DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION 

Advisory Committee on 

Immunization Practices (ACIP) 

Summary Report

February 26-27, 2014 

Atlanta, Georgia 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Table of Contents Page 

Agenda 4-5 

Acronyms 6-8 

Wednesday: February 26, 2014 

Welcome and Introductions 9-13 

Influenza 

 Brief Announcement: Novel Influenza Vaccine Work Group 

 Introduction 

 Influenza Activity Update 

 Interim Estimates of 2013-14 Seasonal Influenza Vaccine Effectiveness 

 Effectiveness of LAIV vs. IIV for Healthy Children (GRADE) 

 Interim Influenza Vaccine Safety Update: LAIV and IIV in Persons <18 Years of Age 

 LAIV vs. IIV comparative safety studies in children 

 Safety of LAIV vs. IIV for healthy children (GRADE) 

 LAIV update 

 Proposed recommendations 

13-44 

Meningococcal Vaccine 

 Introduction 

 Meningococcal Disease among Men who Have Sex with Men (MSM) 

 Meningococcal Disease and Vaccine Response in HIV-Infected Persons 

 Use of Serogroup B Meningococcal Vaccine During Outbreaks on College Campuses 



44-57 

Pneumococcal Vaccines 

 Introduction 

 Update on PCV13 Effectiveness and Herd Effects in the U.S. 

 Reduced Dose Schedules of PCV13 for Children: GRADE of Evidence 

 PCV13 reduced dose schedules for children: considerations and WG conclusions 

58-83 

Yellow Fever Vaccine 

 Introduction 

 Background: Yellow Fever Disease, Yellow Fever Vaccine, and Recent Vaccine Developments 

84-91 

Vaccine Supply 91 

Public Comments Day 1 92 

2 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Thursday: February 27, 2014 

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) 

92-95 

General Recommendations 

 Vaccine Storage and Handling 96-101 

Safety of Tetanus, Diphtheria, and Acellular Pertussis (Tdap) Vaccine 

 Introduction 

 Safety of Tdap vaccine during pregnancy: enhanced surveillance in VAERS 

 Tdap during pregnancy: safety and coverage data from the VSD 

101-113 

Human Papillomavirus (HPV) Vaccines 

 Introduction 

 HPV Type Attribution in Cervical Precancers 

 HPV-Associated Cancers and Type Attribution 

 9-Valent HPV Vaccine Clinical Trial Data 

 Summary and Next Steps 

 Updated ACIP Statement-Bivalent and Quadrivalent Vaccines 

113-134 

Smallpox Vaccine 

 Introduction 

 Use of ACAM2000 smallpox vaccine in laboratory personnel 

134-140 

Public Comments Day 2 140 

Certification 141 

Membership Roster 142-149 

3 

This document has been archived for historical purposes. (3/1/2014)
 

         

   

   

Dr Douglas Campos‐Outcalt (ACIP)

Dr Ruth Karron (ACIP, WG Chair)

Dr Lyn Finelli (CDC/NCIRD)

Dr Brendan Flannery (CDC/NCIRD)

Dr Lisa Grohskopf (CDC/NCIRD)

Dr Maria Cano (CDC/NCEZID)

Dr Emmanuel (Chip) Walter (Duke

University Medical Center)

Dr Lisa Grohskopf (CDC/NCIRD)

Dr Kathleen Coelingh (MedImmune)

Dr Lisa Grohskopf (CDC/NCIRD)

   

                 

   

   

         

           

           

     

     

Adult Immunization

17:00	  Introduction Dr Tamera Coyne‐Beasley (ACIP, WG Chair)

 Update on adult immunization coverage Information Dr Walter Williams (CDC/NCIRD)

 Update on CDC’s adult immunization communication activities Discussion Dr Kristine Sheedy (CDC/NCIRD)

   

   

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 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
 

February 26‐27, 2014
 

AGENDA ITEM	 PURPOSE PRESIDER/PRESENTER(s)

Wednesday, February 26th

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

Dr Larry Pickering (Executive Secretary,

ACIP, CDC)

8:30	 Influenza

 Brief announcement: novel influenza vaccine work group

 Introduction

 Influenza activity update

 Interim estimates of 2013‐14 seasonal influenza vaccine

effectiveness

 Effectiveness of LAIV vs. IIV for health children (GRADE)	 

 Interim influenza vaccine safety update: LAIV and IIV in persons

<18 years of age

 LAIV vs. IIV comparative safety studies in children

 Safety of LAIV vs. IIV for healthy children (GRADE)

 LAIV update

 Proposed recommendations

Information

Discussion

Vote

10:45	 Break

11:15	 Meningococcal Vaccines

 Introduction

 Meningococcal disease among men who have sex with men (MSM)

 Meningococcal disease and vaccine response in HIV‐infected

persons

 Use of serogroup B meningococcal vaccine during outbreaks on

college campuses

Dr Lorry Rubin (ACIP, WG Chair)

Ms Jessica MacNeil (CDC/NCIRD)

Ms Jessica MacNeil (CDC/NCIRD)

Dr Manisha Patel (CDC/NCIRD)

Information  

Discussion

12:30	 Lunch

13:45	 Pneumococcal Conjugate Vaccine (PCV)

 Introduction

 Update on PCV13 effectiveness and herd effects in the U.S.

 Reduced dose schedules of PCV13 for children: GRADE of evidence

 PCV13 reduced dose schedules for children: considerations and

WG conclusions	 

Dr Nancy Bennett (ACIP, WG Chair)

Dr Matt Moore (CDC/NCIRD)

Ms Sara Tomczyk (CDC/NCIRD)

Dr Tamara Pilishvili (CDC/NCIRD)

Information

Discussion

15:45	 Break

16:15 Yellow Fever Vaccine

 Introduction

 Background: yellow fever disease, yellow fever vaccine, and recent

vaccine developments

Information

Discussion

Dr Joseph Bocchini (ACIP, WG Chair)

Dr J. Erin Staples (CDC/NCEZID)

17:30 Vaccine Supply	 Information Dr Jeanne Santoli (CDC/NCIRD)

17:45 Public Comment

18:00 Adjourn

4 

This document has been archived for historical purposes. (3/1/2014)
 

   

   

   

   

   

   

   

         

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

AGENDA ITEM	 PURPOSE PRESIDER/PRESENTER(s)

Thursday, February 27th

8:00	 Agency Updates  

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

8:15	 General Recommendations

 Vaccine storage and handling Information

Discussion      

Dr Jeff Duchin (ACIP, WG Chair)

Dr Andrew Kroger (CDC/NCIRD)

9:00	 Safety of Tetanus, Diphtheria, and Acellular Pertussis (Tdap) Vaccine

 Introduction

 Safety of Tdap vaccine during pregnancy: enhanced surveillance in

VAERS

 Tdap during pregnancy: safety and coverage data from the VSD

Dr Arthur Reingold (ACIP, WG Chair)

Dr Pedro Moro (CDC/NCEZID)

Dr Elyse O Kharbanda (HealthPartners

Institute for Education and Research)

Information

Discussion

09:45	 Break

10:15	 Human Papillomavirus (HPV) Vaccine

 Introduction

 HPV type attribution in cervical precancers

 HPV‐associated cancers and type attribution

 9‐valent HPV vaccine clinical trial data

 Summary and next steps

Updated ACIP statement‐bivalent and quadrivalent vaccines

Dr Joseph Bocchini (ACIP, WG Chair)

Dr Susan Hariri (CDC/NCHHSTP)

Dr Mona Saraiya (CDC/NCCDPHP)

Dr Alain Luxembourg (Merck)

Dr Lauri Markowitz (CDC/NCHHSTP)

Information

Discussion

Vote

12:15	 Smallpox Vaccine

 Introduction

 Use of ACAM2000 smallpox vaccine in laboratory personnel

Information

Discussion

Dr Lee Harrison (ACIP, WG Chair)

Dr Brett Petersen (CDC/NCEZID)

13:00	 Public Comment

3:15	 Adjourn

Acronyms

CDC Centers for Disease Control & Prevention
 

CMS Centers for Medicare and Medicaid Services  
 

DOD Department of Defense
 

DVA Department of Veterans Affairs
 

FDA Food and Drug Administration
 

GRADE Grading of Recommendations Assessment, Development and Evaluation
 

HRSA Health Resources and Services Administration
 

IHS Indian Health Service
 

IIV Inactivated Influenza Vaccine
 

LAIV Live‐Attenuated Influenza Vaccine
 

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

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

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

NIH National Institutes of Health
 

NVPO National Vaccine Program Office
 

SMART Strategic Multi‐Attribute Ranking Tool for vaccines
 

VAERS Vaccine Adverse Event Reporting System
 

VSD Vaccine Safety Datalink
 

WG Work Group
 

5 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Acronyms 

AAFP American Academy of Family Physicians 

AAP American Academy of Pediatrics 

ABCs Active Bacterial Core Surveillance 

ACA Affordable Care Act 

ACCV Advisory Commission on Childhood Vaccines 

ACIP Advisory Committee on Immunization Practices 

ACNM American College of Nurse Midwives 

ACOG American College of Obstetricians and Gynecologists 

ACP American College of Physicians 

ADEM Acute Disseminated Encephalomyelitis 

AE Adverse Events 

AFP American Family Physicians 

AHIP America’s Health Insurance Plans 

AI/AN American Indians/Alaska Natives 

AIM Association of Immunization Managers 

AMA American Medical Association 

ANA American Nurses Association 

AOM Acute Otitis Media 

APhA American Pharmacists Association 

APHA American Public Health Association 

ARI Acute Respiratory Infection 

ASTHO Association of State and Territorial Health Officials 

BARDA Biomedical Advanced Research and Development Authority 

BLA Biologics License Application 

BMBL Biosafety in Microbiological and Biomedical Laboratories 

CDC Centers for Disease Control and Prevention 

CIN Cervical Intraepithelial Neoplasia 

CISA Clinical Immunization Safety Assessment 

CMS Centers for Medicare and Medicaid Services 

CNS Central Nervous System 

COI Conflict of Interest 

COID Committee on Infectious Disease 

CSTE Council of State and Territorial Epidemiologists 

CVD Cardiovascular Disease 

DECIDE Developing and Evaluating Communication Strategies to Support Informed Decisions 

and Practices Based on Evidence 

DHS Department of Homeland Security 

DoD Department of Defense 

DOH-UK Department of Health—United Kingdom 

DSMB Data Safety Monitoring Board 

DTaP Diphtheria, Tetanus, and Acellular Pertussis 

DVA Department of Veterans Affairs 

EHR Electronic Health Record 

EIP Emerging Infections Program 

EMA European Medicines Agency 

EMR Electronic Medical Record 

ET Eastern Time 

FDA Food and Drug Administration 

GAVI Global Alliance for Vaccines and Immunisation 

GBS Guillain–Barré Syndrome 

GERMS-SA Group from Enteric Respiratory and Meningeal disease Surveillance in South Africa 

6 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

GMC Geometric Mean Concentration 

GMTs Geometric Mean Titers 

GRADE Grading of Recommendation Assessment, Development and Evaluation 

GSK GlaxoSmithKline 

GVAP Global Vaccine Action Plan 

HAART Highly Active Antiretroviral Therapy 

HCP Healthcare Personnel 

HHS (Department of) Health and Human Services 

HP2020 Healthy People 2020 

HPV Human Papillomavirus 

HRSA Health Resources and Services Administration 

IAC Immunization Action Coalition 

IARC International Agency for Research on Cancer 

IC Immunocompromising Conditions 

ICD International Classification of Diseases 

IDSA Infectious Disease Society of America 

IgG Immunoglobulin G 

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 

ISD Immunization Services Division 

ISO Immunization Safety Office 

JE Japanese Encephalitis 

LAIV Live Attenuated Influenza Vaccine 

LMP Last Menstrual Period 

LNI Log10 Neutralization Index 

LRTI Lower Respiratory Tract Infection 

MAARI Medically Attended Acute Respiratory Illness 

MAW Medically-Attended Wheezing 

MCV4 Meningococcal Conjugate Vaccine 

MedDRA Medical Dictionary for Regulatory Activities 

MMWR Morbidity and Mortality Weekly Report 

MSM Men Who Have Sex With Men 

NACCHO National Association of County and City Health Officials 

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 

NIH National Institutes of Health 

NIS National Immunization Survey 

NMA National Medical Association 

NNV Number Needed to Vaccinate 

NP Nasopharyngeal 

NPPA National Prevention Partnership Awards 

7 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

 

 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

NREVSS National Respiratory and Enteric Virus Surveillance System 

NVAC National Vaccine Advisory Committee 

NVP National Vaccine Plan 

NVPO National Vaccine Program Office 

NYC DOHMH New York City Department of Health and Mental Hygiene 

OM Otitis Media 

OR Adds Ratio 

PAHO Pan American Health Organization 

PCR Polymerase Chain Reaction 

PCV Pneumococcal Conjugate Vaccine 

PFGE Pulsed-Field Gel Electrophoresis 

PICO Population, Intervention, Comparison, and Outcome 

PIDS Pediatric Infectious Diseases Society 

PKIDs Parents of Kids with Infectious Diseases 

PRAMS Pregnancy Risk Assessment Monitoring System 

PRNT Plaque Reduction Neutralization Test 

RAD Reactive Airway Disease 

RCA Rapid Cycle Analysis 

RCT Randomized Controlled Trial 

rMenB Recombinant MenB+OMV NZ 

RSV Respiratory Syncytial Virus 

RT-PCR Reverse Transcription Polymerase Chain Reaction 

SAEs Serious Adverse Events 

SAGE Strategic Advisory Group of Experts (WHO) 

SES Socioeconomic Status 

SGA Small for Gestational Age 

SME Subject Matter Expert 

SNPs Single Nucleotide Polymorphism 

Td Tetanus-Diphtheria 

Tdap Tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine, adsorbed 

UK United Kingdom 

UN United Nations 

UNC University of North Carolina 

US United States 

USP United States Pharmacopeia 

USPSTF US Preventive Services Task Force 

VA Department of Veterans Affairs 

VAERS Vaccine Adverse Event Reporting System 

VE Vaccine Effectiveness 

VFC Vaccines for Children 

VICP National Vaccine Injury Compensation Program 

VLP Virus-Like particles 

VRBPAC Vaccine and Related Biologic Products Advisory Committee 

VSD Vaccine Safety Datalink 

VT Vaccine-Type 

WER Weekly Epidemiological Record 

WHA World Health Assembly 

WHO World Health Organization 

YF Yellow Fever 

8 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Welcome and Introductions 

Welcome 

Dr. Larry Pickering 

Executive Secretary, ACIP / CDC 

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

February 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: Felicia Betancourt, Natalie Greene, Reed 

Walton, Stephanie Thomas, 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 then recognized the following domestic and international visitors who were in 

attendance at this ACIP meeting: 

 Two Vaccine Science Fellows from the American Academy of Family Physicians (AAFP). 

The AAFP Vaccine Science Fellowship program is intended to develop a cadre of 

physicians with knowledge and practical experience in various aspects of vaccines, vaccine 

policies, and implementation in practice. The Vaccine Science Fellows are: 

 Chris Lupoid, MD, of Lancaster General Health in Lancaster, Pennsylvania 

 Mary Pat Friedlander, MD, from the University of Pittsburgh Medical Center—St. 

Margaret’s in Pittsburgh, Pennsylvania 

 Belinda Schoof and Jennifer Frost from the central office of AAFP, with whom CDC has had 

long-term interactions. 

 Three representatives from the Ministry of Health in Vietnam, and one from Vietnam’s CDC. 

 The head of the Department of Arbovirology and Emerging Viral Infections from the Uganda 

Virus Research Institute. 

 Two epidemiologists from Morocco's Ministry of Health. 

9 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

 Three division directors from the Ministry of Health in Kenya. 

 Two visitors from China, representing the Chinese CDC. 

 Though Ministry of Health representatives from member countries of the WHO Pan 

American Health Organization (PAHO) usually attend each ACIP meeting, a group was 

unable to attend this meeting. CDC will host the next PAHO delegation at the June 2014 

ACIP meeting. 

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. Felicia Betancourt, 

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, June 

25-26, 2014. Registration for all meeting attendees is required and was anticipated to be open 

on the ACIP website during the week following this meeting. The registration deadline is June 

2, 2014 for non-US citizens and June 9, 2014 for US citizens. 

Dr. Pickering offered the following notes regarding liaison representatives and ex officio 

members: 

Liaison Representatives 

 Welcome to Terry Dwelle, the new ACIP liaison representative from the Association of State 

and Territorial Health Officials (ASTHO). Dr. Dwelle is a former clinical Professor of 

Pediatrics at the University of North Dakota School of Medicine, and worked as a medical 

missionary in East Africa. He currently serves as North Dakota’s State Public Health Officer 

and as chair of the Infectious Disease Policy Committee for ASTHO. 

 Carol Hayes attending as the American Nursing Association (ANA) liaison, on behalf of 

Katie Brewer. 

 Pat Whitley-Williams, liaison representative from the National Medical Association (NMA) 

was unable to attend. 

Ex Officio Members 

 Avril (Melissa) Houston representing Vito Caserta as the ex officio member from the Health 

Resources and Services Administration (HRSA) during this meeting. 

 Mary Beth Hance, the ex officio Member from the Centers for Medicare and Medicaid 

Services (CMS), was unable to attend. 

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 

10 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

visit the registration desk in the rear of the auditorium to have Felicia Betancourt 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. 

Dr. Pickering announced several initiatives that are underway in an attempt to improve and 

accelerate communication and information delivery, including the following: 

 CDC is launching vaccine schedule apps for mobile devices, both for the child and adult 

immunization schedules. 

 CDC is working on content syndication of the immunization schedules between ACIP and 

the professional societies that publish them each year. 

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

everyone would hear more about during future meetings. 

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

 Educational sessions are being conducted for ACIP members. On February 25, 2014, a 

health economics overview was held for ACIP members and CDC staff. A review session 

on GRADE (Grading of Recommendations Assessment, Development, and Evaluation) is 

planned for members during a future ACIP 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. 

Applications for ACIP membership are due no later than November 15, 2013 for the 4-year term 

beginning July 1, 2014. 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 submit 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 

11 

This document has been archived for historical purposes. (3/1/2014)
 

ACIP Recommendations Published

Since February 2012 

 

 

 

 

MMWR 

Reference 

 Use of Japanese Encephalitis Vaccine in Children: 11/15/2013 2013;62:898-900 

Recommendations of the Advisory Committee on 

Immunization Practices, 2013 

 Advisory Committee on Immunization Practices 2/7/2014 2014;63:108-109 

Recommended Immunization Schedules for Persons 

Aged 0 Through 18 Years — United States, 2014 

 Advisory Committee on Immunization Practices 2/7/2014 2014;63:110-112 

Recommended Immunization Schedule for Adults Aged 

19 Years or Older — United States, 2014 

 Prevention and Control of Haemophilus influenzae type b 2/28/2014 2014;63(in press) 

Disease: Recommendations of the Advisory Committee 

on Immunization Practices (ACIP) 

Title 

Publication 

Date 

5 http://www.cdc.gov/vaccines/hcp/acip-recs/recs-by-date.html 

 

 

 

 

 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

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

published since the October 2013 ACIP meeting follows: 

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

Vaccine Safety: 

www.cdc.gov/vaccinesafety/ 

Immunization Schedules (2013): 

http://www.cdc.gov/vaccines/recs/schedules/default.htm 

Childhood Vaccine Scheduler (interactive): 

https://www.vacscheduler.org 

Adolescent vaccine scheduler (interactive): 

http://www.cdc.gov/vaccines/recs/Scheduler/AdolescentScheduler.htm 

Adult Vaccine Scheduler (interactive): 

http://www.cdc.gov/vaccines/recs/Scheduler/AdultScheduler.htm 

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 

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: 

 Dr. Tamera Coyne-Beasley: Research support is allocated to the University of North 

Carolina (UNC) by Merck Pharmaceuticals for clinical trials. 

 The remainder of the ACIP members declared no conflicts. 

12 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Temte mentioned a couple of items of interest. The first regarded the Weekly 

Epidemiological Record (WER) that was published earlier in the month, which noted that during 

the timeframe between 2000-2012, measles worldwide has decreased by about 78%. Over that 

12-year span, an estimated 13.8 million lives were saved by measles initiatives. Dr. Temte said 

he mentioned this because earlier in February at his home institutions, a young man who was 

not vaccinated presented from Southeast Wisconsin with a rash illness. The patient was 

diagnosed empirically with a rickettsial illness. Five days later the measles serology came back 

from a commercial lab in Iowa instead of the Wisconsin State Laboratory of Hygiene six blocks 

away where the test could have done immediately. During this timeframe, 97 hospitalized 

patients, 105 visitors, and 362 hospital employees were exposed. This resulted in case-contact 

investigations in 18 of Wisconsin’s 72 counties. Suffice it to say that only 4 people were found 

to be at risk by serologic testing, including 1 infant, and 1 with an unknown serology. At this 

point, everyone had emerged from quarantine without developing measles. However, this was 

a reminder of just how pervasive these situations are and when they occur, their incredible 

impact. Dr. Pickering pointed out that part of the evaluation would include the cost of the 

outbreak to the institution. 

Regarding the 50th year of ACIP, Dr. Temte reported that the agenda from the May 25-26, 1964 

ACIP meeting included introduction of the committee, purpose and function, definition of the 

responsibilities, simplification of the immunization schedule, and relationships to other 

organizations such as the Redbook Committee, the American Public Health Association 

(APHA), and the Armed Forces Epidemiological Board (AFEB). No mentioned was made of 

AAFP, which was not in existence at that time. He read the committee’s responsibilities, which 

follow: 

“The Advisory Committee on Immunization Practices was appointed by the Surgeon 

General in May 1964. The committee is charged with the responsibility of advising the 

Surgeon General regarding the most effective application of public health practice of 

specific preventive agents, which may be applied in communicable disease control.” 

The initial committee had 10 members, and the Chair was Dr. James Goddard who was 

described in the New York Times Magazine as the “wild-eyed crusader with a battle axe flailing 

boldly,” which reminded Dr. Temte of Dr. Pickering. The first item on the agenda of note in 

terms of any immunization was influenza. With that prompt, Dr. Temte requested that Dr. 

Karron come forward to start the February 2014 meeting with a discussion of influenza. 

Influenza 

Novel Influenza Vaccines Work Group 

Dr. Doug Campos-Outcalt 

Chair, Novel Influenza Vaccines Work Group 

Dr. Campos-Outcalt gave a brief announcement regarding the formation of a new work group, 

which he was asked to chair, the Novel Influenza Vaccines Work Group (WG). The rationale for 

this work group is that there are now two Food and Drug Administration (FDA)-licensed H5N1 

vaccines available in the US, only indicated for high-risk populations, not for general or 

commercial use. There was believed to be a need for recommendations for use of these 

13 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

vaccines during a non-pandemic period. This new work group will review the evidence for the 

use of these two vaccines, and will make recommendations for their use only in high-risk 

populations. ACIP was seen as the most appropriate body to develop recommendations for 

these vaccines, and it was thought that the Seasonal Influenza Work Group’s workload 

precluded this additional task. 

The WG was formed and convened its first call. The plan subsequent to the February ACIP 

meeting was to meet every two weeks initially and then monthly as needed. The WG 

anticipates a vote during the October 2014 ACIP meeting. The future of this WG will be 

determined after completion of this initial task. 

In conclusion, Dr. Campos-Outcalt said he felt privileged to be able to chair this group and that 

he looked forward to the work they would be doing over the next year. 

Introduction 

Ruth Karron, MD 

Chair, Influenza Work Group 

Dr. Karron noted that the Influenza Work Group meets every other week and sometimes more 

often than that, and expressed her gratitude to those who take the time to help the work group 

with its deliberations. She particularly recognized Dr. Lisa Grohskopf who completed most of 

the GRADE analyses to be presented during this session, as well Sonja Olsen and Leslie 

Sokolow who contributed tremendously to those analyses. 

The Influenza Work Group has spent a considerable amount of time discussing and reviewing 

the evidence for the relative efficacy and safety of live attenuated influenza vaccine (LAIV) and 

inactivated influenza vaccine (IIV) for children. The group has also reviewed the GRADE 

analyses, and had a safety surveillance update on the Vaccine Adverse Event Reporting 

System (VAERS) and the Vaccine Safety Datalink (VSD). MedImmune has discussed the issue 

of LAIV supply with the WG . The WG has also heard from the US Flu Vaccine Efficacy 

Network about an interim estimate of the 2013-2014 seasonal influenza vaccine effectiveness. 

Dr. Karron pointed out that the deliberations and GRADEing for LAIV versus IIV in children were 

conducted independently, but because we live in a global community, she thought it would be 

useful for everyone to know something about preferential LAIV recommendations currently in 

existence. To her knowledge, LAIV is preferentially recommended in four countries at this point: 

United Kingdom (UK), Canada, Israel, and Germany. The preferential recommendations of 

these countries differ somewhat from country to country and are as follows: 

 United Kingdom: “[LAIV]...is strongly recommended as the vaccine of choice for children 

aged two years up to 18 years in clinical risk groups...” 

 Canada: “Based on effectiveness, efficacy and immunogenicity data, NACI recommends 

LAIV for use in healthy children and adolescents 2 through 17 years of age. Available data 

indicates that LAIV would be preferred over TIV in this population...” 

 Israel: “The Live Attenuated [Influenza] Vaccine is preferable to the Inactivated [Influenza] 

Vaccine in children two through 17 years of age due to its superior efficacy in this group.” 

14 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

 Germany: “STIKO recommends that LAIV should be used preferentially for influenza 

vaccination of at-risk children aged 2 through 6 years.” 

Interestingly and in addition, two US states have a preferential recommendation: Oregon and 

Washington State. These preferential recommendations follow: 

 Oregon: “The Oregon Immunization Program (OIP) preferentially recommends the use of 

Live Attenuated Influenza Vaccine (LAIV) in healthy children 2 through 5 years of age.” 

 Washington State: “Data suggest that LAIV is more effective than inactivated influenza 

vaccine (IIV) for children 2 through 7 years of age. If a provider has access to both LAIV 

and IIV, they should consider using LAIV for healthy children 2 through 7 years.” 

This session included presentations on the following topics: 

 Influenza Surveillance Update 

 Interim Vaccine Effectiveness Estimate, US Flu VE, Network, 2013-14 

 Relative Efficacy of LAIV vs. IIV for Children (GRADE) 

 Interim Influenza Vaccine Safety Update 

 LAIV vs. IIV—Comparative Safety Studies in Children 

 Relative Safety of LAIV vs. IIV for children (GRADE) 

 LAIV Supply Update 

 Annual Influenza Recommendations 

Influenza Activity Update 

Lyn Finelli, DrPH, MS 

Influenza Surveillance and Outbreak Response Team 

Epidemiology and Prevention Branch 

Influenza Division 

National Center for Immunization & Respiratory Diseases 

Centers for Disease Control and Prevention 

Based on the virologic surveillance data from the US World Health Organization and National 

Respiratory and Enteric Virus Surveillance System (NREVSS) collaborating laboratories, Dr. 

Finelli reported that for 2013-2014, there was a predominance of Influenza A virus. Of the 

influenza viruses that were characterized, Influenza A accounted for more than 95% (2009 

H1N1) depending on the week. At the peak, 31% of the viruses characterized were positive for 

influenza. As of February 15th, the percent positive of specimens declined to 14%. 

In terms of antigenic characterization from October 1, 2013 through February 15, 2014, of the 

Influenza A (2009 H1N1) viruses, 99.9% (919/920) were characterized A/California/7/2009-like, 

the H1N1 component of the 2013-14 Northern Hemisphere vaccine. For H3N2, 100% (86/86) 

were characterized as A/Texas/50/2012-like, the H3N2 component of the 2013-2014 Northern 

Hemisphere vaccine. For the Yamagata lineage of Influenza B, 62% (31/50) characterized as 

B/Massachusetts/2/2012-like, an Influenza B component of the 2013-2014 Northern 

Hemisphere vaccine. For the Victoria lineage of Influenza B, 38% (19/50) were from the 

B/Brisbane/60/2008-like, an influenza B component of the 2013-14 Northern Hemisphere 

vaccine. Regarding antiviral resistance, of the H3N2 viruses, none have antiviral resistance. Of 

the influenza B strains, none were resistant to antivirus. Of the influenza A (H1N1) viruses, 

15 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

3471 viruses have been tested. Of those, 26 (0.7%) were resistant to Oseltamivir and none 

were resistant to Zanamivir. 

ILI syndromic surveillance data in the Influenza-Like Illness Surveillance Network (ILINet) come 

from providers, clinics, and health departments that report to CDC the number of total visits they 

see each week and the number that are positive for ILI. There is a significant amount of 

coverage by ILINet throughout the US, with approximately 2900 reporters in the system actively 

reporting this year. Based on these data, this has been a moderate influenza season, which 

peaked in Week 52 at 4.6% contrasted by last year at 6.1%. Last year was a particularly bad 

influenza season. In terms of geographic spread, as of February 15th, there was primarily local 

or regional influenza activity in most of the US, with some widespread activity sustaining in the 

West and Northeast. Notably, these areas had a somewhat later influenza season than other 

areas in the country. 

Hospital surveillance data are reported from the Emerging Infections Program (EIP), which is 

comprised of data from 15 jurisdictions in the US that conduct population-based surveillance. 

Rates from the laboratory-confirmed influenza hospitalization FluSurvNet system from February 

14, 2013 through October 1, 2014 represent the reporting season. During that timeframe, there 

was an overall population rate of 26.1/100,000 which is contrasted with last year during which 

there was a rate of 35/100,000. As noted earlier, last year was a more severe influenza season. 

The highest rates were in those over 65 years of age (55/100,000). The next highest rates were 

in those 50 through 64 years of age (41/100,000). The rates cascade down after that with 

children 0 through 4 years of age (38/100,000) followed by those 18 through 49 years of age 

(18/100,000), and children 5 through 17 years of age (7/100,000). 

Regarding proportions of hospitalizations in different age groups for the last 5 years, 2013-2014 

had the highest proportion of hospitalizations in those 50 through 64 years of age and 18 

through 49 years of age. This compares to the pandemic year in the highest proportions of 

hospitalizations. It is not just that there were the highest proportions of hospitalizations in these 

age groups just because there were not a lot in elderly. In fact, these are the highest rates in 

these age groups since the pandemic. 

With regard to mortality data, there have been 52 influenza-associated pediatric deaths so far 

for 2013-2014. This system tends to lag somewhat compared to influenza activity, so more 

deaths are expected to accrue this year. In terms of the 122 Cities surveillance system, as of 

the peak during Week 2, 8.7% of all deaths in the US were influenza- and pneumonia-related, 

which is contrasted with last year at 9.9%. Again, the middle aged age group was somewhat 

more highly impacted. Looking at all pneumonia and influenza deaths, this change is not 

observed because pneumonia deaths occurred primarily in the elderly. However, just looking at 

influenza deaths, the 25 through 64 year old age group experienced a higher number of deaths 

this year than in the past few years. This is similar to the pandemic year, which was also an 

H1N1 year with 555 deaths in this age group compared to 352 this year, 138 in the 2012-2013 

season, 37 in the 2011-2012 season, and 190 in the 2010-2011 season. There tend to be more 

deaths in the elderly in an H3 year like last year with 556, and fewer in an H1 year like this year 

with 194. 

In summary, influenza activity in the US during the 2013–2014 season began in November 

approximately 4 weeks earlier than usual, and occurred at moderate levels. Activity peaked in 

late December to early January, depending upon the area of the country. Influenza A (H1N1) 

viruses predominated. There are higher rates of influenza-associated hospitalization in 2013­

2014 in persons 18 through 64 years of age than during the past several seasons. There were 

16 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

higher numbers of influenza deaths in the 122 Cities Mortality Surveillance System in 2013­

2014 in persons 25 through 64 years than during the past several seasons. 

In terms of why young and middle-aged adults were at higher risk for severe outcomes this 

season, preliminary vaccination coverage estimates for this season and past seasons indicate 

this age group has substantially lower vaccination coverage than other younger people and 

older age groups. This age group may lack the cross protective immunity to the pandemic 

H1N1 seen in adults over 65 years of age, likely acquired from past infection with antigenicallyrelated viruses. This age group had lower attack rates during the pandemic H1N1 pandemic 

and may have less cross protective immunity from that time as well. As adults reach middle 

age, they start to develop types of underlying conditions such as diabetes mellitus 

cardiovascular disease (CVD), and lung disease that increase the risk for complications from 

influenza and may be at higher risk for serious outcomes if infected. 

Discussion Points 

Dr. Temte inquired as to whether there are any systems that track or monitor deaths of pregnant 

women from influenza. 

Dr. Finelli responded that there are currently no systems. There was a pregnancy-related 

system in 2009-2010 and 2010-2011, but that system is no longer in operation. The pregnancy 

group at CDC is very keen on reinitiating that system, but so far, the states have not been able 

to provide the resources associated with reinitiating that system. 

Interim Estimates of 2013-2014 Season Influenza Vaccine Effectiveness 

Brendan Flannery, PhD 

National Center for Immunization & Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Flannery presented the mid-season estimates of the current seasonal vaccine effectiveness. 

These data are from the US Flu Vaccine Effectiveness (VE) Network through enrollment as of 

January 23, 2014. Current participation in the US includes 5 institutions: Group Health 

Cooperative in Seattle (PIs: Lisa Jackson, Mike Jackson); Marshfield Clinic Research 

Foundation in Wisconsin (PI: Ed Belongia); University of Michigan in the Detroit area (PIs: 

Arnold Monto, Suzanne Ohmit); University of Pittsburgh (Rick Zimmerman, Patricia Nowalk); 

and Baylor Scott and White Health in Temple, Texas (PI: Manju Gaglani). 

Regarding the methods used for estimating vaccine effectiveness in the Flu VE Network, the 

participating sites enroll outpatients 6 months of age and older with acute respiratory tract 

illness with cough of less than 7 days in duration. The data presented during this session were 

for the dates of enrollment beginning December 2, 2013 through January 23, 2014. The sites 

begin enrollment when there is circulating influenza activity in the area. This is a prospective 

case-control design, referred to as a test-negative design, which is slightly different from the 

traditional case-control design. In this test-negative design, all outpatients who are enrolled are 

tested for influenza by real-time reverse transcription polymerase chain reaction (RT-PCR). 

Cases are comprised of outpatients with confirmed PCR-positive influenza, while controls are 

outpatients who test negative for influenza. 

17 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Vaccination status for this analysis is defined as receipt of at least one dose of any 2013-2014 

seasonal influenza vaccine. While the records are used at all of the sites, receipt of vaccine is 

confirmed by medical records and registries at two sites. Self-reports were accepted from three 

sites, because the medical record searches are not complete. VE is estimated as in a 

traditional cases-control study, 1 – adjusted odds ratio (OR) x 100%. The estimates presented 

during this session were adjusted for study site, age, sex, race/Hispanic ethnicity, self-reported 

health, and days from illness onset to enrollment. 

This has been a predominantly H1N1 year, with the vast majority being 2009 H1N1 strain 

(N=742) identified among positive cases at the sites. This analysis included 2319 enrollees, of 

which 1535 (66%) were influenza RT-PCR negative and 784 (34%) were influenza RT-PCR 

positive. Among the 784, 742 were 2009 H1N1, 23 were A non-typed, 13 were H3N2, and 6 

were Influenza B. There were not enough H3N2 or B strains to provide any information about 

vaccine effectiveness for this season against H3N2 or B. 

In terms of enrollment by study week, more negatives were enrolled in every week during the 

period including Weeks 49 through 52 in 2013 and Weeks 1 through 4 in 2014. Positivity 

ranged from about 20% to 30% and declined slightly from the period of time the last group was 

enrolled that is included in this analysis. 

Regarding the interim adjusted VE estimates for 1 or more doses of 2013-2014 seasonal 

influenza vaccine, approximately 50% of influenza negatives were vaccinated among the 

enrollees versus about 29% of influenza cases or positive outpatients. Overall VE for A and B 

was 61% with a confidence interval of 52% to 68%. For 2009 H1N1, the numbers were very 

similar with 50% vaccinated among the negatives, 28% vaccinated among the influenza 

positives, and a VE of 62% with a very similar confidence interval of 52% to 69%. H1N1­

specific VE the percentage vaccinated among controls ranged from 79% among those 65 years 

of age and older to about 38% among 18 through 49 year olds. All of the influenza-positive age 

groups had a much lower percentage of vaccinated among the enrollees. VE estimates ranged 

from 67% with pretty tight confidence intervals (51% to 78%), to 56% in those 65 years of age 

and older with quite a wide confidence interval (7 to 79). Consistent VE is observed across all 

four age groups in contrast to what was seen last season with H3N2, with a wide confidence 

interval in those 65 years of age and older. 

