega-Sanchez, 2013 ACIP Mammography Screening (biennially) 

for Women 50-74 years $87,000 Stout et al 2014 J Natl Cancer Inst Mammography Screening for Women 

40-49 $202,000

Salzmann et al 1997 Arch Intern Med

Lyme Disease vaccine with attack rate 

of 0.5% $255,000 Shadick et al 2001 Arch Intern Med

Value of a Statistical Life Year $492,000 Aldy and Viscusi 2006 ReStat

Pap Smears for Low Risk Women $1,779,000 Eddy 1990 Arch Intern Med

Limitations of this study include uncertainty surrounding QALYs, uncertainty surrounding 

vaccine waning, and projection forward of full PCV7 herd effects on PCV6 types. 

In summary, the cost per QALY is approximately $50,000 to $60,000 under base-case 

assumptions. PCV13 for adults is comparable to other interventions accepted as cost-effective 

when added at age 65 to the current PPSV23 schedule or replacing PPSV23 at age 65 years. 

Simplified strategies that consider only age-based recommendations, excluding the high risk 

polysaccharide recommendation, are generally dominated. Health benefits vary between 

PPSV23 and PCV. PCV13 strategies decrease NBP compared to PPSV23. There is more IPD 

when exchanging a PPSV23 dose for PCV13. After the herd effects from the child program are 

fully realized, PCV13 in adults is much less cost-effective. The estimates range from dominated 

to $270,000 per QALY. 

Discussion Points 

Dr. Temte inquired as to whether any synergistic effects were observed with respect to coadministration of the two vaccines. 

Dr. Stoecker replied that no synergistic effects were assumed. 

Dr. Gorman (NIH) asked whether the vaccine uptake rate factored into the model, and if any 

sensitivity analyses had been done based on coverage. 

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Dr. Stoecker indicated that for the high-risk group, a coverage rate of about 20% was assumed. 

That was for those included in the risk-based recommendation. For healthy 50 through 64 year 

olds, a prediction had to be made since there is not an analogous pneumococcal vaccine in this 

age group. A 37.1% uptake was assumed for that group, and approximately 60% was used for 

those aged 65+. In terms of the multivariate sensitivity analysis, the most important factors 

were herd immunity from the child program and the QALYs. 

Dr. Orenstein (NVAC) asked what the rationale was for why vaccine cost was different by age. 

Dr. Stoecker responded that an effort was made to account for different insurance status by 

age. Those aged 65+ are on public insurance, so the insurer will pay a lower price for vaccine 

than a private insurer. Private insurance generally faces a higher price for vaccine. 

Regarding the strategy that replaced the polysaccharide in those 65 years of age with the 

conjugate vaccine, Dr. Reingold wondered how sensitive that analysis was to assuming some 

efficacy against non-bacteremic pneumonia. Zero efficacy was assumed against nonbacteremic pneumonia, but whether there is efficacy is controversial. He wondered how 

sensitive those numbers were to assuming some level of efficacy against non-bacteremic 

pneumonia. 

Dr. Stoecker indicated that sensitivity analyses have been conducted on that. While he did not 

recall the exact sensitivity, he emphasized that the three main drivers of the cost-effectiveness 

ratios included herd immunity, QALYs, and waning. 

Dr. Kempe said she was trying to reconcile the information from Dr. Hollingsworth’s presentation 

with the herd immunity data in which there was a 10% rate of PCV13 related CAP in a fully 

mature program where there was 95% coverage, and whether Dr. Stoecker’s assumptions 

aligned with that. 

Dr. Stoecker indicated that for the cost-effectiveness model, a 10% CAP attributed to PCV13 

types was used as the base case. That is the current state of the world, and does not account 

for projected changes in herd immunity. To account for projected changes in herd immunity, it 

was assumed that the serotype distribution in NBP is the same as in IPD. The IPD changes 

from ABCs data were applied to what are thought to be the PCV6 types in the 10% of the CAP 

that is due to PCV13 types. The 10% was reduced to account for reduction in PCV6 types. 

Considerations for PCV13 Use Among Adults and Policy Options 

Dr. Tamara Pilishvili 

Respiratory Diseases Branch 

National Center for Immunization & Respiratory Diseases 

Dr. Pilishvili recapped the evidence presented to ACIP over the past couple of years to prepare 

for a discussion regarding age-based recommendations for PCV13 among adults. The policy 

question under consideration is: Should PCV13 be administered routinely to all adults 65 years 

of age or older? The rationale for focusing the key question on adults 65 years or older is that 

current ACIP universal recommendations target this age group, and the CAPiTA trial evaluating 

the efficacy of PCV13 against pneumococcal pneumonia currently ongoing in Netherlands 

targets this age group. The WG considered alternative strategies using both PCV13 and 

PPSV23 in sequence together, as well as the age-based strategies that begin at the age of 50 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

as presented by Dr. Stoecker. However, economic analyses showed that the strategies that 

start at the age of 65 are cost-effective and resulted in increased health benefits for all 

outcomes. 

In 2012, when PCV was licensed for use among adults, an extensive GRADE evaluation was 

conducted of the evidence. The WG concluded at that time that the evidence quality was low or 

Type 3, given that there were limited studies on efficacy against invasive disease. There was 

only one RCT in HIV+ adults conducted in Malawi. There were no data on efficacy against 

pneumonia. The WG concluded and ACIP agreed that there was uncertainty about the 

magnitude of expected health benefits and cost-effectiveness due to two key pieces of data 

missing at that time, including unknown efficacy against non-bacteremic pneumonia and 

uncertainty about the magnitude that PCV13 use in children will reduce the vaccine-preventable 

disease burden among adults. A decision was made to defer the age-based recommendation 

until these two pieces of critical data became available. 

Efficacy data are now available from CAPiTA. The results of which show that the vaccine is 

75% efficacious in preventing vaccine-type invasive disease and 45% efficacious in prevention 

non-bacteremic pneumonia in adults 65 years of age and older. Therefore, the WG wanted to 

estimate what impact might be expected among persons aged 65 and older in the US. The WG 

estimated how many persons aged 65 years and older would need to be vaccinated to prevent 

a single case of PCV13-type IPD or a single case of PCV13-type CAP. The most recent 

incidence data for IPD were used from ABCs for a baseline of 6.5 cases/100,000 of vaccinetype disease. Published sources of inpatient and outpatient data were used for incidence of 

CAP. The rates were obtained for all CAP and the 10% presented in an earlier presentation 

was applied as an estimate of the proportion of all-cause pneumonia that is caused by PCV13 

serotypes. Next, the vaccine efficacy estimates from CAPiTA were applied to estimate the 

number needed to vaccine (NNV). Over 20,000 adults 65 years of age and older need to be 

vaccinated to prevent a single case of IPD. Approximately 1600 inpatients and 1100 outpatients 

need to be vaccinated to prevent a single case of CAP. If the assumption is made that inpatient 

and outpatient cases are two independent events, it also can be estimated that 650 adults 65 

years of age and older need to be vaccinated to prevent a single case of CAP. 

The WG assessed the quality of the new evidence that was not included in the previous GRADE 

evaluation. For the critical outcome of IPD, evidence from CAPiTA was downgraded from Type 

1 to Type 2 due to indirectness. The trial was placebo-controlled so the comparison was no 

vaccine; whereas, in the GRADE evaluation and in the US the standard of care is 

polysaccharide vaccine. The study showed that PPSV efficacy against IPD, depending on the 

study, ranges from 50% to 80%. Therefore, it can be assumed that efficacy against invasive 

disease would be overestimated if comparing efficacy to polysaccharide vaccine instead of 

placebo. Nevertheless, it is still a moderate quality of evidence—Type 2. Based on the CAPiTA 

study results, the quality of evidence is Type 1 for pneumonia. 

The WG updated the quality of the overall evidence from the previous GRADE assessments, 

which included extensive review of immunogenicity studies because that was the bulk of 

evidence available. Immunogenicity data were used as a surrogate for clinical outcomes. 

However, evidence is now available for IPD and pneumonia. The overall quality of evidence 

was assessed based on critical outcomes only, so in this case those are IPD or pneumonia. 

The lowest quality of evidence of Type 2 contributes to the determination of the overall evidence 

type. The conclusion is that a moderate quality of evidence supports the use of PCV13 in 

adults. 

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The answers to 4 questions were considered to determine the recommendation category. The 

following table compares the conclusions reached pertaining to these questions in 2012 with the 

conclusions reached in 2014 once the CAPiTA results became available: 

GRADE Conclusions in 2014 vs. 2012

2012 2014 Comments

Is the evidence 

type/quality of evidence 

considered to be lower? 

Y N Data on efficacy against critical 

outcomes available

Is there uncertainty about 

the balance of benefits 

versus harms and 

burdens?

Y N

Y

Short-term: No uncertainty about 

the balance

Long-term: Indirect effects likely 

reduce net benefits

Is there high variability or 

uncertainty in relative 

importance assigned to 

outcomes? 

N N General consensus reached on 

which outcomes are critical to 

prevent

Is there uncertainty about 

whether the net benefits 

are worth the costs?

Y N

Y

Short-term: No uncertainty

Long-term: uncertainty about 

whether the net benefits are worth 

the costs due to continued herd 

effects

The evidence is now of higher quality at Type 2, which is a change from the 2012 assessment 

of the Type 3 quality of evidence. There is no uncertainty about the balance of benefits versus 

harms in the short-term; however, there is uncertainty about the magnitude of expected benefits 

in the long-term due to expected indirect effects. There is no uncertainty in the relative 

importance assigned to various health outcomes. There was no uncertainty about costeffectiveness in the short-term; however, in the long-term there is uncertainty about whether the 

net benefits are worth the costs due to continued herd effects. 

The WG updated ACIP on herd effects from pediatric PCV13 use continuously, leading up to 

this meeting. The most recent ABCs data show that indirect effects of PCV13 use in children on 

the IPD burden among adults 65 years of age and older continue to be observed. A significant 

reduction of 53% has been observed in overall IPD post-PCV13 introduction in children 

compared pre-PCV13 periods. These reductions are driven by PCV13 serotypes. Reductions 

have also continued to be observed in PCV7 serotypes. An additional 71% reduction in PCV7 

serotype disease was observed post-PCV13 compared to the pre-PCV13 period. 

In terms of indirect effects of pneumonia, the studies have documented reductions on nonbacteremic pneumonia following introduction of PCV7 in children. Several studies were 

conducted using administrative datasets to document the impact on all-cause pneumonia and 

non-bacteremic pneumonia. These data have been shared previously with ACIP. A recently 

conducted study also documented the indirect effects of PCV13 use on the non-bacteremic 

disease burden in adults. Using administrative dataset hospitalizations for pneumonia using 

International Classification of Diseases (ICD-9) codes, this study documented a 35% reduction 

in non-invasive pneumococcal or lobar pneumonia following introduction of PCV13 in children. 

Reductions were observed among other adult age groups as well [Simonsen et al Lancet Resp 

Med 2014]. 

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To summarize what is known about the indirect effects of PCV13 use among children, PCV7 

introduction led to near elimination of PCV7-type IPD among adults of all age groups. There is 

evidence of continued declines in PCV7-type IPD in adults due to herd effects. The indirect 

effects of the pediatric PCV13 program have further reduced the proportion of adult IPD and 

pneumonia caused by PCV13 types. Studies report reduction in non-bacteremic pneumonia in 

adults following PCV7 and PCV13 introduction in children. The key point is that the expected 

benefits of PCV13 use among adults will decline over time. 

Similar to what was presented in Dr. Hollingsworth’s presentation, but in a setting of herd effects 

rather than one snapshot of time and one year, the WG estimated the PCV13 type burden 

among adults 65 years of age and older. Extrapolating based on the PCV7 experience and the 

herd effect, the estimated number of cases was determined for 2015, which is the first year that 

PCV13 could potentially be introduced, and for 2019. Based on this, an estimated 2600 cases 

of IPD and nearly 140,000 cases of total CAP are observed in 2013 in the US due to PCV13 

serotypes. In 2015, a 20% reduction was applied due to herd effects based on the post-PCV7 

experience. The number of cases would be reduced slightly to 2000 for IPD and over 100,000 

cases of total CAP. In 2019, again using the projected herd effects based on the PCV7 

experience, an 86% reduction due to herd effects was applied. They number of cases of IPD 

would be greatly reduced to nearly 400 for IPD and close to 20,000 for total CAP. 

Next, the potential direct effects of PCV13 introduction in 2014 in the US were applied. The 

efficacy estimates from CAPiTA for IPD and non-bacteremic pneumonia were applied to the 

projected cases expected in 2015 based on herd effects, incorporating the 20% reduction in 

vaccine type disease. Consideration was also given to what would be a reasonable coverage 

estimate for PCV in the first year after vaccine introduction. The PPSV coverage experience 

was largely used for this. For 2015, a 10% coverage estimate was used and was ranged from 

5% to 30%. This suggested that approximately 160 IPD and 5000 total CAP cases would be 

preventable. For 2019, the disease burden was determined using the 80% reduction due to 

herd effects, and applying the direct effects from PCV13 use using a higher coverage rate of 

30% and ranging it from 20% to 60%. Again, the PPSV experience was used to determine this. 

The largest annual increment that has been observed historically for the polysaccharide vaccine 

has been 3.5%. However, between 2001 and 2008 a 1% increase has been observed on 

average. Using a more liberal approach of 3.5%, coverage from 2015 to 2019 would be 

expected to increase 25% to 30%. As an upper limit, coverage closer to current polysaccharide 

coverage was used. Even if coverage tripled from 2015 to 2019, the number of cases 

preventable would be almost half of the number of cases from 2013 at 80 cases of IPD and 

2600 cases of total CAP. Thus, herd effects alone are expected to reduce the disease burden 

and long-term limit the number of cases preventable through direct PCV use among adults. 