For comparisons with other estimates of the pandemic H1N1 virus, data were assessed from 

several studies in several settings over four influenza seasons. For 2013-2014, these included 

a comparison of mid-season estimates from the USFluVE Network with recently published 

studies from Canada and estimates from Spain. For 2011-2012, these included a comparison 

of estimates from the USFluVE Network with Canada. For the 2010-2011 season, USFluVE 

estimates were compared specifically to Marshfield and estimates from Europe. Notably, all of 

the systems in Europe, Canada, and Spain use the same test negative design for their 

estimates. Therefore, study design does not explain the relatively small differences here. A 

recently published study with Mark Thomas as the first author was conducted among US 

pregnant women for the 2010-2011 and 2011-2012 to assess H1N1 VE for those two periods. 

The take-home messages is that the estimates seen for the mid-season is consistent with 2009 

H1N1-specific estimates observed essentially for every season since the 2009 pandemic. 

18 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

In conclusion, 2009 pandemic H1N1 virus predominated among influenza viruses identified from 

December 2, 2013 through January 23, 2014 in the US. It was also identified as the 

predominant virus in the USFluVE Network. The interim adjusted VE against 2009 pandemic 

H1N1 associated with medically attended acute respiratory infection (ARI) was 62% with a 

confidence interval from 53% to 69%. This estimate was similar for all age groups assessed, 

and was similar to VE estimates for 2009 pandemic H1N1 from previous seasons and in 

different settings. These estimates are consistent with laboratory data for the current season 

showing that the virus and vaccine virus remain a good match. The final analyses for the 2013­

2014 season will investigate the effects of prior vaccination. Hopefully, estimates will also be 

provided for vaccine types, specifically for live attenuated influenza vaccine (LAIV) versus 

inactivate vaccine. The ability to estimate VE for H3N2 or B infections this season will depend 

upon the final sample size. 

Discussion Points 

Dr. Duchin inquired as to whether it was possible to tell whether vaccine effectiveness varies 

according to whether the site used confirmed versus self-reported vaccination status in general. 

He also wondered whether any analyses were planned of VE according duration between 

immunization and illness—the waning protection issue. 

Dr. Flannery responded that an analysis will be performed at the end of the season to assess 

the effect of using confirmed versus self-reported vaccination status. Comparing the self-report 

and medical record data in this analysis from the sites that used both, additional people were 

detected as vaccinated using self-report information, so it is believed that the medical records 

are complete. The data are very similar when limited just to the medical records. Major 

differences are not anticipated in the final analyses. Regarding waning protection, Dr. Flannery 

noted that some of the data shown were from a group that uses sentinel hospital and outpatient 

settings in Europe specifically. They have shown intra-season waning in the second half of the 

season. For several seasons with H3N2 predominance, they have shown lower VE. CDC is 

still trying to address whether those are methodological issues or if there is true decrease in VE 

in the second half of the season. Their hypothesis is that people who are vaccinated early and 

have a long time before being infected may have lower levels of protection from vaccination. 

That would be a contrast to what has been observed with prior year vaccination offering some 

long-lasting protection. CDC is still assessing methodologies to evaluate that through the 

USFluVE Network, but is planning to do that with these datasets. There is a unique opportunity 

to look at a virus that essentially has not changed, and look at prior vaccination as well as the 

question of relation of immunity. 

Dr. Reingold thought it would be interesting to know whether effectiveness varied by whether 

people are healthy or not. 

Dr. Flannery replied that in the final analysis, co-morbid conditions were used that are defined 

based on identification of International Classification of Diseases (ICD)-9 codes, so there is 

verification of co-morbid conditions. This analysis was only adjusted for self-rated health status. 

That has been shown to be correlated with co-morbid conditions, but it is really not an analysis 

by co-morbid conditions. That will be done later. In terms of whether VE varied by whether comorbid conditions were present, adjusting for this made no difference. A separate analysis has 

not been done for levels of self-rated health. 

19 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Regarding the wide confidence intervals for VE in individuals over 65 years of age for the H1N1 

sub-type, Dr. Coyne-Beasley noted that there were very wide confidence intervals in the 

categories of Influenza A and B as well. She wondered whether that was solely related to the 

fact that there were fewer people in that age range who were influenza-positive, or if Dr. 

Flannery thought that other factors contributed to such a wide estimate. 

Dr. Flannery said that essentially, the 65 years of age and older population is a more difficult 

group to enroll in outpatient settings. All five of the sites have made extra efforts to increase 

their enrollment of people 65 years of age and older. The number of people enrolled is the 

actual limitation, so the confidence intervals are wider because the numbers are lower. The 

percentage influenza-positive is similar in this group. Canada has a slightly younger population 

overall. Only about 5% of their population is 65 years of age and older for their enrollees. In the 

US study population it is about 15%, which reflects the additional efforts the sites have gone to 

in order to enroll patients 65 years of age and older. That does not explain the difference shown 

in Canada, but CDC believes the differences are less than the similarities. The estimates for 

H1N1 are pretty similar. 

In response to a question regarding enrollees, Dr. Flannery responded that this is active 

surveillance. Subjects are recruited and consented to participate in the study, and they all 

present to a participating clinic with ARI and cough. 

Dr. Jenkins inquired as to whether self-reports would be included in the analysis of the effect of 

prior vaccination. It seemed like for prior vaccination, reliability might decrease. 

Dr. Flannery responded that self-report was not included for the analysis for vaccine type at the 

end of the season or for prior vaccination. Given that it is very difficult to tease out current and 

prior VE effects, and that this is such a “hot” area right now in influenza, that analysis is limited 

to verified vaccination. 

Dr. Kimberlin (AAP) was struck by the one-third of tested samples that were PCR-positive for 

influenza. In virtually all of the prospectively performed treatment studies, the rate of detection 

using similar methodology in terms of fever, cough, and so forth has been two-thirds positive 

and one-third negative. 

Dr. Flannery replied that for reasons of sensitivity and to try to get as many influenza-positive 

cases as possible, all five participating sites decided to use acute respiratory illness with cough 

as their case definition. If they limit it to ILI (people needing a definition of cough, additional 

respiratory symptoms, and fever for ILI) that would increase the proportion positive. Using an 

ILI definition as is done in Canada, the percentage of influenza positives actually increases 

compared to the outpatients who test negative. Fever especially increases the specificity of the 

case definition. That is a major difference with the USFluVE Network. 

Dr. Gorman (NIH) asked whether the one-month discordance between the CDC dataset from 

early January and the peak of the influenza season that seemed to peak in December had any 

impact on the efficacy data. 

Dr. Flannery did not think so, although there could be a question about timing and whether there 

is some change in VE during the season. Last season, with the very early onset of the influenza 

season, some of the sites had to scramble to begin enrolling patients in the beginning of the 

season. They also had a change at the end of the season to a predominance of B circulating at 

some sites. It was good for the VE estimates to have enough B to assess by B lineage for the 

20 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

final VE that was presented here. There has not been enough antigenic change in the H1N1 

virus to say that there is not an accurate representation of VE, because of the period of time. 

Final analyses do control for calendar time because there are those differences of cases and 

controls who are enrolled by sites depending upon their local influenza circulation and when 

they start. Dr. Flannery did not believe it meant in this particularly case that they missed the 

influenza season or were late in enrollment, because each site essentially begins once they see 

influenza. This is a more efficient approach. 

Dr. Gorman (NIH) observed that two of the sites seemed to have electronic medical record 

(EMR) capabilities and the ability to search medical records. If the previous year influenza 

vaccinations were limited, he wondered whether that would be a possible way to assess that. 

Dr. Flannery responded that all of the sites have EMRs. Most of them also receive data from 

state immunization registries, and may receive vaccination data from other sources. Extra 

effort is made at most sites. If someone says they were vaccinated and they have a provider, 

the study site may actually seek that information to try to document it. A large difference has 

not been observed with the mid-season estimates and the full-season estimates, which includes 

only verified vaccination. Some may not be possible to verify, and the previous year’s estimates 

seem to be decreasing from the early, to the mid, to the end of season. But some of that 

pertains to co-morbid conditions and other variables for which adjustments can be made. He 

did not believe that they were missing things because of the way vaccination status is being 

used here. 

Ms. Stinchfield (NAPNAP) said she appreciated the emphasis on the outpatient. She was 

thinking about how this is communicated, and how it often is translated to whether vaccines 

work and the percentages—people and a number. This is VE and ARI in an outpatient setting, 

which does not fit on a Tweet or headline. She thought it was important as they communicated 

this information, they must emphasize that these are patients in the outpatient setting who 

presented to clinics—not overall vaccine effectiveness against all influenza. She wondered 

about assessing effectiveness with inpatient hospitalizations and impact on deaths. 

Dr. Flannery responded that CDC is interested in evaluating the impact of vaccination on 

hospitalizations, but these are difficult studies to conduct and CDC does not currently have a 

surveillance system that assesses inpatient VE. CDC is also interested in assessing VE against 

pediatric deaths specifically because of the pediatric mortality surveillance system. The 

question regards finding a good comparison group to be able to evaluate what would be 

expected for vaccination in that population. As noted in the MMWR the previous week, overall 

vaccination is much lower than would be expected in groups that have been hard hit this year. 

In the pediatric mortality surveillance, the percentage vaccinated is much lower than what would 

be expected. CDC is very interested in these two areas, especially with regard to the vaccine 

communication messages and how important vaccination is to prevent severe outcomes. 

Ms. Pellegrini asked whether it was true every year that vaccination rates were lower among 

those 18 through 49 and 50 through 64 years of age. 

Dr. Flannery clarified that regarding the message from the surveillance that those populations 

were hard hit, it would be nice to be able to have VE in inpatients in that age group to say that 

the vaccine is effective against inpatient disease. It is true that every year, those age groups 

have had low vaccination coverage. This year, that has been a focus of media or 

communication of messages about these being important groups to vaccinate because they 

have high severe illness and hospitalization rates. 

21 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Effectiveness of LAIV vs. IIV for Healthy Children (GRADE) 

Dr. Lisa Grohskopf 

Influenza Division 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Grohskopf noted that the next several presentations would be related to the use of LAIV and 

IIV among children, particularly among younger children. No change in the recommendations 

for these vaccines in children was proposed for this meeting. It is anticipated that there will be 

further discussion within the Influenza Work Group, and that this topic would be revisited in June 

2014. 

According to current CDC and ACIP recommendations, healthy children aged 2 through 17 

years may receive either LAIV or inactivated influenza vaccine. Several studies indicate that 

LAIV may have advantages over IIV for children. This is somewhat in contrast for adults, for 

whom comparative studies have generally indicated either that the two vaccines are similarly 

efficacious or perhaps that the inactivated vaccines are somewhat better. Particularly for 

younger children, there are several lines of evidence indicating better vaccine efficacy for LAIV, 

better onset of immune response and duration of immunity, and better heterotypic protection 

against drifted strains [Belshe NEJM 2007; Ashkenazi PIDJ 2006; Bernstein PIDJ 2003; Belshe 

NEJM 1998]. 

Currently, the ACIP recommendations express no preference for LAIV versus IIV for children for 

whom either is indicated. However, recent recommendations (e.g., within the last two years) 

have been published over the last several years in several other countries and US states 

expressing some degree of preference for LAIV for children. The age specifications of this 

preference vary, with Canada, the UK, and Israel stating a preference for children aged 2 

through 17 years and Germany, Oregon, and Washington State limiting the preference to 

younger children. 

To frame some recent background, the ACIP Influenza WG selected the comparison of LAIV 

and IIV for children as the first policy question to be addressed using GRADE. A preliminary 

GRADE efficacy assessment was presented during the October 2012 ACIP meeting. At that 

time, the safety assessment was deferred, in large part because the trivalent formulation of 

LAIV (LAIV3) was anticipated to be replaced with a quadrivalent formulation (LAIV4) in 2013­

2014, which has occurred, and no post-marketing safety data were yet available for LAIV 4. 

The objective of the series of presentations during this meeting was to describe GRADE 

assessments for the safety and efficacy of LAIV versus IIV for healthy children, in particular 

younger children. 

The policy question posed was “should LAIV be recommended preferentially over IIV for healthy 

children.” Healthy children were specified for this initial assessment, because LAIV is currently 

recommended for children without medical conditions that confer a higher risk of severe illness 

from influenza. Data were assessed separately for younger versus older children, stratified into 

ages 2 through 8 years and 9 through 18 years. The rationale for the selected age categories 

and the break point at 8 years was that LAIV is not licensed for children under 2 years of age, 

so the lower limit was relatively simple to define. The upper limit was less straightforward. 

While superior efficacy of LAIV has been demonstrated in children, it has not in adults, and it is 

not clear at what age the better relative efficacy of LAIV begins to decline. Eight years is the 

22 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

upper limit of the age range for consideration of whether a child needs 1 versus 2 doses of 

influenza vaccine, and was selected for simplicity of the recommendations. 

Studies included contained data pertaining to healthy children primarily, although one study 

specifically was of children with asthma; data pertaining to vaccines licensed in the US or similar 

to US-licensed vaccines; and studies including both LAIV and IIV arms. Only literature in 

English was used. Excluded were data for adjuvanted, whole virus, and virosomal vaccines; 

data for LAIV produced using different seed strains from US products; studies in which all 

participants were outside of the indicated age range; and studies with outcomes defined by ICD9 codes only. 

The WG had several discussions about generating lists of relevant outcomes and assigning 

values to them. The outcomes of laboratory confirmed influenza (confirmed by culture or PCR) 

and influenza-associated mortality and hospitalization were considered critical. Medically 

attended acute respiratory illness (MAARI), influenza like illness (ILI), and influenza-associated 

otitis media (OM) were considered important. The literature review through PubMed identified 9 

papers, including 5 randomized trials and 5 observational studies. 

Of the 5 randomized trials, 2 were open label. These included Ashkenazi et al 2006, a study of 

6 through 71 month olds with a history of recurrent respiratory tract infections; and Fleming et al 

2006, a study of children aged 6 through 17 years with asthma. Belshe (2007) assessed 

children 6 through 59 months. Regarding the blinded studies, with the exception of Neuzil et al 

(2001), which included data from 5 influenza seasons, each study was conducted over a single 

season. Not surprisingly, not every study included every outcome. The most data were 

available for laboratory confirmed influenza, and there were no data for influenza-related 

mortality. Of note, Fleming (2006), Neuzil (2001), and Clover (1991) included both age groups 

of interest, and the results for the outcomes needed were not age-stratified, such that the data 

as reported spanned both age groups of interest. These data were examined separately as a 2 

through 18 year old group, without stratification into the two age groups of interest. This 

analysis was not part of this presentation. 

In terms of the characteristics of the observational papers and studies, Treanor et al (2002), 

Ohmit et al (2013), and Fry (2013) summarize three successive seasons for data from the US 

Flu VE network. Macintosh (2013) and Eick-Cost (2013) come from the Department of Defense 

(DoD). The observational studies reported only laboratory-confirmed influenza as an outcome, 

and contributed to the assessment of laboratory-confirmed influenza. 

Because lab-confirmed influenza is an important outcome that figured heavily into this 

presentation, Dr. Grohskopf took some time to describe how this information was collected in 

the various studies—particularly, what the criteria were for collecting specimens for culture. The 

main thing to note is that collection of cultures in each case was prompted by symptoms of 

clinical illness in the participants. The specific criteria used, as reported in the papers, varied 

somewhat, with some criteria (such as that of Ashkenazi and Fleming) being more detailed than 

others. The take home message is essentially that in general, there was manifestation of an 

illness, although in Ashkenazi and Belshe cultures could also be obtained at the investigators’ 

clinical discretion, even if the child did not quite meet the definition that was cited. The outcome 

with the most data was lab-confirmed influenza, with all 10 papers contributing. Seven papers 

contributed to the assessment of children ages 2 through 8 years. Five papers contributed to 

the assessment of children ages 9 through 18. No papers contributed data on mortality due to 

influenza. For hospitalizations, two papers contributed to assessment of children ages 2 

through 8 and one contributed to assessment of children ages 2 through 18. For MARRI, two 

23 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

papers contributed to assessment of children ages 2 through 8 and one contributed to 

assessment of children ages 2 through 18. For ILI, one paper contributed to assessment of 

children ages 2 through 8 and one contributed to assessment of children ages 2 through 18. 

For OM, two papers contributed to assessment of children ages 2 through 8 and two contributed 

to assessment of children ages 2 through 18. 

Next, Dr. Grohskopf presented results for the younger age group, 2 through 8 years. 

Laboratory-confirmed influenza, which was considered a critical outcome, included two studies: 

Ashkenazi et al and Belshe et al. Both of these studies included children who are younger than 

2 years of age, the indicated age for Flumist®, but the majority were 24 months and older. 

Studies were not downgraded for risk of bias, inconsistency, indirectness, or imprecision. In 

pooled analysis, significant relative benefit of LAIV was noted, with a risk ratio of 0.46 for labconfirmed influenza and a 95% confidence interval of (0.39 to 0.54). Overall evidence quality 

was therefore rated as high. 

Data from the same two studies restricted to those aged 24 months and older were published by 

Ambrose et al in a subsequent meta-analysis [Vaccine 2012]. In this paper, lab-confirmed 

influenza was the only outcome discussed. Studies were not downgraded for risk of bias, 

inconsistency, indirectness, or imprecision. In pooled analysis, significant relative benefit of 

LAIV was noted, with a risk ratio of 0.47 and only a slight widening of the confidence interval, 

which would be anticipated due to having slightly less data. Overall evidence quality was 

assessed as Type 1 or High. 

Regarding summary information for lab-confirmed influenza from observational studies, as 

noted earlier these various reports included children of different age groups. For this analyses, 

however, the authors were able and kind enough to provide the data stratified specifically to the 

work group’s age categories of interest. There is some heterogeneity in the point estimates; 

however, there is also appreciable overlap of the confidence intervals, so there was no 

downgrade for inconsistency in that regard. The confidence interval was somewhat on the wide 

side, and on that basis the Results were downgraded for imprecision. This downgraded the 

overall quality of evidence for this outcome from 3 or Low (the initial rating for observational 

studies) down to Very Low. 

The next outcome is hospitalization, which was also a “critical” outcome. Influenza-specific 

hospitalizations were desired rather than all-cause hospitalizations. Such data were not 

available; however, Ashkenazi reported hospitalizations for respiratory illness. This was more 

similar to ILI-related hospitalization than influenza-related hospitalization. Therefore, this study 

was downgraded for indirectness, since they were not influenza-related hospitalizations 

specifically. The study was also downgraded for imprecision, given the width of the confidence 

interval, which straddles 1. No significant difference was observed between the two vaccines. 

Overall evidence quality was Type 3, Low. 

Medically-attended acute respiratory illness was also a “critical” outcome, for which Ashkenazi 

et al provided data. This study was downgraded for indirectness because the outcome is not 

influenza-specific. No significant difference was noted. Overall evidence quality was 2, or 

Moderate. 

The influenza-like illness outcome was valued as “important.” The results were downgraded for 

indirectness, as this outcome is not influenza-specific. No significant difference was noted 

between the two vaccines. Overall evidence quality was Moderate. The last outcome for this 

age group is otitis media, which was deemed “important.” Both the Ashkenazi and Belshe 

24 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

studies included this outcome. No serious concerns were identified for risk of bias, 

inconsistency, indirectness, or imprecision. Overall evidence quality was deemed high. The 

pooled risk ratio was 0.47, and was significant. 

For the age group 9 through 18 years, laboratory-confirmed influenza was considered to be a 

“critical’ outcome.” The 5 observational studies contributed data. These results were 

downgraded for imprecision, given the width of the confidence interval around the pooled 

estimate. This downgraded the overall quality of evidence for this outcome from 3 or Low (the 

initial rating for observational studies) to 4 or Very Low. The pooled odds ratio was not 

significant for a difference between LAIV and IIV. 

In addition to the relative efficacy of LAIV versus IIV among young children, there are other 

important considerations as the WG moves forward and formulates a decision. Harmonization 

with the American Academy of Pediatrics (AAP) recommendations is an important 

consideration, and it is anticipated that there will be more discussion on that matter in the 

coming months. LAIV supply is also an important issue if there is going to be a preference. As 

mentioned earlier, the safety of the newer quadrivalent vaccines, for which no data are available 

among the cited studies, is an important consideration. Another important matter is the relative 

cost of the two vaccines. Direct comparisons are somewhat complicated by the fact that in 

contrast to LAIV, for which there is only one formulation, there are numerous presentations for 

IIV available (e.g., trivalent, quadrivalent, single and multidose vials, and syringes). Per the 

Vaccines For Children (VFC) private sector prices, for 2014-2015, the cost of LAIV4 is roughly 

similar to that of the most expensive quadrivalent inactivated vaccine. 

To summarize the outcomes, for the critical outcome lab-confirmed influenza decreased risk 

with LAIV was noted, and overall evidence quality was 1 or High. Quality was 3 or Low for 

hospitalization, and 2 or Moderate for MAARI. No differences in these two outcomes were 

noted. For the important outcomes, no differences were observed between the two vaccines for 

otitis media and evidence quality was moderate. For otitis media, decreased risk was observed 

with LAIV and evidence quality was 1 or High. For 9 through 18 year olds for lab-confirmed 

influenza, there were no differences and overall quality of evidence was 4 or Very Low. 

Discussion Points 

Dr. Temte noted that GRADE was starting to feel routine. 

Dr. Kempe asked whether the other four countries with a preferential LAIV recommendation for 

young children were assessing different data that are non-English, and what kind of criteria 

those countries were using in terms of precautions for children with asthma. 

Dr. Grohskopf replied that the literature cited is not known for all countries, but based on what is 

known, the literature appears to be essentially the same overall. For Germany, for example, 

Falkenhorst et al published a GRADE analysis of this very recently, and the literature is largely 

the same. However, they did their analysis for older children slightly differently using a paper by 

Fleming. CDC is highly interested in children with chronic illnesses, particularly with asthma, 

because that group is at higher risk for influenza complications. Thus, it is important to have the 

best possible vaccine for them. There is some variability in Canada in that for controlled 

asthma, there would not be any prohibition to using LAIV and it would be preferred in that 

population. Not everything reads the same way that it does for the current US 

recommendations. More discussion is anticipated in the WG about that particular issue. 

25 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Warshawsky (NACI) added that Canada updated its preferential recommendation in their 

statement in November 2013, acknowledging that there is clear evidence for children 2 through 

6 year olds. However, the evidence for children through 17 years of age is not quite as clear, so 

it is not clear when the cutoff would be. Canada used the Fleming article in its assessment of 

the older age group, which is the one RCT that goes up to that age group and is in asthmatics. 

Canada thought that it offered some evidence that there is some superior efficacy in that age 

group, although it is not clear when that cuts off and it is only one study. That was the reason 

Canada reviewed its recommendations to state that they are clear on the evidence up to 6 years 

of age, but that beyond that they were not clear on higher age groups or the cutoff. Canada’s 

recommendations are for healthy children only, and recommended that the vaccine be used in 

chronic illness conditions. However, Canada does not have a preferential recommendation in 

chronic illness because there are no data to support that. 

Dr. Decker (Sanofi Pasteur) acknowledged that the data overall suggested that there is an 

efficacy relationship benefit in younger children, that there are benefits from IIV in older people, 

and that it is not clear what the transition is. Presumably the difference is because of 

experience with the virus previously or experience with vaccine previously—something like that. 

In that regard, the fact that the newest study assessing efficacy was conducted over a decade 

ago and the oldest almost two decades ago, raised a question in his mind. It was not influenza 

that had changed, but the population. He believed that CDC showed that younger children were 

far more likely to be vaccine-experienced now than they were 10 or 20 years ago. In that 

regard, he knew that MedImmune was in the process of conducting a post-marketing 

commitment trial to generate current estimates of efficacy by year of age. In light of that, he 

wondered if the committee planned to wait to review those data, or go ahead on the basis of the 

10 or 20 year old data. 

Dr. Grohskopf responded that at this point, the WG was continuing to have discussions about a 

number of topics. It is true that the Belshe and Ashkenazi studies were conducted at a time 

when most children were vaccine-naïve simply because of the recommendations at that time. 

She anticipated that the WG would continue to have discussions regarding this issue. 

Dr. Karron added that it certainly is true that fortunately many more children are currently 

immunized against influenza than when those studies were conducted. Currently, a relatively 

small proportion of children are receiving LAIV. Data that she saw most recently indicated 

about 7% to 10% of children in that age group. It is certainly known that with IIV, immunity 

wanes—even by the springtime. She wondered if they assessed children with an IIV 

immunization background, who are most likely to be the majority of children immunized, if that 

would make a difference. She thinks the best way over time to evaluate repeated LAIV 

immunizations will be through the type of data collected by the VE Network that actually stratify 

by immunization status. 

Dr. Decker (Sanofi Pasteur) thinks the concern is that as one acquires immunity over repeated 

experience, and there is enough nasal antibody, LAIV does not have the chance to stimulate an 

immune response before getting squashed by what someone already has. That is the 

conjecture as to why there is an age transition, and after a while, IIV works better than LAIV. 

26 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Interim Influenza Vaccine Safety Update: LAIV and IIV in Persons <18 Years of Age 

Maria Cano, MD, MPH 

Immunization Safety Office 

Centers for Disease Control and Prevention (CDC) 

Dr. Cano gave an interim influenza vaccine safety update for LAIV and IIV influenza vaccines in 

persons less than 18 years of age in the US for the time period July 1, 2013 through December 

31, 2013. Recently licensed influenza vaccines that became available during the current 

season are listed in the following table: 

Vaccine Abbreviation Brand Name (Manufacturer) Recommended Age 

Group 

Quadrivalent live 

attenuated influenza 

vaccine 

LAIV4 FluMist®

 Quadrivalent (MedImmune) 2 through 49 yrs 

Fluarix® Quadrivalent (GlaxoSmithKline) 

Fluzone® Quadrivalent 

(Sanofi Pasteur) 

Flulaval® Quadrivalent 

(GlaxoSmithKline) 

>3 years 

>6 months 

>3 years 

Quadrivalent inactivated 

influenza vaccine IIV4 

Cell culture-based trivalent 

inactivated influenza 

vaccine 

ccIIV3 Flucelvax® 

(Novartis) >18 years 

Recombinant trivalent 

inactivated influenza 

vaccine 

RIV3 FluBlok® 

(Protein Sciences) 18 through 49 years 

There was a complete switch to quadrivalent LAIV influenza vaccine this season, so comparison 

between the trivalent and quadrivalent forms will be between seasons. For IIV, both trivalent 

and quadrivalent forms are available, and the comparison is done within the current season. 

CDC reviewed US VAERS reports after LAIV or IIV, with report dates from July 1, 2013 through 

January 31, 2014 and vaccination dates from July 1, 2013 through December 31, 2013. LAIV4 

this season is compared to last season’s LAIV3. IIV4 versus IIV3 is a within season 

comparison. Adverse events that were reviewed and coded into the VAERS database using the 

Medical Dictionary for Regulatory Activities (MedDRA). MedDRA terms of note are not mutually 

exclusive, and a report may have several different MedDRA terms. FDA conducted empirical 

Bayesian data mining to detect disproportional reporting in the VAERS database [Banks D, et 

al. Comparing data mining methods on the VAERS database. Pharmacoepidemiology and drug 

safety 2005;14:601-9]. 

As a reminder, VAERS is co-managed by CDC and FDA. The strengths of VAERS is 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. 

27 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

A summary of reports to VAERS following LAIV among those aged 2 through 17 years, the 

recommended age group in children, are shown in the following table: 

LAIV4 

2013-14* 

Total N = 276 

N (%) 

LAIV3 

2012-13* 

Total N = 244 

N (%) 

Serious reports 

† 25 (9) 23 (9) 

Male 128 (46) 115 (47) 

Median age (yrs) 7 7 

Median onset interval (days) [range] 1 [0-99] 0 [0.5-44] 

LAIV given alone 163 (59) 127 (52) 

A report is considered “serious” based on the Code of Federal Regulations if one of the 

following is reported: death, life-threatening illness, hospitalization or prolongation of 

hospitalization or permanent disability. A limitation of this classification is that any reporter can 

classify an adverse event even if it does not appear to be a life-threatening condition, which is 

one of the criteria for a serious report. It is important to look at the percentage rather than the 

actual numbers when comparing the results. Of the reports 9% were classified as serious for 

both vaccines, 46% were males for LAIV4 versus 47% for LAIV3, and the rest of the findings for 

LAIV 4 and LAIV 3 are comparable. 

In comparing adverse events that are of particular interest for LAIV, the grouping of terms were 

based on MedDRA codes. For anaphylaxis and seizures, the onset interval was 0 (day of 

vaccination) to 1 day after vaccination. Overall results for LAIV4 are comparable to those of 

LAIV 3. For the current season, approximately 12.5 million LAIV4 doses were distributed in 

2013-2014, and approximately 13 million LAIV3 doses were distributed in 2012-1413 for all 

ages. There was no disproportional reporting in data mining for the pre-specified terms for the 

season of Guillain-Barré Syndrome (GBS), seizures, febrile seizures, or anaphylaxis for the 

2013-2014 season as of January 31, 2014. 

With respect to the top 12 MedDRA terms following LAIV given alone in children ages 2 through 

17 years, pyrexia is the most common adverse event for both vaccines. Most of the top adverse 

events (e.g., cough, vomiting, urticaria, headache) following LAIV4 also appear for LAIV3 for 

last season. With regard to US reports to VAERS following IIV in those ages 6 months through 

17 years, as a reminder this was an in-season comparison between IIV4 and IIV3. There were 

121 total reports for IIV4 and 715 for IIV3. Of the reports, 10% were classified as serious for 

IIV4 versus 7% for IIV3. Gender, median age, median onset interval, and percent IIV given 

alone were similar for both vaccines. In terms of the adverse events noted for inactivated 

influenza vaccines, the results were comparable for IIV4 and IIV3. For this season, 

approximately 12.9 million IIV4 and about 122.6 million IIV3 doses were distributed for all ages. 

There was no disproportional reporting in data mining for GBS, seizures, febrile seizures, or 

anaphylaxis for the 2013-2014 season as of January 31, 2014. Regarding the top 12 MedDRA 

terms following IIV given alone in those ages 6 months through 17 years, injection site erythema 

was the most frequent adverse event for IIV4 and IIV3. As expected, the most frequent adverse 

28 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

events were injection-type reactions such as injection site erythema, warmth, swelling, and pain 

for both vaccines. 

Turning to Vaccine Safety Datalink (VSD) surveillance for the 2013-2014 influenza season, 

Rapid Cycle Analysis (RCA) was performed for the pre-specified outcomes of anaphylaxis, 

acute disseminated encephalitis, encephalitis, transverse myelitis, GBS, Bell’s palsy, and 

seizures. With the exception of anaphylaxis, the outcomes were neurologic adverse conditions. 

Interim data for RCA analysis during the current season show that as of January 16, 2014, 

approximately 194,080 doses of LAIV4 Dose 1 and approximately 3 million doses of IIV3 Dose 

1 had been administered. Thus far, there has been limited uptake of IIV4 (19,182 Dose 1 

doses), the cell culture-based IIV3, and recombinant IIV3. There were no signals in RCA during 

the 2013-2014 influenza season for any of the pre-specified outcomes. 

Dr. Cano briefly described one of the Clinical Immunization Safety Assessment (CISA) projects, 

a fever study in children ages 24 through 59 months after LIAV IIV using text messaging for US 

influenza vaccines. Columbia University and CDC are conducting an observational study of 

influenza vaccine safety during 2012-2013 and 2013-2014. The primary aim of this study is to 

assess rates of fever in 24 through 59 month old children receiving LAIV compared to children 

receiving IIV in the 0 to 10 days after vaccination. Regarding the design, children receive LAIV 

or IIV per usual care, with or without other childhood vaccines. Temperatures are monitored 

daily via text messaging. Preliminary data are expected by June 2014. 

In summary, no new safety concerns were detected for LAIV4, IIV4, or IIV3 during the 2013­

2014 influenza season in persons less than 18 years of age. VAERS and VSD surveillance 

data were both studied. A comparable safety profile was observed for LAIV4 versus LAIV3 and 

IIV4 versus IIV3 in persons less than 18 years of age. Influenza vaccine safety monitoring in 

VAERS, VSD, and CISA is continuing. 

Discussion Points 

Regarding the top MedDRA terms following LAIV administration, Dr. Karron noted that one of 

those was injection site erythema and requested that Dr. Cano comment on that in the context 

of LAVI. 

Dr. Cano replied that LAIV is also given with other injectable vaccines, which was why there 

were local types of reactions. 

Dr. Sawyer (PIDS) was surprised by the low uptake of IIV4 in the VSD study population, and 

wondered whether that was representative of the distribution across the country or if it was an 

artifact of the VSD sites and decisions by groups like Kaiser to not use that vaccine. 

Dr. DeStefano (ISO) responded that he was not familiar with the national data in terms of uptake 

or coverage with LAIV. 

Dr. Rubin asked whether it was possible to break out the VSD data in terms of seizures looking 

at the younger age group 2 through 8 years of age versus 2 through 49 years of age to 

determine whether there was any difference in seizures. 

Dr. DeStefano (ISO) responded that it is possible to stratify the data in other age groups, but 

that had not yet been done. The strata shown are the ones used thus far. 

29 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

For reference, Kim Bradley (GSK) reported that GSK distributed 10 million doses of quadrivalent 

vaccine during the last season. 

Phil Hosbach (Sanofi Pasteur) indicated that Sanofi Pasteur distributed about 7.5 million doses 

of quadrivalent vaccine. Their estimates from publicly available data are that of all of the 

quadrivalent vaccines available, which would probably include LAIV4, 80% went into 6 month 

olds to 18 year olds. Therefore, it seemed as though the data were somewhat off for these 

groups. 

LAIV vs. IIV Comparative Safety Studies in Children 

Emmanuel (Chip) Walter, MD, MPH 

Duke University Medical Center 

Dr. Walter discussed the comparative safety studies in children for trivalent LAIV and IIV 

influenza vaccine. The Pediatric Influenza Vaccine Safety Evidence Review Group was 

charged with trying to assist the GRADE process by conducting an evidence review for 

influenza vaccine safety in children 2 through 8 years of age. This group consists of experts 

from CDC and CISA. CISA is a collaborative national network of vaccine safety experts from 

the CDC’s Immunization Safety Office (ISO), seven medical research centers, and other 

partners, which is charged with providing a comprehensive vaccine safety public health service 

to the nation. CISA conducts research and reviews clinical cases and issues about vaccine 

safety. 

The objective for the evidence review for influenza vaccine safety in children 2 through 8 years 

of age was to evaluate the evidence for the safety of trivalent live, attenuated influenza vaccine, 

compared with trivalent inactivated, influenza vaccine in children aged 2 through 8 years using 

the ACIP GRADE process. The safety outcomes selected and considered to be “Critical” 

included immediate hypersensitivity/anaphylaxis, febrile seizure, medically-attended wheezing 

(MAW), and GBS. The safety outcomes selected and determined to be “Important” included 

other neurologic outcomes and respiratory symptoms. 

All of these safety outcomes were discussed intensively in the smaller WG , as well as in the 

larger CISA WG. Other neurologic outcomes and respiratory tract symptoms, which were 

GRADEd as “Important,” were fairly non-specific. Thus, there were not included in the final 

safety analysis. Several outcomes were assessed (anaphylaxis, immediate hypersensitivity, 

febrile seizure, and GBS) that were not selected as final safety outcomes for this review, given 

that these events are fairly rare or uncommon and there is limited information for review in terms 

of comparative studies of LAIV versus IIV. The decision was made to keep MAW for review 

because it is common and clinically important. Fever was added as an outcome for these 

studies because it is common, it is medically important, it is somewhat comparable across the 

studies, and it is a potential proxy for febrile seizure risk. SAEs were also added as an outcome 

because they are considered to be important, they have been used in other safety reviews, and 

they include some of the rare and less common events. 

In terms of the methods used for this evidence review, eight publications directly comparing 

LAIV to IIV3 were selected for review. These manuscripts were reviewed by members of the 

work group using grading sheets. The WG reviewed outcome definition, study design, season, 

ages of study population, sample size, and limitations or potential for biases. For the 

randomized trials, allocation concealment, blinding, loss to follow-up, failure to adhere to an 

intention to treat analysis, stopping early for benefit, and failure to report an outcome were 

assessed. For the observational studies, failure to apply and develop appropriate eligibility 

30 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

criteria, flawed measures for exposures or outcome, and failure to control for confounding were 

evaluated. Each study was also reviewed for indirectness in terms of population; intervention; 

outcomes differing from those of interest; and whether vaccines were each compared with a 

placebo, but not one another. Assessments were reviewed by the Pediatric Influenza Vaccine 

Safety Evidence Review Group, CISA investigators, and the ACIP Influenza WG. 

Amongst the trials, three were initially chosen but were then excluded for various reasons from 

the safety assessment. The Clover study was conducted in the years 1986-1987 in a 

population of children 3 through 19 years of age. It was a double-blind placebo controlled study 

of approximately 200 children comparing IIV and nasal saline placebo to saline placebo injection 

and bivalent LAIV. However, no safety outcomes were described in that study so it was 

eliminated from the safety assessment. The Neuzil study was conducted for the years 1985­

1990 in healthy persons 1 through 65 years, and reported on subjects less than 16 years of age. 