To summarize the presented evidence, a moderate quality of evidence (Type 2) supports the 

use of PCV13 among adults. PCV13 is safe for use among adults, and is efficacious in 

preventing IPD and non-bacteremic pneumonia among adults 65 years of age and older. The 

vaccine preventable disease burden remains among adults 65 years or older. Adding a dose of 

PCV13 to existing recommendations for PPSV23 is a cost-effective strategy and prevents 

illness among adults 65 years of age and older. However, herd effects will continue to reduce 

PCV13-type disease burden and limit the utility of PCV13 use among adults in the long-term. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

The two policy options under consideration by the WG are as follows: 

 Add a dose of PCV13 at age > 65 years to currently recommended PPSV23 regimen 

– PCV13 dose followed by a dose of PPSV23 at age > 65 years 

– Risk-based recommendations for PCV13 and PPSV23 use remain unchanged 

 Replace a dose of PPSV23 at age > 65 years with a dose of PCV13 

– PCV13 at age > 65 years 

– Risk-based recommendations for PCV13 and PPSV23 use remain unchanged 

The first option would add an extra layer of complexity to the recommendations, and potentially 

would impact the uptake of the new recommendations. The second option does not add an 

extra layer of complexity because it assumes replacing a dose of PPSV with PCV. However, 

based on the assumptions of efficacy against IPD and the serotype coverage provided by the 

polysaccharide vaccine, the second option may lead to additional IPD cases. For both of these 

options, discussions are ongoing because appropriate intervals in a sequence of PCV followed 

by PPSV should be defined, and recommendations and appropriate intervals must be 

determined for adults who have previously received polysaccharide vaccine and/or the 

conjugate vaccine, which is currently recommended for adults with immunocompromising 

conditions. As shown in Dr. Stoecker’s presentation, consideration was given to simplified 

strategies that include age-based recommendations with PCV and removing the PPSV, and 

keeping only age-based strategies and removing the risk-based strategies. However, all of the 

strategies that remove the polysaccharide vaccine have the potential to lead to additional cases 

of IPD even though some of the strategies were more cost-effective than others. Most of the 

age-based strategies were dominated; that is, they led to higher costs and worse health 

outcomes. 

In terms of the desirable characteristics of pneumococcal vaccine for universal use among 

adults 65 years of age and older, prevention of IPD and pneumonia is critical. Data are now 

available showing that PCV13 leads to 75% efficacy against IPD and 45% efficacy against nonbacteremic pneumonia. Adequate coverage of disease-causing serotypes is needed. It is 

known that at least in the short-term, the strategies under consideration for PCV would result in 

adequate coverage. There is still vaccine-preventable disease burden remaining, and adequate 

coverage by PCV of disease-causing serotypes would be provided. However, in the long-term, 

the herd effects may change that balance and result in a smaller fraction of vaccine-preventable 

disease burden remaining. Given the level of complexity of the current recommendation for 

PCV and PPSV use, the potential new age-based recommendation could provide an opportunity 

to simplify the recommendations. Thus far, the policy options under consideration do not allow 

for that simplification. Therefore, some of the WG members have concern with respect to 

implementation issues related to those policy options. It would be beneficial to have a costeffective option. At least short-term, some of the strategies are cost-effective. However, in a 

setting of fully realized herd effects, the same strategies are no longer cost-effective. 

To summarize the WG’s conclusions thus far, a recommendation for universal PCV13 use is 

warranted in the short-term. However, continued herd effects may limit the utility of a universal 

recommendation in the long-term. The policy options under consideration add complexity to the 

current PCV13/PPSV23 recommendations in terms of the appropriate sequence and intervals 

between PCV13 and PPSV23, and previous PCV13 and/or PPSV23 history. Policy language 

must be drafted to address concerns pertaining to the complexity of current pneumococcal 

recommendations, as well as the time-limited utility of universal PCV13 use. There is an 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

opportunity to prevent disease during the 2014-2015 respiratory season that is rapidly 

approaching. However, timely implementation may require a decision before the October 2014 

ACIP meeting. 

The Pneumococcal WG will continue refining the policy options, and requested input from ACIP 

on the following questions: 

 What concerns do you have about the proposed policy options? 

 How should the expected decline in the utility of the recommendation influence PCV13 

recommendations? 

 How feasible would it be to have a time-limited recommendation? 

Discussion Points 

Dr. Karron inquired as to whether there are any efficacy data on simultaneous or sequential 

administration of PPSV and PCV13, and in what order, that could be drawn upon. 

Dr. Pilishvili replied that there are no clinical efficacy data on sequential administration of PCV13 

and PPSV. The immunogenicity studies used for licensure of PCV13 for adults evaluated the 

sequence of PCV13 followed by PPSV, and the sequence of PCV13 alone among naïve adults 

and adults who previously received a polysaccharide vaccine at an interval of three to six years 

prior to enrollment in the study. Those data contributed to the recommendation for 

immunocompromised adults, and consideration was given to sequence. PCV13 given before 

PPSV seems to be the most optimal sequence. There are limited data validating what the 

optimal interval should be, so this was based on the evidence from the immunogenicity studies 

available that suggest that certain intervals are acceptable. The WG will have this discussion 

for immunocompetent adults going forward to deliberate what the appropriate intervals would 

be. 

Dr. Karron asked whether there are creative ways to monitor the decline in utility by assessing 

CAP and IPD in the 50 to 65 year age group, or in unimmunized individuals over 65 years of 

age. She wondered whether something could be proposed going forward other than a timelimited recommendation in order to have some data. 

Dr. Pilishvili thought these were good ideas. She pointed out that if an age-based 

recommendation for 65 and older was made, it would be very difficult to tease apart direct 

versus indirect effects in the future. For younger age groups, it might be easier since there is no 

age-based recommendation. But, there is a risk-based recommendation for 

immunocompromised adults, so there will still be a mixture of the direct and indirect effects. 

Noting the age 60 platform for zoster vaccine and the age 65 platform for PPSV23, Dr. Moore 

(AIM) was curious as to whether the WG or others had considered the option of a 

recommendation at age 60 for PCV13 and at age 65 for PPSV23, given the known advantage of 

receiving the PCV13 first. 

Dr. Pilishvili indicated that this exact strategy was not considered. The closest consideration to 

that was presented by Dr. Stoecker, which was the dose of PCV at age 50 and then at 65. 

Switching it to 50 could be explored. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Dr. Temte pointed out that in a very poor manner, clinicians attempt to provide zoster vaccine at 

age 60. There are natural points in time for vaccinating the elusive group of adult patients. 

Trying to get someone in for a PCV13 vaccine and follow it up with that in 8 weeks is very 

impractical in real life. But, having a platform as suggested would be worthwhile to consider. 

Given that indirect effects are so vital in all of the models, Dr. Byington (COID) wondered what 

could be predicted about indirect effects should the schedule for children change. 

Dr. Pilishvili pointed out that indirect effects were considered when evidence for reduced 

schedules for children was evaluated. The data available are from countries that have 

introduced reduced three-dose schedules from the beginning, and have observed a herd effect 

very similar to what the US data show. 

Dr. Schuchat recognized that there has been a lot of uncertainty about the next few years in 

terms of the herd effect, and that an attempt was made to apply the trajectory observed 

following implementation of the 7-valent vaccine in 2000 to predict what would happen after 

2010. When the 7-valent vaccine was introduced, increased coverage in young children took a 

while. However, when the 7-valent vaccine was replaced with the 13-valent vaccine, there was 

already pretty high coverage and the committee also recommended a fifth dose in older 

children. While catch-up was not perfect, many children under 5 years of age received 13­

valent protection pretty quickly compared to the first 5 to 7 years of the 7-valent era. Coverage 

with four doses is just now reaching 80%. 

Luis Jodar (Pfizer) emphasized that all of the studies conducted to measure the proportion of 

the 13 serotypes contributing to CAP were done in North America in a mature program. The 

proportion of the 7 serotypes included in the data presented was about 25%. This is 14 years 

after the introduction of PCV7, so he was not necessarily sure that what is being observed with 

IPD in the ABCs data could be extrapolated to what is being observed with CAP. This is 

important because there is persistent disease. He also cautioned about extrapolating the 6 

additional serotypes with what has been observed with the 7 serotypes. For instance, serotypes 

1 and 5 are covered for a very short time, so the impact from herd protection on those serotypes 

might not necessarily be extraporable to what is observed with the 7 serotypes. For serotype 3, 

for instance, there is some evidence of direct protection as seen with CAPiTA and the casecontrol that Merck presented during the previous meeting. This impact is not being observed in 

coverage. Complementary to Dr. Karron’s comments, there is a simple tool that can be used 

immediately for monitoring. The reason all of the models have used 10% is due to the ability to 

use the UAD tool measure the proportion of the 13 serotypes that contribute to CAP in the US. 

Continuous monitoring is being done in 10 sites. Pfizer offered the UAD assay to test this in the 

EPIC study, and can continue to monitor the proportion of the 13 serotypes and how that activity 

is reduced or not over time. From 2010 and 2011, 11% to 13.6% was observed, so it is 

important to be cautious. A reduction in CAP is being observed in ABCs, and UAD is a simple 

tool for monitoring over time. Pfizer will continue monitoring and will offer this assay to any 

investigator who would like to monitor as well. 

Dr. Pilishvili recalled that Dr. Hollingsworth mentioned that 25% of serotypes are due to PCV7 

serotypes for CAP, which she thought needed to be explained. It is 25% out of the 10% of all 

CAP that is due to PCV13 types, which translates to around 2% of all CAP that is due to those 7 

serotypes. IPD data were assessed in a similar fashion looking at the percent distribution of 

PCV7 types out of PCV13 types, and the picture is similar. It is not actually different for IPD 

versus CAP; however, the percent distribution does not offer a full picture of the dynamic state 

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We serve hundreds of thousands of seniors every day, providing nutrition and nutrition 

education. Our goal is to keep seniors independent. We’re in the nutrition and the prevention 

business. We’re here today to urge a broader use of pneumococcal vaccine in adults, 

especially older adults, and considering lowering the age of older adults to 60 to match the age 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

of serotype distribution and how disease rates are changing. PCV7 rates continue to decline 

through PCV13 even though the percent distribution has remained the same. The different herd 

effects observed depending on the serotypes in PCV13 were taken into account in all of the 

analyses during a snapshot of time post-PCV7, which was 2003 through 2009. This time period 

does not include the full post-PCV7 herd effects observed. After that period, a plateau was 

assumed for Dr. Stoecker’s analysis as well as the projected 2019 data that Dr. Pilishvili 

showed, which assumes that perhaps some remaining disease will persist. In other words, a 

conservative approach was taken to account for post-PCV13 herd effects. 

Dr. Paradiso (Paradiso Biologics Consulting) indicated that the observation is that about 3% of 

the community-acquired pneumonia is currently PCV7 types, which was observed in the study. 

The herd effect applied for 2019 assumes that there is an 86% reduction to 1.4% of the PCV13 

types. That assumes that the PCV13 types will be reduced in 6 years to below the PCV7 types 

14 years after introduction. He does not think that is occurring is really understood. CAP 

serotypes seem to be somewhat different, but it is important to be careful about the amount of 

indirect effect. He agreed with the committee comments that it will be somewhat difficult to 

dissect direct and indirect effects, but there are ways to do that since not all of the population, 

even over 65, are going to be vaccinated. 

Dr. Grabenstein (Merck) indicated that Merck is the producer of the 23-valent vaccine. He 

acknowledged the many hours of the work group and Dr. Stoecker, because this is not an easy 

task. However, he thought the situation was brighter than that model showed fundamentally 

because the 23-valent vaccine has a greater efficacy against non-bacteremic pneumonia than 

was shown of zero percent. The reference provided for this comes from three old, small studies 

that largely relied on sputum analysis or pneumolysin assays. One drew blood in only 6 of the 

200 cases. The urine antigen test did not exist then. It does now, so the assays that are 

available should be used for the 23-valent vaccine. The principle one to his mind is the 

Murayama study published in BMJ where 49 of the pneumonia cases were urine antigen 

positive. Only 3 of them were from blood culture diagnosis. This study’s 64% efficacy is in stark 

contrast to zero percent efficacy. The last time that was part of the sensitivity analysis, and 

should at least be that way this time. There’s also the Ochoa-Gondar observational study. 

Some of the slides shown looked at 13-type disease only as if that was all of the disease there 

is. However, there are 90 serotypes. The 23 non-13 serotypes now account for 30% to 40% of 

US adult IPD. Dr. Grabenstein said he was confident that ACIP would not leave American 

adults vulnerable to IPD and pneumonia from the 23 non-13 types, which the 23-valent vaccine 

can handle quite well. Therefore, he requested that the model be reassessed in terms of its 

assumptions. At least the cost per dose would have to be recalculated, because Medicare 

providers do not pay the CDC list price. He asked that the committee consider maximizing the 

number of serotypes that are targeted to protect American adults. 

Public Comment Period 

Robert Blancato 

Executive Director 

National Association of Nutrition and Aging Services Programs (NANASP) 

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Autoimmune diseases, according to NIH, affect up to 24 million Americans and that’s looking at 

26 of the more than 100 autoimmune diseases. Most autoimmune diseases, other than the 

endocrine ones like type 1 diabetes or thyroiditis, are treated with immunosuppressants. Those 

immunosuppressants include Prednisone, which has been a long stay treatment for multiple 

autoimmune diseases. In the last decade, the targeted immunosuppressants of biologics have 

also been added to that and have actually been very effective. But these therapies do suppress 

the immune system significantly. The autoimmune diseases are caused actually by 

dysregulation of the immune system, which has a hyper-response to yourself. The only 

treatment is to down-regulate that immune system for the disease. This makes the patient very 

vulnerable to infections and pneumonia particularly, which many are hospitalized as a result of 

that each year. Of the average person who would get an autoimmune disease, 75% are women 

and it usually occurs before the age of 50, so the childbearing years, so it’s a younger 

population. We would like to suggest that you increase the numbers of people vaccinated to 

protect these people, even though I understand the recommendation for immunocompromised 

people is there. But, when you look at even the percentage of older folks who are not 

vaccinated and then you consider the numbers, I mean really millions of young people with 

autoimmune disease, you will see the percentage of them that will not be vaccinated. So, the 

herd effect is very important for this population and lowering the age will increase the herd effect 

faster than 2019. Thank you. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

of eligibility in our programs, like the Older Americans Act (OAA), and to start raising awareness 

earlier. We know that pneumococcal kills 1 in every 4 to 5 people over 65 who contract it, or 

90% of the deaths that occur from complications of influenza and pneumonia. In 2012, CDC 

indicated that only 20% of adults at high risk for pneumonia had received the vaccine. It has 

consequences, including more than 600,000 annual hospitalizations and a direct cost of $14 

billion a year. Our association adopted a resolution at our 2014 annual meeting calling for 

greater public and private efforts to raise awareness about immunizations for older adults 60 

and older as a preventative health goal. Our program serves thousands of seniors, hundreds of 

thousands of seniors, every day. One case of flu at our centers can and does spread, and it 

could have been prevented. Let us and other national aging organizations work with this 

committee to increase awareness about immunizations for at-risk older adults. Thank you very 

much. 