This was a randomized controlled trial; however, in terms of the outcomes of interest in the 

manuscript, only fever was described. The study was also somewhat problematic in making 

comparisons in that Group 2 who received the LAIV only containing two Influenza A strains also 

received an inactivated monovalent B strain, so a head-to-head comparison could not be done. 

Thus, it was omitted from the analysis. The Holloran study was an open label non-randomized 

community-based intervention conducted over several years in children 5 through 18 years of 

age, with a fairly large number of subjects. However, the safety outcomes were not described in 

this study so it was eliminated from the assessment. 

That left five evaluations for the safety assessment. The Ashkenazi and Fleming studies are 

fairly comparable studies conducted in the same year or same season. The Ashkenazi study 

was conducted in younger children who had recurrent respiratory tract infections; whereas, the 

Fleming study was conducted in children 6 through 17 years of age with asthma. They were 

both open-label randomized studies with about the same number of subjects (N=~2000 in 

each), and children and adolescents were randomized to get either IIV3 or LAIV. The Belshe 

paper described a study conducted in the years 2004-2005 that was conducted in children 6 

through 59 months of age. This study included some children with wheezing or history of 

asthma. It did not exclude those children. It was a double-blind placebo-controlled study in 

which children received either IIV and LAIV placebo, or received IIV3 placebo and LAIV. About 

8000 children were enrolled in that study. The Toback and Baxter studies were observational 

studies conducted over slightly different time periods. The Toback study was conducted in 

younger children 24 through 59 months of age; whereas, the Baxter study included children in a 

slightly older age range. These studies were conducted primarily through the Kaiser system, 

which included fairly large study populations. In terms of the outcomes of interest (fever, MAW, 

and SAEs), Ashkenazi, Fleming, and Belshe describe those as outcomes. The Toback and 

Baxter studies can be used to assess MAW and SAEs. 

The WG began by assessing fever, thinking that would be a fairly simple outcome. However, 

fever was described somewhat differently in each study. Each of the articles described fever, 

and the measurements were different from study to study (axillary or rectal; oral; or axillary, oral, 

or rectal) depending upon the study. The measurement intervals differed from study to study 

from 10 to 15 days. Also, how fever was described in the methods differed somewhat from how 

fever was described in the results. From paper to paper, there were quite different descriptions 

of fever, making it somewhat more challenging. However, based on the outcomes, a direct 

comparison can be made in each of the studies children who received LAIV to children who 

received TIV. The Ashkenazi study measured temperature during an 11-day period. In terms of 

temperature over 37.5 ̊C and 37.6 ̊C, after Dose 1 and Dose 2 there were not significant 

differences between the LAIV and TIV groups. The Fleming paper assessed fever over a 15­

31 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

day period. They reported four different levels of fever. Recall that these were older children. 

They only received a single dose of vaccine. Again, there were no observed differences 

between children who received LAIV and children who received TIV or IIV. The Belshe paper 

did observe some differences in fever rates. Reported in the paper is Day 2 fever. However, 

this is broken out over a several day period in the Biologics License Application (BLA). The 

paper only reported Day 2 fever after the first dose. For fever over 37.8 ̊C there was a 

significant difference in the rate of fever being 5.4% in the children who received LAIV versus 

2% in children who received TIV. For higher fevers over 38.9 ̊C, no difference was reported. 

In grading the evidence, the WG assessed the four papers. In the Ashkenazi paper, the 

population differed somewhat from that of interest. Some of the children were younger, and 

these were children who had recurrent respiratory tract infections. The Fleming paper was 

downgraded somewhat because some of the children were older, and asthmatics were also 

included. In the Belshe paper, some of the children were younger and none of the children 

were in the 60 to 96 months age range in the population of interest, which is 2 through 8 years 

of age. In terms of grading the evidence for limitations and potential biases for RCTs, 

Ashkenazi and Fleming were downgraded because these were not blinded studies. In the 

Ashkenazi, Fleming, and Belshe studies, there was some loss to follow-up for which the 

evidence was downgraded. 

Moving to the second outcome of interest, MAW, the definitions were somewhat different from 

study to study, making it somewhat difficult to compare among the studies. The Ashkenazi 

paper definition was “wheezing episodes observed by a medical practitioner.” The Fleming 

paper definition was “incidence of asthma exacerbation (acute wheezing illness associated with 

hospitalization, any unscheduled clinical visit, or any new prescription including rescue 

medication).” The Belshe paper definition was “presence of wheezing on a physical 

examination conducted by a health care provider, with a prescription for a daily bronchodilator; 

respiratory distress; or hypoxemia.” The Toback and Baxter definitions were similar, “asthma 

and wheezing – asthma/reactive airway disease (RAD) encompassed individual diagnosis of 

asthma, cough variant asthma, and exercise-induced asthma; the term wheezing/shortness of 

breath (SOB) included the diagnosis of wheezing and dyspnea/SOB.” The time intervals for 

each of these events for MAW differed somewhat from paper to paper as well. Ashkenazi 

admitted the first 10 days after the dosing in their observation period, which one might consider 

an important time interval to look for MAW after dosing. Fleming looked at the 42 days after 

each dose, as did Belshe, Toback, and Baxter. 

The results for each of these studies were reported somewhat differently, which was confusing. 

The Ashkenazi and Fleming papers looked at the percent difference in wheezing between the 

LAIV and TIV groups, and basically they did not observe any difference in wheezing episodes 

between either of their groups after the first dose, and for the Ashkenazi paper after the second 

dose. Belshe reported adjusted rate differences in wheezing between the LAIV and TIV groups. 

There was some difference in the overall group, but when age-stratified, most of that difference 

was really in those children less than 24 months of age, with the difference being 1.18%. This 

held true for those who were previously unvaccinated, but not in those who had previously been 

vaccinated and not after a second dose. This becomes more problematic looking at the 

observational studies, which assessed hazard ratios, comparing rates of wheezing or MAW in 

children after receiving LAIV or IIV. The hazard ratios are 0.38% comparing LAIV to IIV, 

meaning a lower rate in the LAIV group to the IIV group. This was true for the Toback and 

Baxter comparisons. This really has to do mostly with the current recommendations for how 

LAIV and TIV are given, meaning that LAIV is not recommended for children who have 

underlying medical conditions such as asthma; whereas, IIV is recommended. Natural 

32 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

wheezing episodes would be expected to occur at a higher rate in the IIV group. So, these data 

are confounded. 

In terms of GRADEing the evidence, the population differs from that of interest for Ashkenazi, 

Fleming, Belshe, Toback, and Baxter. The evidence was downgraded for the Ashkenazi paper 

because MAW was not reported in the first 10 days after receipt of the vaccine dose. Regarding 

other limitations for the RCTs, Ashkenazi and Fleming were not blinded. And there was loss to 

follow-up in all three studies. For the observational studies, Toback and Baxter were 

downgraded for failure to control for confounding. For SAEs, the definitions differ somewhat 

and some of the papers were not well-described in terms of what constitutes an SAE. The 

Fleming and Belshe papers used fairly standard definitions. The time intervals for monitoring 

SAEs for most of the studies from the time of enrollment through the influenza surveillance 

period differed, except for the Toback and Baxter papers for which the time interval was 0 

through 42 days post-vaccination. Relatedness in most of these studies was determined, with 

the categories ranging from possibly, probably, potentially. All studies were determined as per 

investigator in each of the studies. 

The rates of SAEs were fairly comparable in the Ashkenazi paper between the LAIV group and 

the TIV group at 5.8% and 4.7%, respectively. A small number of SAEs were considered 

related to study product in that particular paper. In the Fleming paper, the rates for SAEs were 

comparable, with a few of these events in the LAIV group and TIV group being ascribed as 

related to the vaccine. There was one episode of pneumonia and asthma attack in the LAIV 

group on Day 2 that was considered vaccine-related. The Belshe paper reported similar rates 

of SAEs in both groups. They do note in the manuscript that most of the SAEs were 

hospitalizations. Interesting, hospitalizations usually constitute an adverse event in all studies, 

the rates were fairly similar in terms of the whole population at 3.1% and 2.9%. However, when 

age-stratified, for children 6 through 11 months of age, all-causes hospitalization was higher in 

that group at 6.1% (LAIV) versus 2.6% (TIV). Again, this is outside the age range of interest for 

this particular evidence review. There were no differences in the other age groups. In terms of 

vaccine-related SAEs, there were a fair number of respiratory tract events in the LAIV group 

(e.g., bronchiolitis, asthma exacerbation, wheezing, RAD). Likewise, there were several in the 

TIV group (e.g., pneumonia, wheezing, febrile convulsion, febrile convulsion and pneumonia, 

viral gastroenteritis). 

In the Toback observational study, the rate of SAEs was slightly higher in the TIV group at 1.14 

versus 0.91 per thousand person months. Again, one might ascribe that to the fact that the TIV 

group is generally a potentially sicker population with more medical compromise or underlying 

medical conditions. A few vaccine-related SAEs were described in the LAIV group (e.g., one 

child with RML infiltrate, fever, RSV and one child with intussusception and viral infection). In 

the Baster article, the rates for SAEs were not noted to be different between the two groups of 

interest. In the LAIV group there were two vaccine-related SAEs (e.g., one dystonic tongue 

posturing 3 days post-vaccination, and one Bell’s Palsy 2 days post-vaccination). 

In terms of GRADEing the evidence for SAEs, the population for all studies differed from that of 

interest. The limitations for the RCTs were the same as described for the other outcomes. The 

observational studies failed to control for confounding for SAEs. For the Toback paper, all of 

the SAEs were described as being diagnosed in the hospital setting, possibly excluding some 

children who may have had SAEs outside the hospital setting. 

In conducting this review, there were several limitations. Few studies directly compare LAIV 

and IIV. Some studies did not assess outcomes of interest. The definitions for the outcomes of 

33 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

interest are not standardized, which is a particularly problem for studies. Follow-up intervals 

varied across studies. The observational studies were somewhat confounded. The findings 

observed for fever and MAW pertained to only one study during a single season. It is difficult to 

judge any risk of SAEs from these trials. It is difficult to distinguish if a temporal association 

between influenza vaccine and an adverse event is coincidental or causal. This review was 

limited to trivalent influenza vaccines giving according to current indications, and does not 

include any data on the new quadrivalent products. 

In summary, when given according to current indications, there is no evidence for an increased 

risk of SAEs or MAW after LAIV versus TIV in this age group. There is evidence for some 

transient increased risk of mild fever after LAIV versus TIV, but this was only noted during one 

influenza season. 

Safety of LAIV versus IIV for Healthy Children (GRADE) 

Dr. Lisa Grohskopf 

Influenza Division 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Grohskopf expressed her hope that Dr. Walter’s presentation set the stage to illustrate that 

the safety evaluation was somewhat complicated relative to efficacy. Dr. Walter laid out the 

characteristics of individual studies, while Dr. Grohskopf indicated that she would be discussing 

the pooling of data from those studies. She emphasized that this is not always easy to do 

because of the way that definitions and procedures vary across studies. An effort was made to 

pull out information that is clinically meaningful, but not overwhelmingly complicated. 

As outlined in the last presentation, the GRADE assessment for safety of LAIV versus IIV 

focused on three outcomes (e.g., fever, MAW, and SAEs). The focus of this presentation was 

on younger children 2 through 8 years of age. For these analyses, observational studies were 

excluded, because of concerns that differences in the underlying health status of the two 

populations (e.g., over-representation of less healthy children in the inactivated vaccine groups) 

may affect the results and interpretation of safety outcomes. This analysis focused exclusively 

on the RCTs and children 2 through 8 years of age. 

Several outcomes related to wheezing, which was valued as a “Critical” outcome. All of the 

data for these outcomes were provided by the Belshe et al 2007 study, given that it was 

possible to get a fairly consistent definition across several categories of children who 

participated in this study. It was also possible to obtain information limited to children 25 

through 59 months of age, which the work group thought was important because there has been 

some concern about the younger children and the occurrence of wheezing in younger 

populations who are not recommended to received LAIV, but were also included in the 

Ashkenazi paper. 

Children in the Belshe study received either 1 or 2 doses of influenza vaccine, depending upon 

whether they had previously been vaccinated. Those children who had received influenza 

vaccine previously received one dose, while those who were vaccine-naïve received 2 doses. 

The data are reported along the lines of after Dose 1 and after Dose 2, so it was possible to 

break this out in several ways just as it is in the paper. In terms of data following Dose 1 without 

regard to previous vaccinations, follow-up was 42 days post-vaccination. These data were 

restricted to those children aged 24 through 59 months, so they were all within the indicated age 

34 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

population for LAIV. Considering all of the characteristics that fall under “Risk of Bias” and 

“Indirectness,” the WG decided that there was not a serious risk of bias or indirectness. They 

did, however, downgrade the data for imprecision due to the fairly wide confidence interval that 

straddles 1.0. Overall in this particular slice of the data, there was not a significant difference 

the risk of wheezing between the two vaccines. The evidence quality for this outcome was 

assessed as Type 2, or Moderate quality evidence. 

Regarding wheeze after Dose1 restricted to children who were not previously vaccinated, there 

was no significant difference in risk. Results were downgraded for imprecision due to the width 

of the confidence interval. The point estimate of risk fell more on the side of favoring IIV. 

However, the confidence interval was fairly broad and straddled 1.0. The evidence quality was 

again Type 2, or Moderate. In terms of risk of wheeze over days 0 through 42 for children 24 

through 59 months olds, again following Dose 1, there was no significant difference in risk for 

children with a history of previous vaccination. The point estimate falls more on the side 

favoring LAIV, which might be anticipated because the children were not vaccine-naïve. Still 

there was a broad confidence interval that straddled 1.0, so the results were again downgraded 

for imprecision due to the width of the confidence interval, and the evidence quality was again 

Type 2, or Moderate. With regard to the risk of wheeze over days 0 through 42 for children 24 

through 59 months olds, this time following Dose 2, there was no significant difference in risk. 

The point estimate was actually fairly well over into the side favoring LAIV, although it did cross 

1.0 just barely with an upper bound of 1.06. This would still be considered a non-significant 

difference between the two vaccines. Again, results were downgraded for imprecision due to 

the width of the confidence interval and the evidence quality was determined to be Type 2, or 

Moderate. 

The outcome of “Fever” was valued as important. As noted in the last presentation by Dr. 

Walter, fever is complicated in that the definitions and data reported vary. This made pooling of 

data across studies difficult. Ideally, pooling data from multiple studies allows for larger 

numbers. However, it was somewhat tricky to determine the best way to do that in this 

particular circumstance because the definition of fever did vary across the studies and were 

reported out in different ways. For this analysis, data were pooled from Ashkenazi et al and 

Belshe et al. The temperature thresholds for fever used in the respective studies differed 

slightly, but were roughly comparable. For Ashkenazi, the information was reported for fever of 

39.6 ̊C, or roughly 101.5 ̊F, and up. For Belshe, the information was reported for fever for 

38.9 ̊C, or about 102 ̊F, and up. In this analysis, follow-up was day 0 through day 10, which is 

somewhat longer than what Dr. Walter reported when discussing some of the earlier fever 

outcomes such as the slightly increased risk of fever during one seasons for two days postvaccination. Pooling these data, there was no significant difference in fever risk. The GRADE 

handbook recommends downgrading for imprecision when the lower bound crosses 0.75 and 

this goes to 0.73, so the WG made a call to downgrade for imprecision. The evidence quality 

was determined to be Type 2, or Moderate. 

Focusing on SAEs deemed by the study investigators to be related to vaccination, a value was 

not assigned for this outcome because it is unclear how meaningful it is. There was not readily 

apparent consensus from the WG about how they would want to value it, but they did feel it 

was important to consider because some of the more rare and serious outcomes are so rare, it 

was not possible to get an accurate assessment for them. They were hoping to use this as 

some sort of proxy to see if they could find anything. However, they did not. The rates of 

related SAEs were rather low for both vaccines in both studies, leading to a wide confidence 

interval, for which there was downgrading for imprecision. Overall evidence quality was 

determined to be Type 2, or Moderate. 

35 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

To summarize the safety outcomes, no difference was observed for medically attended 

wheezing, fever, or related SAE. Overall evidence quality was judged to be Type 2, or 

Moderate. There are several limitations to this assessment, including that as illustrated by Dr. 

Walter, definitions of the outcomes of interest were not standardized across the studies. Some 

differences made it fairly tricky to determine how data might be pooled in a way that was both 

meaningful and would allow for a better assessment and somewhat better power from better 

numbers. The available studies also were not adequately powered to detect differences in rare 

but serious outcomes, such as GBS or anaphylaxis. In addition, all of the studies related to 

trivalent vaccine because that was what was available when these studies were conducted. 

Discussion Points 

Referring to the first dose in naïve children where the confidence interval clearly crossed 1.0, 

but it looked like there was a trend, Dr. Karron recalled that in the WG also looked at a shorter 

interval than 0 to 42 days that was related more to the period of LAIV replication. She thought 

the FDA had perhaps given them those data, and she wondered how that looked relative to the 

0 to 42 day period. 

Dr. Grohskopf responded that while it was not included here because strictly speaking it did not 

meet the criteria for MAW, the Ashkenazi paper reported for days 0 through 11 that they did 

record wheezing as an outcome. However, it was as reported on diary cards from the parents 

so there was no practitioner verification that it occurred. The take home point from that was that 

there was no difference between the two. The WG was able to obtain some information from 

the FDA with regard to wheezing during earlier intervals for children 24 months and older, which 

basically following the first 10 days following vaccination showed no difference in the rates of 

wheezing. Those data came from the Belshe study, which Dr. Grohskopf said she would 

disseminate following the meeting. 

LAIV Update 

Kathleen Coelingh, PhD 

Senior Director, Medical Affairs 

MedImmune, Specialty Care Division of AstraZeneca 

Dr. Coelingh first presented information about the relative efficacy of LAIV in vaccine-naïve 

children, children who have been vaccinated previously, or children who have experienced 

influenza. Four randomized placebo-controlled studies were conducted during the clinical 

development of LAIV. All four of those studies were two-season studies. This was absolute 

efficacy compared to placebo. During the first season of the Belshe study, absolute efficacy 

was 93%, and during the second season was 100% after revaccination. In the 

Vesikari study, absolute efficacy was 85% in the first season and 89% in the second season 

after revaccination. In the Bracco study absolute efficacy was 74% during the first season and 

the second season after revaccination. In the Tam, absolute efficacy was 73% in the first year 

and 84% during the second year after revaccination. These studies were performed in children 

who were not in the exact age group of interest of 2 through 8 years of age, but were generally 

younger. Also relevant is that in the large Belshe study, which was a head-to-head trial of LAIV 

versus TIV, children who had been previously vaccinated with IIV were assessed and that was 

compared to children not previously vaccinated with IIV. The efficacy was similar regardless of 

whether the children were previously vaccinated. If they were previously vaccinated, the 

efficacy was 51% fewer cases in the LAIV group compared to the IIV group. When they were 

36 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

not previously vaccine, the efficacy was 57% fewer cases in the LAIV group compared to the IIV 

group. 

In terms of the supply update, seasonal LAIV is approved in the US for eligible individuals 2 

through 49 years of age. It contains 106.5 to 7.5 fluorescent focus units (FFU) of each vaccine 

strain per dose. The quadrivalent vaccine was introduced in the US starting in the 2013-2014 

season. It contains no preservatives or adjuvants, it is stored refrigerated at 2°C to 8°C, and it 

is administered as a nasal spray. Over 75 million doses of LAIV have been distributed in the US 

since its licensure in 2003. In the early years following licensure, production was very modest 

but increased around 2008 when the product was licensed down to age 2, when it no longer had 

to be stored frozen in a freezer, and when ACIP recommended routine annual vaccination of all 

children. There was a large spike in 2009, which was a combination of the pandemic and 

seasonal vaccines. There was a gradual increase in production for the 2013-2014 season. 

MedImmune produced 22 million doses during that timeframe, of which about 13 million have 

been distributed in the US. The plan is to produce about 24 million doses in the upcoming 

2014-2015 season, unless additional information justifies either increasing or decreasing that 

number. 

LAIV has been increasingly administered to US children 2 through 17 years of age based on 

national insurance claims data, excluding the pandemic doses. Over the time period from 2007­

2008 through 2011-2012, the use of multi-dose preservative-containing vials decreased from 

69% in 2007-2007 to 35% in 2011-2012. In contrast, the use of the prefilled syringes of IIV 

increased from 19% to 25% during this same period. The use of LAIV increased from 12% to 

40% during the same time frame. While the information for the current season is just beginning 

to come in, it appears that these trends are continuing and that LAIV use is about 44%. 

Regarding MedImmune’s capacity for responding to LAIV manufacturing compared to a 

potentially greater demand for LAIV in the US, the estimates assume a 50% overall vaccination 

rate among US children 2 through 17 years of age for any vaccine type. For the 2013 current 

season, there has been a demand for LAIV of 16 million doses—13 million in the US and 3 

million ex-US. The manufacturing capacity is 30 million doses, so there is a large amount of 

unused manufacturing capacity. Looking forward to the 2014-2015 season, if there were a 

theoretical demand that 70% of all children eligible for LAIV would receive it, demand would still 

be adequately met by MedImmune’s manufacturing capacity. With a prediction for 2014-2015 

of excess manufacturing capacity, because manufacturing capacity will increase to 35 million 

doses then. Assuming that going forward in the US, if the goals of Healthy People 2020 are met 

with a 70% coverage rate, MedImmune will be able to manufacture a sufficient number of doses 

even with higher market shares due to plans to increase manufacturing capacity to 47 million 

doses for the 2016-2017 influenza season. 

In summary, MedImmune’s current and projected manufacturing capacity for LAIV is sufficient 

for eligible US children 2 through 17 years of age at current and higher future LAIV use, current 

and higher future vaccination coverage levels, and to meet both US and ex-US demand. 

Additional increases in demand could be met by further increases in manufacturing capacity. 

37 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Discussion Points 

Dr. Karron requested further information about the relationship between capacity and supply in 

any given year, and how those potentially relate to future policy decisions. For example, there 

might be a situation in which there is a clear preferential recommendation for LAIV in a certain 

age group. There might be a situation for consideration of use of LAIV in various age groups. 

Dr. Coelingh responded that it is difficult to predict what kind of demand would be triggered by a 

preference in the US. MedImmune chose to look at 70%. Historically when ACIP has made a 

recommendation for a new vaccine, it does not trigger an automatic movement toward following 

that recommendation. It always takes a few years for that to go into effect. While it is 

somewhat of a guess, MedImmune thought that modeling this over the next few years would 

provide some reassurance that capacity is adequate. MedImmune is using only half of its 

capacity for the current season, which will expand to 47 million doses for the 2016-2017 season, 

which would be adequate in their estimation to cover everybody who would be likely to want to 

get the vaccine. 

Dr. Karron pointed out that influenza vaccine is the most perishable vaccine of all, and obviously 

a company has to weigh demand against capacity and might not produce all that could be 

produced if it could not be used. What she was driving at was not just in terms of absolute 

capacity to produce, but also regarded trying to understand more about the forecasting process 

depending on policy recommendations. 

Dr. Coelingh replied that policy recommendations are taken into account, but people do not 

typically follow recommendations right away. She said that because she was not involved in 

forecasting, it was somewhat difficult for her to answer that question. Clearly, policy plays a 

major role in the demand for vaccines and will be even more so going forward with the changes 

in healthcare. 

Dr. Sawyer inquired as to whether there was a coverage rate at which MedImmune would no 

longer be able to meet the demand, for example, a 70% coverage rate with 70% of those 

children receiving LAIV. 

Dr. Coelingh responded that MedImmune did model that, but she did not include it for simplicity. 

If the coverage rate is increased to 70% and the market share is also 70%, capacity is 

adequate. 

Ms. Stinchfield (NAPNAP) asked Dr. Coelingh to comment on the true eligible children. The 

work group talked a lot about those children for whom influenza vaccine is contraindicated, so 

she wondered what the true contraindications are versus the ACIP statement that talks about 

healthy children. Defining that clearly impacts who the vaccine is given to, as well as the supply 

and projected capacity. She thought it was important to highlight the difference between the 

true contraindications versus healthy 2 year olds and older. 

Dr. Coelingh responded that the contraindications in the label, which is issued by the FDA, are 

for children who are on aspirin therapy or anyone who is allergic to a previous dose of vaccine. 

Dr. Karron added that in terms of the label and true contraindications, immune-compromised 

should be included. She wondered whether their colleagues from places where LAIV is being 

used in children with previous history of wheezing, NACI or the UK DOH, could comment on 

whether they have any type of registry or data collection to monitor adverse events that occur in 

this population. LAIV is used differently in some other countries. 

38 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Warshawsky (NACI) responded that Canada does have a vaccine adverse event registry as 

the US does, which is a passive system for reporting. She was not aware of a particular 

analysis conducted on LAIV, but she was also not aware of any safety signals. Nothing has 

been brought to their attention with regard to LAIV and wheezing. 

Dr. Salisbury (UK DOH) replied that so far the UK has only been vaccinating 3- and 4-year olds 

this winter. There is 40% coverage in those two age groups. He also was unaware of any 

specific adverse events, because so far they have only been using the license-specified 

indications and contraindications. Anything that may come from use outside of the 

recommendations has not yet surfaced. The other difference is that the UK is only using one 

dose in all age groups from 2 years of age and older, on the basis that the incremental 

advantage of the second dose does not really seem to warrant its use. 

Dr. Karron thought that the contraindication for the European product was children with severe 

wheezing or active wheezing at the time of immunization, which would be outside the label, but 

it would not exclude children with any history. 

Dr. Salisbury (UK DOH) replied that it was closer to the Canadian situation. 

With respect to the question regarding forecasting versus planning, Lance Minor (MedImmune 

Operations Strategy and Planning) reported that MedImmune does plan to produce additional 

bulk and finished goods material every season above and beyond the expected demand. There 

are also options mid-season to produce even further. 

Proposed Recommendations 

Dr. Lisa Grohskopf 

Influenza Division 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Grohskopf noted that for the 2013-2014 influenza season, the ACIP Influenza Statement 

was published in an MMWR recommendations and reports document. For next season, 2014­

2015, the plan is to return to the smaller policy note format. The current draft of this document 

was distributed to the ACIP members, and at present contains information on those topics 

anticipated to remain the same for next season. No changes to the recommendations or groups 

recommended for vaccination were proposed at this time. Any proposed changes to the 

recommendations, or new recommendations, will be discussed during the June 2014 meeting. 

No new influenza vaccine products have been licensed since the last guidance was published. 

Currently licensed vaccines were listed in the policy note in the draft table, and were essentially 

identical to those for the current season. This will be updated as any new package inserts come 

out, and with any new licensures as they occur. Any new licensures will be discussed during 

the next meeting. During this session, the WG proposed reiterating the core recommendation 

that annual influenza vaccination is recommended for all persons aged 6 months and older. 

39 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

In terms of the vaccine strain selection for the 2014-2015 season, WHO recommends the same 

composition for the Northern Hemisphere 2014-2015 influenza vaccines as for 2013-2014, 

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 

 For quadrivalent vaccines, these viruses and a B/Brisbane/60/2008-like virus 

The FDA’s Vaccine and Related Biologic Products Advisory Committee (VRBPAC) will make a 

final decision regarding the US vaccine composition. 

Discussion Points 

In terms of proposed changes, Dr. Harrison wondered what information would be available in 

June that they did not have during this meeting. 

Dr. Grohskopf responded that one issue with regard to any language related to LAIV and IIV, 

even if there were not to be a preference, the GRADE analysis has been done and a summary 

of that will be presented either in or linked to the policy note. Because the policy note is such a 

short format document, there will probably be a URL link in the document. Typically, the entire 

document is not put into the MMWR. Another issue regards harmonization with AAP, and AAP 

will not be meeting on this topic until April 2014. 

Dr. Duchin clarified that the Influenza WG is strongly considering a preferential 

recommendation for LAIV, and it would be beneficial if ACIP members would actively think 

about that before the June 2014 meeting since they would not be voting on that during this 

meeting. Many WG members feel that this is long overdue, and a vaccine is available that 

even CDC has acknowledged on a public webpage as superior in young children. However, the 

step has not been made to make that recommendation which does influence a lot of healthcare 

providers. 

Dr. Temte inquired as to whether the ACIP members would request that the Influenza WG 

proceed with language and such a recommendation for a preferential use of vaccine, keeping in 

mind the timing for clinicians and health systems to place orders. He asked Drs. Neuzil and 

Duchin, from Washington State where there is a preferential recommendation for LAIV in 

children, to provide further information on that. 

Dr. Duchin responded that unfortunately, their recommendations do not carry the weight of a 

recommendation from ACIP, and it is not really clear that they have the penetration desired 

throughout the clinical community. He always takes the opportunity to remind their clinical 

colleagues that there are data that suggest that LAIV is better in younger children, and that CDC 

has more or less endorsed those data by posting that on the CDC website without making a 

formal recommendation. In the context of ordering vaccine, clinicians should keep in mind that 

there are already data available to suggest that that is a wise thing to do for younger children. 

There is not a specific cutoff yet, which would be useful. There has not been any issue with 

shortage. The supply has been adequate, and many physicians are aware but do wait for more 

clear guidance from ACIP before changing large system practices. 

Dr. Harrison requested a sense of AAP’s stand on this issue. 

40 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Brady (AAP) responded that AAP has not really discussed this, but will do so in April as 

mentioned. Therefore, he was unable to say whether there was consensus amongst the group. 

Some of this information will be presented for the first time during the April meeting. 

Dr. Kempe thought that the data seemed strong and compelling in many ways. If, in fact, a 

preferential recommendation is made, it is going to put front and center the issue of wheezing. 

While well-defined asthma is fairly straightforward, many young children have wheezed or have 

wheezed in the last year but do not have a diagnosis of asthma. If ACIP makes a preferential 

recommendation, she would like to discuss further where the current precaution, not 

contraindication, came from and whether this can be pinned down better given data of whatever 

type from other countries, for example. 

In terms of the yearly MMWR on influenza, Dr. Bennett asked whether Dr. Grohskopf was 

saying that if ACIP made a preferential recommendation in June, it would be too late. 

Dr. Grohskopf replied that it would not. There have been votes in June in the past. It is too late 

in the sense that ordering has occurred by that point. On the other hand, because there is 

always so much going on with influenza, the argument can be made that ACIP has to consider 

issues as they come along and try to keep things moving. It would not be too late to go into the 

MMWR. Among the concerns that some people on the WG have expressed about having a 

preference, there is the fact that ordering has occurred already, so it would be difficult to 

implement for the 2014-2015 season. On the other hand, there is precedent for having a 

recommendation that stated, “Vaccinate this age group if feasible this season. Implement 

completely by the following season.” That can be done. 

Catia Ferreira (GSK Medical Affairs) wondered when there would be a review of the efficacy 

data for the quadrivalent vaccines and the recent study just published regarding the efficacy in 

the 3 through 8 year old population. 

Dr. Grohskopf responded that as usual with influenza, there are many topics to be discussed. 

This will likely be discussed at a future date, though she did not yet know when that would be. 

As a member of the WG , Dr. Loehr (AAFP) respectfully disagreed with Dr. Kempe and 

suggested that the focus should be mostly on whether a preferential recommendation could be 

agreed upon versus worrying about the details of wheezing at this time. He requested that 

ACIP give guidance to the WG regarding what they would need to feel comfortable voting on a 

preferential recommendation in June, which was what the work group was wrestling with 

currently. His understanding was that there has not been a preferential recommendation, so he 

wondered whether there were other issues ACIP would like for the WG to explore before 

bringing this back to them in June. Many of the work group members would like to have a vote 

on this, with some language for a preferential in recommendation, in June. 

Dr. Rubin said he was compelled with the data as well. As discussed in a previous meeting, 

one of the hang-ups was that the quadrivalent LAIV was a new product. He would like to see 

the VSD honed down on the age group that might potentially be given a preferential 

recommendation to see if there are signals for seizures in particular, and of course quadrivalent 

inactivated vaccine as well if there are sufficient data. 

41 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Bocchini emphasized that harmonization with AAP is very important so that there is a single 

message. Therefore, he would like to see what the Committee on Infectious Disease (COID) 

reviews and to have their input so that ACIP and AAP could potentially move forward in a 

harmonized way. 

Dr. Temte agreed that this would be a very reasonable approach. 

Dr. Karron noted that the recommendations as sent to ACIP members had a red highlight for 

issues related to contraindications with respect to LAIV. She thought that was an issue that the 

WG was going to specifically consider , and that might arise again during the June meeting. As 

they voted, she wondered whether there would be a way to incorporate that because those are 

part of the annual recommendations, yet they may reconsider those. 

Dr. Temte said that as part of the minutes, a strong suggestion could be made to the WG to 

consider those issues as opposed to putting this in the recommendation per se. 

Dr. Karron asked for clarification as to whether, if she voted “yes,” she would be voting to 

approve the current recommendations for limitations of use and how that would work. 

Dr. Grohskopf replied that her understanding was that for the last several seasons, there has 

been a footnote in the table of available vaccines that concerns issues surrounding groups for 

which there is a precaution against LAIV use, for example those with chronic medical conditions 

and those with asthma. That footnote was red and was marked with a comment in the draft 

provided to ACIP members, indicating that there would be further discussion about that between 

this meeting and the next. Her further understanding was also that there would be an 

opportunity to make changes at any point if necessary and the committee votes on it. For 

example, there tend to be updates to the tables based on new package inserts and other 

information. 

Dr. Temte noted that there is currently a package insert that states the contraindications and 

precautions. He expected that those would not be changed. 

In terms of background, Dr. Sun (FDA) reminded everyone that there are only certain ways in 

which the FDA can revise a package insert. The most common way is when presented with 

data from the manufacturer concerning the specific topic for change. The second method is if 

specific safety concerns are raised that have come to be known, and that are of such 

seriousness this needs to be in the label. Those are the only true mechanisms to change 

labels. MedImmune would have to comment on whether they planned to submit further data or 

work with FDA to develop such data. 

Dr. Karron clarified that currently, the label from the FDA has fairly narrow contraindications. 

The current ACIP recommendations as she read them lump together the contraindications and 

the precautions. The question the WG wants to work on regards whether those should be 

lumped together as one, or because precautions are different from contraindications, whether 

those should be considered separately. That would not require something from the FDA. That 

would require ACIP to review what is already in its recommendations. 

Dr. Kempe said she personally had enough information to be in favor of making a 

recommendation in June, but she also thought it was important to get into this more specifically 

because it is going to put it front and center. She stressed that she did not mean to imply that 

this would hold up the decision. 

42 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Rubin requested clarification regarding what they were being asked to vote on during this 

meeting. Best he could tell, it would be only a reaffirmation of last year’s statement with a 

change from 2013-2014 to 2014-2015. 

Dr. Temte confirmed that this was correct. 

Following up on Dr. Karron’s comments, Dr. Sun (FDA) thought it would be beneficial to make a 

distinction between contraindications and warnings and precautions in the package insert. FDA 

has very specific definitions of those. According to the FDA a contraindication describes a 

situation in which the drug should not be used because the risks clearly outweigh any possible 

benefit, and there is substantial risk of the patient being harmed. These are supposed to be 

known hazards, not theoretical possibilities. Whereas warnings and precautions merely 

describe clinically significant information—information that would affect a decision on whether to 

prescribe that drug, any recommendations for patient monitoring that are critical for safe use of 

the drug, and any measures that can be taken to prevent or mitigate harm. That is very different 

from a contraindication in that the risk-benefit may be very different, and then it becomes a 

judgment call based on advisory committees or healthcare providers. 

In response to the question regarding submission of data, Chris Ambrose (MedImmune Medical 

Affairs) indicated that MedImmune has an active submission with the FDA in which the data 

have been submitted from the Fleming study that has the safety data in children with asthma, as 

well as data from the Belshe and Ashkenazi studies with younger children with a history of 

wheezing or asthma. MedImmune is in conversations with the FDA about this, and looks 

forward to working with them to determine the resolution of that submission. 

Ms. Stinchfield (NAPNAP) noted that with a preferential LAIV but use of existing language that 

precludes use in children with metabolic disorders, as a clinician she would have a hard time 

telling a diabetic that this is a better vaccine, but they cannot have it because they are not 

considered healthy. Wheezing aside, she thought they should be clear about the true 

contraindications and those precautions that would allow them to open it up for use more. 

Dr. Fryhofer (ACP/AMA) pointed out that ordering must be done now, and she thought this 

would put clinicians in a strange position if they order now based on the current 

recommendations and then in June, the order does not align with what is recommended. 

Dr. Duchin agreed with Ms. Stinchfield, and said he thought it would be a task for the work 

group to clarify the language and to address those concerns. Many feel that the language is not 

beneficial the way it is currently described in the statement. Regarding the issue of ordering, 

there is always a problem with ordering. Things never synchronize, so there are two good 

vaccines available for children. Clinicians already know that LAIV may be better in younger 

children, and they can take that into account when they order now, and they can anticipate that 

they may be seeing some more directive language from ACIP on this. However, it is not going 

to put them in a very poor position to have more or less LAIV versus IIV either way because 

both vaccines are good. There is always a transition period when new recommendations are 

made before everybody comes on board. People may not have the optimal mix that they would 

desire, but they certainly will have good vaccines they can use in all of their patients either way. 

43 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Temte noted that the biggest problem in his mind was that influenza vaccines are 

underutilized in general for children, especially school-aged children. 

Vote: Reaffirmation of the 2013-2014 Statement for 2014-2015 

Dr. Bocchini made a motion to accept the recommendations as proposed. Dr. Duchin 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 

0 Opposed: N/A
 

0 Abstained: N/A

Meningococcal Vaccines 

Introduction 

Lorry Rubin, MD 

Chair, Meningococcal Working Group 

Advisory Committee on Immunization Practices 

Dr. Rubin noted that the purpose of this session was informational in order to describe how both 

licensed and unlicensed meningococcal vaccines have been used in response to recent 

outbreaks in the US, and that no votes would be taken. The topics discussed during this 

session included meningococcal disease among men who have sex with men (MSM); 

meningococcal disease and vaccine response in HIV-infected persons; and use of serogroup B 

meningococcal vaccines during outbreaks on college campuses. 

In terms of additional activities of the work group, the comprehensive meningococcal vaccines 

statement was published in March 2013. The updated Hib vaccines statement was scheduled 

to be published February 28, 2014. A Policy Note from a previous vote on the use of Menveo® 

in infants at increased risk for meningococcal disease was scheduled to be published in March 

2014. The work group has been involved in early thinking about the approach to 

recommendations for routine use of meningococcal serogroup B vaccines. 

An ad hoc meningococcal work group has been convened that is comprised of ACIP 

Meningococcal Work Group members, ACIP members, state public health officials, college 

health professionals, and CDC members. The objectives of this ad hoc work group are to 

review available data on the recent epidemiology of meningococcal disease and outbreaks; 

consider options for updating the current meningococcal disease outbreak guidelines; and 

develop guidance for use of meningococcal vaccines (both licensed and unlicensed) in an 

outbreak setting. 

44 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Meningococcal Disease Among Men Who Have Sex With Men (MSM) 

Jessica MacNeil, MPH 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

With respect to meningococcal disease, Ms. MacNeil discussed outbreaks that have been 

reported in men who have sex with men (MSM). The first outbreak occurred in Toronto in 2001. 

Subsequent outbreaks have been reported in Chicago (2003) and New York City (2012). These 

outbreaks have all been caused by serogroup C sequence type 11 (ST-11), a common invasive 

strain of Neisseria meningitidis and a frequent cause of outbreak cases. Pulsed-field gel 

electrophoresis (PFGE) patterns have differed in each of the MSM outbreaks, which suggest 

that different strains have been responsible in each of those outbreaks. 

The largest and most recent outbreak among MSM occurred in New York City and it spanned 

from August 2010 through February 2012. A total of 22 cases and 7 deaths were reported in 

this outbreak, the mean age of cases was 34 years, and 55% were HIV-infected. In October 

2012, the New York City Department of Health and Mental Hygiene (NYC DOHMH) began 

recommending meningococcal vaccine for all HIV-infected MSM who met certain high-risk 

criteria. These recommendations were later expanded to include vaccination of all HIV-infected 

MSM and MSM regardless of HIV status who had regular close or intimate contact with men 

and met through an online website, digital application (“app”), or at a bar or party. 

Meningococcal vaccination of MSM in New York City began in October 2012. Uptake was 

relatively slow in the target population from October 2013 until March 2013. The final case in 

the outbreak occurred in mid-February 2013. Increased awareness and press related to the 

outbreak and vaccination campaign began after the expanded vaccination recommendations in 

March 2013, which increased uptake over the next several months. During the 5-month period 

between December 2012 and April 2013, 4 cases of serogroup C meningococcal disease and 2 

deaths were also reported among MSM in Los Angeles County. The mean age of these cases 

was 31 years, and all were HIV-negative. 

Little is known about the epidemiology of meningococcal disease among MSM, and most states 

do not routinely collect information on MSM status during their meningococcal case 

investigations. With the outbreak in New York City and the additional cases in Los Angeles 

County, CDC felt that there was a need to better understand the burden of disease and potential 

risk factors for meningococcal disease in the MSM population. A call for meningococcal cases 

among MSM was posted on Epi-X on May 14, 2013, which asked states to review all of their 

meningococcal case reports among males 16 years of age or older occurring between January 

2012 through May 2013 to determine if MSM status was recorded. Questionnaires were 

completed for cases that occurred among MSM which collected demographic, risk factor, 

clinical, and laboratory information. Cases were classified as either MSM cases residing in New 

York City (MSM-NYC); MSM cases residing in Los Angeles County (MSM-LAC); MSM sporadic 

cases (all other MSM cases) (MSM-Sporadic); or Men, not known to be MSM (other men). The 

MSM population in each reported jurisdiction was estimated using 2012 Census data for males 

18 through 64 years of age, and published estimates of the proportion of MSM in the US, which 

is 3.9%. 

All contacted health departments responded to CDC’s request for information. Of these, 45 

health departments reported 1 or more meningococcal disease cases in a male between 18 

through 64 years of age from January 2012 through May 2013 for a total 235 cases. Of these, 

33 reported from 10 health departments were identified as occurring among MSM. Of the 33 

45 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

MSM cases. 17 resided in New York City, 4 resided in Los Angeles County, and an additional 

12 cases identified as occurring among MSM were considered sporadic. 

Serogroup C accounted for all of the New York City and Los Angeles County MSM cases, and 

the majority of MSM sporadic cases. Serogroups B, C, and Y each accounted for approximately 

20% of cases occurring among other men, and serogroup W accounted for 7%. Serogroup 

information for 34% of the cases was unknown. Among the MSM cases, 5 cases (15.2%) has a 

record of travel within 2 weeks prior to disease onset, 11 (35%) cases reported current drug 

use, 7 of the 11 who reported current drug use were related to the New York City cluster, the 

prevalence of smoking among MSM cases and cases among other men was similar, 

meningococcal vaccination history for MSM cases was largely missing. 

HIV prevalence was higher among sporadic MSM cases and MSM cases occurring in New York 

City when compared to cases occurring among other men. No MSM cases from Los Angeles 

County were HIV-positive. In terms of the estimated annualized rate of meningococcal disease 

among MSM and other men, for other men the estimated annualized rates were similar for men 

living in areas where sporadic cases only were reported and for those living in New York City 

and Los Angeles County. The estimated rate for MSM living in New York City was 11.7/100,000 

and in Los Angeles County was 2.3/100,000. The estimated rate for MSM living in areas where 

only sporadic cases were reported were 0.24/100,000. 

Several considerations regarding estimated rates for meningococcal disease among MSM 

should be noted. First, most health departments in the US do not systematically collect 

information on MSM status during case investigations. While this information is sometimes 

captured during case interviews, the number of meningococcal disease cases occurring among 

MSM may be underestimated. Additionally, MSM population estimates were not available for 

the majority of queried jurisdictions, and a single population proportion estimate was uniformly 

applied across all jurisdictions. Therefore, MSM population denominators may be over- or 

underestimated for certain geographic areas. 

CDC has continued to request passive reporting of meningococcal cases occurring among 

MSM since May 2013. During that time, 10 additional cases have been reported from 7 states. 

Of these, 6 were serogroup C, 3 were serogroup B, and 1 was serogroup Y. None of these 

states has met the current outbreak definition of more than 3 cases of the same meningococcal 

serogroup occurring in less than a 3-month period that results in a primary attack rate of more 

than 10 cases/100,000 persons. 

In conclusion, outbreaks of meningococcal disease do occur among MSM. A small increase in 

risk was identified among MSM living in areas where only sporadic cases were reported. 

However, the overall burden of disease is low. In addition, a high proportion of MSM-sporadic 

cases were also HIV-infected. The ACIP Meningococcal Work Group does not propose 

recommendations for vaccination of all MSM in the US at this time. ACIP recommendations for 

HIV-infected persons will be discussed in the following presentation. CDC supports state and 

local health department recommendations for vaccination during identified outbreaks, and 

continued study is needed to better understand transmission and risk factors in the MSM 

population. 

46 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Meningococcal Disease and Vaccine Response in HIV-Infected Persons 

Jessica MacNeil, MPH 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Regarding meningococcal disease in HIV-infected persons, Ms. MacNeil HIV pointed out that 

HIV is an established risk factor for several bacterial infections. However, the current incidence 

of meningococcal disease and HIV infection in the US has made evaluating the risk for 

meningococcal disease in HIV-infected persons challenging. HIV infection is not an indication 

for routine vaccination in the current ACIP recommendations; however, if a HIV-infected person 

is vaccinated the recommendation is that they should receive a 2-dose primary series. 

Data on the relationship between HIV and meningococcal disease has historically been limited. 

An analysis of surveillance data from 1988 through 1993 from an 8-county Atlanta metropolitan 

area found that HIV-infected adults had a nearly 24-fold increased risk for meningococcal 

disease1

. More recently, a study from Group for Enteric, Respiratory and Meningeal disease 

Surveillance in South Africa (GERMS-SA)2

 reported that the incidence of meningococcal 

disease for HIV-infected persons was 11 times greater than that among HIV-uninfected 

persons, and HIV-infected cases had a higher case fatality ratio [1

Stephens DS, Hajjeh RA, 

Baughman WS, Harvey RC, Wenger JD, Farley MM. Sporadic meningococcal disease in adults: 

results of a 5-year population-based study. Ann Intern Med. 1995: 123:937-40; 2

Cohen C, Singh 

E, Wu HM, Martin S, de Gouveia L, Klugman KP, et al; Group from Enteric Respiratory and 

Meningeal disease Surveillance in South Africa (GERMS-SA). Increased incidence of 

meningococcal disease in HIV-infected individuals associated with higher case-fatality ratios in 

South Africa. AIDS. 2010; 24:1351-60]. 

A chart review of HIV-infected meningococcal disease cases reported through the Active 

Bacterial Core surveillance system (ABCs) has recently been completed. Incidence calculations 

from this analysis were limited to cases that met the CDC-AIDS surveillance case definition 

because name-based HIV reporting was not available in all of the states during the study years. 

During 2000 through 2008, 32 HIV-infected meningococcal disease cases were reported in 

ABCs sites. Of these, 25% were caused by serogroup B, 39% by serogroup C, and 29% 

serogroup Y. In the four years since the review was completed, an additional 9 cases of 

meningococcal disease have been reported in HIV-infected persons in ABCs. 

HIV-related clinical data were collected for meningococcal cases with HIV infection as part of 

the expanded chart review. In general, patients presented with a wide range of CD4 counts and 

several had a history of an AIDS defining condition or met the CDC AIDS surveillance case 

definition. The majority were also reported to currently be taking highly active antiretroviral 

therapy (HAART) at the time of meningococcal disease presentation. Of the 32 cases, 17 met 

the CDC AIDS surveillance case definition and were included in the incidence calculations. 

Meningococcal disease incidence among persons with AIDS was 3.48/100,000 compared to 

0.28/100,000 among persons not meeting the CDC AIDS case definition, with a rate ratio of 

12.6. 

In New York City, meningococcal surveillance data was matched to death and HIV registries, 

and as part of the study and age-matched case-control analysis was also performed among 

HIV-infected persons, which included a subset of cases with CD4 count and viral load 

measurements near the time of meningococcal disease. In New York City during 2000 through 

2011, 40 HIV infected meningococcal disease cases were reported. Of these, 33% were 

47 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

caused by serogroup C, and 48% by serogroup Y [Miller L, Arakaki L, Ramautar A, Bodach S, 

Braustein S, et al. Elevated Risk for Invasive Meningococcal Disease Among Persons with HIV. 

Ann Intern Med. 2014; 160:30-38]. Incidence of meningococcal disease among persons 

infected with HIV was calculated for an incidence of 3.4/100,000 in HIV-infected persons, 

compared to 0.34/100,000 among HIV-uninfected persons for a risk ratio of 10. A higher case 

fatality ratio was observed among HIV-negative cases compared to HIV-positive cases. The 

risk of meningococcal disease decreased during the study period for both HIV-infected and HIVuninfected persons in New York City. Meningococcal disease incidence among HIV-infected 

persons decreased from 4.7/100,000 in 2000 through 2002 to 1.9/100,000 in 2009 through 

2011. An increased incidence was also observed for both HIV-infected women and men, 

although the risk ratio was slightly higher for male cases compared to female cases. In the 

case-control study among persons with HIV, patients with meningococcal disease were 5.3 

times as likely as age-matched control patients to have a low CD4 count and 4.5 times as more 

likely to have a high viral load [Miller L, Arakaki L, Ramautar A, Bodach S, Braustein S, et al. 

Elevated Risk for Invasive Meningococcal Disease Among Persons with HIV. Ann Intern Med. 

2014; 160:30-38]. 

To summarize the epidemiologic data, there is an increased incidence of meningococcal 

disease in HIV-infected persons. Among HIV-infected persons, a low CD4 count or high viral 

load increases risk. However, risk of disease is declining along with meningococcal disease 

incidence in the US. Data on the case-fatality ratio for HIV-infected meningococcal disease 

cases is mixed. 

Regarding vaccine response in HIV-infected persons, rates of seroresponse to a single dose of 

MenACWY-D at Week 4 by serogroup were compared in HIV-infected and healthy adolescents. 

The data for HIV-infected adolescents were based on approximately 300 adolescents included 

in the study, and the proportion of HIV-infected adolescents with more than a 4-fold increase in 

rSBA titers at Week 4 was 52% for serogroup C and 63% for serogroup Y. For HIV-infected 

adolescents who received a single dose of MenACWY-D, the response was significantly lower 

for those with either a low CD4 count or a high viral load [Phase I/II, Open-Label Trial of Safety 

and Immunogenicity of Meningococcal (Groups A, C, Y, and W-135) Polysaccharide Diphtheria 

Toxoid Conjugate Vaccine in Human Immunodeficiency Virus-Infected Adolescents. Pediatric 

Infectious Disease Journal. 29(5):391-396, May 2010]. 

In terms of the geometric mean titers (GMTs) for serogroup C, for those with low CD4 counts at 

study entry, despite a second dose of vaccine at 24 weeks, response remained low through 72 

weeks. In subjects with higher CD4 counts at study entry who received one dose of 

MenACWY-D, after an initial response at 4 weeks, GMTs waned rapidly. In subjects with higher 

CD4 counts at study entry who received a second dose of MenACWY-D, response waned 

quickly after both Dose 1 and Dose 2. While the overall the response of GMTs to serogroup Y 

was higher than for serogroup C, the same pattern of rapidly waning titers was observed. In 

terms of the percent of subjects who still had antibody at Week 72, or approximately 1.5 years 

after 1 or 2 doses of MenACWY-D, the primary study endpoint was the percent of subjects with 

rSBA titers greater than 1:128. For serogroup C, titers waned to 21% to 35% and for serogroup 

Y, titers waned 63% to 71%. The proportion of subjects with rSBA titers greater than 1:8 were 

slightly higher for each group than subjects with rSBA titers 1:128 [Immunogenicity and Safety 

of 1 vs 2 Doses of Quadrivalent Meningococcal Conjugate Vaccine in Youth Infected with 

Human Immunodeficiency Virus. The Journal of Pediatrics. 161(4):676-681. October 2012]. 

48 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

In summary, seroresponse to MenACWY-D in HIV-infected adolescents is suppressed 

compared to healthy adolescents. A low CD4 count or high viral load suppresses the response 

even further. In addition, immune response to MenACWY-D wanes rapidly and although a 

boost response is seen to second dose, duration of protection is still an issue. 

In conclusion, there was a modest increase in absolute risk of meningococcal disease among 

HIV-infected adults of about 2 to 4 cases/100,000 persons, but the risk is declining over time. 

As a comparison, the incidence of pneumococcal disease in adults with AIDS was 298 

cases/100,000 in 2007 in the US1

. Overall, the number of preventable cases is low. Given 

current incidence of both meningococcal disease and HIV infection in the US, the total number 

of meningococcal disease cases in HIV-infected persons is likely low, and the duration of 

protection from vaccine is short in HIV-infected persons. The Meningococcal Work Group does 

not propose changes to the current ACIP recommendations for HIV-infected persons at this time 

[

1

Cohen AL, Harrison LH, Farley MM, Reingold AL, Hadler J., et al. Prevention of invasive 

pneumococcal disease among HIV-infected adults in the era of childhood pneumococcal 

immunization. AIDS 2010, 24:2253-2262]. 

The rationale for the Meningococcal Work Group’s support of no changes to the 

recommendations is that persons with HIV are at lower risk compared to other recommended 

groups (e.g., microbiologists, complement component deficiencies, et cetera); however, the risk 

is lifelong and there would be a need for multiple booster doses. In addition, it is not known if 

persons vaccinated when CD4 counts are high will be protected when CD4 counts decline. A 

cost-effectiveness analysis has not been done for the use of meningococcal vaccines in HIVinfected persons, but would likely not impact the work group’s conclusions. 

Discussion Points 

Dr. Harrison inquired as to whether there were any data on immunogenicity in HIV-positives with 

MCV4-CRM. 

Ms. MacNeil responded that she did not believe any data were available on that. There is 

nothing published. 

Dr. Zahn (NACCHO) pointed out the importance of getting a sense in all communities of how 

many cases occur in the MSM community. Los Angeles County wrestled for a while with 4 

cases in a community of 10 million. Los Angeles County concluded that there was nothing and 

they did not make recommendations compared to New York City, but they received a lot of 

noise from the community regarding whether they should do something. Local counties make 

recommendations about vaccinations. For example, meningococcal vaccination is considered 

to be a travel vaccine, so multiple counties in California made recommendations that MSM who 

were traveling to New York City should be vaccinated. The point is that from what he saw in the 

data in New York City, whatever was occurring there seemed to be subsiding. His thought was 

that we are a lot better at letting people know that there is an issue as opposed to letting them 

know that it is subsiding. Making that clear so that local counties and providers can make 

recommendations about whether any of this is necessary anymore would be worthwhile. 

Ms. MacNeil indicated that these data would be published in the MMWR in a couple of weeks. 

Dr. Duchin inquired as to whether the work group’s deliberations identify any areas that would 

help or lead to changes in the approach to outbreaks among communities where there are high 

numbers of HIV-infected persons. 

49 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Ms. MacNeil replied that the work group had not discussed this issue specifically, but has been 

discussing outbreak guidelines in general for institutional and community settings. 

Dr. Reingold asked whether there had been a study assessing risk factors predicting 

meningococcal disease in MSM in terms of their behaviors, such as use of bath houses. He 

was curious what New York City’s recommendations were based on. 

Ms. MacNeil responded that there have not been any formal studies. CDC did try to acquire 

some of that information through the Epi-X, but she did not believe they were aware of any 

specific behaviors for MSM that would present an increased risk. 

Dr. Cohn (SME) added that New York City’s specific recommendations were based on the 

epidemiology investigations they conducted. They found that numerous of these cases had 

recently used some of these apps and had been visiting these bars that they were trying to 

target. 

Dr. Harrison pointed out that there is a lot of behavioral data in the non-MSM population to show 

that behavioral risk factors are very important (e.g., drinking, going to pubs and discos, kissing). 

Dr. Temte asked whether the rates of vaccine uptake were known for these two populations for 

other vaccines that are commonly recommended (e.g., hepatitis B, recommended suite for HIV). 

Dr. Schuchat said she did not believe there were great data. Years ago, there were some data 

on pneumococcal polysaccharide vaccine in HIV-infected individuals that was in the 50% range 

or so. However, she was not aware of the hepatitis data for instance. She thought some of the 

coverage surveys tended to group immunosuppressive groups together so that they do not 

identify those with HIV. However, CDC can check to determine whether there are data and if 

so, will make those available. 

Dr. Reingold noted that historically in San Francisco, it has been difficult to get men to take all 

three doses. The follow-up after the first dose has been very strong and the coverage with 

three doses remains quite low. 

Dr. Zucker (NYC DOHMH) indicated that from their perspective, and the persistent increased 

risk for invasive meningococcal disease in their MSM and HIV populations, they are currently 

struggling with what to do about recommendations going forward. In fact, NYC DOHMH is 

leaning toward the need for a routine recommendation for meningococcal vaccine in this group, 

and has had internal deliberations as well as with partners. A large population would there 

would have an indication for vaccine. The department was somewhat disappointed that there 

had not been a more formal review in GRADE, and deliberation by the full work group regarding 

whether there should be a recommendation. NYC DOHMH has also struggled with whether 

they should be out in front of ACIP on this recommendation. While they appreciated the results 

and conclusions, they requested that a more formal consideration and GRADE review of those 

recommendations. 

Dr. Bennett asked whether the vaccination status of the cases was known, given that many of 

them may have been young enough to have received previous meningococcal vaccine. 

Ms. MacNeil replied that the vaccination status of most of them were unknown. 

50 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Use of Serogroup B Meningococcal Vaccine During Outbreaks on College Campuses 

Manisha Patel, MD, MSc, Medical Officer 

Meningitis and Vaccine Preventable Diseases Branch 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Dr. Patel presented on the use of serogroup B meningococcal vaccine during outbreaks on 

university campuses. The incidence of meningococcal disease in the US has been steadily 

decreasing, and reached an all-time low in 2013 with a provisional count of 519 cases among all 

serogroups. Serogroups B, C, and Y cause the majority of disease, with each serogroup 

contributing to about a third of cases. Although outbreaks of meningococcal disease are 

typically caused by serogroup C, recently serogroup B outbreaks have been observed, 

particularly on college campuses. Meningococcal disease rates peak in less than 1 year olds 

and again in adolescents and young adults between the ages of 16 through 21 years. The peak 

in adolescents occurs similarly for all serogroups, and possibly reflects the frequency of 

exposure to people from whom one can acquire carriage. With the recommendation of 

conjugate MenACWY vaccines for adolescents in 2005, serogroup B now accounts for the 

highest incidence of disease in this age group. Over the past five years, five serogroup B 

outbreaks on college campuses have been reported to CDC. Universities 1 and 2 both had 

small clusters in which cases occurred within a relatively short time of each other. The 

epidemiology at University 3 differed in that the outbreak spanned over two academic years. 

With the availability of a meningococcal serogroup B (MenB) vaccine in 2013, there was now a 

potentially different approach to control the outbreaks at Princeton University and University of 

California—Santa Barbara (UCSB). 

Eight cases of MenB were reported among Princeton University students or persons with links 

to Princeton University from March through November 2013. The attack rate was 134/100,000 

among undergraduates, which was more than 1400 times higher than the background incidence 

rate for 17 through 22 year olds in the US. There have been no fatalities, but there were 2 

cases with sequelae, including 1 with a neurocognitive deficit and 1 with partial hearing loss. 

Although laboratory testing demonstrated that all of the strains isolated from the cases were 

identical by sequence type, PFGE patterns, and molecular antigen typing, there was no direct 

epidemiologic link between cases. Cases were reported in all 4 class years among students 

living in dorms, and occurred 2 to 4 weeks apart during the academic year over an 8-month 

period. 

With this evidence of sustained transmission in a large population at risk in which the majority of 

students reside on campus, Princeton University, the New Jersey Department of Health, and 

CDC decided to implement a vaccination campaign to prevent additional cases. Although there 

is no currently licensed MenB vaccine in the US, Pfizer has a MenB vaccine currently in 

development. Novartis, the manufacturer of Bexsero®, a recombinant MenB+OMV NZ (rMenB), 

had its vaccine recently licensed in Europe, Australia, and Canada. Effectiveness was inferred 

based on immunogenicity of a 2-dose series, with an immune response seen after 1 dose. 

Safety data in almost 1600 adolescents showed that greater than 10% reported non-serious 

adverse events; however, no serious adverse events were reported. rMenB contains 4 

antigenic components (fHBP, NHBA, NadA, PorA). The isolates from Princeton expressed 2 of 

the 4 antigens (fHBP and NHBA) in sufficient quantities to suggest protection with rMenB. 

Additional testing demonstrated that isolates from 4 of the cases was killed by pooled postimmunization sera. 

51 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Based on recent licensure of rMenB elsewhere, a good safety profile, and the concern for 

occurrence of additional cases upon commencement of the new academic year at Princeton 

University, CDC and FDA began to explore the use of rMenB in outbreak settings under an 

expanded access Investigational New Drug (IND) Protocol in August 2013. Expanded access 

INDs provide investigational products for serious or life-threatening conditions when there are 

no otherwise adequate approved alternatives. Expanded access INDs are not intended for 

product development or clinical trials. As part of the IND submission process, Novartis 

performed testing of isolates between September and November 2013 to determine vaccine 

antigen matching. CDC and the New Jersey Department of Health conducted an epidemiologic 

investigation at Princeton in October 2013 to identify the target population. The IND was 

officially submitted in November 2013, and included a safety monitoring plan, consents, vaccine 

information sheets, and data collection instruments. Approval by both FDA and CDC 

Institutional Review Boards (IRBs) shortly followed. Additionally, negotiations and contractual 

agreements between the various stakeholders were finalized in early December 2013. 

The recommended population for vaccination included all undergraduate students, graduate 

students living in dorms, other persons with medical conditions putting them at increased risk for 

meningococcal disease, and spouses or parents living with undergraduates in dorms. The total 

number of people in the target population was 5772. To date, there have been 3 vaccination 

clinics. The first dose clinic was held over a 4-day period in December 2014, and the second 

dose clinic was held the week of February 17-20, 2014. Over 75 people from Princeton 

University, Maxim Healthcare, and CDC were onsite during these clinics. High coverage was 

seen for both doses, with 95% of the target population receiving the first dose and 88% of firstdose recipients receiving the second dose. An additional catch-up clinic is planned for March 

2014. 

Mandatory reporting of all SAEs is required to FDA and includes death, a life-threatening AE, 

hospitalizations, substantial disruption in the ability to conduct normal life functions, or a 

congenital anomaly or birth defects. To date, the rate of SAEs reported is 2.0/1,000 vaccinees 

following the first dose and 0.2 /1,000 vaccinees following the second dose. No SAEs have 

been determined to be causally related to rMenB. Additionally, there have been no concerning 

patterns among other types of AEs reported to date. 

In November 2013, 4 cases of MenB with no direct epidemiologic links occurred among 

undergraduate students at UCSB. All 4 cases recovered, with complications in 1 case patient 

resulting in bilateral foot amputation. During the epidemiologic investigation, an additional case 

associated with UCSB was identified in March 2013. This suggested that there was sustained 

transmission of MenB occurring at the university and that vaccination would be an appropriate 

strategy to control the outbreak. The attack rate was 21.1/100,000 or 230-fold higher than the 

background incidence rate for 17 through 22 year olds in the US. Isolates from the 4 cases 

were ST-32 with identical antigens. There were two different PFGE patterns, which is thought 

to be due to horizontal gene transfer between the circulating strains, and thus still considered to 

be the same outbreak strain. Although this strain is different from the Princeton strain, 

additional testing of isolates from 3 of the cases demonstrated killing using pooled rMenB postimmunization sera. 

Due to the concern that additional cases would occur, a CDC-sponsored expanded access IND 

was approved by FDA for use in the UCSB outbreak. The target population was similar to 

Princeton University and included all undergraduates, graduate students or faculty living in 

dormitories, and others with high-risk conditions for meningococcal disease. The estimated 

target population was approximately 20,000 people. The first dose campaign began February 

52 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

24, 2014 and will continue through March 7, 2014. A second dose clinic is planned for April 

2014. A safety surveillance plan is in place in collaboration with UCSB and CDC. 

Although the primary objective for implementing a vaccination strategy is to prevent additional 

cases, there are a number of challenges associated with using an unlicensed vaccine to control 

outbreaks. The IND preparation process is unique for each setting, and must address the 

specific epidemiologic and laboratory findings for each outbreak. There are also specific safety 

monitoring requirements that must be followed when using an unlicensed product under an 

Expanded Access IND. There are also the logistics of vaccine procurement, and 

implementation requires participation from multiple stakeholders in order to conduct a campaign 

in a timely and effective manner. Despite these challenges, both Princeton University and 

UCSB demonstrated extraordinary efforts in rapidly standing up these campaigns. 

Although an increase in MenB outbreaks in college campuses is not expected, CDC has 

recently formed a Meningococcal Outbreak Work Group comprised of ACIP Meningococcal WG 

members, ACIP members, state public health officials, college health professionals, 

representatives from university administration and the insurance industry, and CDC to address 

potential issues related to management of these outbreaks. The objectives are to review the 

available data on the recent epidemiology of meningococcal disease and outbreaks; consider 

options for updating the current meningococcal disease outbreak guidelines; and develop 

guidance for use of meningococcal vaccines (both licensed and unlicensed) in an outbreak 

setting. 

In summary, vaccination now possible in response to MenB outbreaks. Implementation of an 

unlicensed vaccine requires coordinated efforts between the institution, state and local health 

departments, the manufacturer, FDA, and CDC. An ACIP outbreak workgroup is currently 

developing guidance for management of MenB outbreaks. This interim guidance will be 

presented during the June ACIP meeting. 

Discussion Points 

In each of these cases, Ms. Pellegrini wondered which entity was responsible for drawing up 

and submitting the IND to FDA. 

Dr. Patel responded that for the CDC-sponsored IND, CDC is the principal investigator and 

each site has its own site investigators. 

Dr. Zahn (NACCHO) pointed out that a lot hinged on the one UCSB case that occurred in 

March. He inquired as to how common this specific strain is. If it is a common type, one could 

argue that this was a random event that did not necessarily attach to everything else. 

Dr. Patel responded that ST-32 is the second most common MenB strain seen in the US. The 

key is that the PFGE patterns were similar to the outbreak cases. The other issue is that it is 

not possible to predict what will happen, which is one of the greatest issues. In the setting of 

having a vaccine potentially available, all stakeholders were interested in pursuing that route. 

Dr. Pickering said he believed in Canada, MenB was the major serogroup causing disease in all 

people, not only infants. He inquired as to whether there was any history of travel to Canada in 

the Princeton group, particularly in the early cases. 

53 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Patel replied that for Princeton, there was one traveler to Greece. None of the others 

traveled outside of the country. This is not known for UCSB. 

Dr. Warshawsky (NACI) confirmed that serogroup B is Canada’s most common serogroup 

largely because they control serogroup C, and is still a very rare disease in Canada. As 

mentioned, the Bexsero® vaccine was recently authorized for use in Canada and the NACI plans 

to issue recommendations in the next few weeks. 

Dr. Harrison inquired as to how it was determined that the PFGE variability was due to 

horizontal gene transfer as opposed to single nucleotide polymorphism (SNPs) in the restriction 

site. 

Dr. Patel indicated that there was a complicated discussion with the laboratories involved. 

Dr. Cohn (SME) added that that was the hypothesis. Additional genetic analyses are underway 

to assess SNP variation and sequencing. The preliminary suggestion was that the isolate from 

March may be a progenitor for both of these two strains, but there is a lot more work to be done. 

Dr. Clark (SME) added that the PFGE patterns were dramatically different in multiple bands, so 

this seemed like some large event rather than small ones, but that is just a hypothesis. 

Dr. Plotkin (Vaccine Consultant) said he was surprised not to hear any carriage studies, and 

that it would be extremely interesting to know whether the MenB vaccine has any effect on 

carriage and, indeed, to know how widespread the organism was at Princeton or UCSB. 

Related to that, it would be interesting to know what the carriage rate is in group C in MSM 

related to the previous discussion. He pointed out that the advantage of the conjugate vaccine 

is to affect carriage, so that there might be some argument for using the conjugate vaccine in 

population with widespread carriage regardless of the rate of active disease in order to 

terminate an outbreak more quickly. 

Dr. Temte noted that as someone who does a lot of nasal swabs for influenza, coupling a 

vaccine clinic with 97% attendance with a nasal swab would provide an incredibly rich set of 

data to assess issues such as carriage. 

Dr. Duchin requested further information about the visitor to Princeton University, such as 

whether the individual was a non-student or there was anything remarkable that would explain 

why that person would become part of the outbreak. 

Dr. Patel responded that this student was visiting the campus as part of an athletic recruitment. 

In April, the university has Princeton Preview where students spend a day or night with 

Princeton students. This was somewhat different in that this student engaged in social 

behaviors and activities similar to other college students in general, and then developed disease 

shortly after that. 

Dr. Duchin inquired as to whether any consideration had been given to changing the 

surveillance form, or the recommendations, or working with the Council of State and Territorial 

Epidemiologists (CSTE) on the national surveillance for meningococcal disease to include HIV 

status and/or sexual preference. 

54 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Cohn (SME) replied that all of these are under consideration. Changes to national to 

reporting forms are complicated and can take a long time to implement. Consideration is being 

given to recommendations for what data state and local health departments can collect on their 

own. How they report that may be challenging. 

Dr. Harriman indicated that some state health departments have already made this decision. 

For example, California is now collecting this information routinely and trying to go back in time 

to get it for as many as they can. However, this is not something that always comes up or is 

discussed necessarily. Having that asked regularly might be an issue, but an effort is being 

made. 

To expand on Dr. Duchin’s question, Dr. Clark (SME) said he thought the prospective student 

was the exception in that this person was a resident in the dorm for just a couple of days. The 

risk is not zero to visitors, but it is quite low. Once concern that was expressed was the risk of 

ongoing transmission when students return home, and whether the outbreak would spread. 

There is no indication that that occurred, as there were no secondary cases. Consideration has 

been given to carriage studies, and Dr. Dull could comment on what is known about the impact 

of this vaccine on carriage. CDC has discussed and is still thinking through carriage surveys 

after vaccination, but in this case, IRB approvals would have to be in place and the urgent goal 

was to stand up the vaccination program. 

Peter Dull (Novartis) thanked CDC and the organizations that brought this effort to happen. He 

thought it was a great example of collaboration with FDA, manufacturers, recommending 

bodies, and various state health departments. However, he cautioned everyone that this is not 

a sustainable solution for outbreaks of MenB. Aside from the work with FDA approving the IND 

and setting up the campaigns, the manufacturers are not in surge capacity such that they can 

label and ship unlicensed vaccine to someplace in the US very quickly. These outbreaks 

occurred fast, and it is necessary to have a more sustained solution for this. Novartis is actively 

talking to FDA about how to get this vaccine licensed in the US as well. Novartis has conducted 

a large carriage study in the UK, with approximately 3000 subjects enrolled. They showed 

some data during a conference in the UK last fall that showed some effect on MenB carriage 

with the Bexsero® vaccine. In order to see a true impact on a herd effect, there would have to 

be broader implementation, but there is an early assessment of the impact on herd immunity 

with this vaccine. 

Dr. Temte indicated that between the meningococcal and pneumococcal sessions, public 

comments would be presented. 

Public Comment 

Frankie Milley 

Founder / National Director 

Meningitis Angels 

I just want to say thank you for all the work that this body did to make sure that these kids were 

protected, and you stopped this outbreak at these two universities. I also want to say that I think 

moving forward, and my opinion and $5 will get a cup of coffee most places, okay, and I know 

my opinion compared to the people that sit here at this table every day and work hard to make 

sure that we’re all protected, is nothing in comparison. But, I would really encourage this 

committee moving forward that we make sure that we don’t pick and choose groups that should 

be vaccinated against other groups that should be vaccinated. I think moving forward, as we do 

55 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

have new and better vaccines, more vaccines to cover meningococcal disease, especially in 

infants, we need to move forward with recommendations to protect infants all the way through 

that recommended ACIP group plus MSMs and anybody else who might be at risk. I also 

believe that we risk too many lives when we wait for an outbreak somewhere. You know, we’ve 

seen it in Oologah Elementary School. We’ve seen it recently in Princeton and California. We 

need to be proactive. Public health is the best thing—the best money—that we can spend in 

this country. I firmly believe that if we put our money into public health, vaccinations and public 

health, that our health care bills are going to go down and health care overall will go down—the 

cost. It’s the best money we can spend. Again, thank you for allowing us to have a say in these 

committee hearings. 

Robin, Keith, and Gregory Kephurt 

Parents of a Child Who Developed Pneumococcal Meningitis 

Hello. My name is Robin and this is my husband Keith and my son Gregory. We also have a 

daughter Kayla, at home staying with friends. 

I would like to start off reading a paper that Kayla wrote recently as an assignment for school. 

The assignment was about a formula, if you could create a formula what would it be? Here is 

her shortened version of her 3rd grade response with no help from us. She nailed many of what 

we are dealing with Gregory because of his illness with meningitis. 

“I seek a formula that will make my big brother able to walk. Gregory was diagnosed with 

meningitis when he was a baby. Gregory is in a motorized wheelchair. Gregory needs braces 

on his arms and AFO’s on his legs and feet. Gregory plays soccer for kids with disabilities. He 

is the only one in a gait trainer. Gregory and I have a cat named Oliver and a dog named 

Apollo. Greg is funny, fun, sweet and kind. Gregory would not have so many seizures. He 

would have seizures when he was sick. If Gregory could walk he could pet Apollo and Oliver 

like the rest of us. He could feed himself with no help. It would be so much easier for my dad to 

get him up and down the stairs. He can have fun with me in the sandbox. He would be able to 

give me a hug by himself. He could ride more rides at Disney. He can play more games with 

my friends and I instead of sitting with the parents. He could play tag and hide and seek. If it 

works, I hope for all of the boys and girls that have disabilities to be able to walk. I hope that 

Gregory can walk soon.” 