Virginia T. Ladd, RT 

President and Executive Director 

American Autoimmune Related Diseases Association, Inc. (AARDA) 

Frankie Milley 

Founder/National Executive Director 

Meningitis Angels 

I’m the mother of an only child who died from meningococcal disease, and I’m also the Founder 

and National Director of Meningitis Angels. I usually don’t do this, but I made a few points 

because I didn’t want to forget anything. First of all, I want to thank the committee, the voting 

committee, the work groups, and everybody here who spends so many hours of their lives 

dedicated to making sure that we’re all protected against vaccine-preventable diseases. Many 

of us owe you our lives and the lives of the children and our family members. Again, I want to 

speak to the infant pneumococcal vaccine. Again, as the committee moves forward, I’m kind of 

disappointed that you guys didn’t just go ahead and vote and put this to bed. With that being 

said, as you move forward in still discussing this that you need to be reminded that in my world 

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of dealing with parents, which I deal with many every day on both sides of fence, some of them 

with their little space-cadet theories and that you guys all came from a space ship, but I just 

want you to know that I think we have several risks by deleting this dosage. The first one being 

that most parents, if you told them they need 4 doses of something, they may get 3. My fear is 

that if you say, “You need 3 doses of pneumococcal vaccine,” they’re only going to get 2 and 

we’re going to see a big problem resurface. Another one is that you need to be reminded, I’ve 

spent years of my life working, volunteering, and making sure that requirements and rules are 

made and passed state-to-state requiring daycare entry, and middle school entry, and college 

entry laws regarding meningitis. My fear is that—and a lot of these laws and rules actually spell 

out indication and dosage recommendations. If we go back and change the dosage 

recommendations, then we’re going to have to go back and adjust a lot of those rules and laws, 

and I’m going to tell you right now, we’re going to lose them. We’re going to lose those laws. 

We’re going to lose those rules, because the anti-vaccine movement is strong. It’s stronger 

than ever, and they’re going to be fighting us on every turn. I have spent 13 years of my life. 

Ryan’s 16th anniversary was Tuesday, okay, from his death. I have spent 13 or more of those 

years since his death fighting to make sure our kids are vaccinated. I’m afraid when you start 

talking about changing all of the rules, whether it’s HPV, pneumococcal, meningococcal, we risk 

losing the laws that we already have in place in the requirements. Thirdly, I think we send 

mixed messages when we start changing dosages after we know they’ve worked, and they’ve 

been proven to work, and we’re seeing declines in disease. I think we’re sending mixed 

messages to those parents out there who are resistant or anti-vaccine to say—okay, they’re 

going to start to get confused and they’re going to say, “See, they’re proving our point. We 

didn’t need all of these to begin with.” So, finally, as we say in Texas once more, “If it ain’t 

broke, don’t fix it.” Some of these just aren’t broke. You guys do a good job. I know at the end 

of the day when this is over with, you’re going to vote to keep it. I just know you will, because I 

think it’s the right thing to do. I want to say one last thing. Gregory, that was with me a few 

months ago in February with his parents, and his mother came up and spoke, Greg is in the 

hospital right now. He’s having surgery to try to stop the seizures again, and also some 

reconstructive surgery on some of his bones and hip. You know, our kids that fight 

meningococcal and pneumococcal disease, they don’t just come home from the hospital and it’s 

over with. They either die or they come home from the hospital and they face lives full of 

surgery, and torment, and torture, and ridicule, and hurt, and disappointment. Don’t start 

changing rules that you’ve already made and recommendations when they’re for the right thing, 

and that’s to save lives. Thanks again. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Open Discussion 

Dr. Temte requested that the committee take a few minutes to provide feedback for Dr. Bennett 

and the WG. He recapped some of the suggestions, including adding PCV13 at age 65 and 

sequencing that with PPSV23; replacing the PPSV23 with 13; assessing alternative ages, for 

example, age 60 in conjunction with current recommendations for zoster vaccine at that age. 

Dr. Schuchat said she was expecting the committee to discuss the idea of a vote before the 

October meeting and whether that should be planned for. Since this was a public meeting, she 

thought they should have this conversation. 

As a new member, Dr. Reingold requested clarity about the advantage of potentially convening 

a meeting and making a decision prior to October and whether that was to try and influence 

immunization in advance of this year’s influenza season. 

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Dr. Schuchat replied that if the committee deliberated on this and was ready to vote during the 

summer, clinicians and the public seeking vaccination this fall in conjunction with influenza 

vaccine would know what vaccine they ought to be seeking. Or, they at least would have heard 

ACIP’s formal position on this. A significant amount of vaccination occurs in September, 

October, and onward. 

Dr. Duchin noted that number of concerns expressed by pediatric colleagues about the short 

time interval between a new recommendation and the ability of providers to stock the 

recommended vaccine. He wondered how much of a concern would that be if ACIP were to 

make a recommendation in the late summer or early fall in an attempt to influence immunization 

practices that same fall. 

Dr. Schaffner (NFID) said that while he did not have an answer to the conundrum, he wanted to 

discuss the issue of the difficulty of translating the best epidemiologic science into practical 

recommendations. The current pneumococcal recommendations are the single most complex 

set of recommendations of any vaccine for any age group, and they are directed toward the 

least effective immunizers—healthcare providers. Anecdotally, local attempts to translate the 

immunocompromised recommendations for pneumococcal vaccines into practical effect have 

run into serious difficulty. Approaching this philosophically, seeking perfection is often the great 

enemy of the current good. As noted, adult providers do not respond rapidly to new 

recommendations. He suggested clarifying and simplifying the whole array of pneumococcal 

vaccine recommendations moving forward in an attempt to make them work most effectively for 

the most people. 

Ms. Pellegrini pointed out that in addition to the practical issues for providers, there are practical 

issues for insurance coverage. This has implications as well for the age selected. She 

requested clarification from the CMS representative regarding how quickly Medicare would 

cover a newly recommended age if it was 65 and older. 

Dr. Hance (CMS) responded that Medicare currently covers PCV13. The issue is that there is 

currently one vaccine administered under Medicare. Often, Medicare does not follow the ACIP 

recommendations. It is a statutory requirement that Medicare provide the one pneumococcal 

vaccine. There are issues, and CMS is working with CDC on these. 

Dr. Schuchat clarified that the polysaccharide and conjugate vaccines currently are included in 

Medicare Part B coverage. The issue is that one dose is permitted at age 65. For the Medicare 

population who are typically offered the pneumococcal vaccine, there would not be a delay in 

determining which one. 

Dr. Temte emphasized that the issue pertained to whether both vaccines would be covered if 

the recommendation were to administer PCV13 followed by a PPVS23. 

Dr. Hance (CMS) replied that this is being looked into. 

Regarding a vote before October, Dr. Campos-Outcalt thought that while an email could be 

distributed to the members for a vote, convening a teleconference with discussion would be 

preferable. 

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Dr. Pickering indicated that the Federal Advisory Committee Act (FACA) rules and regulations 

require that all ACIP meetings are open to the public and transparent, so it would not be 

permissible to have a vote by email. A teleconference must be published in the Federal 

Register 15 working days before the call, and an effort would be made to use other means of 

notification as well, such as through the ACIP website. The public would be permitted to call in 

to make comments just as is done in open, in-person meetings. FACA is an advisory committee 

that advises Dr. Frieden, CDC’s director. If Dr. Frieden wanted a meeting convened 

intermittently due to a public health emergency or public health need, that would be possible. 

Given that it did not seem that sufficient data have been distributed and digested to vote during 

this meeting, there would be a possibility of having a vote before the next meeting if considered 

necessary. 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Susan Silverman (Pfizer) indicated that in the event that the committee should decide to make a 

decision before October, vaccine would be available for physicians who do not already stock it. 

Pfizer has a number of adult physicians who already stock PCV13. Claims databases show that 

50% of all adult immunizations in the US occur between September and December. Dr. 

Schuchat was right in saying that if there is a possibility to have a discussion and vote before 

then, there would be an opportunity to address the majority of this year’s respiratory season. 

Dr. Schuchat said CDC appreciated how complex the information was, and did not expect the 

committee to vote during this meeting. However, the hope was that there would be enough 

input for the WG to continue to deliberate, and that a virtual meeting could be arranged following 

all FACA laws if the committee was ready for a vote before October. Regardless of how 

confusing it may be or how long it might take to achieve acceptable uptake, there will be a lot of 

CAP this winter. The vaccine is already licensed and covered by Medicare, so the question 

regarded whether consumers, clinicians, pharmacists, and public health know ACIP’s plans. 

Dr. Moore (AIM) pointed out that a recommendation for age 60 would shift some of the burden 

onto Affordable Care Act (ACA)-compliant private insurance programs. That would avoid many 

of the issues faced with Medicare. This would allow some of the age group to potentially take 

advantage of the vaccine with the zoster platform at age 60 when they are covered potentially 

by ACA-compliant insurance plans. 

Dr. Duchin expressed confusion about the Medicare coverage situation. While Drs. Schuchat 

and Hance indicated that the vaccine is covered, it seemed that if 13-valent vaccine is used, 23­

valent would not be covered. 

Dr. Hance (CMS) indicated that Medicare currently pays for both. The issue is that a person is 

eligible for one vaccine. Potentially, if someone received 13-valent vaccine, they would no 

longer be eligible for the 23-valent. There may be situations for which it is covered, which they 

are working on now. 

Dr. Duchin inquired as to the timeline for resolving this issue, given that knowing this would be 

important for the WG and ACIP. 

Dr. Hance (CMS) said that she was not in a position to give a timeline as they just began to 

explore the options, and emphasized that Medicare coverage is based on a statutory provision 

and statutory requirement. 

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Dr. Kempe thought this was crucial information to know before voting, given that there could be 

a shift from the 23-valent to the 13-valent, which was not a desirable alternative. 

Dr. Fryhofer (AMA/ACP) noted that while pneumococcal vaccination is very important and is 

lifesaving, as Dr. Schaffner also pointed out it is very confusing and dysfunctional to implement 

the appropriate vaccination program. Clarity is needed and this recommendation must be 

simplified as much as possible moving forward. However, if a recommendation is made for 65 

year olds and above, without Medicare coverage, they would be stuck before they began. This 

is not a $20 or $23 vaccine. She requested that the manufacturers indicate the price they are 

charging practitioners. Patients and physicians cannot “eat this.” It has to be covered, or this 

could be a big barrier. Time is of the essence. There is a great vaccination opportunity by 

combining this with influenza vaccine, but it is not going to be successful in the 65 and older age 

group if Medicare does not buy in and provide coverage for patients. 

Dr. Temte agreed that this is a very complicated issue, and that it would be difficult to reach a 

resolution during this meeting. He suggested devoting a 3- to 4-hour period in August to revisit 

the issues via a web or teleconference. There also needs to be a relatively formal GRADE 

presentation, parts of which have already been done, to inform the deliberations if a decision is 

going to be made. 

Dr. Bennett summarized that she was hearing that people were interested in moving the 

timeline on this decision forward if possible and, therefore, having an additional meeting. She 

thought the WG needed to reconvene quickly to consider some of the issues that were raised 

during this meeting about feasibility, implementation, and simplification of the schedule to 

determine whether they could come forward with a strong recommendation by August. 

Dr. Pickering emphasized that if a meeting were to be held, notification would be made via the 

Federal Register, the ACIP website, and through emails. CDC will do everything possible to 

ensure that the public is involved in this meeting. 

Dr. Reingold inquired as to whether they would also have to deal with the question of what is 

recommended about use of the conjugate vaccine in people who already received a dose of the 

polysaccharide vaccine. 

Dr. Bennett agreed that this is a problem and said she did not necessarily think there was a way 

to make this simple. Additional thought should be given to the possibility of simplification, but if 

there is no hope of simplification, then there is no point in holding back. 

Dr. Schuchat suggested that the WG consider a narrow vote that could be implemented quickly, 

while addressing much of this later. While clinicians would appreciate everything being done at 

once, other issues could be addressed at a later stage. 

Dr. Kempe agreed, but stressed that they need an answer about coverage because if this 

means one vaccine versus the other, that is a very different decision. 

Dr. Duchin endorsed this, and thought it would be counterproductive for people to be 

disqualified from receiving a vaccine they need because they have already received a 

complimentary vaccine. That is intimately tied to whether the Medicare issue will be resolved, 

and he did not see the point in moving forward without knowing this. 

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It was Ms. Pellegrini’s recollection that under the ACA requirement, private plans are not 

required to cover new vaccinations until the next year’s plan. That could be at the end of the 

next vaccination season or after that. 

Dr. Temte requested that Dr. Netoskie clarify, if a decision were made in August or October for 

someone under the age of 65, when would that be implemented under ACA for insurers. 

Dr. Netoskie (AHIP) said it was his understanding that coverage could be deferred until the next 

planned year. However, many plans do implement this upon the recommendation by ACIP, so 

it will be somewhat variable in the marketplace. 

Dr. Schuchat added that plans actually have until the next planned year coming up 12 months 

after publication in the MMWR, so it could be longer than 12 months after publication. That 

means it could be a couple of seasons. 

Dr. Bennett expressed appreciation for the input from the committee, and indicated that the WG 

would get back to them very soon. 

Dr. Temte concluded that the Secretariat would explore the possibility of a conference in 

August, as well as people’s availability. 

Measles Updates 

Global Update 

Mr. James L. Goodson 

Global Immunization Division 

Center for Global Health 

Centers for Disease Control and Prevention GID 

During this session, Mr. Goodson discussed the Global Vaccine Action Plan (GVAP), the 

Measles and Rubella Strategic Plan, measles and rubella targets that come from those two 

documents. He also discussed the Measles & Rubella Initiative vision and the global and 

regional progress toward measles elimination. 