There was a shortage of the vaccine. My son was unable to get his booster. He developed 

pneumococcal meningitis. As a result, Gregory suffered brain infarcts with traumatic brain 

injury. His ongoing diagnosis includes spastic quadriparisis, dystonia, seizure disorder, learning 

disability and speech delays. He is unable to care for himself, is not potty trained and wears 

diapers, cannot feed himself, cannot sit unsupported, or even walk. He will need therapy for the 

rest of his life. He will need one-on-one aide to help assist him with simple everyday task such 

as feeding, dressing, changing his diaper, transfer him from wheelchair to bed and other things, 

and as simple as hold a toy or whatever he wants to hold. He will need hip surgery in the near 

future. 

Is it cost-effective for the booster? Let’s look at the financial burden we had to pay due to 

Gregory’s illness. His anti-seizure meds are $800/month. His therapy bills are over $1000 a 

month. His ongoing doctor appointments with all the specialists to manage his ongoing care 

and treatment. He requires braces and AFO's annually because he is still growing. His 

motorized wheelchair is $20k. An accessible conversion van is additional $25k. To date we 

have incurred close to 1/2 million dollars in medical expense. Gregory is on both of our 

56 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

insurance through our employer. We maximize our out of pocket expense every year. All this 

could have been prevented had Gregory received his booster for a vaccine preventable 

disease. Think of how many lives we could save with the 1/2 million we spent on care of 

Gregory. One child is too many. 

I am pleading with you not to change the dosing schedule as we may see more children like 

Gregory, or worse, more children die. Thank you. 

Trish Parnell 

Parents of Kids with Infectious Diseases (PKIDS)
 

Last summer, I read an article in Pediatrics that looked at the cost-effectiveness of using two, 

rather than three, primary doses of 13-valent pneumococcal conjugate vaccine. We talked 

about this at PKIDs, and, while we were surprised, we thought it was probably more of an 

intellectual exercise than a course of action that our public health leaders in the US would take. 

After all, our tradition in the US is to use all of the tools we have to protect our citizens and 

prevent infections. But, here we are, looking at this as a real option. If a primary dose is 

removed, we may have an opportunity to save money, $400 to $500 million, but it’s not a riskfree deal. In order to save that money, we have to be willing to see harm come to a lot of 

people. This flies in the face of what we, as immunization advocates, say every day to the folks 

we meet, which is: “Get immunized!” 

Use the safe and effective prevention tools that we have. It’s easier to make this kind of 

decision and to talk about the numbers of folks who will be harmed if it’s not personal. But, as 

goes ACIP, so goes the nation when it comes to prevention through immunization. We have to 

consider the personal side of this decision. We can’t dehumanize our people, our loved ones, 

friends, and neighbors, by thinking of them only as numbers. If the third primary dose is 

removed, an average of 2.5 more people will die each year. Who are those people? One could 

be my niece, Millie, who’s just learning to crawl. Another could be your grandson, who loves 

cheerios and bananas. 

Forty-four more people will get invasive pneumococcal disease. My daughter could get 

meningitis, and your son could get a bloodstream infection. Fifteen hundred more people will be 

hospitalized for pneumonia. When my oldest was a toddler, she was hospitalized for 

pneumonia. It’s a terrifying experience and one that I would not have anyone else go through, if 

possible. An additional 10,000 of our friends and neighbors and loved ones will have to be 

treated for pneumonia as outpatients. Twenty three hundred more ear tubes will have to be 

inserted into the tiny ears of children that we know. A staggering 261,000 more children will get 

earaches, fevers, and possibly ruptured eardrums. All of this happens if we decide to save 

money and remove a primary dose of PCV13. It’s all about the numbers. We just have to 

decide which numbers are more important to us as a nation—the dollar amounts or our people? 

57 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

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 by outlining the 

Pneumococcal Vaccines Work Group’s terms of reference, which are as follows: 

 Review current data on efficacy, effectiveness, immunogenicity, and cost-effectiveness of 

pneumococcal vaccines 

 Review current recommendations considering up-to-date evidence, including 

epidemiological studies conducted post-licensure, and assess strength of the evidence 

 Revise or update recommendations for pneumococcal vaccine use, as needed 

The focus of this session was the routine infant immunization schedule for 13-valent 

pneumococcal conjugate vaccine (PCV13), and the emerging evidence supporting use of a 3­

dose PCV13 schedule. A 3-dose PCV13 schedule is approved by the European Medicines 

Agency (EMEA) and other licensing bodies. The World Health Organization (WHO) recognizes 

a 3-dose schedule as an acceptable alternative to a 4-dose schedule [Pneumococcal vaccines 

WHO position paper, Wkly Epidemiol Rec, 2012]. A 3-dose schedule is routine in many lowincome countries. At least 21 high- and 13 upper-middle income countries have also introduced 

PCV13 or PCV10 with 3 doses or have switched from 4- to 3-dose schedule. It is important to 

recognize that the value of a 3-dose schedule is being observed throughout the world. 

The evidence supporting the use of a 3-dose PCV schedule is emerging, the perceptions 

among parents that the vaccine schedule has become crowded and confusing, and safety 

concerns that too many simultaneous injections are being given have grown1,2. This may lead 

an increasing number of parents to delay or refuse recommended vaccines3

. Rare safety 

issues associated with co-administration of routine vaccines are emerging (e.g., febrile seizure 

with co-administration of PCV; diphtheria, tetanus, and pertussis (DTaP), and influenza 

vaccines) [1

Bardenheier Arch Ped Adol Med 2004, 2Gust Pediatrics 2008, 3Freed Pediatrics 

2010]. 

Another issue that has driven the WG to consider this change is that PCV7 use has led to 

dramatic reductions in disease burden in the US, including invasive pneumococcal disease 

(IPD) and pneumonia in children and adults and reductions in otitis media in children. PCV7 

serotypes have virtually been eliminated from all age-groups, which is a remarkable 

accomplishment, and the US now has a mature PCV program. Disease due to PCV13 

serotypes is also rapidly declining. Evidence supporting the use of 3-dose PCV schedules is 

emerging. PCV7 use led to dramatic reductions in disease burden. 

Dr. Bennett emphasized that this would be an information-only session, with no specific 

recommendations presented at this time. The session included review of the GRADE of 

evidence, discussion of ACIP’s questions from October 2013, and discussion of considerations 

for including a 3-dose PCV13 schedule for infants. The following questions were posed to the 

58 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

committee subsequent to the presentations: Is the evidence adequate to consider including a 3­

dose PCV13 schedule for infants? If not, what additional data or information would be required? 

Update on PCV13 Effectiveness and Herd Effects in the US 

Matthew R. Moore, MD, MPH 

Captain, USPHS 

Medical Epidemiologist 

Dr. Moore reminded everyone that CDC monitors IPD using active, population-based 

surveillance conducted in 10 areas around the United States (US) through the Active Bacterial 

Core surveillance (ABCs). ABCs is part of the Emerging Infections Program (EIP) at CDC. 

Rates of IPD over time have been evaluated. Subsequent to the introduction of PCV13, the 

focus has been primarily on the impact of that vaccine on 5 additional PCV13 types not affected 

by PCV7. There is a focus on those 5 additional serotypes because it is known that the 7-valent 

vaccine included an antigen against serotype 6B, but that antigen actually has activity or crossprotection against a serotype that is not included in the vaccine, 6A. 6A is also included in the 

13-valent vaccine. PCV7 includes serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. If the 8 

serotypes are removed that are affected by PCV7, the 5 additional serotypes remain. 

Evaluation has also been done for emergence of serotype replacement. This occurs initially at 

the level of the nasopharynx when children are vaccinated with pneumococcal conjugate 

vaccines. These vaccines eliminate carriage of vaccine types and are replaced by non-vaccine 

types. With the PCV7 experience, what was observed over time was that some of those nonPCV7 types began to cause invasive disease. Monitoring began for a similar type of effect after 

PCV13 introduction. In addition to discussing these evaluation efforts, Dr. Moore presented an 

update on individual-level vaccine effectiveness (VE) evaluated among children 2 through 59 

months of age using a case-control method. 

Regarding annual trends in IPD from 2006 through 2013, a major reduction has occurred 

among children less than 5 years of age in disease caused by the additional serotypes included 

in the 13-valent vaccine, which is driving the reduction in the overall invasive disease. Because 

there has not been much uptake in 13-valent vaccine in adults, especially not in adults 18 

through 49 years of age, it is believed that much of what is being observed in reductions in 

adults is related to use in children and the prevention of transmission of those vaccine types 

from children to adults. The picture is slightly different in adults 50 through 64 years of age, with 

a decline in the additional serotypes in PCV13 after vaccine introduction in 2010 and the 

suggestion of an increase in the non-vaccine types that are not included in the 13-valent 

vaccine. A similar pattern is observed among adults 65 years of age and older. 

When a modeling approach is used to estimate percent changes in disease in each of these 

groups, the general pattern is that the largest reduction observed following the first year after 

vaccine introduction was in children under 5 years of age. Reductions were lower for 

unvaccinated populations and older age groups through the herd effect. In each successive 

year, the reductions were larger than in previous years. This shows that with each successive 

year of use of PCV13, reductions continue to be seen in the additional vaccine types affected by 

PCV13. This is all very good news. With respect to the non-PCV13 types, it was only in 2012­

2013 and in the 50 through 64 year old age group that a small and statistically significant 

increase was observed in non-vaccine types in that particular age group. This is not present is 

any of the other age groups. When all of these data are combined (e.g., the residual effects on 

the 7-valent types, the new effects on the additional types in PCV13), even after accounting for 

59 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

the small increase and the changes in all groups, IPD is still moving in the right direction. That 

is to say that in each of these age groups, there are primarily statistically significant reductions, 

especially in the latter years in the older age groups. If that is evidence of serotype replacement 

in the 50 through 64 year olds, it is not overshadowing the continued reductions being observed 

in those serotypes included in PCV13. 

As of June 2013, approximately 30,000 cases of IPD have been prevented following PCV13 

introduction, roughly a third among children under the age of 5, about a quarter among adults 

65 years of age and older, and about a quarter in adults 50 through 64 years of age. 

Approximately 3,000 deaths from IPD have been prevented over the first three years of the 

program. Relatively smaller numbers of children actually die of IPD compared to adults. This is 

why, when the distribution of the deaths prevented is examined, most deaths are being 

prevented in adults who are not actually receiving the vaccine—again speaking to the herd 

protection of the vaccine. 

Regarding the ongoing case-control study of PCV13 effectiveness, children 2 through 59 

months old with IPD residing in 10 ABCs areas, New York City, Los Angeles County, and Utah 

have been enrolled. From May 2010 through September 2013, the program enrolled 760 

cases. Of these, 224 (29%) had PCV13-type IPD and 209 (93%) were caused by serotypes 

19A, 7F, and 3. Also enrolled were 3,519 controls (3 controls per case). Preliminary data show 

that receipt of 1 or more doses among controls increased from 38% in June through November 

2010 to 96% in May through September 2013. Compared to data presented during previous 

ACIP meetings, there are now individual level estimates of serotype-specific effectiveness. 

Evaluation of the individual serotypes shows vaccine effectiveness of about 90% for serotype 

19A, 100% for serotype 7F, and about 76% for serotype 3. All of these are statistically 

significant, so these data are encouraging. 

In summary, reductions are being observed in IPD caused by the additional serotypes in PCV13 

among all age groups, which is indicative of direct and indirect effects. There is early evidence 

of increases in non-PCV13 serotypes in adults 50 through 64 years of age, which is possibly 

suggestive of serotype replacement—an experience that was similar with PCV7. The increases 

in non-PCV types are not overshadowing the reductions in the PCV13 types. There is now 

preliminary evidence of serotype-specific effectiveness for the 3 most common PCV13 

serotypes. Additional analyses are pending. 

Discussion Points 

Referring to Slide 8, Dr. Michael Decker (Sanofi Pasteur ) submitted that the data suggested 

that there was an increase in the lower three age groups (e.g., the positive numbers in the right 

hand column). The sample size is simply not large enough to offer a confidence limit that does 

not cross null. The point estimates for all three of those is a positive number. Therefore, he 

cautioned against excluding the possibility that the point estimates are actually telling the truth. 

He noted that Dr. Moore said that only the one in red differed, which was not true. 

Dr. Moore clarified that he said that only the one in red was statistically significant, but said that 

Dr. Decker’s point was well-taken. 

Dr. Vazquez inquired as to whether there was a trend in the non-vaccine type disease type 

toward a specific type of illness (e.g., pneumonia, bacteremia) or particular serotype. 

60 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Moore replied that an assessment had not yet been done to determine whether a particular 

syndrome was rising to the top. With respect to individual serotypes, what was being observed 

were very small and not statistically significant increases in any individual serotype. At least six 

or seven appear to be somewhat higher than they were before, but each of those increases is 

very small. The statistically significant change was observed in that particular group only when 

the serotypes were all added together. 

Recalling the data presented earlier in the morning about last year’s influenza season being 

more severe than usual, Dr. Gorman (NIH), wondered whether that would have impacted the 

numbers for this year. 

Dr. Moore responded that it appears that in some of the ABCs areas, there was at least a 

temporal relationship between influenza activity and increases in some of the non-vaccine 

types. However, this was not consistent across all sites and in some of the sites there was no 

increase in non-vaccine types at all. That was not necessarily associated with an absence of 

influenza. There may be the beginning of a signal, but he would not call it a clear-cut message. 

Reduced Dose Schedules of PCV13 for Children: GRADE of Evidence 

Sara Tomczyk 

EIS Officer 

Respiratory Diseases Branch 

NCIRD, CDC 

Ms. Tomczyk presented the results of the Grading of Recommendation Assessment, 

Development, and Evaluation (GRADE) process evaluating the evidence for 3-dose schedules 

of the 13-valent pneumococcal conjugate vaccine. The policy question posed was: Should a 3­

dose schedule of PCV13 be recommended for generally healthy infants in the US? This 

presentation addressed the GRADE process and GRADE conclusions. The GRADE process 

begins with defining the population, intervention, comparison, and outcome (PICO). 

The population of interest for this policy questions was comprise of children 2 through 15 

months of age with no underlying chronic medical conditions present. The interventions and the 

comparisons were addressed in two different steps. In step one, all evidence was graded for 

each PCV schedule compared to no vaccine to assess the strength of the evidence supporting 

each individual schedule as if policy decisions were considered pre-PCV7. Thus, the 

intervention for step one included the currently used schedule of 4 doses of PCV13 given at 2, 

4, 6, and 12 through 15 months (3+1) and two different 3-dose schedules with 3 doses given at 

2, 4, and 6 months (3+0) or at 2, 4, and 12 through 15 months (2+1). The comparison was no 

PCV13 or a placebo. In step two of the GRADE process, only studies with direct comparisons 

of schedules available within each study were graded. This included the 3-dose schedules of 

3+0 and 2+1, as compared to the currently used 4-dose schedules (3+1). 

A modified Delphi process was used to rank the importance of possible outcomes. A survey 

was conducted of WG members and their colleagues, practitioners, and public health 

professionals. Pediatricians (14; 29%) and public health professionals (21; 44%) represented 

the majority of the 48 total respondents. The respondents were asked to rank a list of outcomes 

1 through 9, and the rankings were used by the work group to select “critical” or “important” 

outcomes for which GRADE review of evidence would be conducted. Outcomes rated 7 to 9 

were determined to be “critical” for decision-making according to GRADE guidelines in step one 

(e.g., mortality, IPD, bacteremic and non-bacteremic pneumonia, serious adverse events, and 

61 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

indirect effects on IPD). Indirect effects ranked slightly below the critical outcomes threshold, 

but the WG determined that it was still critical. Pneumococcal meningitis and hospitalizations 

were also ranked as critical, but were incorporated primarily in the IPD outcome. Additional 

outcomes ranked but not included because of low ranking were office visits for pneumococcal 

disease, vaccine-type carriage, systemic adverse events, local reactions to the vaccine 

administration, and cost-effectiveness. In step two, any outcomes with studies providing direct 

comparisons between schedules were included as determined by the work group (e.g., 

immunogenicity or antibody response as surrogate for IPD, lower respiratory tract infection, and 

acute otitis media). 

Ms. Tomszyk presented the GRADE framework for each step. For step one, she presented a 

summary of included studies and assessed the quality of evidence for each schedule and by 

outcomes. Randomized controlled trials (RCTs) were selected first for each schedule and 

outcome. When data from RCTs were not available for an outcome and schedule, 

observational studies were considered. The data combined for all outcomes were then used to 

determine the overall type of evidence for each schedule. Lastly, values and preferences of 

outcomes were considered according to the a priori rankings of outcomes and a judgement on 

recommendation category of each schedule was made. Step two was organized according to 

comparisons between the schedules 3+0 versus 3+1, 2+1 versus 3+1, and 2 versus 3 primary 

doses; and the identified outcomes including immunogenicity data as surrogates for IPD, lower 

respiratory tract infection, and acute otitis media. The final recommendation category was 

judged for each 3-dose schedule (3+0 and 2+1) as compared to a 4-dose schedule (3+1). 

Starting with step one to present the GRADE of evidence for each schedule compared to no 

vaccine to assess the strength of evidence supporting each schedule, for the 3+1 schedule and 

IPD and pneumonia outcomes, 4 RCTs were included in the US, US Navajo community, 

Finland, and Brazil. These studies evaluated the efficacy of PCV7 and PCV10. Vaccine 

efficacy for IPD ranged from 83% to 100%. Vaccine efficacy for radiographic confirmed 

pneumonia ranged from -8% to 20.5%. A focus was placed on chest radiographic confirmed 

pneumonia for all of the pneumonia outcome data. 

For estimates of baseline disease incidence among unvaccinated, pre-PCV7 incidence per 

100,000 population was used of PCV13-type IPD or all-cause pneumonia among US children 

less than 2 years of age. The pooled vaccine efficacy estimates were applied for vaccine-type 

IPD and pneumonia based on the studies shown previously to the baseline incidence to 

estimate incidence among the vaccinated per 100,000 population. Using these data, the 

absolute risk difference per person and numbers needed to treat or vaccinate calculated. 

On a 3+1 schedule, PCV had a 94% vaccine efficacy for IPD and 11% vaccine efficacy for 

pneumonia, and the number needed to treat or vaccinate estimate showed that 613 people 

need to be vaccinated in order to prevent one case of IPD. Numbers needed to treat for 

pneumonia was not meaningful because the VE estimate was not statistically significant. 

To evaluate the indirect effects of PCV introduction on IPD at the population level, data were 

used from a pooled analysis of 21 surveillance datasets among countries with different PCV7 

schedules. In spite of the differences in surveillance methods and extent of catch-up, the effect 

estimates across all countries were between 0.20 and 0.80 or 80% to 20% reduction in vaccinetype IPD among adults despite a few estimates in Canada and the Netherlands that were not 

statistically significant. PCV use in children has led to large indirect effects on IPD among 

adults of all age groups in countries using PCV on 3+1 schedule. 

62 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

In the GRADE process, the evidence type for 3+1 schedule data was determined by first 

assigning an initial evidence type as follows: Type 1 included mainly RCTs or overwhelming 

evidence from observational studies, type 2 included RCTs with important limitations or strong 

evidence from observational studies, type 3 included observational studies or RCTs with even 

more notable limitations, and type 4 included clinical experience and observations, 

observational studies with important limitations, or RCTs with several major limitations. Next, 

the initial evidence type could be downgraded or upgraded according to pre-specified GRADE 

criteria, including: risk of bias, inconsistency, indirectness, imprecision, and other 

considerations such as strength of association, dose-response, opposing plausible residual 

confounding or bias. Evidence could be downgraded minus 1 or 2 when any GRADE criterion 

was serious or very serious. It could be upgraded plus 1 or 2 if the strength of association was 

large or very large and there was no apparent risk of bias. 

Thus, for the 3+1 schedule, the type of evidence was assessed according to the GRADE 

criteria. Both for IPD and pneumonia, the WG started with 3 RCTs and there were no serious 

concerns for any criteria, so the type of evidence for both outcomes was determined to be 1. 

For indirect effects, the 3 surveillance studies were a part of a pooled analysis, so the initial type 

of evidence was 3 and it was upgraded by 1 due to strength of association and no apparent risk 

of bias for a final evidence type of 2. The key point here is that there is high quality evidence 

which shows that the 3+1 PCV schedule is effective against IPD and pneumonia and, in 

addition, has demonstrated large indirect effects. 

For the 3+0 PCV schedules, for invasive pneumococcal disease and pneumonia, 3 RCTs were 

included. These were conducted in South Africa, the Gambia, and the Philippines. These 

studies evaluated efficacy of PCV9 and PCV11. Vaccine efficacy against IPD ranged from 77% 

to 83%, and for radiographic confirmed pneumonia ranged from 23% to 37%. As before, data 

from included studies were used to obtain pooled VE estimate for each outcome, which were 

then applied to the baseline (pre-PCV) incidence rates among US children less than 2 years of 

age for each outcome to calculate incidence among the vaccinated per 100,000 population. 

PCV had a 74% vaccine efficacy for IPD and 26% for pneumonia. The number needed to treat 

or vaccinate estimate showed that 779 people need to be vaccinated in order to prevent one 

case of IPD, and 370 people need to be vaccinated in order to prevent one case of pneumonia. 

To evaluate the indirect effects of PCV introduction on IPD at the population level for 3+0, the 

same pooled analysis of 21 surveillance datasets was used. This included Australia, which has 

used the 3+0 schedule. The effect estimates ranged between 0.20 and 0.50 or 50% to 80% 

reduction in IPD rates. The key point here is that the use of PCV on a 3+0 schedule among 

children in Australia also resulted in large reductions in IPD among adults of all age groups. 

The abstracted data were then used to determine the evidence type for the 3+0 schedule. For 

both IPD based on 2 RCTs and pneumonia based on 3 RCTs, there were no serious concerns 

for any criteria, so the type of evidence was determined to be 1. For indirect effects, based on 

surveillance data evaluation from one country using a 3+0 schedule, the initial type of evidence 

was 3, but it was upgraded by 1 due to strength of association and no apparent risk of bias for a 

final evidence type of 2. The key point to be made after the review of data supporting the 3+0 

schedule is that there is high quality evidence which shows that PCV use on the 3+0 schedule 

leads to large benefits, is effective against IPD and pneumonia, and has demonstrated large 

indirect effects. 

63 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

For the evidence review supporting 2+1 schedule, for the IPD outcome 1 RCT was included that 

was conducted in Finland evaluating efficacy of PCV10. In that study, vaccine efficacy for IPD 

was 92%. For pneumonia outcome assessment, 3 observational studies were included that 

were conducted in Quebec, Canada; Italy, and Poland. Studies in Canada and Poland 

evaluated impact of PCV7 introduction on chest x-ray confirmed pneumonia in children. The 

Quebec study demonstrated a 72% reduction in lobar pneumonia before and after introduction 

of PCV7 on 2+1 schedule. In Poland, there was a reduction in radiographic confirmed 

pneumonia 4 years after PCV7 introduction on 2+1 schedule, with 65% in 0 through 1 year olds 

and 23% in 2 through 4 year olds. The study in Italy was a large cohort study, which showed a 

65% vaccine efficacy for radiographic confirmed pneumonia. 

As presented for 3+1 and 3+0 schedule, vaccine efficacy estimates for each outcome were 

applied to the baseline (pre-PCV7) incidence of PCV13 type IPD and all-cause pneumonia 

among US children less than 2 years of age to calculate incidence among the vaccinated per 

100,000 population. PCV had a 96% vaccine efficacy against IPD and 70% against pneumonia. 

The number needed to treat or vaccinate estimate showed that 600 people need to be 

vaccinated in order to prevent one case of IPD, and 139 people need to be vaccinated in order 

to prevent one case of pneumonia. 

To evaluate the indirect effects of PCV introduction on IPD at the population level for the 2+1 

schedule, the same pooled analysis of 21 surveillance datasets was used. The effect estimates 

across all countries were between 0.20 and 1.20 or 80% reduction to no change in cases; and 

the estimates in Switzerland, Denmark, and Scotland were not statistically significant. Although 

there was some variability, there was also good evidence that the use of PCV on a 2+1 

schedule leads to large reductions in IPD among adults. 

The abstracted 2+1 data were then used to determine the evidence type for 2+1 schedule. For 

IPD, the evidence relied on 1 RCT and there were no serious concerns for any criteria, so the 

type of evidence was 1. For pneumonia and indirect effects, observational studies were used 

but the type of evidence was upgraded by one due to the strength of association for a final 

evidence type of 2. The key point here is that there is high quality evidence which shows that 

PCV use on the 2+1 schedule is effective against IPD and pneumonia, and has strong indirect 

effects which have been observed in several countries using PCV on this schedule. 

The take-away point for the mortality outcome was that mortality due to IPD is low in highincome countries, including the US. None of the studies were powered to detect the impact of 

any schedule on this outcome, so the WG was unable to assess the impact of PCV schedules 

on mortality. 

The last outcome in step one was serious adverse events, which was assessed across all 

schedules and by dose number where possible. Three different types of evidence were used to 

grade this outcome. Evidence comparing PCV13 to no vaccine were not available. Thus, data 

comparing PCV13 to PCV7 as part of PCV13 licensure application and comparisons between 

PCV7 and the Meningococcal C vaccine from 1 RCT conducted in the US were used. 

Additionally, an observational study was included to assess the incidence and timing of febrile 

seizures associated with PCV13 alone and when co-administered with influenza vaccine. 

Using the data from the Prevnar® licensure application, a comparison was made of incidence of 

overall serious adverse events between PCV13 and PCV7 groups. There were 3 deaths in the 

PCV13 group and 1 death in the PCV7 group. In the PCV13 group, the date of death included: 

one 3 days post-dose 1, one 14 days post-dose 2, and one 76 days post-dose 3. In the PCV7 

64 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

group, the date of the one death 13 days post-dose 1. For overall serious adverse events, there 

were small differences between the two groups. Investigators believed that these serious 

adverse events were related to the vaccine. Regarding the incidence of deaths in the PCV7 

group as compared to the control group, in the PCV7 group, there were 4 deaths or 0.2 

cases/1000 children. In the control group, there were 8 deaths or 0.4 cases/1000 children or 8 

deaths in the control group. Although investigators reported that these deaths were not related 

to the vaccine. 

The WG also reviewed a published study using Vaccine Safety Datalink (VSD) Project data that 

evaluated the risk of febrile seizures in children following a co-administration of influenza 

vaccine and PCV13. Risk difference estimates varied by age due to the varying baseline risk 

for seizures in young children, with the highest estimates occurring at 16 months, around the 

time when PCV booster is administered. The risk differences peaked at 13.7 per 100,000 doses 

for PCV13 without co-administration of the influenza vaccine, and at 44.9 per 100,000 doses for 

both the influenza vaccine and PCV13. The lowest estimates occurred at 59 months. Overall, 

there are many unique vaccine combinations given, so it may be difficult to estimate the risk for 

each combination due to lack of statistical power. Additional analyses assessing different 

vaccine combinations and comparing risks within different age groups are ongoing and will be 

presented to this committee at a future date. 

The evidence type was then determined for serious adverse events. Fourteen RCTs were 

included for an evidence type 1. However, due to indirect comparisons made where PCV13 

was compared to PCV7 and PCV7 was compared to a control vaccine, the evidence type was 

downgraded by 1 for a final evidence type of 2. The key point here is that PCV appears to be 

safe across all schedules. 

Next, the evidence types were combined per outcome for each schedule to assess overall 

evidence type by schedule. The lowest evidence quality from critical outcomes assessed for 

each schedule was used. Thus, each schedule was supported by type 2 or strong evidence. 

The WG next considered prevailing values and preferences. WG members determined that the 

values and preferences were high for IPD, pneumonia, and serious adverse events, but were of 

relatively lower value for indirect effects. 

Lastly, the data were assembled to make a judgment of recommendation category for each 

schedule. WG members were asked to respond to the following 4 questions: 

1. In response to the question: Is the evidence quality low? The work group determined that 

evidence quality supporting each schedule was high. 

2. In response to the question: Are the net benefits low or is there uncertainty about the 

balance of benefits versus harms? The WG determined that there was no uncertainty about 

each schedule providing protection against critical outcomes. 

3. In response to the question: Is there variability or uncertainty in what outcomes are 

important to prevent? The WG agreed on which outcomes are important to prevent. 

4. In response to the question: If there is uncertainty about whether the net benefits are worth 

the costs? The intervention was determined to be cost-effective. Cost-effectiveness studies 

for PCV have been conducted and published, and for the sake of time these data were not 

presented again during this session. 

65 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

These answers indicate that each schedule is supported by a category A recommendation, 

which is a recommendation for which the desirable effects clearly outweigh the undesirable 

effects. Overall, the GRADE process suggests that if policy decisions had to be made to 

recommend PCV on either schedule for the first time, the data would support the use of any of 

these schedules. 

In terms of step two of the GRADE process focusing on the GRADE of only studies with direct 

schedule comparisons, most of the direct schedule comparisons were obtained from 

immunogenicity studies. Data were abstracted on IgG antibody concentrations and the 

proportion achieving a response with concentrations >0.35μg/mL following the primary series of 

PCV or following a booster dose for each schedule. A threshold of >0.35μg/mL is a reference 

point which was developed for antibody comparisons in infant vaccine trials to support an IPD 

indication. Comparisons between schedules were made using: 1) Risk ratios comparing % 

>0.35 between groups, and 2) Ratios of geometric mean concentrations (GMCs) in each group. 

For step two, immunogenicity RCTs with direct schedule comparisons included were studies 

conducted in Israel, the United Kingdom (UK), one across Europe, in Fiji, in Iceland, and in 

Gambia. Four studies had comparisons between 2+1 or 3+0 versus 3+1, while two studies had 

comparison between 2 versus 3 primary series. PCV7, PCV9, and PCV10 were evaluated in 

these studies. 

Regarding the comparison of immunogenicity data for 3+0 versus 3+1 showing proportions with 

antibody levels >0.35 μg/mL for each group, and the risk ratio comparing the percentage above 

the threshold and GMC for 3+0 versus 3+1, antibody levels for 3+0 schedule were assessed 

post-primary, or at approximately 7 months, and for 3+1 were assessed post booster at 

approximately 13 months. Three serotypes (6B, 23F, and 1) had a significantly lower proportion 

above 0.35 μg/mL threshold in the 3+0 schedule group as compared to 3+1. For all serotypes, 

GMCs were significantly lower for 3+0 schedule. These results highlight a strong boosting 

effect observed when the last does is given in the second year of life following a primary series. 

However, it is important to note that both groups had high proportions above the 0.35 μg/mL 

cut-off. 

In the same comparisons for 2 versus 3 primary doses, the response in each group was 

measured approximately 1 month post-last dose. No serotypes showed differences by the 

percentage above the threshold, and two serotypes (6B and 23F) had a significantly lower GMC 

for 2 compared to 3 primary doses. However, again, both groups still had high proportions 

above the 0.35 μg/mL cut-off. In the comparison for 2+1 versus 3+1, only one serotype (6B) 

had a significantly lower proportion above 0.35 cut-off for 2+1 schedule, as compared to 3+1 

and two serotypes (6B and 18C) that had a significantly lower GMC ratios. However, again, 

both groups still had high proportions above the threshold. 

To summarize the key points for immunogenicity, the proportions >0.35 μg/mL are high for 

schedules with 3- and 2-dose primary series. Post-primary, the 3-dose schedule appears to be 

better than 2-dose schedule for some serotypes according to the GMC ratio data. In the second 

year of life (pre-booster and post-booster dose), there were small but significant differences for 

some serotypes according to the GMC ratio data. The differences appeared to be more 

pronounced after the primary series and when comparing GMC values or ratios rather than 

proportions >0.35 μg/mL. 

66 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

However, it is also important to draw attention to some caveats that need to be considered with 

respect to the immunogenicity data. Regarding a cut-off of 0.35 μg/mL, WHO determined a cutoff value that correlated with protection against IPD through various stages. First, the results of 

the US PCV7 trial showed that a 0.2 μg/mL cut-off post-dose 3 correlated with 97.3% vaccine 

efficacy against IPD. Later, data from two RCTs were added, one PCV7 trial among American 

Indians that showed a cut-off value of 1.0 μg/mL which correlated with 76.8% VE, and one 

PCV9 trial in South African infants which showed a cut-off value of 0.68 μg/mL which correlated 

with 90% VE. After adding data for these 3 trials, the aggregate cut-off value was raised to 

0.35μg/mL. What these data illustrate is that children at a higher risk for pneumococcal 

disease, such as those with HIV, may require higher antibody levels to achieve an equivalent 

protective efficacy. The key point here is that the cut-off for IPD of 0.35 μg/mL is likely higher 

than necessary US population of generally healthy infants. 

Overall, the GMC cutoff of 0.35 μg/mL should be interpreted with caution. It was developed as 

an aggregate cutoff for all serotypes combined and its clinical significance is not established for 

individual serotypes, post-booster measurements of antibody levels, and for non-IPD endpoints. 

In addition, GMC ratios presented to compare the schedule should also be interpreted with 

caution because they do not take into account absolute values for antibody levels for groups 

compared. For example, the values of 2 versus 4 μg/mL and 0.35 versus 0.7 μg/mL have the 

same GMC ratios. The key point here is that differences may not always be meaningful and it is 

important to look at both the %≥0.35 μg/mL and absolute values. 

Thus, for all immunogenicity comparisons, the type of evidence is 1 because the evaluation 

started with RCTs and no serious concerns were noted across the GRADE criteria. Two 

observational studies were also identified with direct schedule comparisons in the US using 

PCV7 on lower respiratory tract infection (LRTI), and on acute otitis media. Although it should 

be noted that acute otitis media was not ranked as one of the critical outcomes in step one. 

The first observational study using a propensity-score-matched case-cohort design in the US 

evaluated the rate of hospitalizations and ambulatory visits for pneumonia in a 2002 birth cohort, 

comparing 2 versus 3 primary doses. The study found that there was a statistically significant 

rate difference of 7.8 cases per 1000 children or fewer pneumonia-related admissions in those 

who received 3 doses versus 2 doses. This difference disappeared after the booster dose was 

administered. The same study was repeated for 2003 birth cohort. Post-primary, 3+1 had 

greater incidence as compared to 2+1, but the absolute rate difference was not statistically 

significant. Post-booster, 3+1 had lower incidence as compared to 2+1 but again the absolute 

rate difference was not statistically significant. It is difficult to interpret these results, given that 

pre-booster, the 2-dose primary series had lower rates and post-booster, the 3-dose primary 

series had lower rates. As mentioned before, none of the differences are statistically significant. 

The authors of the paper concluded that there were no differences observed between schedules 

for this 2003 birth cohort. They hypothesized that by 2003, or 3 years after introduction of 

PCV7, herd effects had lessened the difference in risk between the two groups. 

The second observational study compared the incidence of acute otitis media in children born in 

2002 who received two or three doses in the primary PCV7 series using propensity score 

matched data from an insurance claims database. The study assessed acute otitis media rates 

after completion of the primary series and before the booster dose, and after the booster dose 

until four years of age. The results showed that pre-booster dose incidence rates were 0.38 per 

person for children receiving 2-doses primary series and 0.35 per person for children receiving 

3-dose series, but these rates were not statistically different. Post-booster incidence rates were 

67 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

also not statistically different between the groups. The key point here is that there were no 

differences between schedules with 2 versus 3 doses in the primary series pre- or post-booster. 

The direct comparisons of clinical pneumonia-related hospitalizations and acute otitis media 

were observational studies, so the initial evidence type of both started as 3 and remained this 

type because no GRADE criteria were applied for downgrading or upgrading. The key point 

here is that there are limited studies with direct head-to-head comparisons and clinical 

endpoints, so the evidence quality for critical outcomes is low. 

Using the evidence type tables presented by schedule and outcome, the overall evidence type 

was determined for each schedule. The lowest evidence quality from critical outcomes 

assessed for each schedule comparison was used. Thus, all schedules had a type 3 evidence. 

WG members determined that the values and preferences were high for pneumonia, but of 

relatively lower value for acute otitis media and immunogenicity. Immunogenicity data was 

ranked as relatively lower value because the clinical significance of these surrogate data is not 

established for non-IPD outcomes, post-booster dose, or individual serotypes. 

Lastly, the assessment data were assembled to make a judgment of recommendation category 

for each schedule. The WG members were asked to respond to the following 4 questions: 

1. In response to the question: Is the evidence quality low? The WG determined that the 

evidence quality supporting each 3-dose schedule compared to 4-dose schedule was low 

because limited head-to-head comparisons were available, and the available 

immunogenicity data were used as surrogates for IPD but not other critical outcomes. 