The GVAP is the key global document that currently provides the vision statement and serves 

as the guide for global immunization efforts worldwide. The GVAP was developed by a group of 

global partners through the Decade of Vaccines Project, which was largely funded by the Bill 

and Melinda Gates Foundation. The GVAP document was published by the World Health 

Organization (WHO) and approved by the World Health Assembly in 2012. 

Another key document is the Global Measles and Rubella Strategic Plan, 2012-2020 developed 

by the Measles & Rubella Initiative. This initiative is a global partnership that was established in 

2001 by five core partners: American Red Cross (ARC), CDC, United Nations Foundation 

(UNF), UNICEF, and WHO. The strategic plan took over 15 months to develop, with extensive 

consultation and consensus building. It was signed off by the Heads of Agency of the five core 

partners. The targets in the strategic plan are aligned with those in the GVAP, and the strategic 

144 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

plan provides a common vision, which is to “Achieve and maintain a world without measles, 

rubella and congenital rubella syndrome.” 

At global level, there are three targets to be achieved by 2015. These include: 1) measlescontaining vaccination coverage (MCV1) of at least 90% at the national level and 80% in every 

district of the first dose; 2) reported incidence of measles of less than 5 cases/million population; 

and 3) measles mortality reduction of 95% compared with 2000 levels. The 2020 GVAP goal is 

measles and rubella elimination in five of the six WHO regions of the world. Since September 

2013 when the Southeast Asia Region adopted an elimination goal for measles, all six regions 

of the world now have a set date for measles elimination: 2000 American Region (AMRO); 

2012 Western Pacific Region (WPRO); 2015 European Region (EURO) and Eastern 

Mediterranean Region (EMRO); and 2020 African Region (AFRO) and Southeast Asian Region 

(SEARO). In addition, two of the six regions have established rubella elimination targets: 2010 

AMRO; and 2015 EURO. 

Regarding progress toward the global 2015 targets, this year marks the 40th anniversary of 

WHO EPI program, which was an offshoot of the smallpox eradication program. The EPI was 

established globally in 1974, so it is worth looking back at the impact of measles vaccination 

over time. Since 1980, MCV1 coverage has increased and a 94% reduction has been observed 

in reported measles cases globally from approximately 4 million cases in 1980 to little over 

200,000 in 2012. Since 1985, there has been an impressive 90% reduction in estimated 

measles deaths worldwide. Progress for this indicator has been monitored since 2000. From 

2000 to 2012, there was a 77% decrease in incidence, with a 78% decrease in deaths. 

Although short of the 2015 target of a 95% reduction, 13.8 million deaths have been averted 

through measles vaccination since 2000. 

There has been great public health success in measles and rubella elimination in the Region of 

the Americas. Both of those endemic viruses have been eliminated in the Western Hemisphere. 

Today, the Region of the Americas continues to be the model for achieving measles and rubella 

elimination around the world. The vaccination strategies of routine immunizations combined 

with mass vaccination campaigns successfully stopped endemic measles virus transmission in 

2002 and rubella in 2009. 

In terms of the secular trend in coverage with the first dose of measles-containing vaccine or 

MCV1, MCV1 coverage has leveled off at 84% for the past four years globally. Three regions 

still have MCV1 coverage of less than 90%: AFR, SEA, and EMR. So, there is still work to be 

done. The AMR, EUR, and WPR have sustained MCV1 above 90% for at least the past eight 

years. 

WHO recommends that all children receive two doses of measles vaccine. Global routine 

coverage of a second dose of measles-containing vaccination (MCV2) remains low at 56% in 

2012. This was primarily due to a number of countries that have yet to introduce a routine 

second dose of measles-containing vaccines. The number of countries with MCV2 is increasing 

each year, with an additional planned for 2014. Each year, additional countries will be 

introducing a second dose. It is important to recognize that the routine second dose in many of 

these countries can provide an important opportunity for EPI vaccinations to extend beyond the 

first year of life. This can establish an important child health platform. 

In addition to routine delivery of measles vaccinations, 33 countries implemented mass 

vaccination campaigns with measles vaccine or combined measles/rubella vaccine in 2013. 

145 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Through these campaigns, nearly 200 million children were vaccinated. Over three quarters of 

all campaigns provided other vaccines in addition to measles vaccine, which primarily included 

rubella and oral polio vaccine (OPV). 

In addition to vaccinations, another critical component of elimination strategies is the 

implementation of case-based surveillance. The Global Measles and Rubella Laboratory 

Network (LabNet) was fully established in 2000, and has grown from 80 laboratories in 2001 to 

over 700 labs currently. The CDC laboratory in the Division of Viral Diseases (DVD) serves as 

a global specialized measles and rubella laboratory within the LabNet. The network has 

established standardized testing procedures and maintains a strong quality assurance program, 

annual proficiency testing (PT), and laboratory accreditation of LabNet laboratories. The 

LabNet also has established global measles virus reference strains and nomenclature, which 

are updated periodically and are published in the MMWR. 

The global database for countries to submit virus genotypes and sequences allows for 

phylogenetic analyses to help track transmission of virus pathways. In terms of the global 

distribution of measles virus genotypes detected, during April 2013 through March 2014 of the 

24 known measles virus genotypes historically, eight were detected and some have clearly 

been eliminated. In 2014 the Western Pacific Region experienced an increase in cases that 

was largely due to an increase in reported cases in China and a very large outbreak in the 

Philippines. For the 12-month period from May 2013 to April 2014, a number of countries 

experienced a high measles burden, including the Philippines. The countries experiencing a 

burden of 50 or more measles cases/million population, well above the incidence target, are 

shown in red in the following map: 

! ! ! ! ! ! ! ! ! ! ! ! !

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Reported Measles Incidence Rate*, May 2013 to Apr 2014 

(12M period)

*Rate per 1'000'000 population

Data source: surveillance DEF file

Data in HQ as of 10 June 2014

No data reported 

to WHO HQ

<1 (83 countries or 43%)

≥1 - <5 (28 countries or 14%)

≥5 - <10 (11 countries or 6%)

≥10 - <50 (43 countries or 22%)

≥50 (14 countries or 7%)

(15 countries or 8%)

Not applicable

Prior to 2013, the Philippines experienced two large measles outbreaks in 2010 and 2011, each 

reporting over 6,000 cases. The current outbreak appears to have started in October 2013, and 

it is much larger than previous outbreaks. It peaked in January 2014, with over 8000 reported 

cases in that month alone. Findings from the outbreak investigation, to which CDC contributed 

along with the Ministry of Health and WHO, assessed data through 2014. Based on this 

assessment, there were over 26,000 suspected measles cases, including 6000 that were 

laboratory-confirmed, and over 100 reported measles deaths. Of the confirmed cases, 42% 

were in the Metro Manila area. The majority of cases overall were among children less than 5 

years of age who were unvaccinated or had an unknown vaccination status. 

146 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

In conclusion, Dr. Goodson highlighted the importance and great appreciation of the US support 

to local efforts. This support is critical, not only for reducing morbidity and mortality globally, but 

also for lowering importation pressure in the US and thereby helping to maintain elimination in 

the Region of the Americas. 

Domestic Measles Update 

Gregory S. Wallace, MD, MS, MPH 

Lead, Measles/Mumps/Rubella/Polio Team 

Epidemiology Branch, Division of Viral Diseases 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Wallace reported that the outbreak in the Philippines has imported virus into several other 

countries, including the US. While most of the importations have been genotype B3, another 

genotype (D9) is circulating in a different region of the Philippines that has also been imported 

into the US. It is important to remember that from year-to-year, importations are influenced not 

only by what is occurring in neighbouring countries, but also by travel patterns. The US tends to 

be less sensitive to travel patterns to what may be occurring in Africa, but is very sensitive to 

what is occurring in Europe. Europe has been a dominant importation site in recent years, but 

this year has been very low. Nearly half of US importations this year have been from the 

Philippines. 

In terms of the number of reported cases by month since the beginning of elimination in the US, 

for the period from 1997-2001, there was a range of cases over time that was relatively low. 

From the period right after the documentation of elimination, the range was even lower with no 

new cases after about June. In 2008, a couple of outbreaks attributed to a larger number of 

cases than observed in recent years. 2011 was influenced by a lot of transmission within 

Western Europe that led to more importations than usual. While 2012 was closer to a good or 

normal year, there were three independent outbreaks in 2013 that led to an increase in the 

relative number of cases. In 2014, increases began earlier than ever because the Philippines 

experienced an early outbreak and there were many US importations that led to outbreaks. 

One importation led to a very large outbreak that is still ongoing. 

To summarize 2014, 514 cases had been reported from 20 states including 16 outbreaks as of 

June 20th. There have been 48 importations, of which 23 were from the Philippines reflecting 

their epidemiology and travel patterns between our two countries. It is important to note that the 

vast majority of cases of importations are US residents who travel abroad, so there is an 

opportunity even with what is occurring globally to have an intervention. There has been a 

lower than usual number of reported hospitalizations of 56 cases (11%). Some of that may 

have to do with the characteristics of the community suffering the large outbreak this year. 

Amongst the cases in US residents (N=506), 81% were unvaccinated, 12% had an unknown 

vaccination status (78% of those were adults), and 7% were vaccinated (including 5% with 2 or 

more doses). Among the unvaccinated, 87% were personal belief exempters, 3% were 

unvaccinated travellers ages 6 months through 2 years, and 5% were too young to be 

vaccinated. 

The following table depicts the list of the US outbreaks of 20 or more linked cases since the 

documentation of elimination in the US: 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Measles Outbreaks with >20 Cases, 

United States, 2001-2014*

Year

Outbreak

Name

State

# of 

Cases

Import Status Genotype Setting

1st & last rash 

onsets

Duration Median Age

Age

Range

2014 Knox County OH 340* Imported 

(Philippines) D9 Community 3/22/2014 –

13 weeks 

and 

counting

23 y (early)

13 y (late) 2 wks – 52 y

2013 Brooklyn NYC 58 Imported (UK) D8

Household/

community

3/13/2013 –

6/9/2013 13 weeks

10 y (early)

19 mos (late) 0 mos – 32 y

2005

Tippecanoe

County

IN 34

Imported 

(Romania)

D4

Church/

household

5/16/2005 -

6/24/2005 6 weeks 12 y 9 mos - 49 y

2008

DuPage/Cook

County

IL 30

Importedvirus

D4 Homeschool

5/17/2008 -

7/3/2008 7 weeks 10 y 8 mos - 43 y

2014 Manhattan NYC 25 Imported-virus B3 Community

2/11/2014 –

3/24/2014 6 weeks 22 y 3 mos – 63 y

2013

Stokes/Orange

County

NC 23 Imported (India) D8 Community

4/5/2013 –

5/7/2013 5 weeks 14 y 12 mos -59 y

2014 KC Metro MO/KS 22* Imported-virus B3 Community 5/5/2014 –

7 weeks and 

counting

5 y 2 wks – 37 y

2013

Tarrant/Denton 

County

TX 21

Imported 

(Indonesia)

D9 Church

7/21/2013 –

8/21/2013 5 weeks 11 y 4 mos – 44 y

2011

Hennepin

County MN 21

Imported

(Kenya)

B3 Shelter

2/15/2011 -

4/24/2011 10 weeks 23 m 3 mos - 51 y

2008

Brooklyn/

Kings County

NYC 21

Imported

(Israel, Belgium)

D4 Community

2/17/2008 -

4/25/2008 10 weeks 15 m 5 mos - 11 y

*as of June 20, 2014

In terms of the features of the outbreaks, all have occurred in recent years, are larger than they 

were previously, and some begin in older age groups. It is not uncommon for an outbreak to 

begin in an older age group, but to impact younger age groups as households are exposed. 

Two outbreaks are currently ongoing, one in Ohio and another in Missouri and Kansas. In Ohio, 

the initial three cases had travelled to the Philippines to engage in relief work to help them 

rebuild following a hurricane. Then it reached US communities where the outbreak is 

predominately occurring in three counties that have very complex mixing patterns. CDC 

believes that transmission is beginning to slow down, but case ascertainment has been an 

issue. There has also been a significant amount of vaccination within the community. 

To put this into perspective, prior to vaccination, the US had approximately 3 to 4 million 

estimated cases annually and approximately 500,000 reported cases; 48,000 hospitalizations; 

4000 encephalitis cases; and 450 to 500 deaths. There was a quick drop in reported cases with 

vaccination programs. There were some challenges, many of which were attributable to onedose outbreaks in school aged children. That led to a second dose recommendation just as the 

resurgence was occurring in 1989 through 1991, which primarily affected inner city children who 

lacked access to vaccines. This helped lead to the VFC program. The combination of the 

second dose recommendation and the VFC program removing barriers to vaccine quickly 

resulted in a large decrease in cases, along with the ability to declare elimination. 

Prior to elimination, most US importations were from the Americas. In addition to our two-dose 

recommendation and the VFC program, the PAHO organization simultaneously committed to 

elimination. This significantly contributed to the reduction of importations into the US. Then 

importations came from other areas, and were influenced by the epidemiology and travel 

patterns. By the late 2000s, most cases were coming from Europe. This year, there was a shift 

to the WPRO region, which is dominated by the Philippines this year. There is less travel to 

China, but certainly what is occurring there is of concern. 

Coming out of the resurgence in 1993, though a multi-state outbreak occurred, there began to 

be evidence of a lack of endemic transmission and very quickly a low number of cases. This 

was followed by an observation that was more concerning. In 2008, there was not an increase 

in the number of importations, but there were a couple of outbreaks that led to an increase in 

the number of reported cases. In 2011, there was an increase in importations and one relatively 

large outbreak. There were still a number of importations in 2013, with three individual 

outbreaks contributing to that transmission. In 2014, the pattern was similar to 2013. However, 

the Ohio outbreak contributed the most. 

148 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Most importations lead to no transmission, or transmission to one person. Often, these are 

household transmissions. However, some transmissions lead to 10 or more cases. This year, 

the majority of US cases are only one or two cases of linked transmission. However, some do 

include 10 or more transmissions, which is more than observed in the past. Whenever there is 

an increase in the number of cases in the US, the incidence rates increase in the youngest 

children. The children are the most vulnerable to complications, and some of them are too 

young for vaccination. 

With regard to what is working in the US, national vaccine coverage remains high and the 

vaccine works. Public health departments continue to take a very aggressive stance in terms of 

every case and contact to interrupt transmission. If the first couple of cases had been identified 

in the Ohio outbreak, transmission would not be as high as it is now. There has also been 

improvement with the implementation of healthcare worker recommendations, and electronic 

health records for hospital staff to keep transmission from occurring in those settings. 

There are a number of challenges. Heterogeneity is one issue. Outbreaks reveal groups of a 

high enough proportions of people who do not get vaccinated who are accumulating and aging 

over time. What occurs globally certainly influences what occurs in the US, and importations 

are going to continue. Most importations are via US residents who could have been vaccinated 

before leaving the country. Early diagnosis of initial cases is still a challenge and has 

consequences. It is important to think about measles when thinking about other rash illnesses 

in travellers. The initial Philippine importations into Ohio were first suspected to be dengue, 

which often occurs. Children were also worked up for Kawasaki’s disease and who actually had 

measles. Implementing travel recommendations continues to pose challenges. The 

recommendation is for children to be vaccinated down to age 6 months before travelling, but 

there is still a lack of awareness. Adults who are now too old to have been recommended to 

receive two doses should be required to receive a second dose before traveling. This is a 

resource-intensive public health response. Every time there is a case, public health 

departments have to divert resources to try to stop transmission early, and there is also a 

concern of mission fatigue as this continues. 

The key messages are that measles in the US is a global issue, with most importations coming 

from US travellers. There is an opportunity to intervene with US travellers. Measles is very 

contagious, so when it is transported to the US, it is going to impact those who are 

unvaccinated. It is important to keep measles in the differential diagnosis of febrile rash 

illnesses. Obtaining travel history, exposure to travellers, vaccine history, and viral specimens 

is important. Measles outbreaks have revealed that a huge variety of groups do not get 

vaccinated in the US. Each year, a different group is identified who may not have been 

considered in the past. The intervention for these groups must be tailored for the reasons that 

they may or may not be getting vaccinated. 

Discussion Points 

Dr. Temte inquired as to whether there are any efforts with highly mature registries to map out 

pockets of high risk across the country in an effort to preempt potential outbreaks. 

Dr. Wallace responded that this is something CDC would like to do, and has made some 

attempt to implement such an effort. Some modeling work is being done to try to use those 

registries to assist health departments in understanding the potential consequences of what is 

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being observed in their registries. This could help them to leverage resources to try to 

intervene. 

Dr. Fryhofer (AMA/ACP) noted that the adult schedule states that adults born before 1957 are 

generally considered immune to measles and mumps. All adults born in 1957 or later should 

have documented one or more doses of MMR vaccine. She requested clarity regarding 

whether Dr. Wallace was saying that more should be done with even adults born before 1957 

before they travel. 

Dr. Wallace clarified that the 1957 recommendation still holds, and that those born after 1957 

and who have had only one dose should receive a second dose before traveling. 

Dr. Reingold thought the regional elimination goals were heartening, but noted that a close look 

suggests that at least two of the regions will not meet their current goals in terms of measles 

elimination. There is clearly more work to be done, and there is certainly an ongoing risk to 

travelers. Given the data shown, he was curious as to what is being done to ensure that US 

travelers are actually immune before they leave the US and return. 

Dr. Wallace replied that every opportunity is taken to reiterate the travel recommendations and 

reinforce that message. Even early in 2011 when an increase was observed in importations, 

many of the cases were in 6 through 15 month olds. Many times young families are bringing a 

child back from the country from which they immigrated, and that can be a source of 

importation. With the current situation, CDC is spending a lot of time conducting clinical 

provider- and physician-based webinars and discussions to keep this information before them. 

Dr. Schuchat added that since April, CDC has been ramping up the outreach related to risk in 

travelers. The travel health site on the web, as well as their partners, did a lot more. In addition 

to risk in the Philippines, CDC did a lot in advance of the World Cup. While this may or may not 

have reached all travelers, there was a lot of media and clinician outreach to try to get to those 

travelers and their clinicians. 

Dr. Wallace indicated that the Division of Quarantine and Migration (DQM) makes a lot of efforts 

related to travel alerts and educational efforts that appear at airports and so forth. 

Dr. Seward (SME) added that CDC also works with AAP to target young children ages 6 

through 11 months old and 12 through 15 months old, who are missed opportunities. However, 

many travelers are personal belief exempters. Many people who travel, including the two who 

came back from the Philippines into Ohio, had chosen not to be vaccinated after knowing the 

recommendations. CDC’s effort is to communicate as much as possible, and to try to deal with 

other issues. 

Dr. Hahn (CSTE) asked whether new pockets were being discovered. If so, it would be helpful 

to advertise this to states so that they can begin looking for these pockets to try to persuade at 

least some people to get vaccinated. 

Dr. Seward (SME) indicated that CDC convened a nationwide conference call with CSTE the 

previous week to alert people, especially with regard to the outbreak among the Amish 

population in Ohio. That is a very large group in many states. CDC is doing everything they 

can within that population, which is highly at risk. 

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Dr. Zahn (NACCHO) indicated that in Orange County where he works in California, there have 

been 22 cases of measles since the beginning of the year. Of those, 5 were in healthcare 

workers. By and large they are immunized, they received two doses of documented measles 

vaccine, and they have serology documenting that they are immune. The issue is that they are 

considered immune and go about working. They probably have some immunity and have 

somewhat attenuated disease, so for the first few days when they have a runny nose and 

cough, they continue to work and see patients. In terms of mission fatigue, it takes a lot of work 

for all of these responses. A healthcare worker in an emergency department may, in the four 

days before the appearance of a rash, see over 1000 patients in close contact. Those are 

extremely difficult responses. One of the major emphases that NACCHO has been trying to get 

out to healthcare providers is that they should get immunized, and if they have been immunized, 

that they still need to practice infection control precautions because they cannot be 100% sure 

that they are immune. 

Dr. Wallace added that this includes early recognition or at least suspicion so that the patient is 

isolated as soon as possible. It is not uncommon for a case to have been in a healthcare 

system for some time before they are recognized. 

Dr. Zahn (NACCHO) noted that some providers insist that they are immune because they 

received their two doses, so they may not wear their N95 mask in a negative pressure room as 

a result because they think it is annoying. 

Dr. Temte added that that is coupled with the fact that studies have shown that up to 70% plus 

of physicians present to work when they are sick and continue to work. 

Related to a healthcare worker taking care of children, Ms. Stinchfield (NAPNAP) surveyed all of 

the children’s hospitals across the country that are on their Infection Prevention Director’s 

listserv about the question of wearing masks. Some people do not wear them because they are 

counting on their immunity, some people wear surgical masks, and some people wear N95 

masks. Some states have very strict Occupational Safety and Health Administration (OSHA) 

laws, while others do not. This area would be helpful to clarify. 

Dr. Wallace indicated that those recommendations are in the surveillance manual. When he 

recently spoke with several health departments, he also got a variety of responses with respect 

to compliance. 

Dr. Seward (SME) added that those are the recommendations made by Healthcare Infection 

Control Practices Advisory Committee (HICPAC) and CDC for isolation guidance, and ACIP in 

the 2013 recommendations. A healthcare worker with evidence of immunity with two doses 

should be protected with an N95 or higher when entering a room. That message must be 

disseminated. 

Dr. Kempe inquired as to whether more aggressive means of decreasing under-vaccination 

could be undertaken, such as decreasing personal exemptions or other implementing policy 

regulations like publishing the percentage of unvaccinated children in preschools, schools, et 

cetera. 

Dr. Wallace reiterated the efforts being undertaken by PAHO in the Americas, the VFC program 

removing barriers, and the two-dose recommendation. Another important part of that was also 

school laws and having a second dose, school-based recommendation where people got 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

caught up before there was a lot of mixing. That was critical to what was done in the US, and 

what other nations have not been able to do because of their unwillingness to institute schoolbased laws. There has been a lot of battle back and forth every year in probably almost every 

state where the degree of ease to become a personal exempter goes back and forth. At least 

anecdotally, if the ability to opt out is made more strenuous, that helps and is definitely an area 

that is worth continued pursuit. 

Mr. Goodson added that there seems to have been some momentum change in vaccine 

acceptance in the last couple of years, which is a positive sign. It is important to better 

understand the groups who are philosophical exempters, because there is quite a continuum. 

In some communities where there has been low vaccine coverage, once an outbreak occurs, 

they have accepted vaccine. 

Dr. Pickering inquired as to whether the recommendations for traveling children down to 6 

months of age to receive vaccine, and for those 4 to 6 years of age to receive their second dose 

if they have not had it, are being implementing in the communities where there are outbreaks. 

Dr. Wallace replied that going down to 6 months of age has occurred in limited situations. This 

is a local decision, so if the epidemiology of the outbreak being experienced within the US 

indicates that, there are times when the first dose is administered early down to 6 months. In 

2011 in Minnesota with the distribution that was happening in homeless shelters, that did occur. 

There is no contraindication to administering the second dose before 4 to 6 months of age. 

Again, when the epidemiology has pointed in that direction, it has been done. Sometimes it is a 

question of resources. The first prioritization is always to administer one dose in those who 

have had no doses. Certainly, getting the second dose early before 4 to 6 is completely 

acceptable even when there is not an outbreak. Going down to 6 months is reserved for when 

the epidemiology demands it. 

Mr. Goodson added that globally, the WHO recommends that for a measles response, 

vaccination should begin at 6 months of age. The challenge is that the early doses should not 

count toward the two doses that all children need. Families need to be reminded when they 

receive a dose during an outbreak response that the child still needs to receive their two 

regularly scheduled doses. The reason for that is that vaccine effectiveness at 6 months of age 

is reduced down to 50% to 60%, so even though they are vaccinated, a large number of them 

may not be protected. 

Meningococcal Vaccines 

Introduction 

Lorry Rubin, MD 

Chair, Meningococcal Work Group 

Advisory Committee on Immunization Practices 

Dr. Rubin indicated that this session would focus primarily on outbreaks of meningococcal 

disease and the potential use of serogroup B vaccines. At present, a meningococcal B vaccine 

(MenB) has not been licensed in the US. However, two investigational MenB vaccines are 

under development. Both vaccines have received a “Breakthrough Therapy” designation from 

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An ad hoc WG was developed that is comprised of ACIP Meningococcal Work Group members, 

ACIP members, state public health officials, college health professionals, and CDC. This WG’s 

first meeting was convened January 30, 2014 with biweekly meetings. This WG has three 

objectives, which are to: 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

the FDA. Pfizer Vaccines has submitted a complete Biologic License Application (BLA) to the 

FDA, and Novartis Vaccines has submitted a rolling BLA to the FDA. The Novartis vaccine is 

licensed in Europe, Australia, and Canada. 

In 2013, two universities experienced outbreaks of serogroup B meningococcal disease, with a 

combined 13 cases and one death reported. MenB vaccination campaigns were conducted at 

both universities in response to the outbreaks using an investigational MenB vaccine from 

Novartis Vaccines that was obtained through an expanded access Investigational New Drug 

(IND) application sponsored by CDC. 

 Review available data on the recent epidemiology of meningococcal disease and outbreaks 

 Develop guidance for use of MenB vaccines under a CDC-sponsored IND in an outbreak 

setting 

 Update the current meningococcal outbreak guidelines once MenB vaccines are licensed in 

the US 

Regarding additional Meningococcal WG activities, a Policy Note on the use of Menveo® in 

infants at increased risk for meningococcal disease was published on June 20, 2014. This 

publication summarizes the use of three meningococcal conjugate vaccines in children aged 2 

through 23 months at increased risk. The WG is also discussing the approach to 

recommendations for use of serogroup B vaccines once they are licensed. 

Epidemiology of Meningococcal Disease Outbreaks in the US 

Sarah Meyer, MD, MPH 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

In this presentation, Dr. Meyer reviewed the epidemiology of meningococcal disease in the US, 

outbreaks of meningococcal disease, and results of the recent evaluation of clusters and 

outbreaks in organizational settings. 

Since the early 2000s, rates of meningococcal disease due to all serogroups, including 

serogroup B, have declined to historic lows in the US. In addition, vaccination coverage of the 

adolescent MenACWY vaccine has increased in recent years since introduction in 2005. With 

this high vaccination coverage, serogroup B is now the predominant cause of meningococcal 

disease in the adolescent age group, as opposed to prior to vaccine introduction when 

serogroups C and Y were the most commonly reported. 

Despite the higher rates of serogroup B disease in adolescents, it is important to note that the 

overall burden of disease is very low, with an average of 29 cases reported annually from 2010­

2012 in 11 through 24 year olds. Outbreaks of meningococcal disease are rare in the US, 

historically causing only 2% to 3% of US cases. Reports of school- and organization-based 

clusters or outbreaks are uncommon in the published peer-review literature. From 1989-2004, 

during the pre-MenACWY vaccine era, 22 school-based outbreaks were reported in the US. Of 

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these, 7 were serogroup B outbreaks and 14 were serogroup C outbreaks. The majority of 

these outbreaks consisted of 2 or 3 cases. Little difference was seen between serogroup B and 

C outbreaks in terms of duration of the outbreak and interval between reported cases, with a 

median of 3 days between cases for serogroup B and 2 days for serogroup C. 

Since 2009, 5 universities have reported serogroup B clusters or outbreaks, with 2 to 13 cases 

reported in each. With these most recent university outbreaks factored in, as well as a 

serogroup C outbreak in an elementary school in 2010, the size of outbreaks appears larger, 

with more outbreaks reporting greater numbers of cases. In addition, the median interval 

between cases is increased, creating a more indolent pattern for serogroup B outbreaks. 

However, it is unclear if these differences are real or if the differences are related to increased 

recognition of cluster-associated cases in the setting of historically low disease rates. 

In summary, serogroup C meningococcal outbreaks are less frequently reported since high 

adolescent coverage with the MenACWY vaccine has been achieved in the US. The 3 most 

recent university-based serogroup B outbreaks were atypical compared to previous outbreaks, 

with a greater number of cases reported and longer intervals between cases. 