2. In response to the question: Are the net benefits low or is there uncertainty about the 

balance of benefits versus harms? The WG determined that there was some uncertainty 

about the balance given the observed differences for some serotypes in antibody response 

and clinical relevance of these differences. 

3. In response to the question: Is there variability or uncertainty in what outcomes are 

important to prevent? The work group reached a consensus on which outcomes are 

important to prevent. 

4. In response to the question: If there is uncertainty about whether the net benefits are worth 

the costs? As mentioned earlier, the cost effectiveness analysis comparing the 2+1 

schedule to 3+1 was presented last October to this committee. This study was published 

and based on the results, it was determined that when compared to a 2+1 schedule, the 3+1 

schedule is less cost-effective. 

To conclude the findings of GRADE review, in step one, there was strong evidence supporting 

each individual schedule as compared to no vaccine. In step two, there was more limited 

evidence with few studies showing direct schedule comparisons. Thus, the GRADE process 

supports an overall category B recommendation for each 3-dose PCV schedules: 2+1 and 3+0 

as compared to the 4-dose schedule (3+1), meaning one for which the desirable consequences 

probably outweigh undesirable outcomes. 

Discussion Points 

Dr. Harrison inquired as to whether there were longer-term persistence data for all three 

schedules comparing the three. He said he was thinking of data from the UK with the 

meningococcal C conjugate vaccine where the accelerated 3+0 schedule had limited 

persistence of antibody and efficacy disappeared after one year. 

68 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Ms. Tomczyk replied that they did not find any of these data. The measurements shown were 

limited to what was available in the studies. 

Regarding the UK study, Dr. Matt Moore (SME) pointed out that it was a completely different 

vaccine. That is a 2-, 3-, 4-month accelerated schedule versus what was presented by Ms. 

Tomczyk of a 2-, 4-, 12- or a 2, 4, 6-month schedule. That probably makes an important 

difference. 

Regarding the importance of timing between vaccines, Dr. Vazquez said she understood that 

RCTs offer the best information because they are experimental. However, effectiveness tends 

to be lower than efficacy. In the trials Ms. Tomczyk showed, the intervals were adhered to in 

controlled studies. In thinking about the real-world, a change to the 2+1 schedule, someone 

might receive a 2-month dose, not receive another vaccine until they are 9 or 10 months of age, 

and then return potentially for a booster. If the initial short interval is important, it will remain 

unknown whether administration outside of the recommended interval work as well. 

Ms. Tomczyk agreed that this was a good point, noting that interval was not addressed in the 

GRADE process in particular. 

Referring to Slides 24, Dr. Gorman (NIH) asked whether, if the incidence of these diseases in 

the countries where the studies were conducted was higher, the number needed to treat might 

well have fallen. 

Ms. Tomczyk responded that this was correct. 

Regarding Slide 25, Dr. Gorman (NIH) inquired as to whether the rate ratio was the same as the 

US rate or if those rates were specific for those countries before and after the introduction of the 

vaccines. 

Ms. Tomczyk replied that the rates were specific to those countries, because they were from a 

completely separate study of a pooled analysis of specific countries’ surveillance data. 

Regarding Slide 48, Dr. Doskey (AHIP) inquired as to whether the statistically significant 

increase in hospital admissions for lower tract infections during the primary series until prebooster was expected to hold up now that there is some herd protection . 

Referring to Slide 49, Dr. Matt Moore (SME) in the 2003 birth cohort, this has been interpreted 

by the authors of the study and others to mean that once the herd effect increases, those 

serotypes are less available to cause disease so the differences between the schedules are 

smaller. 

Dr. Brady (AAP) said he thought the GRADE system worked well for GRADEing the evidence, 

but sometimes it does not help with the conclusions. In terms of invasive pneumococcal 

disease, with the 3+0 schedule, vaccine efficacy was only 74% and the 2+1 and 3+1 schedules 

were in the mid-90s. He did not think these could be said to be equivalent. A 3+1 schedule 

prevents pneumococcal disease, it is not equivalent for the other schedules. The 3+0 studies 

were conducted in Africa countries. The US has done a really nice job of eliminating the 

difference of disparity in pneumococcal disease in African American children. It would be 

unfortunately to find that higher levels of antibody are actually needed to protect African 

American children, and that disparity levels would return in that group with a 2+1 or 3+0. That 

issue needs to be addressed. 

69 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Moore (SME) pointed out that the trials in Africa were conducted with schedules of 6, 10, 

and 14 weeks so there are only 4 weeks in between. It is known with pneumococcal vaccine a 

better response is achieved if the doses are spread out to at least 2 months. Two months are 

better than one month. The balance that must be stricken is that the interval cannot be spread 

too far, because a single dose is not believed to offer enough protection. This is one possible 

difference between the African versus the Kaiser trials. 

PCV13 Reduced Dose Schedules for Children: Considerations and WG Conclusions 

Tamara Pilishvili, MPH 

Respiratory Diseases Branch 

National Center for Immunization & Respiratory Diseases 

Dr. Pilishvili acknowledged that GRADE has a somewhat narrow focus that does take away 

from the conclusions. She pointed out that several factors must be considered when deciding 

whether a policy change is warranted, but first and foremost consideration must be given to 

whether the available evidence supports the change. During the October 2013 ACIP meeting, 

the results of the extensive evidence review by the work group were presented. This review 

included studies with two different 3-dose PCV infant schedules, 2+1 and 3+0. The work group 

reviewed RCTs evaluating the efficacy of these schedules, post-licensure effectiveness studies 

(case-control or indirect cohort analysis), and ecological studies evaluating the impact of PCV 

introduction on a population level. Key studies were highlighted and the conclusions were 

presented for each outcome, including invasive pneumococcal disease, pneumonia, acute otitis 

media (AOM), nasopharyngeal colonization, and immunogenicity studies; as well as indirect 

effects of 3-dose schedules. This included the outcomes that GRADE did not consider, 

because it is limited to the critical outcomes. 

Following the suggestion received from the full ACIP committee to assess the quality of the 

evidence, the WG applied the GRADE framework to the review of evidence, which was 

presented by Ms. Tomczyk during this session. GRADE procedures narrowed the scope of the 

evidence review to only those outcomes which were deemed as critical based on ranking. 

Using each schedule (3+1, 2+1, 3+0) as compared to no vaccination, the GRADE conclusion 

was that there is strong quality of evidence (type 2) supporting each individual schedule when 

compared to no vaccine, and a category A recommendation. When comparing the schedules 

only to each other (2+1 versus 3+1 and 3+0 versus 3+1), the WG was limited to only those 

studies that made such comparisons and to three outcomes: immunogenicity (surrogate for 

IPD), pneumonia, and AOM. Because of the limited evidence with direct comparison, the 

evidence was of lower quality (type 3), and the consensus of the WG was that GRADE supports 

a category B recommendation. However, policy conclusions are not yet being made. 

Some key issues were not covered by GRADE review. As noted, the outcomes were limited 

because of the ranking and only critical outcomes were included. For example, data on 

nasopharyngeal carriage were not included in the GRADE review. Observational studies for 

IPD also were not included. According to the GRADE guidelines, if sufficient data are available 

through RCTs, only RCTs are included. However, a vast amount of post-licensure data has 

been accruing over the years from countries that have used these various schedules. Those 

data were overlooked by GRADE. GRADE does not conclude anything other than the type of 

evidence and the category of the recommendation. Some of the conclusions are missing, so 

perhaps the main conclusions that largely remain unchanged by outcome as presented in 

October should be revisited. 

70 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

During this session, Dr. Pilishvili presented a summary of PCV13 breakthrough cases and 

failures; programmatic considerations for policy change (e.g., NIS, PCV13 coverage data, 

parental acceptance of vaccines, and factors influencing refusals and delayed vaccination); 

work group conclusions so far, and next steps. She also revisited the evidence not accounted 

for by GRADE (e.g., observational studies for PCV impact on IPD, effects of reduced schedules 

on nasopharyngeal carriage). 

The work group assessed three case-control studies and 3 studies using indirect cohort method 

evaluated effectiveness of various schedules of PCV7, including the following: 

 Canada (Deceuninck 2010) 

 USA (Whitney 2006) 

 Spain (Barricarte 2007) 

 USA (de Serres 2008) 

 USA (Mahon 2006) 

 Germany (Ruckinger 2010) 

For the 2+0 schedule that some of the studies were able to evaluate, the effectiveness 

estimates ranged from 70% to 99%. Two studies evaluated the effectiveness of a 2+1 

schedule, with the effectiveness estimates ranging from 98% to 100%. It is important to keep in 

mind that none of these studies were powered to make across study comparisons, especially 

when comparing two values that show high effectiveness. None of these studies were powered 

to detect a difference between 99% effectiveness and 100% effectiveness. Also important is to 

consider the difference in settings in countries and the methodologies. It can be concluded that 

all of these schedules are quite effective at reducing invasive disease. 

In terms of surveillance studies conducted in 10 countries (11 populations) describing the 

impact of national PCV introduction on vaccine-type-IPD among young children by 

country/schedule and year post-vaccine introduction, the impact was measured as rate ratios for 

vaccine type (VT) IPD rates post-vaccine introduction compared to pre-vaccine baseline. In this 

analysis, an effort was made to control time since vaccination introduction and the country’s 

vaccination schedule. The similarities in the magnitude of the impact observed between the 

schedules and between the countries are striking. Although surveillance methods varied and 

each study only reported the impact of one particular PCV dosing schedule, some general 

comparisons between schedules can be made across this group of reports. One similarity 

observed among nearly all studies was a large and significant impact of PCV introduction on 

VT-IPD over time in populations routinely using 2+1, 3+0, and 3+1 schedules as soon as 1- to 

2-years post-vaccine introduction, with reductions ranging from 65% to almost 100%. In 

general, the reductions for all countries and schedules were greater with more years postintroduction. 

Very relevant to the objective of this session was the example of PCV impact from the 

experience with PCV introduction in Canada. In Calgary, PCV7 was introduced as a 4-dose 

program in 2002 and PCV13 replaced PCV7 using a 3-dose, 2+1 program (2, 4, 12 months) for 

healthy children in 2010. High risk children receive 4 doses, and there was a brief catch-up 

PCV13 program for preschool children. Following the introduction of PCV7 on a 3+1 schedule, 

rates of PCV7 type IPD have dropped dramatically among children less than 2 years of age. 

The rates have also declined among older children and adults. In 2010, PCV13 replaced PCV7 

on a 3-dose schedule, and the rates of PCV7 type disease continued to decline for all age 

groups. In 2013, rates of PCV7 type IPD were at less than 1 case per 100,000 for all age 

71 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

groups. The rates of PCV13 type IPD increased post PCV7 introduction but then in 2010, 

PCV13 was introduced and 2+1 PCV13 directly and indirectly reduced vaccine-serotype IPD 

quickly and continued to decline through 2013 [Ricketson LJ et al. ISPPD 2014]. 

To summarize the findings for IPD, evidence from RCTs and observational studies suggests 

each schedule (3+1, 3+0 and 2+1) is highly effective at preventing IPD. None of the studies 

were designed to compare any of the 3-dose schedules to a 4-dose schedule head-to-head. It 

is also important to note that direct comparisons across studies are not meaningful, because 

they do not take into account differences in populations and methodology, and they are not 

powered to detect a difference between two highly effective schedules. 

To summarize the findings for the pneumonia outcome, evidence from RCTs and observational 

studies shows that each schedule (3+1, 2+1, and 3+0) prevents pneumonia. One observational 

study showed that a 3-dose primary series is better than 2-dose primary series before the 

booster dose against pneumonia early in the US immunization program. There are no 

statistically significant differences observed post-booster or for later birth cohorts. The 

conclusion is that a schedule with 4 doses maybe more beneficial early post-introduction; 

however, later in vaccine introduction those differences may disappear. 

Carriage data were not considered as part of the GRADE because nasopharyngeal (NP) 

carriage was not ranked as a critical outcome. However, NP carriage data are important to 

consider because NP colonization is necessary before infection can occur; reductions in 

vaccine-serotype colonization means that those serotypes are less available to cause disease; 

and these data provide direct evidence of reduced transmission expected with each schedule in 

addition to evidence observed through indirect (herd) impact on IPD. In October, the work 

group presented studies showing effects on nasopharyngeal carriage of different PCV 

schedules. Results of a carriage study evaluating the impact of PCV13 on carriage of PCV13 

serotypes were also presented at that time. 

To summarize the key points, all schedules (2+1, 3+0, and 3+1) reduce acquisition of 

colonization with vaccine serotypes compared with no PCV. A 3-dose primary is better than 2­

dose primary before booster dose at 1 through 7 months following the series. There are no 

differences at 12 months of age before a booster dose, and no differences have been observed 

after a booster dose. Post-PCV13 introduction US carriage data suggest PCV7 types are very 

rare and PCV13 type carriage is decreasing. 

To conclude the overall evidence review, 3-dose PCV schedules are effective against IPD, 

pneumonia, and otitis media. Immunogenicity and carriage studies show that a 3+1 schedule 

may be better than a 2+1 schedule before a booster dose. However, no differences have been 

observed post-booster for most serotypes. Strong direct and indirect (herd) effects have been 

observed in countries using 3-dose PCV schedules. It is important to interpret the results of the 

evidence review in the context of the US PCV13 program. Differences in antibody response 

between schedules may lead to differences in carriage and, potentially, in disease rates. 

Differences in antibody response between schedules may lead to differences in carriage and, 

potentially, in disease. Differences may not be meaningful in a setting of a strong national 

immunization program and already observed large direct and indirect benefits of PCV use. 

PCV7 serotypes are very rare in the US and are, therefore, less likely to cause disease. Rates 

of PCV13 type IPD are extremely low among children 6 through 11 months of age and continue 

to decline among all age groups. The population level impact of 3-dose PCV programs (both 

direct and indirect effects) are similar to the ones observed in the US. 

72 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

The risk of invasive pneumococcal disease among children less than 2 years of age is low. 

Overall rates are 14.6/100,000 and PCV13 type rates are 2 cases/100,000. The rates of 

meningitis are 1.2 cases/100.000 and rates of PCV13-type meningitis 0.3 cases/per 100,000. 

The -+WG wanted to determine, given the window of time during which the differences in 

antibody responses following the primary series were observed, what the risk is of disease 

among children 6 through 11 months of age. More than 1/3 of PCV13 type cases in this age 

group occur before 2 months of age, and only one PCV13-type case was reported in 2012-2013 

among children 6 through 11 months of age. 

Vaccine failure and breakthrough infections reported to the ABCs surveillance system were 

reviewed in order to evaluate whether any particular incomplete PCV schedules were 

associated with breakthrough infections. From 275 cases of IPD who also received at least 1 

PCV13 dose, 44 cases were caused by PCV13 serotypes and were classified as breakthrough 

cases. Of these, 5 received the full 4-dose PCV13 schedule and were true failures. The 

vaccination status was assessed of breakthrough cases by serotype and PCV13 schedule. 

Only 4 serotypes were associated with breakthrough infections. The majority of breakthrough 

cases (74%) were caused by type 19A, followed by type 3 (22%), and one case of 7F. Only one 

PCV7 serotype (19F) was associated with one breakthrough infection. The majority of 

breakthrough cases were vaccinated using schedules other than 3+1, 3+0, or 2+1 and the 

majority of those in the “other” category received only one PCV13 dose. All 4 meningitis cases 

followed 1 dose of PCV13. No deaths were associated with breakthrough infections, and only 7 

cases had underlying conditions. 

Though not discussed in detail during this session, Dr. Pilishvili highlighted the points discussed 

by the WG so far. An economic analysis was presented to the committee in October 2013 and 

was considered as part of the GRADE process, although the analysis did not consider that the 

vaccine price may be adjusted. Safety data were presented as part of the GRADE review. 

There is an additional analysis ongoing using VSD data to evaluate the risk of febrile seizures 

associated with co-administration of childhood vaccines. The results of this study will be 

presented to the committee at a future meeting. The WG also discussed programmatic 

considerations. 

Programmatic considerations discussed so far by the WG include evaluating the performance of 

the vaccine program to deliver high coverage at each time point in the immunization schedule. 

They took into consideration adherence to the currently recommended schedule, as well as 

delay in the timing of each dose and the effects on completion of the recommended schedule. 

The potential for non-adherence to introduce disparities in coverage was also evaluated. 

National Immunization Survey (NIS) data were utilized to assess parental acceptance of the 

recommended vaccination schedule and factors contributing to delays and refusals. 

Based on cumulative PCV uptake for children included in the 2012 NIS, 84% of children 

surveyed received their first dose on time (<3 months of age); 73% received their second dose 

on time, 63% received their third dose on time (or before 7 months of age), 63% received their 

booster as recommended between 12 through 15 months of age, and 84% of children received 

their primary series before 12 months of age (and therefore, would have still been eligible for a 

booster in their 2nd year of life). 

73 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

With regard to how timeliness of doses in the primary series affects uptake for the rest of the 

recommended doses, among children starting the series on time, 86% and 74% received doses 

2 and 3 on time, and 73% received a booster dose on time; and 94% competed the 3-dose 

primary series before age 12 and, therefore, were still eligible to receive a fourth booster dose. 

In contrast, among children who started the series on or after 3 months of age, less than 10% 

received doses 2 and 3 on time, only 29% received a fourth booster on time, and only 47% 

completed the 3-dose series before age 12 and were eligible to receive a fourth dose in the 

second year of life. 

In terms of uptake for the third and fourth doses among children who received the second dose 

on time versus those who received their second dose late, a similar picture is observed. Among 

children, high proportions received their third and fourth doses on time; whereas, among 

children who were late in receiving dose 2, less than 10% received dose 3 on time and 36% 

received the fourth dose booster on time. Fifty-nine percent of those who delayed dose 2 

versus 98% of those who did not delay dose 2 completed the 3-dose primary series before 12 

months of age and, therefore, were eligible for a fourth dose in the second year of life. 

PCV13 coverage among children receiving currently only 3 doses was also assessed to 

understand which 3-dose schedules they received. According to 2012 NIS data, around 10% of 

children received a total of 3 doses. Also assessed was the timing of administration for the third 

dose. For example, 22.5% of children who received a total of 3 doses received a third dose at 

age 6 months and, therefore, were vaccinated on a 3+0 schedule. Similarly, 43% of children 

who received a total of 3 doses received their third and last dose at 13 months or after and, 

therefore, were vaccinated on a 2+1 schedule. Given that only a small percentage of children 

overall received a total of 3 doses, these data cannot provide input on what the preferred 3-dose 

schedule would look like. However, the data show that children are receiving 3-dose schedules 

and the third dose may be given anywhere between 6 months of age to 13 months or later. 

Coverage was also evaluated by schedule and poverty status. The data in the 2nd and 3rd 

column are coverage estimates (%vaccinated and 95%CI) for children receiving at least 3 doses 

before age 12 months by poverty status. The next 2 columns are estimates for children 

receiving at least 2 doses before 12 months of age and 1 dose in the 2nd year of life, and the last 

2 columns, estimates for children vaccinated with 3+1. For each schedule evaluated, the 

coverage decreases with increasing poverty level. Overall and within each poverty level strata, 

the coverage is lowest for 3+1, and highest for the schedule with at least 2 primary doses and a 

booster. There are actually no statistically significant differences between schedules 1 and 2 

within any of the poverty strata. However, the overall difference between schedules 1 and 2 

(84.4 versus 85.9) is significantly different. 

To summarize PCV13 coverage in the US, the vast majority of children receive PCV doses in 

the primary series on time. A majority of children complete the PCV primary series by 11 

months of age and, therefore, are still eligible for a fourth (booster) dose in the second year of 

life. Among children for whom either dose 1 or dose 2 is delayed, a smaller proportion is eligible 

for and/or complete a 4-dose schedule. A small proportion receives a total of 3 doses. It is 

difficult to identify which 3-dose schedule would be preferred if ACIP were to make that 

recommendation. The coverage decreases with increasing poverty level for all schedules. 

Within each poverty strata, coverage is lowest for 3+1 schedule. 

74 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Next, published studies were reviewed that evaluated parental acceptance of vaccinations and 

factors influencing vaccine refusal and delay. As part of 2009 NIS survey, parents of children 

24 through 35 months old were interviewed to evaluate the association between parents’ beliefs 

about vaccines and their decision to delay or refuse vaccines for their children. The results of 

the survey showed that approximately 26% of parents delayed one or more vaccine doses, 8% 

refused, and almost 6% both delayed and refused. Delays and refusals were associated with 

parental beliefs that children receive too many vaccines (58.6% vs. 29.1%, p<0.05), too many 

vaccines can overwhelm a child’s immune system (48.6% vs. 28.3%, p<0.05), and that vaccines 

have serious side effects (63.1% vs. 30.9%, p<0.05). Delays and refusals were more likely 

among parents with higher socioeconomic status (SES), and among children with lower 

coverage for all 10 recommended vaccines that were assessed [Smith P. et al Public Health 

Rep. 2011]. 

According to the results of 2010 HealthStyles Survey, from the top concerns reported by parents 

or guardians of children less than 6 years of age, 38% reported concern that “it is too painful for 

the children to receive so many shots,” 36% reported that their child is receiving too many shots, 

and 34% believed that overall children get too many vaccines in their first year of life [Kennedy 

et al Health Affairs 2011]. 

A cross-sectional internet-based survey of a nationally representative sample of parents of 

children 6 months through 6 years of age found that more than 1 of 10 parents of young children 

currently use an alternative vaccination schedule, non-black race and not having a regular 

provider were associated with increased odds of alternative schedule, a large proportion of 

parents currently following the recommended schedule seem to be “at risk” for switching to an 

alternative schedule, 28% believed that delaying vaccine doses was safer than the schedule 

they used, and 22% disagreed that the best schedule to follow is the one recommended by the 

experts. This study also found that among parents who reported refusing some vaccines, 31% 

refused PCV. Among parents who reported delaying some vaccines, 10% delayed PCV to 

older age than recommended. Among parents who prolonged dosing intervals for some 

vaccines, 33% did so for PCV [Dempsey et al Pediatrics 2011]. 

Overall, the studies on parental acceptance of vaccines reviewed support the following 

conclusions: 

 The majority of parents surveyed adhere to and do not have concerns about the 

recommended schedule. 

 Parent decisions do lead to delays (13%-25%) or refusals (6%-10%) for one or more 

recommended vaccine doses. 

 Parents who delay and refuse vaccine doses are more likely to have concerns about 

vaccine safety or multiple injections at each visit 

 Parents who follow the recommended schedule also report exhibiting doubts and have 

considered alternative schedules or refusing vaccine doses in the future. 

 It is unclear whether removing a PCV dose at 6 months (2+1) or 12-15 months (3+0) will 

help reduce refusals or delays of other recommended vaccines. 

75 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

With regard to the WG conclusions, the GRADE review suggests that 3-dose schedules are 

likely equivalent to a 4-dose schedule. Evidence from countries using 3-dose schedules is 

reassuring. An acceptable schedule in the setting of a mature immunization program and 

strong herd effects may not need to be the same as that chosen at the time of licensure. A 3­

dose PCV13 schedule for infants is likely appropriate to maintain already observed benefits 

from 13 years of PCV use in the US. The WG was not prepared to make a specific policy 

recommendation at this time. Including a 3-dose PCV13 schedule for routine use among infants 

requires careful consideration of implementation issues. Further discussion is needed to define 

groups to be excluded from potential policy change and potential impact on non-adherence. 

As the next steps, the WG will define the groups that should be excluded from the potential 

policy change and the rationale for exclusion of these groups. Discussions have begun related 

to American Indian and Alaska Native (AI/AN) populations. A group of experts working with 

these populations has shared data with the WG on disease burden and disparities in rates of 

pneumococcal disease in these populations compared to general US population. There is a 

history of ACIP recommendations made specific to AI/AN populations. Discussion is still 

needed to identify exactly which population groups to exclude if ACIP changes the 

recommendations for the general population of US children. In addition, the WG will clearly 

define which underlying medical conditions would be indications to continue receiving a 4-dose 

schedule. This decision will be based on known disparities in disease burden, lower PCV 

effectiveness or reduced immune response observed compared to that among healthy children. 

Careful consideration should be given to implementation issues related to timing of diagnosis for 

the medical conditions and schedule selection. 

Listed in no particular order of preference, the WG agreed to give further consideration to the 

following policy options: 

 Option 1: 2+1 for routine use, 3+1 for high-risk groups (to be defined) 

 Option 2: 3+0 for routine use, 3+1 for high-risk groups (to be defined) 

 Option 3: 3-dose schedules (2+1 or 3+0) for routine use, 3+1 recommended at provider 

discretion for healthy infants, 3+1 for high-risk groups (to be defined) 

 Option 4: 3+1 for routine use, 3-dose schedules (2+1 or 3+0) optional for healthy infants, 

3+1 for high risk groups 

 Option 5: Status quo 

In conclusion, the following questions were posed to the full ACIP committee for consideration 

and discussion: 

 What are the gaps in information to consider including a 3-dose PCV13 schedule? 

– 

– 

–

Provider/practice level issues 

Public health program level issues 

Parent considerations 

 What specific concerns does the committee have about potentially including a 3-dose 

PCV13 schedule for routine use among infants? 

76 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Discussion Points 

Regarding the population level impact across all serotypes for introduction of various 3-dose 

schedules in a number of countries, Dr. Karron wondered whether there were any serotype 

differences or any signals that stood out for particular serotypes to suggest that one schedule 

might be better than another, or if the data mirrored what was shown for the composite. 

Dr. Pilishvili replied that there were some differences by population in terms of the serotype 

distribution, but clarified that the data she presented focused on PCV7 serotypes. Within the 

PCV7 types, there is less variation in terms of the distribution of those serotypes across the 

populations for which data were presented. There is more variation for additional serotypes like 

serotypes 1 and 5 that are included in PCV13, but not in PCV7. The data in ABCs for the US 

have been assessed by serotype, and there is sufficient power for certain populations to 

evaluate the individual serotypes, so some of those data could be reviewed. However, there is 

insufficient power for most of these studies to assess the individual serotype data. 

Referring to Slide 18, Dr. Karron thought it would be great to have data from additional years to 

increase the numbers to determine whether the distributions are the same. With regard to this 

and the 12-month and up dose and whether children receive vaccine on time, there always 

seems to be a problem with the 4th dose. It was approximately 50% to 70%. A 2+1 schedule 

concerns her because she does not believe the 4th dose will be administered any sooner if it 

were a third dose in a 2+1 schedule. If the delay is too long, there is invasive disease in the 

12- to 18-month age range. She wondered if the existing data offered any insight about a 2+1 

versus a 3+0 schedule. 

Referring to the HPV vaccine, Dr. Doskey (AHIP) reminded everyone of the quagmire regarding 

permissive recommendations. He spoke against Options 3 and 4, given that they would open a 

quagmire. He foresaw a potential for scattered coverage across the country. The data were 

either strong enough to recommend it, strong enough to not recommend it, or strong enough to 

recommend it for certain groups. 

Dr. Pilishvili responded that several members of the WG shared Dr. Doskey’s concerns. 

Dr. Temte asked Dr. Fryhofer how good internists are in terms of adhering to pneumococcal 

recommendations for high-risk patients. 

Dr. Fryhofer (AMA/ACP) responded that this was a work in progress. 

Dr. Warshawsky (NACI) commented that Canada uses a 2+1 schedule in most provinces. They 

have tried to encourage the +1, the booster, be administered at 12 months. It is not at a range 

of 12 to 15 months, it is at 12 months. Regarding the failures shown on Slide 23, she wondered 

if it were known when the failures occurred for the 2+1 and 3+0 schedule (e.g., how old the 

child was when they failed) and whether that would have been prevented by a booster at 12 

months. 

Referring to Extra Slide 44, Dr. Pilishvili said it was important to keep in mind that the interval 

between the last dose and the occurrence of disease were assessed. There is a pretty wide 

range for each schedule. It may have been soon after the vaccine was given or delayed. 

Because the number of cases were low (n=5), it was not possible to draw any conclusions 

based on whether it was worse after 2+0 or 3+0. 

77 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Warshawsky (NACI) said she had heard this type of data before when Quebec went to a 

2+1 schedule. They talked about the number of cases that would potentially have failed in that 

type of schedule. It may be helpful to say, of the 2+0, how many would have failed in a 2+1 so 

that the true number of failures is known for that scenario—not just the average, but the actual 

number of cases that might have failed under a 2+0 schedule. 

Dr. Bocchini expressed concern with the groups being excluded for potential policy change. 

They would essentially wind up creating three policy recommendations: 1) for healthy children 

with no increased risk; 2) high risk children; and 3) patients who would maintain the 3-dose 

primary schedule and the booster as opposed to a 2+1 or 3+0. He believes this will add 

confusion and it will be very difficult to define those groups effectively for the practitioner. There 

are also subgroups such as children who attend childcare who are under a year of age, and 

others who had a higher risk for pneumococcal invasive disease in the past that disappeared 

under the current vaccine regimen. 

Scanning through the various studies, it appeared to Dr. Harriman that the 2+1 schedule had 

better efficacy than the 3+0 schedule in most of the studies. 

Dr. Vazquez wondered what would happen with coverage by insurance companies if Option 3 

or 4 were selected. 

Dr. Doskey (AHIP) emphasized that HPV was permissive and people could choose, so plans 

chose. He likened what would happen to the big marsh mellow man in “Ghost Busters.” 

In terms of permissive recommendations, Dr. Schuchat pointed out that essentially, the 

Affordable Care Act (ACA) requires insurers to cover vaccines that are recommended by ACIP. 

It is all about what is in the schedule and in the footnotes of the schedule. During the first 

calendar year after the vote, insurers have to cover what is in the schedule and footnotes if 

given by an in-network provider. That means footnotes are where the action is. 

Dr. Middleman (SAHM) wondered whether there were any data regarding the potential message 

of decreasing the number of doses and making it appear as though this vaccine may be 

expendable or perhaps not important for children, and the effect that may have on immunization 

rates. She found this very concerning. 

Dr. Pilishvili responded that she was not aware of any data. 

Dr. Schuchat added that there are many different subsets of parents and attitudes. It is 

important not to over-generalize. People who vaccinate their children regularly express 

questions and concerns about the number of shots at a single visit. Some of the people who 

want to vaccinate want to not have so many shots during the same visits. People do question 

whether all of those shots are really needed. The theoretical implications of a policy change are 

very difficult to predict, but there is certainly a stewardship of the immunization schedule that 

ACIP holds to carefully review the risks, benefits, value, and need for each dose recommended. 

The point of this review was that there is a lot of evidence about ways to give the pneumococcal 

vaccine, and it is one of the vaccines that is given with many other vaccines. 

78 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Harrison said he was fairly troubled by the immunogenicity data of a 3+0 schedule. The 

GMC ratios are only 0.2 to 0.6 compared to the 3+1 schedule. He questioned the durability of 

protection. He wondered what the work group’s thoughts were about that. 

Dr. Kempe pointed out that there was plenty of evidence showing that primary care and 

pediatricians cannot and do not identify high risk children. She expressed concern not about 

dropping a dose, but about offering it as an option. She was worried about having either 

optional or multiple possibilities. 

Dr. Campos-Outcalt said he was not convinced that a change should be made. The schedule is 

confusing for providers and patients. There is something synchronous about having 2, 4, 6 and 

then afterwards that goes with other vaccines and fits in nicely with the schedule. Everybody 

gets the same recommendation. Parsing out by risk and other criteria just confuses the 

schedule more, which is a major problem. He would prefer a 3-dose schedule or a 4-dose 

schedule—nothing in between. To convince him to choose a 3-dose schedule, he would have 

to be convinced that it would be equal to a 4-dose schedule. He did not see that in the GRADE 

evidence. 

Dr. Temte pointed out that consideration must also be given to putting this into immunization 

information systems. If a dose is made optional, physicians do a notoriously poor job of 

capturing high risk conditions in the systems to inform them what to do. This is observed 

repeatedly with high risk conditions for hepatitis B and pneumococcal in adults and HPV in 

optional groups. He concurred with the sentiment that it would be better to have something 

fixed versus variable. 

Dr. Bennett said the laborious GRADE work the WG did convinced her that these schedules are 

equal in efficacy. She was not happy that they did not convince all of the ACIP members of 

that. She also thought it was important to remember that it is ACIP’s obligation morally to 

review any recommendations the committee makes. If that means that removing a dose is 

complicated, that is too bad, but it is the right thing to do. The situation is currently very different 

from when this vaccine started being administered. Very little disease is now circulating related 

to the serotypes in the vaccine. The WG views all of the concerns raised as very serious and is 

trying to work its way through this to think about all of the possible unintended consequences of 

changing this schedule, and how this can be communicated so that people understand that 

ACIP is really just trying to do the right thing for children and parents. That does not undermine 

this vaccine. It simply says that this vaccine has done such a great job, one fewer dose can be 

given. She believes this message can be conveyed with confidence. 

Dr. Brady (AAP) emphasized that there are 3 studies for the 3+0 schedule, and it may be 

methodological because the time between them was not appropriate, but those are the only 

data available and they are not convincing that a 3+0 schedule works. The comparison of 3+1 

to 2+1 is low evidence. They did a really bad job when risk factors were used for influenza 

vaccine in children. Now they were going to say that children at high risk need 3+1 and others 

can use another schedule. This will result in a real problem because this will not happen the 

way the recommendations are stated, and children at risk will get too few doses. Then there will 

be more disease. He believes that the status quo currently provides the best protection and 

creates the opportunity to minimize risk. 

79 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Ms. Pellegrini thought a potentially compelling argument could be made to say that a great job 

has been done with this vaccine, the cases of disease have decreased, and perhaps a dose 

could be removed. However, if they are going to do that, they must also be prepared to say why 

that is not the case for every other vaccine in the schedule. The last naturally occurring case of 

polio was in 1979; however, polio vaccine is still given to every infant. This pertains to some of 

the basic education issues and communication problems that exist for vaccines. 

Dr. Loehr (AAFP) noted that there are already variations mixed into the schedule. While there 

are likely to be more cases with a change in the schedule, that might be appropriate given the 

amount of resources being put into this. He has a large number of vaccine-hesitant parents in 

his practice. CDC and ACIP consciously stating that they do not believe all of the vaccines are 

needed because they have done such a good job shows that they are not just adding vaccines, 

but that they also take them away when they are no longer necessary. He thought that would 

be a very valuable signal to send. 

As an epidemiologist, Dr. Reingold felt that based on the data he had seen from other countries, 

including countries comparable to the US that either began with a 3-dose schedule in the first 

schedule or moved to a 3-dose schedule, the impact other countries have observed is identical 

to the impact the US has observed. A 3-dose schedule costs 25% less. While this may be 

attributable to better coverage in other countries, he thought there was convincing evidence 

from a variety of comparable countries that the same results could be accomplished with a 3­

dose schedule. 

Dr. Kelly Moore (AIM) concurred with those who expressed operational concerns. Although she 

did not yet know what the right answer was, she thought it was incumbent upon them to avoid 

unintended consequences by carefully thinking through the operational implications of a split 

schedule where high risk children still need more vaccine than healthy children. It is known that 

risk-based recommendations are not implemented effectively. If such a recommendation is 

going to be made, they must work out the registries, electronic health records, and other 

operational issues from a programmatic standpoint to ensure that mistakes are not made by 

introducing a risk group into this consideration who was not there as a special consideration 

before. 

Regarding a delayed last dose in the context of Dr. Reingold’s comments, Dr. Sawyer thought it 

was important to assess coverage rates in other countries that have had success. They likely 

do a better job at a more prompt or tighter interval around the recommended age in delivering 

the vaccine. He is very concerned about a 2+1 schedule turning into either a 1+1 or 2+0 

schedule in a significant number of children. 

Rebecca Coyle (American Immunization Association) thought this highlighted a major issue for 

those who work in the electronic health record and information system arena. When high risk 

conditions are added or schedules are separated, it becomes very difficult for electronic 

systems to translate that information into an appropriate clinical decision support for the clinician 

or whomever is making that decision. She emphasized the importance of how cumbersome the 

decisions ACIP makes can be to implement on the technology side as well. 

Dr. Sun (FDA) indicated that the FDA is very concerned about the possibility of a 

recommendation that differs from the label, because in the absence of data presented by 

manufacturers to support a change in the label, FDA will not make any changes in the package 

insert. This would present a lot of ambiguity for health care providers, parents, insurers, and 

vaccine manufacturers. 

80 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Luis Jodar (Pfizer) indicated that he had a number of technical concerns with GRADE. It is 

somewhat ambiguous to state that there is a mature PCV program, when it really is a mature 

PCV7 program. What they are judging is whether to change a PCV13 dosing schedule, which 

includes 6 different serotypes from PCV7. In all of the world, PCV13 was only introduced 3 

years ago. Extrapolating the conclusions being observed after 14 years of PCV7 to PCV13 is 

risky. Pfizer is very encouraged with the effectiveness presented, but this is the first year that 

serotype-specific effectiveness data have been presented. There may be variability in serotypespecific effectiveness in those countries that have introduced 2+1 PCV13. His concern 

regarded whether PCV13 could really be considered a mature program after only 3 years and 

only after just starting to learn about serotype-specific effectiveness. He did not think that 

anyone there believed that all serotypes were equal. His other question about GRADE was that 

they were thinking all conjugate vaccines are created equal. When evidence is presented about 

IPD efficacy, for instance for a 2+1 schedule, the efficacy is for a 10-valent vaccine with 3 

different carrier proteins, which is not even licensed in the US. The 3+0 evidence regards 

PCV9, which was discontinued. PCV11 was discontinued for development for pneumonia. 

ACIP was considering a change for PCV13, which is a completely different vaccine, based on 

evidence for other vaccines. He was surprised that the GRADE assessment of immunogenicity 

was not done with PCV13. A study was published in the Journal of the American Medical 

Association (JAMA) in 2013 comparing different schedules with PCV13 at 2, 4, 6 / 2, 3, 4 / 2, 4 / 

3, 5. It is true that intervals are different. 2, 4 for some serotypes like 6b and 23f are worse 

than 3, 5. Those are worse than 3 doses. Consistently, 6b and 23f have lower percentages of 

individuals reaching the 0.35 μg/ml than 3 doses. That would have been better evidence than 

what was being discussed. 

Dr. Temte noted that another piece of evidence that might be useful for the committee in 

general would be to know whether resurgence of disease was observed in any of the national 

programs that changed from a 4-dose to a 3-dose schedule. 

Dr. Jenkins said she would like to know whether there are disparities in the vulnerability of 

children either based on ethnic diversity or poverty status. She applauded what they were doing 

in terms of assessing the resources to determine whether they are being used optimally. But 

they must also ensure that other children are not placed at greater risk as a result of those types 

of decisions, and that disparities are not created again. 

Given the importance of the ACIP and AAP being harmonized, Dr. Duchin encouraged AAP to 

carefully consider this issue and present ACIP with an official AAP opinion. 

Dr. Schuchat indicated that the Healthy People 2020 targets are 90% for 4-dose coverage of 

pneumococcal conjugate vaccine. Dr. Frieden is very keen to measure and achieve impact. He 

noted that coverage is approximately 80% with 4 doses of pneumococcal conjugate vaccine, 

and asked her how much additional impact could be achieved with 90% coverage. She told him 

zero. It is important to consider what programs and providers are doing in terms of Healthcare 

Effectiveness Data and Information Set (HEDIS) measures in trying to achieve a 4-dose 

completion, and whether there are other considerations beyond the question of whether the 

recommendations should change. 

81 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Pickering pulled up the new 2014 Childhood Immunization Schedule and suggested that 

everyone read the 3 pages of footnotes, particularly with regard to pneumococcal, to think about 

whether there are other ways to potentially simplify things. The reasoning behind making 

recommendations is to have them implemented. 

Dr. Temte said he thought he heard clearly in the discussion that it would be very difficult to 

slice -and-dice the recommendation, and have a recommendation with different schedules for 

various groups. This is not about small groups of high risk children, such as those with 

immunocompromising conditions. Rather, this is about fairly large demographic groups and that 

certainly could be problematic for implementation, especially those groups who may not be 

captured in information systems. In general, the group did not seem to want to recommend a 

2+1 schedule for most children, but a 3+1 schedule for African American or Native American 

children and other issues, because of risk factors make this very hard to implement efficiently. 

Dr. Bennett said the WG heard what everyone was saying about the complexity and about a 

permissive recommendation. However, she thought it was fair to say that if a recommendation 

was made to reduce the number of doses, there would have to be different recommendations 

for certain high risk groups. She did not think this had to be super complicated. To say that 

they could not have a high risk group would be to say that they could not reduce the number of 

doses for anyone. This would result in giving a lot of extra shots to healthy children just to be 

sure other children receive enough. 

Dr. Temte stressed that simply by living in poverty, there is a risk factor for not completing the 

schedule. A dose reduction also introduces the possibility of not completing the new schedule, 

and dropping instead of a 2+1 down to a 1+1. Unfortunately, many children in the US live under 

the poverty line. 

Dr. Bennett said she distinguished between immunologic concerns with a reduced dose 

schedule and programmatic, practical issues. The WG is taking both of these very seriously, 

but she would put them in two different categories as they are making decisions. 

Dr. Harrison inquired as to whether there were any concerns among the WG members 

regarding the immunogenicity data for the 3+0 schedule. 

Dr. Matt Moore (SME) said he did not remember there being tremendous concerns about 

immunogenicity. From a programmatic perspective, some of the WG members seemed to 

think that perhaps a 3+0 schedule would be somewhat easier to implement than a 2+1 

schedule. From an immunogenicity standpoint, there were not great concerns. 

Dr. Pilishvili added that timing of the assessment of the antibody response was considered. 

Some of the studies included followed the most recent dose. The comparisons that Ms. 

Tomczyk presented as part of GRADE were antibody responses following the 3rd third dose in a 

primary series in a 3+0 schedule, and then following a booster dose in the 3+1 schedule. They 

know this is not a fair comparison because of the boosting effect with the last dose 

administered. At the same time, they assessed a subset of studies that considered the 

comparison at 13 months of age for both schedules. The differences were smaller in terms of 

the number of serotypes that showed differences. In other words, by waiting longer, the 

antibody response declines in all groups. The immediate effect of the boosting goes away, but 

it is unclear what that means in terms of clinical protection. 

82 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Kempe emphasized that the data are not perfect. There was the graph showing that 

between 6 months and a booster, 2+1 looks better, but those were old data. One study 

suggested that that was better now because of baseline, but those are limited data. She could 

not say as a WG member that she was totally sanguine about that leap. 

Dr. Bennett expressed the work group’s appreciation for the time everyone had put into 

reviewing these data, and speaking with the work group about the implications of any possible 

change. 

Frankie Milley: Hi. I am Frankie Milley and I am the Founder/National Director, Meningitis 

Angels), which represents hundreds of families across this country. Many of them are 

pneumococcal families. You’ve met a couple of them over the last months. By the way, I vote 

for Option 5. You know, I’m often reminded as I look at the Angels within our network, one of 

my favorite but yet most painful photos of all of our families is of a young mother who held her 

very young toddler in her arms as they took her off of life support because she didn’t get that 4th 

dose of Prevnar®. This is awful. This is just awful. I made notes. I normally don’t come with 

notes, but I didn’t want to forget it. I think we’ve seen in the past when we requested or required 

or recommended a certain amount of doses—if you recommend 3, they’re going to get 2. If you 

recommend 4, they’re probably going to get 3. We see that with HPV, the hepatitis vaccine, all 

of them we see that. We know that that happens. Also, I think when you start changing the 

schedules again, especially when you’re downgrading the requires or recommendations, I think 

that says to those parents, “Well, maybe we can downgrade some of the rest of them.” I realize 

that we need to be very careful what we put into our children, but again, as I said in October, “if 

it ain’t broke, don’t fix it.” I’ve worked really hard around this country for daycare entry 

requirements, which require pneumococcal vaccine. I think if you start changing those 

recommendations, you need to think and consider if that’s going to change all of those daycare 

requirements that we’ve worked for years on. Are we going to have to go back to those policy 

makers, to those states where we’ve worked really hard to save those kids and get those kids 

immunized, especially in states where we do have a high minority rate? I know in Texas when 

we’ve worked with our legislators, one of the things that I said to them when we were trying to 

get daycare entry was, “We are depriving the most at-risk children in this state of this vaccine,” 

and that was our African American and American Indian populations. Without strong 

recommendations, it doesn’t get paid for. We all know that. So, I think we just have to be very, 

very careful. I work with a lot of families out there—a lot of parents. I have a lot of young 

parents that call me all the time. A lot of them I know, a lot of them I don’t know. I tell them that 

you guys work very, very, very hard to make sure that the recommendations you put out are the 

best and the safest for their children. But you know what? I am begging you guys. I was really 

hoping that this would just be gone, but I can see that it’s not. We have so many immunization 

issues, and problems, and diseases, and things that we need to be looking at and deciding how 

we should recommend those vaccines. But, I don’t think Prevnar® is one of them. I think we 

need to move forward, not backwards. You’ve met several of my kids. I don’t want my group to 

grow anymore with pneumococcal kids, and I’m afraid with a change, that’s exactly what’s going 

to happen. But, I want to tell you that I appreciate the work that all of you guys do. You 

volunteer. You have to have a passion for what you do. I appreciate it. Thank you. 

83 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 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 the Japanese Encephalitis (JE) Work Group became the 

JE and Yellow Fever (YF) Vaccines Work Group to address issues with respect to the potential 

change in the recommendation for a booster dose for YF vaccine, based on the Strategic 

Advisory Group of Experts (SAGE) recommendation that booster doses are no longer needed 

for YF vaccine every 10 years. This will certainly affect travelers and laboratory workers who 

work with YF virus. The objectives and plans for the JE and YF Vaccine Work Group are to 

develop recommendations regarding YF vaccine booster doses in travelers and laboratory 

workers; and use the GRADE approach to assess YF vaccine data pertaining to long-term 

immunogenicity, vaccine failures, and serious adverse events. The work group has met on a 

number of occasions, and is in the process of a GRADE approach to assess YF vaccine data. 

With regard to the timeline, the JE and YF Vaccine Work Group has conducted a number of 

teleconferences and has discussed vaccine immunity and booster dose data. The purpose of 

this session was to provide background data on YF, YF vaccine, and the recent change in 

recommendations. Subsequent to that, the work group will continue to complete the GRADE 

analysis, establish recommendations, and bring forward to ACIP in June 2015 the work group’s 

booster dose recommendations for a vote. If completed, the work group will develop a final 

document to be published in the Morbidity and Mortality Weekly Report (MMWR). 

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

J. Erin Staples, MD, PhD 

Arboviral Disease Branch 

Division of Vector-Borne Diseases 

Centers for Disease Control and Prevention 

For those not familiar with the Arboviral Disease Branch, Dr. Staples explained that this group is 

located in Fort Collins, Colorado in the Western US. This branch is responsible for over 100 

mosquito- and tick-borne viral disease, such as YF, Japanese Encephalitis (JE), and West Nile 

Virus. She then provided background information on YF disease. 

YF is caused by YF virus (Flavivirus). The virus is transmitted predominantly by Aedes species 

mosquitoes. It is endemic in equatorial Africa and South America, causing an estimated 

200,000 cases and 30,000 deaths annually. There are three transmission cycles for YF: 

jungle/Sylvatic, intermediate/Savannah, and urban. In the jungle/Sylvatic cycle, the virus 

circulates between non-human primates and tree-top dwelling mosquitoes, either Aedes 

africanus in Africa or Haemagogus and Sabethes species in South America. Humans are 

incidentally affected when they come into contact with these mosquitoes. This is the main 

84 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

85 

 

 

transmission cycle in South America. The intermediate, or Savannah cycle, occurs only Africa 

where it is the main transmission cycle. In this cycle, the virus circulates between semidomestic Aedes species mosquitoes and humans or non-human primates who live on the edge 

of the forest in the Savannah region. In the urban cycle, humans are the primary reservoir and 

Aedes aegypti mosquitoes that live in or around homes are responsible for transmitting the virus 

among humans. The follow maps illustrate the worldwide distribution of YF: 

The areas in orange on the map are considered endemic and are areas that have recurrent 

human disease. These areas also have the vectors and non-human primates needed to 

maintain the virus in the environment. Areas in yellow are considered transitional where the 

virus is active periodically and only causes cases every few decades. Low-risk areas are shown 

in red. In these areas, humans have been found to have antibodies to YF virus. There are the 

right vectors and non-human primates to transmit the virus, but the areas have never 

documented any human disease cases. The areas in gray are not considered to be at risk for 

YF. 

Jen es ES, et al t . Lancet Infec D s t i 2011; 11: 622–632 

Worldwide Distribution of YF 

Following the bite of infected mosquito, most persons will be asymptomatic or do not develop 

disease. For those who develop symptoms, the incubation period is approximately 2 to 6 days. 

Most symptomatic persons will develop a non-specific febrile illness that is often not recognized 

or cannot be distinguished from several other disease conditions that have the same 

presentation. Only a small proportion of those infected will develop fever with jaundice or 

hemorrhage, and approximately 20% to 50% of those persons with severe disease will die. It is 

only the cases with jaundice, hemorrhage, and death who are usually recognized and reported. 

There is no specific anti-viral treatment for YF. Therefore, the mainstay of treatment is 

supportive therapy or care. Given the current lack of treatment, the best way to lower disease 

morbidity and mortality is to prevent the infection either through mosquito control measures or 

vaccination. 

YF vaccine was developed from a strain of YF virus collected in 1927 from a patient named 

Asibi. That strain was passed more than 200 times to develop a live attenuated viral vaccine 

known as 17D Vaccine. 17D Vaccine is the basis for all vaccines and production today, which 

includes two distinct substrains used in vaccines today: 17DD, which is produced in Brazil and 

17D-204, which is the substrain used by manufacturers outside of Brazil. There is one more 

substrain, 17D213, which is maintained by WHO as a reference strain stock. All YF vaccines 

are produced in embryonated eggs and differ in substrain, passage level, and stabilizers. 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

There are 4 prequalified YF vaccines that can be procured and distributed by United Nations 

(UN) agencies. These include vaccines made in Brazil (Bio-Manguinhos, 17-DD), France 

(Sanofi Pasteur, Stamaril®, 17D-204), Senegal (Pasteur Institute Dakar, 17D-204), and the 

Russian Federation (Chumakov Institute, 17D-204). There are also vaccines that are made for 

local uses, including the vaccine manufactured by Sanofi Pasteur US that is used in the US and 

Canada called YF-Vax®. There is also a vaccine produced and distributed locally in China 

(China National Biotech Group, 17D-204). 

From 1937 through 2013, over 600 million doses of YF vaccine have been administered 

worldwide. However, no placebo controlled studies of efficacy were ever performed for the 

vaccine. Following the introduction of the vaccine in the late 1930s, the incidence of YF among 

laboratory workers and endemic areas declined, suggesting it was efficacious. In clinical trials, 

more than 99% of vaccinated persons develop antibody response at 28 days post-vaccination. 

Some of the common adverse events observed for YF vaccine include fever, headache, 

backache 3 through 7 days after vaccination in 5% to 15% of recipients; and injection site 

inflammation 1 through 5 days after vaccination in 1% to 30% of recipients. The overall 

reporting rate for SAEs following YF vaccination in the US population is 4.7 per 100,000 doses 

distributed. Three SAEs have been clearly described following YF vaccination. This includes 

anaphylaxis that occurs at a rate of 0.8-1.4 per 100,000 doses. Anaphylaxis is usually seen in 

persons with pre-existing allergies, and can be the result of a reaction to the egg or chicken 

proteins, gelatin, or latex. The other two SAEs are neurologic disease (0.4-0.8 per 100,000 

doses) and viscerotropic disease (0.3-0.4 per 100,000 doses) [Lindsey et al. Vaccine 2008; 26: 

6077–6082]. 

YF vaccine-associated neurologic disease is a spectrum of illnesses related to either direct viral 

invasion of the central nervous system (CNS) or autoimmune mediated. The most common 

presentation is meningoencephalitis. Guillain–Barré Syndrome (GBS), acute disseminated 

encephalomyelitis (ADEM), bulbar palsy, and Bell’s palsy have also been temporally associated 

with YF vaccination. The absolute number of cases worldwide is unknown, but is likely several 

hundreds of cases. Illness onset usually occurs at a median of 11 days post-vaccination, with a 

range of 2 to 28 days. These events are rarely fatal, with five deaths noted to date. These 

events have been reported predominantly after initial vaccination with YF vaccine. 

YF vaccine-associated viscerotropic disease is a severe illness similar to the disease caused by 

wild-type virus, with vaccine virus proliferating in multiple organs causing multi-system organ 

dysfunction or failure. To date, over 60 cases have been identified since the event was first 

recognized in 2001. The illness onset is a median of 3 days post-vaccination, with a range of 1 

to 8 days. Viscerotropic disease tends to affect younger females and older males, though the 

age range between sexes is similar. Of the cases with a known outcome, 63% were fatal. This 

event has only been reported after initial immunization with YF vaccination. 

Most endemic countries require proof of vaccination for all travelers from endemic areas. 

Certain countries with vectors but without disease, such as India or Australia, require proof of 

vaccination for all travelers from endemic areas. The US has no vaccine requirements for entry 

for YF vaccine. YF vaccine is the only vaccine covered by International Health Regulations 

(IHR). Per these regulations, countries can detain traveler without proof of vaccination for 6 

days. 

86 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Turning to a status update of YF vaccine recommendations, the last ACIP YF Work Group was 

formed in 2008 to update previous ACIP recommendations. The work group focused on 

updating YF epidemiology, including information on the updated IHR from 2005, updating 

information on vaccine safety, and adding and improving the wording for vaccine precautions 

and contraindications. The updated recommendations were published in July 2010. Under 

current ACIP recommendations for the use of YF vaccine in travelers, the vaccine is 

recommended for persons aged 9 months and above who are traveling to or living in areas at 

risk for YF virus transmission. Because of the risk of serious adverse events, health-care 

providers should vaccinate only persons who are at risk for exposure to YF virus or require 

proof of vaccination for country entry. The vaccine is administered as a single subcutaneous 

dose, and IHRs allow countries to require revaccination at intervals of 10 years to boost 

antibody titers. The current contraindications and precautions to YF vaccine administration per 

the ACIP recommendations are shown in the following table: 

Contraindications Precautions 

Allergy to vaccine component Age 6-8 months 

Age <6 months Age ≥60 years 

Symptomatic HIV infection or CD4+ counts 

<200/mm3 Asymptomatic HIV and CD4+ counts 

200-499/mm3 

Thymus disorder Pregnancy 

Primary immunodeficiencies Breastfeeding 

Malignant neoplasms 

Transplantation 

Immunosuppressive and immunomodulatory 

therapies 

The Strategic Advisory Group of Experts (SAGE) formed a YF Vaccine Work Group in 2011 to 

update the World Health Organization’s (WHO) YF vaccine recommendations. The group 

focused on the need for a booster dose every 10 years to maintain protection against YF. The 

safety of YF vaccine in selected special populations, and co-administration of YF and other 

vaccines. The updated position paper was published in July 2013. The primary change to the 

recommendation was the removal of YF vaccine booster doses. 

Dr. Staples reviewed the presentation given by the SAGE work group on YF vaccine booster 

doses as presented to SAGE during their April 2013 meeting. In terms of the overview of YF 

vaccine immunity as presented to SAGE, no YF vaccine efficacy studies have been performed. 

Several observations supported the protective effect of the vaccine, including reduction of 

laboratory-acquired infection in vaccinated workers, development of disease only in 

unvaccinated persons following vaccine introduction, disappearance of cases in outbreaks when 

campaign conducted, and protection of monkeys against virulent virus challenge by neutralizing 

antibodies generated in response to vaccination. These monkey studies have established a 

log10 neutralization index (LNI) of ≥0.7 correlates with protection1

. However, the correlate of 

protection using the more common plaque reduction neutralization test (PRNT) has not been 

established [1

Mason. Appl Microbiol. 1973; 25: 539]. 

More than 99% of vaccinated persons develop neutralizing antibodies at 28 days postvaccination. The 10-year booster dose interval was established in 1965 based on two studies 

documenting roughly 80% of recipients with detectable neutralizing antibodies around 10 years 

post-vaccination. 

87 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

A systematic review conducted for the SAGE work group regarding YF vaccine booster doses 

found that 10 to 20 years post-vaccination, a high proportion of greater than 90% of vaccine 

recipients had neutralizing antibodies. Of persons vaccinated more than 20 years previously, 

approximately 80% had detectable neutralizing antibodies. Neutralizing antibodies were 

detected, at least in one person, as long as 60 years post-vaccination. Twelve vaccine failures 

were documented within 5 years of initial vaccination out of the over 600 million doses of the 

vaccine that have been administered to date. 

Additional considerations that the SAGE work group discussed included YF disease noted only 

in unvaccinated persons during outbreaks, such as in Nigeria during the outbreaks that occurred 

in the 1980s. Data suggest a role for innate and cell-mediated immunity in initial and memory 

immune response. The SAGE work group also had some issues and concerns with YF vaccine 

booster dose data, including different PRNT levels used in published studies, making 

comparability difficult; lack of understanding of protective immunity other than neutralizing 

antibodies associated with protective immune response, but the level of protective titers is 

unknown; unknown significance of innate and cell-mediated immunity; natural boosting likely to 

occur in endemic areas; lack of clarity regarding whether travelers, laboratory personnel, and 

endemic populations are the same in terms of the need for a booster dose; and limited data 

suggesting that certain populations might have lower seroconversion rates, such as children, or 

more rapid antibody decay as observed with HIV-infected persons. Therefore, certain 

populations might benefit from a booster dose. 

To summarize the key findings of the SAGE Work Group on YF Vaccine Booster Doses, no 

efficacy studies have been performed, and neutralizing antibodies are used as surrogate. The 

current booster dose recommendation of every 10 years was established under IHR in 1965 

and was based on limited data. Most vaccine recipients develop antibody titers and will 

maintain titers for several decades, possibly life-long, following YF vaccination. Very few 

primary vaccine failures have been reported, and no secondary vaccine failures have been 

reported, meaning that no vaccine failures have been noted due to waning antibody levels over 

time. Both innate and cell-mediated immunity contribute to the initial and memory immune 

responses. Following this presentation, SAGE issued the following wording regarding YF 

vaccine booster doses: 

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

immunity against YF disease; a booster dose is not necessary.” 

This recommendation now makes ACIP and WHO YF vaccine recommendations discordant 

regarding the need for a booster dose. As presented by Dr. Bocchini at the beginning of this 

session, the focus of the ACIP work group is to develop recommendations regarding YF vaccine 

booster doses that will be presented to ACIP during an upcoming meeting for a vote. 

Discussion Points 

Dr. Reingold inquired as to whether travelers will be able to travel to other countries if they are 

not in compliance with the booster dose, whether there would be changes to the IHR, and 

whether countries would recognize the new recommendations or if they would still force 

travelers to acquire a booster dose. 

Dr. Staples responded that there have been several discussions, even when SAGE was 

considering making the change to drop the booster dose recommendation, because IHR is also 

at WHO. The current IHR have not been addressed at this time, so countries still can require 

88 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

proof of booster doses. Some countries have indicated that they will continue to require the 

booster dose. It appears that those who work in the IHR group will be approaching each 

country individually to ask them to potentially provide waivers about the booster dose 

requirement or to change their personal requirements for need for a booster dose. 

Dr. Plotkin (Vaccine Consultant) said that he was comforted by the SAGE recommendations, 

but it seemed to him that some things remain missing from our knowledge. For example, he 

would like to see a study of adverse effects in a population that is receiving vaccine routinely. 

That would be primarily the African and Brazilian populations. In addition, this is a vaccine that 

is accompanied by viremia regularly. The viremia is very likely responsible for the viscerotropic 

and neurotropic reactions. One means that was used years ago was to give gamma globulin 

with the vaccine. A recent study was published regarding viremia after administration of the 

vaccine co-administered with immunoglobulin G (IgG) that concluded that IgG did not influence 

viremia. Dr. Plotkin thinks that result is questionable because the IgG very likely contained little 

or no YF antibody. One possible study that could be conducted, in animals and humans, is to 

use gamma globulin obtained from vaccinated individuals, which would have antibody. It would 

be useful if the vaccine could be given to the elderly together with gamma globulin to prevent 

the possible reactions by reduction of viremia. Finally, he would be comforted if there was an 

immunologic study of booster vaccination in individuals who have received a dose of YF vaccine 

many years previously to determine what type of anamnestic response they have, because the 

incubation period of YF is not very long. Therefore, one needs the booster response fairly 

promptly. Although one can discuss innate immune and cellular responses, it is pretty clear that 

antibody is protective. Although 80% of travelers may have long-lasting antibody, there remain 

20% to be concerned about. 

Dr. Fryhofer (AMA/ACP) inquired as to whether anyone could update them on what various 

countries are recommending. Many of her patients have had YF vaccine more than 10 years 

previously, and many of them are over 60. This is a very expensive vaccine. 

Dr. Staples replied that there is some information available. In general, different groups have 

suggested or supported the SAGE recommendations. The Pan American Health Organization 

(PAHO), an extension of WHO, has supported and endorsed the SAGE recommendation and 

many countries have begun to remove the booster dose. Based on a review of their current 

data, Brazil is continuing to recommend booster doses every 10 years to its population. These 

data were not available to SAGE, although the ACIP work group is hoping that these data will 

be available for ACIP, because that swayed Brazil to continue with booster doses. 

Dr. Fryhofer (AMA/ACP) noted that while Africa removed the booster dose requirement, it is still 

shown on the ACIP website as being a requirement. 

Dr. Staples responded that there are differences between IHR and requirements versus what a 

country will choose to recommend for their own population. A country may choose not to 

recommend booster doses. But for instance, if Columbia removed the booster dose 

requirement, a person still could be required when traveling to another endemic place in Africa, 

South America, or India to show proof of a booster dose even if that country does not 

recommend it anymore. That is a discrepancy between regulations and recommendations. 

Dr. Karron emphasized that people lose their YF immunization cards. They might keep them for 

10 years, but many people will not keep them for their lifetime. She wondered whether an 

antibody test would be developed, not to assess protective levels of antibody, but essentially to 

substitute for the immunization card. 

89 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Staples indicated that there has been some discussion about this among the SAGE work 

group members in terms of having proof of vaccination. Ultimately, it was determined that 

having some sort of test that is readily available is not on the horizon in the near future. 

Unfortunately, IHR requires that whomever issued the original yellow card be the re-issuer if a 

person loses it. 

Dr. Decker (Sanofi Pasteur) said he thought this would remain a confusing area for a while, 

because unless he was mistaken, the World Health Assembly (WHA) has not yet voted to adopt 

the SAGE recommendation. That is the first global legal step that has to occur. Then they have 

to promulgate new IHRs. Then the corresponding countries throughout the world will have to 

modify their national regulations to reflect the new IHRs. All of that will take a while, and until 

that all works through the system, this will stay confusing and websites will not quite be up to 

date. There is no way around that, but eventually, this will probably be adopted worldwide. It 

has been long recognized that there is life-long immunity from a single effective YF vaccination. 

The main reason the regulations did not reflect that was administrative. That is, if it is lifetime, 

how do you handle the paperwork issue? Perhaps now, in the day of computers, a way will be 

found around that. In any event, once this all works through the system and ACIP modifies the 

YF recommendations for the US, there will once again be a situation such as that which arose a 

couple of years ago when ACIP modified the rabies recommendation for the US, and the same 

situation that Dr. Sun mentioned earlier with regard to possibly dropping a pneumococcal dose, 

which is that there will be perfectly founded and correct public health national recommendations 

that are at variance with the package insert. That variance will probably never be reconciled. 

Dr. Decker said that this was not a reason not to do the right thing, but that he was just pointing 

it out. With respect to rabies and YF, it is intuitively obvious that giving less vaccine will not 

result in non-inferior antibody levels. Therefore, there is no way to prove that doing less is not 

inferior to doing more immunologically, which means under US regulations the only way to 

modify the package insert is by a randomized, blinded, active controlled clinical trial to show that 

on the one hand people who do not get a 10-year booster of YF vaccine do not have higher 

rates of YF disease then people who do get a booster, or people who get 4 doses of rabies 

vaccine do not have higher rates of rabies following exposure to a rapid animal than people who 

get 5 doses. Those studies are not going to be done. It is important to recognize that this is 

going to be a growing dilemma. It is already a dilemma, because when anyone calls Sanofi 

Pasteur, they are legally required to tell them that they need 5 not 4 doses. It would be really 

nice if the interagency work group would have a discussion about this, because there ought to 

be a way for the regulatory authorities in various countries around the world to have an 

administrative mechanism for reconciling new public health recommendations that are based on 

valid global experience with the package insert. For example, if the package insert could say 

what it says now but add, “More recently, ACIP or WHO has recommended . . .” which at least 

would reduce the level of conflict. 

Dr. Temte inquired as to how many doses are administered each year to the US civilian 

population. 

Dr. Staples responded that Dr. Decker could best respond, as Sanofi Pasteur is the sole 

provider for the US. The military is the largest consumer of the vaccine in the US. 

Dr. Decker (Sanofi Pasteur) responded that he would have to check with someone and report 

back to the committee. 

90 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Schuchat indicated that the program conducted a survey of travel medicine clinics and 

estimated that approximately 200,000 to 250,000 doses are administered in the US per year to 

the civilian population. 

Dr. Temte indicated that in his state, providers are required to have a YF certificate. He 

wondered whether that was true across the country. 

Dr. Staples responded that this is true across the country. While states control licensure, there 

is a process for providers to obtain a YF stamp that is necessary to make the yellow cards valid. 

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. She indicated that Sanofi Pasteur resumed shipping their pertussis-containing 

vaccines, Daptacel® (DTaP), Pentacel® (DTaP-IPV-Hib), and Adacel® (Tdap) in mid-October 

2013. While product availability continues to increase, supply is expected to remain constrained 

over the next several months as inventories rebuild. 

GlaxoSmithKline (GSK) has taken steps to meet increased demand for pertussis-containing 

vaccines and anticipates being able to address gaps related to constrained supply, using a 

combination of products and presentations. However, during this time period, backorders and 

delays in deliveries may occur related to Tdap vaccine, but these are expected to be short in 

duration. Also, provider preference for vaccine presentation (syringes/vials) may not be able to 

be accommodated at all times during this period. 

CDC’s Vaccine Supply/Shortage Webpage can be found at: 

http://www.cdc.gov/vaccines/vac-gen/shortages/default.htm 

Discussion Points 

Dr. Grogg (AOA) inquired as to whether there were any supply problems with YF vaccine. 

Dr. Santoli replied that there is a supply issue with regard to YF vaccine. CDC’s focus is on the 

vaccine contracts for routine vaccines for which the agency is responsible, so she was unable to 

discuss any data there may be for YF vaccine. She called on the manufacturer to address this 

question. 

Dr. Hosbach (Sanofi Pasteur) indicated that they were still working to determine for ACIP the 

total number of doses distributed annually. During the first quarter of 2014, there was a 

manufacturing delay. While there are constraints, vaccine is still available. Normal supply is 

anticipated to resume by April. 

91 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Day 1: Public Comment 

No public comments were offered during this session. 

Agency Updates 

Centers for Disease Control and Prevention (CDC) 

Dr. Schuchat announced that the week of April 28th would be the next National Infant 

Immunization Week. This year, CDC plans to mark the 20 years since the Vaccines for 

Children (VFC) Program was implemented as a special highlight to that week. In addition, a 

recent issue of The Pediatric Infectious Disease Journal highlighted the rotavirus burden in 

Africa as a way to promote the introduction of rotavirus vaccines throughout Global Alliance for 

Vaccines and Immunisation (GAVI)-eligible countries. Also, an intergovernmental board that is 

somewhat like ACIP has been established to advise CDC on immunization information systems 

and the agency’s strategic plan, in order to acquire the best of state and local governmental IT 

thinking about how to best improve immunization systems information technology 

underpinnings. 

Centers for Medicare and Medicaid Services (CMS) 

CMS has a couple of updates that Dr. Temte has graciously agreed to share. CMS is sorry that 

we are not able to attend the meeting in person. However, we are participating by phone and 

will address any issues that come up during the meeting. 

Medicare Flu Vaccine Data: CMS has worked with the Health Resources and Services 

Administration (HRSA) and the National Vaccine Program Office (NVPO) to post Medicare flu 

vaccination information for those in fee-for-service on the NVPO website. The website is 

http://www.hhs.gov/nvpo/flu-vaccination-map and is updated weekly. 

Coverage of Preventive Services for Adults Currently Enrolled in Medicaid. While the 

benefit package for adults who receive health care coverage under the Affordable Care Act 

(ACA) is required to include coverage of preventive services, including coverage of all ACIP 

recommended vaccinations, states continue to have the option to cover preventive services for 

adults currently enrolled in Medicaid. The Affordable Care Act addressed this by including a 

provision (section 4106) that provides an incentive to states that provide coverage of all ACIP 

recommended vaccines and their administration as well as the Grade A/B US Preventive 

Services Task Force (USPSTF) recommended services. To date, eleven states have submitted 

a request to CMS to cover these services and receive the incentive and 8 states have been 

approved (California, Colorado, Kentucky, Nevada, New Hampshire, New Jersey, New York, 

and Ohio). CMS continues to work with all states to encourage coverage of preventive 

services. 

92 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Ms. Pellegrini noted that this really does have meaningful impact for many people. In particular, 

March of Dimes is working with a number of states. For example, Louisiana is not currently 

covering tetanus and reduced diphtheria toxoids (Tdap) for pregnant women. 

Department of Defense (DoD) 

Dr. Geibe reported that DoD service members (e.g., Active Duty, Reservists, National Guard) 

reached a 90% influenza vaccination rate as of December 2013 and was at approximately 95% 

at the time of this meeting. The challenge always seems to be catching up with Reservists and 

others because they are spread out. He quipped that while he was in great competition with the 

Veteran’s Administration (VA) and Indian Health Services (IHS), DoD can force its members to 

get their shots a little quicker, so it always works out. Regarding Japanese encephalitis vaccine, 

there have been ongoing efforts in Japan and Korea to expand screening and vaccination 

based on areas of risk, which continues to be a challenge. DoD is offering human 

papillomavirus (HPV) to males and females during their routine appointments, and is working to 

target the adolescent population to help improve completion rates as well. Regarding smallpox 

vaccine, DoD recently updated its screening forms to clarify questions and ensure safety based 

on customer feedback, but made no real changes in the program. Vaccination against 

adenovirus types 4 and 7 continues, which was instituted in all military basic training centers in 

November 2011. Since then, febrile respiratory illness rates and the proportion of febrile illness 

related to adenovirus among the recruit population has decreased dramatically. In 2013, there 

were only a few rare sporadic cases in the recruit population, so this has proven to be a 

success. 

Department of Veteran’s Affairs (DVA) 

Dr. Kinsinger reported that the DVA has recorded nearly 2 million influenza doses administered 

to its veteran patients thus far, and continues to promote the delivery of influenza vaccine. The 

DVA’s influenza surveillance data matches very closes with national trends in terms of the 

number of cases and proportion of Influenza A, and the largest number of hospitalizes are in the 

45 through 64 year old age group just as in the national data. DVA is working on a number of 

immunization IT-related projects to improve data collection and data records so that they are 

easier to use. DVA’s wonderful electronic medical record (EMR) was built over the years locally 

and has been in place for a long time; however, it needs to work much more carefully together. 

DVA is working on a number of projects with the Indian Health Service and CDC to develop a 

composite influenza vaccine measure. To improve information for its providers, DVA has 

developed two algorithms—one for pneumococcal vaccines and the other for meningococcal 

vaccines. Given that those are such complicated vaccines, the decision was made to develop 

visual graphics to walk providers through when to administer each vaccine. 

Food and Drug Administration (FDA) 

Dr. Sun indicated that since the last ACIP meeting, FDA approved Q-Pan H5N1, which is an 

adjuvant influenza vaccine that has an indication for those 18 years of age and older. Q-Pan 

H5N1 is a 2-dose vaccine that is mixed prior to administration and is given 21 days apart. The 

FDA also has been working very closely with CDC and the sponsor to address the use 

meningococcal B vaccines for the outbreaks on college campuses. Dr. Sun also indicated that 

on February 28, 2014, the FDA advisory committee would meet for the 2014-2015 influenza 

strain selection meeting. 

93 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Health Resources and Services Administration (HRSA) 

Dr. Houston indicated that the Notice for Proposed Rule Making to amend the Vaccine Injury 

Compensation Table to add intussusception as an adverse event associated with rotavirus 

vaccines was published July 24, 2013. The public comment period has ended, and a second 

public comment hearing will be scheduled soon. The Advisory Commission on Childhood 

Vaccines (ACCV) made recommendations to amend the Vaccine Injury Compensation Table 

during the September 5, 2013 and December 5, 2013 meetings based on the Institute of 

Medicine’s (IOM) review of the scientific literature on vaccines and adverse events. These 

recommendations are being considered. Finally, increasing numbers of petitions are being filed 

with the National Vaccine Injury Compensation Program each year. In fact, this has increased 

by 100 petitions from 2012 to 2013, and more claims are being compensated each year. 

Indian Health Services (IHS) 

Ms. Groom shared preliminary data on influenza vaccination of IHS’s healthcare personnel, 

reporting that after four years of stagnating and remaining at about 74%, there has been a slight 

increase to approximately 78%. Though still far short of the Health People 2020 goal, at least 

IHS is making some progress. In addition, IHS has been working in collaboration with the VA 

on a developmental performance measure for the IHS that would be a composite measure to 

assess what proportion of adults have been appropriately vaccinated for age with the routinely 

recommended vaccines. Consideration is being given to rolling that out to IHS sites, and 

developmental data will be collected on that. 