In light of these recent serogroup B outbreaks, an evaluation was conducted to understand the 

current epidemiology of meningococcal clusters and outbreaks in the US. Prior to revising 

guidance for use of meningococcal vaccines in an outbreak setting, including use of an 

unlicensed serogroup B vaccine under a CDC-sponsored IND, it is important to understand the 

full breadth of epidemiologic features of meningococcal clusters. This includes identifying 

previously unreported clusters and understanding whether the recent serogroup B university 

outbreaks are representative of the current epidemiology of meningococcal disease outbreaks. 

Although information on outbreak-associated cases is collected through the National Notifiable 

Diseases Surveillance System (NNDSS), reporting is likely incomplete. Complete and 

systematically collected data on clusters and outbreaks of meningococcal disease occurring in 

the US is important when evaluating outbreak guidelines. Thus, a retrospective review of 

meningococcal cases reported since January 1, 2009 was conducted by state health 

departments and CDC to identify clusters of meningococcal disease. An Epi-X announcement 

with a call for cases and clusters was published on January 24, 2014, followed by a standard 

questionnaire administered to each state. 

For the purposes of this evaluation, a meningococcal cluster is defined as follows: 

2 or more cases of the same serogroup in an organization in ≤ 3 months (not including 

secondary cases) OR 

An increase in disease rates of the same serogroup in a community or a specific population 

in a community (rate 2 times the rate during the same time period in prior years). 

A meningococcal outbreak is defined as: 

 3 or more primary cases of the same serogroup in ≤ 3 months 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Clusters and outbreaks are classified as: 

 Organization-based OR 

 Community-based 

From January 1, 2009 to December 31, 2013, 3,745 cases of meningococcal disease were 

reported in the US through NNDSS. Eighteen states reported 71 clusters or outbreaks through 

the Epi-X announcement. Fifty-two clusters met the cluster definition with 207 cases, 

comprising 5.5% of all US cases. Among these, 22 clusters also met the outbreak definition 

with 146 cases or 3.9% of all US cases. All subsequent analyses represent primary cases from 

clusters meeting the cluster definition. 

From 2009-2013, cluster-associated cases occurred throughout the year in each of the years of 

the evaluation. The distribution of clusters has been widespread, and the number of clusters 

per year has ranged from 6 to 17. The majority of clusters in the US are community-based 

clusters, with 37 reported from 2009-2013. Also reported were 14 organization-based clusters 

and 1 unknown cluster. 

Given the need to develop interim guidance for the use of unlicensed serogroup B vaccines 

under a CDC-sponsored IND in organizational settings, Dr. Meyer focused the rest of the 

presentation on results from organization-based clusters. 

In terms of serogroup distribution, approximately 60% of organization-based clusters are due to 

serogroup B, compared to approximately 35% of sporadic cases. The median population size 

of the cluster is over 14,000 persons. The median number of cases per cluster is 3. The 

median duration of the cluster is 48.5 days. The median age of cases in organization-based 

clusters is 19 years, compared to 35 years among sporadic cases reported to NNDSS. The 

case-fatality ratio in organization based-clusters is 17%. 

Among the 14 organization-based clusters reported, 7 occurred in universities. The other 

organizations reported included a fraternity party associated with a university parents weekend 

in which parents of the students became ill, a long-term care facility, a correctional facility, a 

meditation center, a homeless shelter, an elementary school, and a hockey league affiliated with 

a university. Among the 7 non-university-based clusters, 2 were due to serogroup B. The 

number of cases per cluster ranged from 2 to 8 and the duration of the cluster from 2 to 245 

days. Among the 7 university-based clusters, 5 were due to serogroup B. The number of cases 

per cluster ranged from 2 to 10. The median number of days between cases ranged from 3 to 

75 days, for a total duration of the cluster of 25 to 616 days. The overall case-fatality ratio in 

organization-based clusters was 17%, but differed by serogroup. Serogroup B clusters had a 

case-fatality ratio of 6.1%. In serogroup C clusters, the case-fatality ratio was 42.9%. 

In the setting of historically low cases of meningococcal disease, meningococcal clusters 

account for a greater proportion of cases than in years past, and are likely recognized and 

reported more readily. A substantial proportion of organization-based clusters are associated 

with universities and are due to serogroup B. The three recent serogroup B university-based 

clusters have appeared atypical compared to clusters in years past in terms of number of case 

and duration. However, the course of a cluster is unpredictable, and it is difficult to determine if 

and when additional cases will occur. 

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During this presentation, Ms. MacNeil reviewed interim guidance that has been developed for 

the use of the serogroup B meningococcal vaccine under CDC’s sponsored expanded access 

IND application. 

 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

The comparison of current meningococcal cluster or outbreak epidemiology to historical data 

has limitations. Over time, there have been changes in the definitions, recognition, and 

reporting of meningococcal clusters. In addition, advances in molecular genotyping may alter 

the interpretation of which cases are associated with a particular cluster. Regardless, 

meningococcal disease clusters and outbreaks cause substantial concern necessitating a public 

health response. 

In conclusion, serogroup B organization-based clusters are rare and heterogeneous, limiting the 

ability to make definitive interim vaccination recommendations based on data alone. Interim 

guidelines for use of serogroup B vaccines under a CDC-sponsored IND should provide 

concrete guidance, yet allow for the flexibility to evaluate each outbreak on a situational basis. 

Interim Guidance: Use of Serogroup B Meningococcal Under a CDC-Sponsored IND 

Jessica MacNeil, MPH 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

As noted, there is currently no vaccine for serogroup B meningococcal disease licensed in the 

US. Recent outbreaks on college campuses highlight the difficulty and challenges of controlling 

serogroup B meningococcal disease. Vaccination campaigns were conducted at two 

universities experiencing serogroup B outbreaks in 2013 using an investigational MenB vaccine 

developed by Novartis Vaccines under an expanded access IND sponsored by CDC. 

The FDA’s current regulations allow for the use of a drug or vaccine that is not approved for use 

in the US to treat serious or immediately life-threatening diseases or conditions when there are 

no comparable or satisfactory alternative treatment options. The mechanism allowing for this 

use is known as an expanded access IND. 

In January 2014, an ad hoc Meningococcal WG was convened with the following terms of 

reference: 

 Review available data on the recent epidemiology of meningococcal disease and outbreaks 

 Develop guidance for use of MenB vaccines under a CDC-sponsored IND in an outbreak 

setting 

 Update the current meningococcal disease outbreak guidelines once MenB vaccines are 

licensed in the United States 

The first two of these objectives have been completed, with the outcomes presented during this 

session. Once a MenB vaccine is licensed in the US, the WG will complete the final objective. 

During the development of the interim guidance, several key issues and challenges were 

discussed based on the experience with providing MenB vaccine under an IND mechanism at 

the two universities experiencing outbreaks in 2013. When providing a vaccine under an IND, 

there are additional steps to getting a vaccination campaign in place; therefore, there is a need 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

to consider options early in an outbreak. In addition, there was a need to reduce confusion 

about how to define populations within organizations. There was also recognition that waiting 

for additional cases to occur before acting is difficult for organizations, and that there needed to 

be clear steps for each case outlined in the document. Finally, there is no evidence that MenB 

vaccines eliminate carriage, so providing primary protection to vaccinees must be the goal of 

vaccination in this setting. 

The current comprehensive meningococcal B guidelines are included as an appendix in the 

2013 “Prevention and Control of Meningococcal Disease” MMWR. In these guidelines, 

vaccination of a population at risk should be considered when 2 to 3 cases of the same 

serogroup occur during a 3-month period with an attack rate of 10/100,000 in the affected 

community. This threshold is based on data from outbreaks of serogroup C prior to routine 

adolescent meningococcal vaccination. However, defining the denominator for calculating an 

attack rate in the affected community is often challenging for health departments and 

organizations. The population at risk can either be defined as organization-based when cases 

have a common affiliation but no close contact, or community-based when cases occur in the 

geographic area but no close contact or affiliation is identified. 

The purpose of the interim guidance document is to identify serogroup B outbreaks early so that 

there is time to vaccinate in response to the outbreak if it is determined to be necessary. The 

current document provides guidance for use of MenB vaccine using an expanded access IND 

sponsored by CDC, but it does not provide definitive guidelines or recommendations. In this 

document, the WG tried to simplify the criteria for when vaccinations should be considered. 

Importantly, this guidance applies only to serogroup B outbreaks in organizational settings and 

does not apply to community outbreaks or outbreaks caused by other serogroups. This 

guidance is only intended to be in place until a licensed vaccine is available in the US, which 

may be as short as a year. 

There are three key differences between the interim guidance and the comprehensive 

meningococcal outbreak guidelines that were published previously. In the interim guidance, 

recommendations for organizations are divided into two groups based on organizational size 

versus requiring calculation of an attack rate. The interim guidance also increases the 

timeframe during which cases may occur from 3 months to 6 months. In addition, the language 

around mass chemoprophylaxis has been revised to allow for some instances where it may be 

considered for use in conjunction with a vaccination campaign for outbreak response. 

The objectives of the interim guidance document are to assist decision-makers with determining 

the need for vaccination with MenB vaccines; clarify the process for obtaining the vaccine; and 

improve the timeliness of implementation of vaccination campaigns. Clear definitions are 

provided in the guidance document for cases that should be included in outbreak case counts, 

what represents and organizational-based outbreak, and how to determine population size and 

the vaccination group. 

Serogrouping of clinical specimens should be initiated within 24 hours of identification of 

Neisseria meningitidis from a normally sterile body site whenever possible. Laboratories that 

cannot initiate serogrouping within 72 hours should transfer the isolate or specimen to a 

laboratory that can perform this testing or to CDC within 24 hours. Genotyping data may 

provide supportive evidence for an outbreak among meningococcal cases. The data from 

isolates should be interpreted in the context of the epidemiology of the cases. 

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CDC will work with state and local health departments and organizations as just described to 

determine the need for MenB vaccine on a situational basis. Organizations that provide MenB 

vaccine via the FDA’s expanded access IND sponsored by CDC are required to identify a local 

co-investigator on the IND, and are required to participate in safety follow-up activities required 

under the IND. To date, universities implementing MenB vaccination campaigns have been 

responsible for funding the cost of the vaccine and its administration. Vaccination under CDC’s 

IND has been limited to persons affiliated with the two universities where outbreaks have 

occurred. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Decisions to vaccinate should be evaluated on a situational basis in consultation with the local 

and state health department and CDC, taking into account all circumstances specific to the 

organization and epidemiology of the outbreak. Factors to be taken into consideration include 

the following: 

 Number of cases 

 Population size of the organization 

 Time interval between cases 

 If strains causing cases are identical 

 Feasibility and cost of mass vaccination campaign 

 Vaccine availability 

 If outbreak strain is likely to be covered by a MenB vaccine 

 Public concern 

The WG has divided its guidance by organizational size. For organizations with a population 

size of less than 5000, when one case of meningococcal disease occurs, routine public health 

practices should be followed, including serogrouping of the isolates, conducting a case 

investigation, and providing chemoprophylaxis to close contacts. The situation should be 

monitored closely and the isolates should be saved for future molecular genotyping. In 

organizations of this size, the trigger point is reached when 2 or more cases occur within 6 

months. The recommendation is to complete all of the same public health response activities as 

following a single case. In addition, all isolates should be sent to CDC for molecular genotyping 

and additional testing. If all isolates are identified as serogroup B and are likely covered by a 

MenB vaccine, then a MenB vaccination campaign may be considered. 

In organizations with more than 5,000 persons, the recommendations are similar after a single 

case. When two cases occur in 6 months and both are identified as serogroup B, the state 

health department should contact CDC to discuss the cases and should continue to monitor the 

situation closely. In organizations of this size, the trigger point is reached when 3 or more cases 

occur in 6 months. Isolates should be sent to CDC for molecular genotyping and additional 

testing. If all isolates are identified as serogroup B and are likely covered by a MenB vaccine, a 

vaccination campaign may be considered. 

In developing the interim guidance, the WG also felt it was important to better understand the 

current recommendations and available data on the use of mass chemoprophylaxis for outbreak 

control. A review of the literature from 1971 through the present was completed, and 18 

instances where mass chemoprophylaxis was used as an outbreak response were included. 

The WG conclusions from this review were that there is limited data available on the use of 

ciprofloxacin for mass chemoprophylaxis during outbreaks, but that overall, decreases in 

carriage were seen soon after chemoprophylaxis was administered. Carriage was not 

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The plan was to publish the interim guidance document on the CDC website shortly after this 

meeting so that it will be available to interested health departments and organizations before the 

next school year. As mentioned previously, updates to CDC’s comprehensive meningococcal 

disease outbreak guidelines will be developed and shared with the ACIP once serogroup B 

meningococcal vaccines are licensed in the US. CDC will also work to identify opportunities to 

evaluate the impact of using MenB vaccines in outbreak response. 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

eliminated and generally returned over time, and there was an unclear impact of mass 

chemoprophylaxis on prevention of additional cases. 

The purpose of chemoprophylaxis is to eradicate nasopharyngeal carriage of N. meningitidis 

and thus prevent disease in close contacts of a patient with invasive meningococcal disease. 

Antimicrobial chemoprophylaxis of close contacts is important to prevent secondary cases. The 

guidance emphasizes that mass chemoprophylaxis is not recommended as a stand-alone 

measure to control outbreaks of meningococcal disease, and should only be considered as an 

interim measure to reduce carriage and transmission in the period before potential protection 

from vaccination can be achieved. Situations where mass chemoprophylaxis is likely to be 

successful include small or closed populations where high antibiotic coverage can be rapidly 

achieved, and where there is limited mixing with outside populations. 

There are several challenges to successfully implementing mass chemoprophylaxis, including 

the following: 

 Identifying a smaller logical “at risk” population 

 Ensuring all persons in the target group receive treatment within a short time frame 

 Potential for multiple sources of transmission within a population 

 Prolonged risk for exposure in outbreak setting 

 Cost of the drug and its administration 

 Drug side effects and idiosyncratic reactions 

 Interactions with frequently used medications such as anti-depressants 

 Emergence of drug-resistant organisms 

If mass chemoprophylaxis is undertaken, it should be administered to all targeted persons at the 

same time, ideally in less than 24 hours. In many outbreak settings, particularly when a small, 

closed at-risk population cannot be defined, the disadvantages of providing mass 

chemoprophylaxis outweigh the possible benefits to prevent future cases. If the decision to 

offer mass chemoprophylaxis prior to implementation of a vaccination campaign is made, 

communicating the need for vaccination for potential protection for the duration of the outbreak 

is critical. Additionally, use of mass chemoprophylaxis should not delay implementation of a 

vaccination campaign. 

Other control measures, such as restricting travel to an area with an outbreak, closing schools 

or universities, or canceling sporting or social events or meetings are generally not 

recommended as part of outbreak control because these interventions are unlikely to alter the 

course of the outbreak. However, educating communities, physicians, and other health-care 

personnel about meningococcal disease to promote early case recognition and early careseeking behaviors is an important part of managing suspected meningococcal disease 

outbreaks. These education efforts should be initiated as soon as an outbreak is suspected. 

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In summary, meningococcal disease is a rare but serious infection. Fortunately, outbreaks are 

rare, but they do occur and the timing of additional cases in an outbreak is not easy to predict. 

Serogroup B cases will continue to occur, especially in the adolescent age group, which means 

that it is difficult to differentiate between sporadic cases versus catching an outbreak in its early 

stages. Vaccination is now possible to control serogroup B outbreaks, but implementing a 

vaccination campaign under an IND is a complex process. Licensure of serogroup B vaccines 

in the US will be an important step to protect individuals during serogroup B meningococcal 

disease outbreaks. 

Discussion Points 

Dr. Temte asked Dr. Sun whether he could provide further information on licensing of the 

menincogoccal B vaccine in the US. 

Dr. Sun (FDA) replied that this information is now in the public domain. Both manufacturers, 

Novartis and Pfizer, have submitted licensing applications to the FDA. These applications are 

under review. Because both products were given breakthrough therapy status, the review 

process is more abbreviated. Data still have to be reviewed. Pending review and if all goes 

well, the timing for the regulatory decision will be toward then end of 2014 or early part of 2015. 

In terms of revising the meningococcal outbreak guidelines in general, Dr. Duchin inquired as to 

whether the WG planned to align the current ACY recommendations similarly to what was done 

with meningococcal type B disease. He also asked what was known about the impact of the 

vaccine on carriage rates in the outbreak settings. 

Ms. MacNeil responded that the main focus of the WG so far has been on developing the 

interim guidance, and they have not started working on the full revisions. The idea is to move 

more toward this model versus the calculation of an attack rate, but it will be necessary to wait 

to see what occurs after the MenB vaccine is licensed. There is not a lot of evidence to support 

that these vaccines will eliminate carriage or potentially prevent someone from acquiring 

carriage. 

Dr. Warshawsky (NACI) inquired as to whether the purpose of genotyping was to tell if there 

was a match with the meningococcal strains covered by the vaccine, or to tell whether the 

strains match each other. She wondered whether the cutoff would still apply if there were two 

different strains circulating. 

Ms. MacNeil replied that the molecular genotyping would be to determine whether the strains 

match each other. Additional testing is done to determine whether a vaccine would cover that 

strain. The WG tried to make the guidance relatively flexible in order to address each situation 

independently. Sometimes there are changes in the genotype during an outbreak, so they may 

not exactly match. The WG did not want to set up a situation in which nothing could be done 

because of the guidelines. 

Dr. Cohn added that the genotyping from almost every outbreak in the last several years always 

matched, or they were very close and over the course there was a small change. To answer 

the question regarding if there is a small change and one is covered by the vaccine and one is 

not, the expectation is that most strains will be covered by these vaccines. But, that issue would 

have to be addressed if that occurred. People felt like, in the college community especially, 

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even if several cases did not match phenotypically, it would still be causing the same amount of 

concern in the community and the drive toward vaccination would still exist. 

Dr. Schaffner (NFID) informed everyone of a new report from the NFID entitled, “Addressing the 

Challenges of Serogroup B Meningococcal Disease Outbreaks on Campuses.” The report was 

based on a roundtable that NFID held in April 2014 with CDC colleagues, external public health 

experts, and some college health officials. Some of the experts included Paul Offit, Carol 

Baker, and Jim Turner. Dr. Schaffner shared a few key points from the panel’s conclusions, 

which nicely complemented Ms. MacNeil’s presentation. First, despite its rarity, the severe 

nature of meningococcal disease makes advanced planning, particularly in the college setting, 

very advantageous if not imperative. The second is that increased efforts are needed to 

educate healthcare professionals and raise awareness about the early signs and symptoms of 

meningococcal disease so that cases can be identified promptly. Third, educational resources 

need to be readily available for the public when outbreaks do occur. Lastly, licensure of 

meningococcal serogroup B vaccines will have the single greatest impact on improving the 

timeliness of responses to these outbreaks. Copies of the report were made available on the 

information table outside of the meeting room, and are also available on the NFID website. 

In terms of logistics, Dr. Zahn (NACCHO) inquired as to whether the IND has an expiration date. 

Ms. MacNeil replied that there is not currently an expiration date on the IND. Each university 

had separate amendments done for the IND. Each university is considered as a separate 

group, and future outbreaks would have to be considered separately as well. 

A representative from Novartis responded to the question regarding whether meningococcal B 

vaccine would prevent carriage, indicating that it is very difficult in a clinical trial before licensure 

and implementation of vaccination to determine whether a vaccine is going to prevent carriage. 

Nevertheless, Novartis conducted a study in the United Kingdom (UK) that is soon to be 

published that shows that there is an impact on Neisseria meningitides carriage. Obviously, the 

numbers are low, but the impact on overall meningococcal carriage is there. There is also a 

published paper from a vaccine which has been used in Normandy where carriage was reported 

to be reduced by 60%. Hopefully, data will be published before ACIP has to make a decision. 

Hepatitis Vaccines 

Art Reingold, MD 

ACIP Hepatitis Work Group Chair 

In years past, ACIP had a Hepatitis Vaccine WG, but it was not active last year. The decision 

was made earlier in 2014 to reconvene a WG on hepatitis A and B vaccines, two important early 

vaccines in the armamentarium. There are existing hepatitis A and B vaccine 

recommendations. The hepatitis A vaccine recommendations are from 2006, while the hepatitis 

B vaccine recommendations are from 2005 and 2006. The primary purpose of reconvening a 

WG is to oversee the updating of these two sets of recommendations, and to bring them to the 

ACIP for consideration. Additional updates and recommendations have been made for use of 

both vaccines in the interim. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

The current recommendations and updates for hepatitis A vaccine include the following: 

 ACIP Routine Recommendation for Hepatitis A Vaccine (2006). MMWR 2006 May 

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

 Update: Prevention of hepatitis A after exposure to hepatitis A virus and in international 

travelers. Updated recommendations of the ACIP. MMWR 2007 Oct 19;56(41):1080-4. 

 Updated recommendations from the ACIP for use of hepatitis A vaccine in close contacts of 

newly arriving international adoptees. MMWR 2009 Sep 18;58(36):1006-7. 

 FDA Approval of an Alternate Dosing Schedule for Twinrix®. MMWR 2007 Oct 

12;56(40):1057. 

The primary goal of the WG with regard to hepatitis A will be to combine these various 

documents into a single up-to-date set of recommendations for the use of hepatitis A vaccine. 

After a number of interesting challenges in trying to deal with hepatitis A outbreaks in 

hyperendemic areas, and interesting and innovative ways of implementing the vaccine, a 

decision was finally made in 2006 to recommend hepatitis A vaccine as a routine immunization 

for all children ages 12 through 23 months old. 

Based on 2012 NIS data, children in the 19 through 35 month age group were at about 53% 

coverage with two doses. The 2020 target is 85% with two doses, so there certainly is room to 

improve coverage with hepatitis A vaccine. At the time the universal vaccination 

recommendation was made, there were no recommendations for catch-up in older children or in 

older individuals. Coverage among children 13 through 17 years of age is approximately 48% 

with two or more doses of hepatitis A vaccine. By 2018, this age group will begin to realize the 

effects of the vaccination of children 12 through 23 months of age when the first cohorts of 

children coming of age after the universal recommendation will begin to reach adolescence. 

Over the next several decades, if vaccination coverage increases, there will be a more fully 

vaccinated population. However, large numbers of children, adolescents and adults remain 

unvaccinated. So, catch-up vaccination is another area of interest. 

The WG plans to consider a couple of issues. The current recommendation for post-exposure 

prophylaxis (PEP) for persons one through 40 years of age is to receive vaccination; however, 

for those over the age of 40 the emphasis is on the use of immunoglobulin. In large part 

because of the dearth of data regarding the effectiveness of vaccine for post-exposure 

prophylaxis in people over the age of 40 in terms of immunogenicity and other aspects of the 

response, the WG will consider whether any changes are needed with regard to the 

recommendation for PEP in older individuals. 

Simultaneously, the WG expects to discuss whether any other risk groups might benefit from 

immunization. There have been foodborne outbreaks in which food handlers with hepatitis A 

are involved. These are very expensive outbreaks for local and state health officials. The 

turnover of food handlers is extraordinarily high, and many may not regularly access healthcare. 

The question of vaccination of food handlers is likely to raise a number of challenging issues for 

health departments. Nevertheless, the WG will be discussing whether any other risk groups 

might benefit from hepatitis A vaccination. The WG expects to bring any issues that might 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

require further discussion to the full committee, as well as a fully integrated and updated 

statement regarding the use of hepatitis A vaccine. 

With regard to hepatitis B vaccine, the WG’s mandate is to create a fully integrated current 

document describing the use of hepatitis B vaccine. The current recommendations and updates 

for hepatitis B vaccine include the following: 

 ACIP Routine Recommendation for Hepatitis B Vaccine 2005 (Infants/Children). MMWR 

2005 Dec 23;54(RR-16):1-31. 

 ACIP Routine Recommendation for Hepatitis B Vaccine 2006 (Adult). MMWR 2006 Dec 

8;55(RR-16):1-33. 

 Use of hepatitis B vaccination for adults with diabetes mellitus: recommendations of the 

ACIP. MMWR 2011 Dec 23;60(50):1709-11. 

 FDA Approval of an Alternate Dosing Schedule for Twinrix®. MMWR 2007 Oct 

12;56(40):1057. 

The specific timeframe for bringing the integrated current information to the full committee for 

discussion has not yet been determined. 

Vaccine Supply 

Dr. Jeanne M. Santoli 

Immunization Services Division 

National Center for Immunization and Respiratory Diseases 

During this session, Dr. Santoli reported on the vaccine supply status of pertussis-containing 

vaccines and influenza vaccines. She indicated that supplies of Pentacel®, Daptacel®, and 

Adacel® vaccines have steadily increased during 2014. During the second quarter, the 

availability of additional supplies of these vaccines has allowed both the VFC and private 

providers to order these vaccines without restrictions. GSK continues to have sufficient supply 

of Pediarix®, Boostrix®, Infanrix®, and Kinrix® to cover the anticipated demand levels of its 

pertussis-containing vaccines, although presentation preference may be impacted on occasion. 

Each year during the National Influenza Vaccine Summit, US-licensed influenza vaccine 

manufacturers provide projections of influenza vaccine production for the US market for the 

upcoming season. CDC reaches out for periodic follow-ups to confirm/adjust manufacturer 

projections. In May 2014, manufacturers projected an aggregate total of approximately 157 

million doses of vaccine for the 2014-2015 season. In June 2014, follow-up queries resulted in 

a revised projection of 153-158 million doses of vaccine for the 2014-2015 season. Changes in 

these projections are due to adjustments made by manufacturers based on demand for 

vaccines during the pre-book process that was not yet completed when the information was 

shared in May. GSK’s recently updated its projections from 35 million doses in May 2014 to 28­

33 million doses in June 2014 following a Warning Letter from the FDA relating to an inspection 

at their FluLaval® influenza vaccine manufacturing facility in Canada. GSK’s Fluarix®, 

manufactured at a different facility, is not impacted by the Warning Letter. 

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First of all, I’d like to congratulate the CDC for working so quickly to address the outbreaks at 

Princeton and UCSB in providing meningococcal B vaccination and symptoms education for the 

students and faculty at both campuses. As most of you know, NMA was founded by parents 

like me who have been devastated by the loss of a child due to meningococcal disease. I lost 

my son, Casey, in 2000. I’ve worked with NMA since it was founded in 2002. Since then, the 

immunization community has made great strides in meningococcal disease prevention. Teen 

vaccination rates are at a high, and disease incidence is at a historic low. But, we can’t stop 

now. This disease is devastating and it still affects families all across America. Soon we’ll have 

the ability to provide routine protection against serogroup B disease in adolescents. Just within 

this past year at NMA, we’ve heard from many families whose lives have been changed forever 

because of serogroup B disease. I’m here today on their behalf. We have all worked together 

over the years—advocates, policy makers, public health experts, healthcare professionals, and 

vaccine manufacturers. We cannot now pass up opportunities to provide better protection for 

our children. I hope this committee considers this as discussions surrounding meningococcal b 

vaccines continue. Thank you. 

Hello. I’m Kora Peters, and I’m here today representing the adult industry. I’m here today to tell 

you that, as you know, adult performers are at high risk for sexually transmitted diseases 

(STDs). I want to specifically talk about hepatitis A. Men who have sex with men (MSM) are 

considered a high risk group for hepatitis A, presumably because of sexual behaviors that put 

them at risk of infection. But female and male adult performers who are not MSM regularly 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

CDC’s Vaccine Supply/Shortage Webpage can be found at: 

http://www.cdc.gov/vaccines/vac-gen/shortages/default.htm 

Day 2: Public Comment 

Rich Greenaway 

Immunization Coalition of DC 

I’m just really impressed with the presentation that we got this morning about PCV13, and I think 

that it is really important that the ACIP consider this for movement. I encourage the ACIP, in 

light of this new data and in context of the disease burden, to take the additional steps 

necessary and meet in August and do something so that we can help to prevent disease in the 

fall. You know, we can’t just shelve the fact that we’ve got a vaccine. I mean, we can’t forget 

about the fact that we’ve got a vaccine because it’s inconvenient for us to follow through and get 

all of the players to work on it and basically, you know, pay for the vaccine. I like the idea of 

putting the 50-year old recommendation in play, because then we don’t have to worry about 

people who are on public health plans. Their personal health plans will pick it up. So, I just 

encourage the ACIP to look at this and consider it in August. 

Tama Lee 

National Meningitis Association 

Kora Peters 

Adult Industry 

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engage in the same high risk behaviors as MSM. Because of this, I believe ACIP should 

consider recommending that all adult performers be given occupational high risk status. Adult 

performers are not getting hepatitis A vaccinations, and I believe that if it were made a specific 

CDC recommendation that they would be more likely to protect themselves and each other by 

getting vaccinated. We don’t know how common hepatitis A infection is among performers 

because the industry does not currently test for it, although they did add hepatitis B to the panel 

in August of last year. I know ACIP requires evidence before making any new 

recommendations, so I would like to request that the new Hepatitis Work Group take up this 

issue. The studies suggest that all adult performers are at increased risk for hepatitis A, which I 

believe they are, then ACIP should consider recommending the vaccination for them. I think 

that that would make what is a risky lifestyle choice a little safer. Thank you for your time. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Certification 

Upon reviewing the foregoing version of the June 25-26, 2014 ACIP meeting minutes, Dr. 

Jonathan Temte, ACIP Chair, certified that to the best of his knowledge, they are accurate and 

complete. His original, signed certification is on file with the Management Analysis and Services 

Office (MASO) of CDC. 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

ACIP Membership Roster 

CHAIR 

TEMTE, Jonathan L., MD, PhD 

Professor of Family Medicine 

University of Wisconsin School of Medicine and Public Health 

Madison, WI 

Term: 07/01/2011-06/30/2015 

EXECUTIVE SECRETARY 

PICKERING, Larry K., MD 

Senior Advisor to the Director 

Centers for Disease Control and Prevention 

National Center for Immunization and Respiratory Diseases 

Atlanta, GA 

MEMBERS 

BENNETT, Nancy, MD, MS 

Professor of Medicine and Community and Preventive Medicine 

University of Rochester School of Medicine and Dentistry 

Rochester, NY 

Term: 07/01/2011-06/30/2015 

BOCCHINI, Joseph A., Jr., MD 

Professor and Chairman 

Department of Pediatrics 

Louisiana State University Health Sciences Center 

Shreveport, LA 

Term: 07/01/2011-06/30/2015 

CAMPOS-OUTCALT, Douglas, MD, MPA 

Chair 

Department of Family, Community and Preventive Medicine 

University of Arizona College of Medicine - Phoenix 

Phoenix, AZ 

Term: 07/01/2011-06/30/2015 

COYNE-BEASLEY, Tamera, MD, MPH 

Director, NC Child Health Research Network 

Associate Director, Community Engagement NC TraCS Institute - Child Health Core 

Professor of Pediatrics and Internal Medicine 

Division of General Pediatrics and Adolescent Medicine 

University of North Carolina School of Medicine 

Chapel Hill, NC 

Term: 10/04/2010-06/30/2014 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

DUCHIN, Jeffrey, MD 

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 

Seattle, WA 

Term: 10/04/2010-06/30/2014 

HARRIMAN, Kathleen, PhD, MPH, RN 

Chief, Vaccine Preventable Disease Epidemiology Section 

Immunization Branch 

California Department of Public Health 

Richmond, CA 

Term: 07/01/2012 – 06/30/2016 

HARRISON, Lee H., MD 

Professor of Medicine and Epidemiology 

Infectious Diseases Epidemiology Research Unit 

University of Pittsburgh 

Pittsburgh, PA 

Term: 07/01/2012 – 06/30/2016 

JENKINS, Renée R., MD 

Professor and Chair Emeritus 

Department of Pediatrics and Child Health 

Howard University College of Medicine 

Washington, DC 

Term: 10/06/2010 – 06/30/2014 

KARRON, Ruth A., MD 

Professor and Director 

Center for Immunization Research 

Department of International Health 

Johns Hopkins Bloomberg School of Public Health 

Baltimore, MD 

Term: 07/01/2012 – 06/30/2016 

KEMPE, Allison, MD, MPH 

Professor of Pediatrics 

Director of Primary Care Fellowship 

University of Colorado School of Medicine 

Director of Research 

Division of General Academic Pediatrics 

Director of Children’s Outcomes Research Program 

The Children’s Hospital of Denver 

Denver, CO 

Term: 07/01/2013 - 06/30/2017 

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RUBIN, Lorry, MD 

Director 

Pediatric Infectious Diseases 

Steven and Alexandra Cohen Children’s Medical Center of New York 

North Shore-Long Island Jewish Health System 

New Hyde Park, NY 

Professor of Pediatrics, Hofstra-North Shore LIJ School of Medicine 

Hempstead, NY 

Term: 07/01/2012 – 06/30/2016 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

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 

VÁZQUEZ, Marietta, MD 

Associate Professor of Pediatrics 

Department of Pediatrics 

Yale University School of Medicine 

New Haven, CT 

Term: 07/01/2011-06/30/2015 

EX OFFICIO MEMBERS 

Centers for Medicare and Medicaid Services (CMS) 

HANCE, Mary Beth 

Senior Policy Advisor 

Division of Quality, Evaluations and Health Outcomes 

Children and Adults Health Programs Group 

Center for Medicaid, CHIP and Survey & Certification 

Centers for Medicare and Medicaid Services 

Baltimore, MD 

Department of Defense (DoD) 

GEIBE, Jesse, MD, MPH, MBA 

CDR, Medical Corps 

Defense Department Liaison Officer 

Centers for Disease Control and Prevention 

Atlanta, GA 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Department of Veterans Affairs (DVA) 

KINSINGER, Linda S., MD, MPH 

Chief Consultant for Preventive Medicine 

Office of Patient Care Services 

National Center for Health Promotion and Disease Prevention 

Durham, North Carolina 

Food and Drug Administration (FDA) 

SUN, Wellington, MD 

Director, Division of Vaccines and Related Product Applications 

Office of Vaccines Research and Review 

Food and Drug Administration 

Rockville, MD 

Health Resources and Services Administration (HRSA) 

HOUSTON, A. Melissa, MD, MPH, FAAP 

Chief Medical Officer 

Division of Vaccine Injury Compensation 

Health Resources and Services Administration 

Rockville, MD 

Indian Health Service (IHS) 

GROOM, Amy, MPH 

Immunization Program Manager 

Indian Health Service 

Albuquerque, NM 

National Vaccine Program Office (NVPO) 

GELLIN, Bruce, MD, MPH 

Director 

National Vaccine Program Office 

Department of HHS, Public Health and Science 

Washington, DC 

National Institutes of Health (NIH) 

GORMAN, Richard L., MD 

Associate Director for Clinical Research 

Division of Microbiology and Infectious Diseases/NIAID 

National Institute of Health 

Bethesda, MD 

LIAISON REPRESENTATIVES 

American Academy of Family Physicians (AAFP) 

LOEHR, Jamie, MD, FAAFP 

Cayuga Family Medicine (Owner) 

Ithaca, NY 

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American College of Physicians (ACP) (alternate) 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

American Academy of Pediatrics (AAP) 

Chair, Committee on Infectious Diseases 

BRADY, Michael T., MD 

Professor and Chair, Department of Pediatrics 

The Ohio State University and Nationwide Children’s Hospital 

Columbus, OH 

American Academy of Pediatrics (AAP) 

Red Book Editor 

KIMBERLIN, David, MD 

Professor of Pediatrics 

Division of Pediatric Infectious Diseases 

The University of Alabama at Birmingham School of Medicine 

Birmingham, AL 

American Academy of Physician Assistants (AAPA) 

LÉGER, Marie-Michèle, MPH, PA-C 

Senior Director, Clinical and Health Affairs 

American Academy of Physician Assistants 

Alexandria, VA 

American College Health Association (ACHA) 

EVEN, Susan, MD 

Executive Director 

Student Health Center 

University of Missouri 

Columbia, MO 

American College of Obstetricians and Gynecologists (ACOG) 

RILEY, Laura E., MD 

Associate Professor, Obstetrics, Gynecology and Reproductive Medicine 

Harvard Medical School 

Maternal Fetal Medicine 

Massachusetts General Hospital 

Boston, MA 

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 

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American Nurses Association (ANA) (alternate) 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

American Geriatrics Society (AGS) 

SCHMADER, Kenneth, MD 

Professor of Medicine-Geriatrics 

Geriatrics Division Chief 

Duke University and Durham VA Medical Centers 

Durham, NC 

America’s Health Insurance Plans (AHIP) 

NETOSKIE, Mark J., MD, MBA, FAAP 

Market Medical Executive, CIGNA 

Houston, TX 

American Medical Association (AMA) 

FRYHOFER, Sandra Adamson., MD, MACP 

Adjunct Associate Professor of Medicine 

Emory University School of Medicine 

Atlanta, GA 

American Nurses Association (ANA) 

BREWER, Katie, MSN, RN 

Assistant Director 

Patient Care Services 

Fairfax County Government 

Fairfax, VA 

HAYES, Carol E., CNM, MN, MPH 

Advanced Practice Nurse 

American Nurses Association 

American College of Nurse Midwives 

DeKalb Board of Health 

Decatur, GA 

American Osteopathic Association (AOA) 

GROGG, Stanley E., DO, FACOP 

Associate Dean/Professor of Pediatrics 

Oklahoma State University-Center for Health Sciences 

Tulsa, OK 

American Pharmacists Association (APhA) 

FOSTER, Stephan L., PharMD, FAPhA 

Professor and Vice Chair, Department of Clinical Pharmacy 

University of Tennessee Health Sciences Center, College of Pharmacy 

Memphis, TN 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

Association of Immunization Managers (AIM) 

MOORE, Kelly, MD, MPH 

Medical Director, State Immunization Program 

Tennessee Department of Health 

Nashville, TN 

Association for Prevention Teaching and Research (APTR) 

McKINNEY, W. Paul, MD 

Professor and Associate Dean 

University of Louisville School of Public Health and Information Sciences 

Louisville, KY 

Association of State and Territorial Health Officials (ASTHO) 

DWELLE, Terry L, MD, MPHTM, FAAP, CPH 

State Health Officer 

North Dakota Department of Health 

Bismarck, ND 

Biotechnology Industry Organization (BIO) 

LEWIN, Clement, PhD, MBA 

Head, Medical Affairs and Immunization Policy 

Novartis Vaccines and Diagnostics 

Cambridge, MA 

Council of State and Territorial Epidemiologists (CSTE) 

HAHN, Christine, MD 

State Epidemiologist 

Office of Epidemiology, Food Protection and Immunization 

Idaho Department of Health and Welfare 

Boise, ID 

Canadian National Advisory Committee on Immunization (NACI) 

WARSHAWSKY, Bryna, MDCM, CCFP, FRCPC 

Associate Medical Officer of Health 

Middlesex-London Health Unit 

London, Ontario, Canada 

Healthcare Infection Control Practices Advisory Committee (HICPAC) 

Vacant 

Infectious Diseases Society of America (IDSA) 

NEUZIL, Kathleen M., MD, MPH, FIDSA 

Vaccine Development Global Program (PATH) 

Clinical Professor 

Departments of Medicine and Global Health 

University of Washington School of Medicine 

Seattle, WA 

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Infectious Diseases Society of America (IDSA) (alternate) 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report June 25-26, 2014 

BAKER, Carol J., MD 

Professor of Pediatrics 

Molecular Virology and Microbiology 

Baylor College of Medicine 

Houston, TX 

National Association of County and City Health Officials (NACCHO) 

ZAHN, Matthew, MD 

Medical Director, Epidemiology 

Orange County Health Care Agency 

Santa Ana, CA 

National Association of Pediatric Nurse Practitioners (NAPNAP) 

STINCHFIELD, Patricia A., RN, MS, CPNP 

Director 

Infectious Disease/Immunology/Infection Control 

Children's Hospitals and Clinics of Minnesota 

St. Paul, MN 

National Foundation for Infectious Diseases (NFID) 

SCHAFFNER, William, MD 

Chairman, Department of Preventive Medicine 

Vanderbilt University School of Medicine 

Nashville, TN 

National Immunization Council and Child Health Program, Mexico 

VILLASEÑOR RUIZ, Ignacio 

Directora del Programa de Atencion da la Salud de la Infancia y la Adolescencia / Director 

General, Child and Adolescent Health 

Centro Nacional Para la Salud de la Infancia Y La Adolescencia / National Center for Child and 

Adolescent Health 

Ministry of Health / Secretaría de Salud 

Mexico 

National Medical Association (NMA) 

WHITLEY-WILLIAMS, Patricia, MD 

Professor and Chair 

University of Medicine and Dentistry of New Jersey 

Robert Wood Johnson Medical School 

New Brunswick, NJ 

National Vaccine Advisory Committee (NVAC) 

ORENSTEIN, Walt, MD 

Chair, NVAC 

Associate Director, Emory Vaccine Center 

Emory University 

Atlanta, GA 

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Pediatric Infectious Diseases Society (PIDS) 

SAWYER, Mark H, MD 

Professor of Clinical Pediatrics 

University of California, San Diego School of Medicine 

San Diego, CA 

Pediatric Infectious Diseases Society (PIDS) (alternate) 

ENGLUND, Janet A., MD 

Professor, Department of Pediatrics 

Seattle Children's Hospital 

University of Washington 

Seattle, WA 

Pharmaceutical Research and Manufacturers of America (PhRMA) 

BRAGA, Damian A. 

President, sanofi pasteur 

Swiftwater, PA 

Society for Adolescent Health and Medicine (SAHM) 

MIDDLEMAN, Amy B., MD, MSEd, MPH 

Professor of Pediatrics 

Chief, Section of Adolescent Medicine 

University of Oklahoma Health Sciences Center 

Oklahoma City, OK 

Society for Healthcare Epidemiology of America (SHEA) 

WEBER, David, MD, MPH 

Professor of Medicine, Pediatrics, and Epidemiology 

University of North Carolina Schools of Medicine and Public Health 

Medical Director, Hospital Epidemiology and Occupational Health, UNC Health Care 

University of North Carolina 

Chapel Hill, NC 

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This document has been archived for historical purposes. (7/1/2014)