National Institutes of Health (NIH) 

Dr. Gorman highlighted three efforts underway at the National Institutes of Health (NIH). There 

is a new series of efforts to develop a vaccine to protect against respiratory syncytial virus 

(RSV), which is a leading cause of illness and hospitalization among very young children. A 

recent report was published in Science from an National Institute of Allergy and Infectious 

Diseases (NIAID) researcher. Two pharmaceutical companies are also working on early stage 

RSV vaccines, and they will soon be moving into early clinical trials. In terms of partnerships, 

NIH has entered into the Accelerated Medicines Partnership, which is a venture between NIH 

and 10 biopharmaceutical companies and several non-profit organizations that hopes to 

transform the current model for developing new diagnostics and treatments by jointly identifying 

and validating promising biological targets of disease. The ultimate goal is to increase the 

number of diagnostics and therapeutics for patients, and reduce the time and cost of developing 

them. For each pilot that NIH and industry select, research plans will be developed aimed at 

characterizing effective molecular indicators of disease called “biomarkers,” and distinguish 

biological targets most likely to respond to new therapies. Third, a report was recently 

published on the NIAID Bacterial Resistance Program that describes the ongoing research 

portfolio of the basic translation and clinical research in antibacterial resistance, and the 

combination of innovation approaches based on the latest scientific advances to be pursued. 

These strategies draw on the multidisciplinary partnerships which are essential for receiving a 

coordinated and nimble approach to addressing antibacterial resistance threats as they emerge. 

Since that report was published, NIH has been approached by another consortium of 

pharmaceutical companies to create a “Living Protocol,” which Dr. Gorman hopes to be able to 

report on during the June 2014 ACIP meeting. 

94 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

National Vaccine Advisory Committee (NVAC) 

Dr. Orenstein reported on a couple of issues pertaining to the last National Vaccine Advisory 

Committee (NVAC) meeting on February 11-12, 2014. There was a forum on vaccine research, 

development, and innovation. This included a demonstration of the IOM-developed “Smart 

Vaccines” tool, and assessing various values of cost, health burden, effectiveness, safety, and 

public demand and how that influences vaccine priorities and ranking. In addition, Biomedical 

Advanced Research and Development Authority (BARDA) discussed how it incentivizes 

development of products that it considers to be high priority. There was a stimulating talk by Dr. 

Stanley Plotkin dealing with issues of motivating development of new and high priority products, 

which NVAC will continue to follow. Standards for Adult Immunization Practices is now 

published in Public Health Reports, and plans were discussed to implement these standards 

and track implementation. NVAC has three ongoing work groups, including: 1) Vaccine 

Acceptance and Confidence, 2) HPV Vaccines, 3) Maternal Immunization. There is a cancer 

panel that is trying to improve HPV vaccine uptake, and that report is available on the NIH 

website. The Maternal Immunization Work Group is dealing with how to improve 

implementation of ACIP recommendations for vaccination of pregnant women. This group is 

reviewing NVAC comments and expects to put that out for public report sometime during the 

second week of March 2014, with a final vote on recommendations expected during the June 

2014 NVAC meeting. The report urges ACIP to consider developing a statement for pregnant 

women so that for obstetrical providers and others, there would be one place to turn to obtain 

information. 

National Vaccine Program Office (NVPO) 

Dr. Gellin noted that the CMS report included highlights about FluMap, and he encouraged 

everyone to look at this. The map enables users to drill down to view influenza in the CMS 

population at the community level. There has been great feedback from the National 

Association of County and City Health Officials (NACCHO) on how helpful this is at the local 

level. Related to that, the National Vaccine Program Office (NVPO) has also been working with 

the HealthMap group at Harvard. This was initially the HealthMap Flu Vaccine Finder, which 

has now morphed to the Adult Vaccine Finder. This is part of a larger effort to encourage adult 

vaccination more broadly. In addition, an effort is being made to have IOM demonstrate the 

“Smart Tool” during the June 2014 ACIP meeting. The first annual report on The State of the 

National Vaccine Plan” is on the NVPO website. This report offers an update on progress 

toward that plan. Dr. Gellin said he was particularly excited about having outside commentaries 

from a number of people in the field who offered their perspectives. He also reported that a 

funding opportunity announcement (FOA) had been published titled “Mobilization for Health: 

National Prevention Partnership Awards (NPPA),” which recognizes the importance of 

partnership. This FOA is located on the Assistant Secretary for Health’s website for those who 

are interested. Dr. Gellin emphasized that the application deadline would be March 3, 2014 by 

5:00 pm Eastern Time (ET). Finally, in late March 2013, NVPO convened a meeting on 

pertussis. A report on this meeting is anticipated to be published in a JID supplement in March 

2014. 

95 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

General Recommendations 

Introduction 

Dr. Jeff Duchin 

ACIP General Recommendations Working Group Chair 

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

the 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 vaccine-specific 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 topic addressed during this session was Storage and Handling of Immunobiologics. The 

remaining sections to be revised and discussed in future meetings include: 

 Altered Immunocompetence 

 Vaccination Programs 

 Vaccination Information Sources 

Dr. Duchin encouraged ACIP members and others to review the proposed revisions and provide 

feedback. He also called attention to a recent publication that Dr. Rubin led for the Infectious 

Disease Society of America (IDSA) pertaining to guidelines for the vaccination of 

immunecompromised hosts. This topic is also addressed in the General Recommendations, but 

the IDSA guidelines go into a lot more detail and provide guidance for clinicians based on a 

variety of levels of evidence from high quality down to expert opinion on various areas, some of 

which are not addressed by ACIP. There are some conflicting recommendations between ACIP 

and IDSA, so it would be helpful for ACIP members to review the IDSA guidelines so that the 

General Recommendations Work Group can be made aware of those. 

96 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Storage and Handling of Immunobiologics 

Dr. Andrew Kroger 

General Recommendations Working Group 

During this session, Dr. Kroger provided an update on the proposed changes to the Storage and 

Handling of Immunobiologics section of the General Recommendations. The following topics 

were covered in the 2011 General Recommendations document, which is brief: 

 Storage Temperature 

 Storage Units 

 Temperature Monitoring 

 Response to Out-of-Range Temperature Reading 

 Expiration Dates and Windows 

 Multidose Vials 

Since the General Recommendations were published in 2011, CDC’s Storage and Handling 

Toolkit, which is posed on CDC’s website, has been extensively revised. This tool contains best 

practices information for both public and private providers, and includes precise and exhaustive 

details on the following topics: 

 Storage Units 

 Temperature Monitoring 

 Expiration Dates and Windows 

 Multidose Vials 

The website link for the toolkit is: www.cdc.gov/vaccines/recs/storage/toolkit/default.htm Dr. 

Kroger noted that in the draft of the General Recommendations supplied to the ACIP members, 

there were extensive strikeouts because the General Recommendations Work Group believes 

that these topics are adequately covered in the toolkit and do not need to be in the ACIP 

recommendations. Topics in the Storage and Handling Toolkit include the following: 

 Best Practices, which breaks down into the following: 

 Equipment considerations for storage units and thermometers 

 Maintaining the cold chain 

 Routine storage and handling practices 

 Inventory management 

 Emergency procedures for protecting vaccine inventories 

 Equipment considerations for storage units and thermometers 

 Stand-alone units preferred 

 Use of glycol-buffered probes 

 Maintaining the cold chain 

 Required temperatures 

 Routine storage and handling practices 

 Positioning of vaccine 

 Labeling trays and containers 

 Inventory Management 

 Interpreting expiration dates 

 Emergency procedures for protecting vaccine inventories 

 Transporting to off-site facilities 

97 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

The Storage and Handling Toolkit is CDC-cleared, and it represents best practices for the public 

and private sectors. It is harmonized with the VFC regulations described in the VFC Operations 

Manual. 

The following topics will be retained in the ACIP General Recommendations: 

 Retaining the table of temperature ranges (Draft, Page 4) 

 Categories of vaccine 

 Nonlyophilized, aluminum-adjuvanted vaccines 

 Lose potency when exposed to freezing temperatures 

 Nonlyophilized non-aluminum adjuvanted vaccines 

 Might lose potency if exposed to freezing temperatures 

 Lyophilized (nonvaricella) vaccines 

 Do not need to be frozen (but lyophilized pellet can be with exception of 

MenHibrix pellet) 

 Varicella-containing vaccines 

 Must be kept frozen or vaccine virus will degrade 

 Noninjectable vaccines 

 Do not freeze 

 Response to Out-of-Range Temperature Reading (not specifically covered in the toolkit, so 

it is important to maintain in the General Recommendations) 

 Have a plan ahead of time 

 Mark vaccine “do not use” 

 See if temperature deviation has a resolvable solution 

 Door left open 

 Unplugged 

 Move vaccine to alternate site 

 Contact state/local health department or manufacturer to determine if vaccine is 

viable (this is not new language) 

 If doses already administered, contact state/local health department 

 Sample language: As a general rule, vaccines that have been stored at 

inappropriate temperatures should not be administered unless public health 

authorities or the manufacturer determine it is safe to do so. (Draft, Page 3, Line 28) 

 Sample language: If such vaccines already have been administered, vaccine 

exposed to inappropriate temperatures that is inadvertently administered should 

generally be repeated. Clinicians should consult promptly with state or local health 

departments in these situations. Consultation with CDC is available when 

necessary. (Draft, Page 3, Line 31) 

 Table of Storage Temperatures 

 Added PRP-T Hib-MCV2 (MenHibrix®) 

 Added new minimum temperatures for all varicella containing vaccines (negative 58 

degrees Fahrenheit, negative 50 degrees Celsius) 

 Most storage units cannot reach this temperature 

 The cutoff is emphasized because transport on dry ice can cause variations 

in temperature, perhaps as low as negative 58 degrees Fahrenheit 

 Lead to increased gas permeability of rubber vial, theoretically compromising 

sterility (especially in presence of water vapor (dry ice)) 

98 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

 Removed the “Comments” column, given that the most precise information on light 

sensitivity and degree of thermostability can be found in the FDA product information 

 A snapshot of the Vaccine Storage Temperature Recommendation Table (Page 6) is 

as follows, although the column labels are not shown and are Vaccine, Storage 

Temperature, and Diluent Storage Range from left to right: 

 Updated Temperature Logs (borrowed from the Immunization Action Coalition; shown in the 

samples below) 

 One for refrigerator storage, one for freezer storage 

 Has spaces to log the maximum and minimum temperature of the day (per new best 

practice recommendations) 

 Does not have spaces to check off a box if the temperature is out of range 

 Emphasizes the need to take immediate action if temperature is out-of-range 

Discussion Points 

Dr. Rubin noted that his hospital, a multi-dose vial expires after 30 days regardless of the 

expiration date on the vial. He did not know where that came from, or how that conflict is 

resolved in other places. 

Dr. Kroger responded that this is an inventory issue and reading the expiration date on the vial. 

That is in the toolkit, but will not be mentioned in detail in the General Recommendations any 

longer. United States Pharmacopeial (USP) was one of the first organizations to post 

information about the 30-day open rule. There are certain vaccines for which the package insert 

states a longer period of time for multidose vaccines that need to be entered and reconstituted. 

The meningococcal polysaccharide vaccine was one of these. Most vaccines in use are in 

single dose vials that have the 30-day recommendation. Therefore, this is not believed to be a 

major issue. The details will be in the Storage and Handling Toolkit. 

99 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Ms. Hayes (ANA) added that she was fairly certain that it was a Joint Commission requirement 

in hospitals to discard a product after 28 days, which probably does not apply in the outpatient 

setting. 

Regarding the response to an out-of-range temperature, Dr. Hahn (CSTE) suggested that 

perhaps the language should read “should not be administered unless determined to be safe 

and effective to do.” Usually, the concern is more about loss of efficacy than safety. Regarding 

the diluent temperature, she wondered whether there could be confusion in terms of the third 

column for varicella vaccines and whether people may misinterpret that as being the vaccine 

temperature range. Perhaps it should be separated more clearly. 

Dr. Kroger responded that this revision could be made, and that he would ensure that this would 

not be too redundant with other language that appears later. Regarding diluents temperature, 

he emphasized that what he showed was a snapshot of the table. The top header of the entire 

table that contains all of the vaccines will indicate what the columns stand for. He will review 

the table to ensure that it is clear that one table is vaccine temperature and the other is diluent 

temperature. 

Dr. Temte inquired as to what type of ongoing training VFC and non-VFC sites receive, and how 

the recommendations are translated into action. He also wondered about the percentage of 

VFC versus non-VFC sites. 

Dr. Moore (AIM) responded that immunization programs work with the VFC providers very 

carefully. Extensive training is conducted using CDC materials, and AIM is extremely 

appreciative of the newest materials that have been developed, including the more detailed 

toolkit. People can also complete online modules on their own, and there are requirements for 

all VFC providers to undergo education in storage and handling annually that have recently 

begun to kick in. Site visits are conducted at least every other year, if not more often, with VFC 

providers. There is no direct involvement of programs in supervision of those who administer 

vaccines outside of the VFC program. However, tools are available for them to acquire training 

on their own through the CDC website. In terms of the breakdown of VFC versus non-VFC 

sites, while she did not have specific numbers, Dr. Moore noted that most pediatric practices 

and a good number of family physicians participate in VFC. The VFC would not comprise a 

large component of adult vaccines and vaccines administered through pharmacies. 

Dr. Schuchat added that most VFC providers are also providing vaccines to publicly insured 

people. There are over 40,000 VFC provider sites. CDC has also made efforts to be clear that 

pharmacies can be VFC providers if they follow the requirements; however, site visits are not 

being conducted to the adult only providers. There are potentially other oversight groups that 

address that. 

Dr. Temte said his impression was that because pharmacies are used to maintaining inventory 

at appropriate temperatures and so on, that is not as much of a concern as it would be in the 

private adult practice that has some inventory, but does not participate in VFC. 

Dr. Foster (APhA) replied that APhA monitors storage and handling quite carefully. However, 

there is probably not 100% compliance with all of the rules of the toolkit. The toolkit has been 

distributed to pharmacists, but this remains a corporate decision for many pharmacies in terms 

of what they do. Some comply and some do not, given that there really has not been any 

enforcement. Pharmacies do have other medications and requirements, and those are wellmonitored. 

100 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Schuchat added that the Office of the Inspector General reviewed storage and handing in 

the VFC program a couple of years ago and found a number of concerns. CDC issued a 

corrective action plan, and much of the training and toolkit are in response to these findings. 

There has been a major uptick in accessing the toolkit and training, which reflects the work that 

CDC programs and states have been doing in terms of training materials. 

Safety of Tetanus, Diphtheria, and Acellular Pertussis (Tdap) Vaccine 

Introduction 

Art Reingold, MD 

Chair, ACIP Pertussis Vaccine Work Group 

Dr. Reingold reminded everyone that the current ACIP recommendations for Tdap and Td are 

for a single Tdap dose for all persons aged 11 years and older, with preferred administration at 

11 or 12 years of age. Pregnant women are recommended to receive Tdap with every 

pregnancy. A decennial Td booster is recommended for those who have received 1 Tdap 

5 years for wound management. 

The Pertussis Vaccine Work Groups (WG) terms of reference are to: 

 Review existing statements on infants and young children (1997), adolescent (2006), adults 

(2006), and pregnant and postpartum women and their infants (2008) and consolidate into a 

single statement. 

 Review new data on Tdap including: 

 Effectiveness of ACIP recommendations 

 Interval between Td booster and Tdap 

 Use of Tdap in adults ages 65 yrs and older 

 Pregnant and breastfeeding women 

 Use of Tdap 

 Cocooning strategies 

 Vaccinated HCP and need for postexposure prophylaxis 

 Tdap revaccination 

 Pregnant women 

 Healthcare personnel 

 “Cocooning” 

 Review updated epidemiology of tetanus and diphtheria 

101 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Recent WG activities have included reviews and discussion of the following: 

 Pertussis in healthcare personnel, including a review of epidemiology, post-exposure 

prophylaxis practices, Tdap coverage, and cost-effectiveness models and discussion 

regarding the need for additional Tdap boosters 

 Epidemiological and clinical significance of pertactin deficient B. pertussis 

 Baboon model data on pertussis transmission and infection after vaccination 

 Vaccinating pregnant women, including information about ACOG and CDC activities, and 

Tdap safety in pregnancy (VAERS, VSD) 

With regard to the context for this session, in June 2011 ACIP recommended a single dose of 

Tdap for pregnant women who previously have not received Tdap. In October 2012, ACIP 

recommended a dose of Tdap during each pregnancy, irrespective of the patient’s prior history 

of receiving Tdap. ACIP supported ongoing safety monitoring and requested that CDC commit 

to safety studies for Tdap given during pregnancy, especially to women who have previously 

received Tdap. 

There are a number of monitoring activities underway for maternal Tdap safety, including 

ongoing monitoring through VAERS, coverage data and safety studies through VSD, and a 

clinical study of Tdap safety in pregnant women to be implemented during 2014 through CISA. 

During this session, the CDC ISO presented updates from VAERS and VSD on the safety of 

Tdap vaccine during pregnancy. 

Safety of Tdap During Pregnancy: Enhanced Surveillance in VAERS 

Pedro L. Moro, MD, MPH 

Immunization Safety Office 

Division of Healthcare Quality Promotion 

Centers for Disease Control and Prevention 

Regarding background, Dr. Moro reminded everyone that on October 11, 2011, ACIP voted to 

recommend that unvaccinated pregnant women should receive a dose of Tdap. On October 24, 

2012, ACIP voted to recommend the use of Tdap during every pregnancy irrespective of the 

patient’s prior history of receiving Tdap. The optimal timing for Tdap administration is between 

27 and 36 weeks gestation. Tdap is not approved for repeat doses, and ACIP has not 

previously recommended repeat doses in other populations. No pre-licensure trials for Tdap 

were conducted in pregnant women. 

In a review conducted in VAERS for the period 2005 through 2010 before the routine 

recommendation, 132 reports to VAERS in women who received Tdapa

 during pregnancy or 

infants exposed in utero were reviewed.b

 In this study 77% of reports had Tdap during first 

trimester, many of which were inadvertent exposures, and 42% described no adverse events. 

There were no unusual or unexpected patterns of maternal, fetal, or infant outcomes. Some 

selected outcomes identified in that study included 22 spontaneous abortions, 2 fetal deaths, 2 

preterm births, and 1 major birth defect (gastroschisis) [a

Zheteyeva et al. Safety of Tdap in 

pregnancy. Am. J. Obstet Gynecol. 2012;207:59.e1-7.; b

Before routine recommendation for 

Tdap in pregnant women]. 

102 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

The objective of the review was to describe adverse event reports submitted to VAERS of 

pregnant women or their infants who received Tdap during the time period 10/2011 through 

01/2014, since the ACIP recommendations. In terms of the methods, enhanced surveillance 

was initiated on November 26, 2012. A search was conducted in the VAERS database for 

reports of pregnant women or infants exposed in utero after administration of Tdap during the 

time period 10/11/2011 through 01/31/2014. “Exposure during pregnancy,” “drug exposure 

during pregnancy,” “maternal exposure during pregnancy,” and other specific pregnancy 

MedDRA codes were used to search for these reports. Serious reports classified based on the 

Code of Federal Regulations included death, life-threatening, hospitalization, prolonged 

hospitalization, and permanent disability (exception: hospitalization for normal delivery was not 

considered to be a serious report). 

As a reminder, VAERS is a spontaneous reporting system that is co-administered by the FDA 

and CDC. Its strengths are that it allows for rapid signal detection, can detect rare adverse 

events, generates hypotheses, encourages reports from healthcare providers and accepts 

reports from patients and others, and data are available to the public. VAERS’ limitations 

include reporting bias (e.g., underreporting, stimulated reporting), inconsistent data quality and 

completeness, inability of the design to assess whether a vaccine caused an adverse event, 

lack of an unvaccinated comparison group, and lack of a field for pregnancy (making it difficult 

to search for reports). 

Medical records were requested and reviewed for all pregnancy reports associated with Tdap. 

Reports describing maternal and infant events in the same report were treated as separate 

reports. The records were queried for prior administration of tetanus-containing vaccines. In 

addition to vaccination records, the provider or patients were queried regarding whether they 

were exposed to Tdap in the past. A descriptive analysis of adverse events reported was 

conducted. 

In terms of the preliminary findings, thus far a total of 90 reports have been received. Of these 

reports, 22% describe an adverse event of which 16% were serious. The main type of reporter 

was the provider (38%), followed by the manufacturer (38%), other (14%), and the patient/ 

parent (11%). Tdap was the only vaccine administered in 62% of the reports. Most women 

(55%) received Tdap vaccine during the third trimester. Some of the pregnancy-specific 

adverse events that were reported included premature delivery at < 37 weeks (n=5), 

spontaneous abortion at < 20 weeks gestation (n=4), stillbirth (n=4; one with trisomy 12), 

gestational diabetes (n=2), oligohydramnios (n=2), preeclampsia (n=2), chorioamnionitis (n=2), 

polyhydramnios/macrosomia (n=1), placenta previa (n=1), abruptio placentae (n=1), nausea 

and vomiting (n=1), and increased blood pressure (n=1). 

There were 6 infant or fetal adverse events, with 1 each of the following: ectopic kidney in 

newborn (pregnant patient vaccinated at 17 weeks; major birth defect), hypoplastic left heart 

syndrome (pregnant patient vaccinated at 1.4 weeks; major birth defect), polydactyly (pregnant 

patient vaccinated at 28 weeks), intrauterine growth restriction, neonatal respiratory disorder, 

and lockjaw in infant (patient required hospitalization). Non-pregnancy-specific adverse events 

included injection site reactions and pain in extremity/myalgia (n=19); thrombocytopenia (n=4); 

non-anaphylaxis allergic reaction (n=4); systemic reactions including fever, chills, and headache 

(n=4), and 1 each GBS, transverse myelitis, anaphylaxis, hypothyroidism, pyrexia, chronic 

hypertension, and urinary tract infection. VAERS received 10 reports of pregnant women who 

were exposed to Tdap in the past. The interval between the current and previous Tdap 

vaccines for the adverse events reported ranged from 7 days to 3.8 years. 

103 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

In terms of a comparison of the safety data in VAERS before and after the routine 

recommendations for Tdap during pregnancy, before the routine recommendation most women 

(77%) received Tdap during the first trimester. Many of these exposures were inadvertent. 

After the routine recommendation, most women (55%) received Tdap during the third trimester. 

The proportion of serious reports increased from 5% before to 16% after the routine 

recommendation. There also has been an increase in the proportion of some adverse events 

(preterm birth, stillbirth, major birth defects, injection site reactions). These are changes that 

were expected to occur due to the new recommendations. 

In summary, compared to the period prior to the routine recommendation for Tdap during 

pregnancy, an increase was observed in the proportion of serious reports; pregnancy-specific 

outcomes that occur after the first trimester (e.g., stillbirths, preterm deliveries); and nonpregnancy specific outcomes (e.g. injection site reactions) following the routine Tdap 

recommendation during pregnancy in VAERS. In addition, there was a decrease in the number 

of reports describing no adverse events. Most vaccinations were administered during the 

second and third trimesters. Changes in reporting patterns are likely due to the new routine 

Tdap recommendation, increased awareness, and differences in the trimester of vaccination. 

In conclusion, no new unexpected vaccine safety concerns have been noted among pregnant 

women who received Tdap or their infants. A limited number of pregnancy reports with repeat 

Tdap doses have been received by VAERS. CDC will continue to monitor the safety of Tdap 

vaccine during pregnancy, with special emphasis on repeated doses of Tdap. 

Discussion Points 

Dr. Temte reminded everyone that with the October 2012 vote to recommend Tdap for every 

pregnancy, there was a request to have updates on safety at every subsequent ACIP meeting 

until such time as there is sufficient accumulated wisdom on this program. 

Dr. Reingold thought it would be fairly simple to add an indicator on the VAERS form regarding 

whether a woman is pregnant, and was curious as to whether consideration has been given to 

doing so. 

Dr. Moro replied that the VAERS form is in the process of being changed, and will include a field 

for pregnancy and perhaps some additional information (e.g., gestational age or LMP). 

However, it could take two to three years for this process to be completed. 

Ms. Hayes (ANA/ACNM) asked whether the rate of adverse events was calculated for the prerecommendation timeframe based on the number of pregnancies that were completed to fullterm. The rate of miscarriage during the pre-recommendation phase was quite high compared 

to the post-recommendation timeframe. Therefore, the number of full-term pregnancies differed 

in the two study group populations. She recommended that consideration be given to assessing 

those data differently. Regarding the rate of these occurrences overall in all pregnancies, it is 

helpful to look at how often these events occur in the normal pregnancy population compared to 

this population, because for most of these adverse events, the rate is no different. 

Dr. Moro replied that the proportions shown were based on the total number of Tdap pregnancy 

reports received, and are not representative of the population and should not be thought of in 

comparison to the background rate in the general population. 

104 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Ms. Hayes (ANA/ACNM) clarified that she was recommending that a comparison be made to 

the background rate in the general population. 

Dr. Temte inquired as to whether brand-specific information was being received with the VAERS 

reporting, and to whether any differences were being observed between the two. 

Dr. Moro responded that certain adverse events could be assessed by brand, but this has not 

yet been done. Most of the reports (57) have been Adacel®, and about a third have been 

Boostrix®. 

Dr. Riley (ACOG) inquired as to whether there was a sense of how many women received 

influenza vaccine and Tdap simultaneously out of this population. 

Dr. Moro replied that the most common vaccine given along with Tdap was TIV in about 21% of 

the reports. 

Dr. Harriman pointed out if the trimester the vaccine was given was known, along with certain 

adverse events in a fetus that occur at a certain developmental phase of pregnancy, if a vaccine 

was given in the third trimester and an adverse event was known to occur during the first 

trimester, it would be nice to tease that out. 

Dr. Moro responded that for these reports, this information was provided. For example, for the 

ectopic kidney event in the newborn, the pregnant patient was vaccinated at 17 weeks. For the 

infant with hypoplastic left heart syndrome, the pregnant patient was vaccinated at 1.4 weeks. 

Dr. Duchin wondered whether the numbers shown for various conditions for women who 

received Tdap in the third trimester were any different from those who received TIV alone 

without Tdap in the third trimester. The concern was that there may be some unique potential 

adverse events associated with the administration of Tdap to women repeatedly in the third 

trimester. Influenza is also believed to be a very safe vaccine that has been recommended for 

administration in pregnant women as well. So he was curious as to whether the spectrum of 

adverse events being reported for Tdap were any different than those report among women who 

receive just TIV in the third trimester. 

Dr. Moro indicated that for the current season, for some of the events TIV was comparable to 

Tdap. For example, the rate of spontaneous abortions is similar for TIV and Tdap. This is also 

very comparable in previous seasons. Nothing of concern has been observed. 

Dr. Schuchat reminded everyone that VAERS data do not provide rates. The analysts are 

assessing the proportion of VAERS reports that have a particular conditions. It is really helpful 

for the ACIP members to suggest additional analyses they would like to see with these passive 

data that they believe would be useful, and she thought the next presentation regarding the 

VSD would be helpful with regard to information about rates. The point of VAERS is just for 

signal detection. 

Dr. Plotkin (Vaccine Consultant) was troubled by the fact that 45% of women were receiving 

Tdap before the third trimester. This is not influenza. In the case of influenza, the goal is to 

protect the pregnant women. In the case of Tdap, the goal is the transmission of passive 

antibody to the infant. Vaccinating with Tdap in the first or second trimester is not deriving the 

maximum benefit from the vaccination. There is also the issue of confusion with congenital 

anomalies if vaccine is given in the first trimester, which could damage the idea of safety of 

105 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

vaccinations during pregnancy. Thus, it seemed to him that the ACIP recommendation should 

be stronger for third trimester vaccination than for earlier vaccination. 

Dr. Schuchat pointed out that these data do not indicate in what trimester women are getting 

Tdap. These are reports of adverse events and what the circumstances were, but this is not the 

denominator of when women are getting vaccine in pregnancy. The comment about ensuring 

high antibody levels at birth is important, but it should not be assumed that 45% of the Tdap 

doses are being given before the third trimester because that is not what VAERS can tell us. 

Dr. Moore (AIM) is already receiving many questions in her state about how adverse event 

reporting will be dealt with, given the goal for as many women as possible to receive Tdap and 

influenza vaccine. During pregnancy, almost anything is going to be temporally associated with 

administration of those vaccines because of the narrow windows in which they are given. 

Adverse events occur naturally during pregnancy, and that correlation is going to be a 

challenge. She wondered whether there were any signals in the VAERS data that warrant 

further attention based on the data presented during this session. 

Dr. Moro replied that no signals have been detected in VAERS. Of course, these adverse 

events will continue to be monitored. 

Dr. Reingold noted that several women had received a Tdap vaccine fairly recently before the 

dose in question. One received the dose 7 days before, another 29 days before, and another 

159 days before. He was curious as to whether a minimum is given in the recommendation that 

indicates that if a woman has had a dose within a certain time period, she does not need yet 

another dose during pregnancy. 

Dr. Temte clarified that the recommendation is for a dose during pregnancy, preferably between 

27 and 36 weeks. 

Dr. Tom Clark (SME) clarified that it is one dose with each pregnancy, preferred in the third 

trimester. It would be odd for a woman to discover that she was pregnant in the third trimester 7 

days after the previous dose, but the recommendation would still be one dose even if it was 

somewhat too early. 

Dr. Karron inquired as to whether there was a mechanism to know when in pregnancy women 

are getting vaccine. 

Dr. Schuchat indicated that the next presentation would give the details of a managed care 

population denominator and numerator. In addition to that, CDC is periodically conducting 

national surveys of Tdap coverage, which would include timing for those who are pregnant. 

That is not going to be done annually at this point, but that information will be periodically 

updated. The National Health Interview Survey (NHIS) of adult immunization is one of the ways 

that Tdap in adults is monitored. There is only one time point so far on that, but there will also 

be data monitoring through the Pregnancy Risk Assessment Monitoring System (PRAMS) and 

some other systems. 

106 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Tdap During Pregnancy: Safety and Coverage Data from the VSD 

Elyse Olshen Kharbanda, MD, MPH 

Health Partners Institute for Education and Research 

During this session, Dr. Kharbanda presented updated estimates of Tdap coverage during 

pregnancy within 7 of the VSD sites, as well as data on Tdap safety during pregnancy from the 

VSD’s large observational cohort. All 7 VSD sites contributed data for this study, and all 7 sites 

contributed data on Tdap coverage. The safety data are only from the California VSD sites, 

given that for the time period studied, the majority of Tdap vaccinations during pregnancy 

occurred in California. For this cohort, pregnancies from the 7 VSD sites were identified from 

claims and electronic health record data using an automated, validated algorithm. 

Using standardized VSD vaccine files, all vaccines administered to pregnant women in the 

cohort starting in 2005 and ending at 6 weeks postpartum were included. In the coverage data, 

Tdap administrations were assigned as pre-pregnancy, during pregnancy, or postpartum. For 

the safety study, in order to reduce the potential for misclassification of exposure status, women 

vaccinated in the 7 days following their last menstrual period (LMP) or in the 7 days prior to 

delivery were excluded. 

As a reminder, data regarding Tdap coverage during pregnancy through 2011 were presented 

to ACIP during the June 2013 meeting. The updated estimates provided during this session 

pertained to receipt of Tdap for pregnancies ending between 1/1/07 and 11/15/2012. The cutoff 

of November 15th was to allow 6 weeks of postpartum observation. As mentioned previously, 

pregnancies (including pregnancy outcomes and start and end dates) were identified using a 

validated algorithm, and receipt of Tdap was pulled from the electronic health record. Thus, the 

coverage data reflect the 2010 California Department of Health recommendations and the 2011 

ACIP recommendations to administer Tdap to women who were not previously vaccinated, 

preferably after 20 weeks gestation. 

Regarding the findings for all pregnancies identified from the 7 VSD sites for the years 2007 

through 2012, the full cohort includes nearly 400,000 women with pregnancies ending in a live 

birth, of whom 9.5% received Tdap during pregnancy and 14.4% received Tdap postpartum. In 

2010, for all women in the cohort, 9.2% received Tdap during pregnancy. This increased to 

17.1% in 2011, but decreased in 2012 back down to 13.7%. In terms of Tdap coverage among 

live births in the California VSD sites, coverage during pregnancy increased starting in 2010. In 

2011, coverage was up to 30%, but decreased in 2012 to 19.5%. However, this is believed to 

be due to the marked increase in pre-pregnancy receipt of Tdap. 

By 2012, more than half of women in the cohort at the California sites had received Tdap prior 

to pregnancy. Consistent with recommendations at that time, these women were not 

recommended to receive a dose during pregnancy. With respect to data from live births 

occurring at the VSD sites (e.g., Minnesota, Washington, Oregon, Colorado, and Wisconsin), 

the first real increase in Tdap coverage during pregnancy occurred in 2012 when 16% of 

women were vaccinated. Similar to California, at these sites more than half of women received 

Tdap prior to pregnancy and an additional 10% received within 6 weeks Tdap post-partum. 

107 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

In summary of Tdap coverage from 2007-2012 at the California VSD sites, Tdap coverage 

increased substantially in 2010 and 2011, but decreased in 2012. This is likely because many 

women had received Tdap pre-pregnancy. At the Minnesota, Washington, Oregon, Colorado, 

and Wisconsin VSD sites, Tdap coverage during pregnancy increased in 2012, with 

approximately 16% of women vaccinated in response to the 2011 ACIP recommendations. 

Turning to preliminary findings from the Tdap safety study, an observational cohort study was 

conducted of pregnancies with live birth outcomes between January 2010 and November 2012 

from the two California VSD sites. Women were required to have continuous insurance 

enrollment 6 months prior to the start of pregnancy, continuing through pregnancy, and through 

6 weeks postpartum. Multiple gestation pregnancies, women with no medical care during 

pregnancy. and women who received a live virus vaccine were excluded. 

The safety outcomes included two late pregnancy complications and two birth outcomes. Late 

pregnancy complications were identified from diagnoses or ICD-9 codes occurring at medical 

visits. Hypertensive disorders in pregnancy were defined as having a new diagnosis of either 

gestational hypertension, preeclampsia, or eclampsia. The second pregnancy complication 

studied was chorioamnionitis. While these ICD-9 codes have been shown to be valid, in order 

to increase specificity, both eclampsia and chorioamnionitis were required to be inpatient 

diagnoses. The two birth outcomes were preterm delivery and small for gestational age (SGA) 

births. These birth outcomes came from EHR data. Gestational age at delivery was specifically 

based on clinician assessment at delivery. Preterm delivery was defined with a single cut-off of 

delivery before 37 weeks gestation, and SGA was defined as having a weight for gestational 

age at less than the 10th percentile. 

Adjustment was made for multiple covariates in the models using a propensity score. The 

propensity score was created with logistic regression to estimate the likelihood of receiving 

Tdap during pregnancy. Variables included in the propensity score included age, race, SES, 

pre-existing medical conditions, and prenatal care index. Site and receipt of other vaccines 

during pregnancy were also adjusted for. The analytic approach varied for each outcome, 

accounting for the expected timing of the outcome in pregnancy and presumed 

pathophysiology. For hypertensive disorders, women vaccinated before 20 weeks were 

compared to unvaccinated women. This was done for two reasons. First, as the current 

analyses were not matched, there was not an index date for the unvaccinated population. 

Looking at vaccination prior to 20 weeks offered assurance that all vaccination occurred before 

the hypertensive disorder could be diagnosed. A second reason was that although 

hypertensive disorders of pregnancy by definition occur at 20 weeks gestation or later, they are 

thought to be due to insults that occur early in pregnancy and relate to abnormal placental 

growth. A Poisson model was used with robust variance estimate to compare rates of 

hypertensive disorders between vaccinated and unvaccinated women. 

When conducting an observational cohort to study vaccination and preterm delivery, there is 

potential for bias as women who deliver early have less time during pregnancy when they can 

be vaccinated. This bias may be especially pronounced for a vaccine such as Tdap that is 

preferentially administered in the 3rd trimester. Strategies applied to reduce this bias included 

evaluating only vaccination occurring at 36 weeks or earlier for preterm deliveries, and use of a 

time-dependent exposure Cox model in the analyses. For the other two outcomes, 

chorioamnionitis and SGA births, all vaccinated women were compared to all unexposed 

women, and a Poisson model with a robust variance estimate was used. It is important to note 

that “unvaccinated” refers only to women who did not receive Tdap. Women in both groups 

could have received influenza vaccine. 

108 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

In terms of baseline characteristics, the safety cohort included 26,224 women who received 

Tdap during pregnancy and had a live birth delivery and 97,265 unvaccinated women. Most 

vaccination occurred in the 2nd and 3rd trimesters. Most women were between 25 through 34 

years of age. Prior to any adjustments, the cohorts were well-matched in terms of age 

distribution and race/ethnicity. There were some additional baseline characteristics. Of note, 

women who received Tdap during pregnancy were slightly more likely to have received 

adequate or adequate plus prenatal care index, and were much more likely to have received 

another vaccine during pregnancy. However, whether it was the same day as Tdap or a 

different day was not determined. Of note, 4% of vaccinated and more than 45% of 

unvaccinated women had received Tdap pre-pregnancy. 

With regard to the preliminary results, among more than 26,000 women who received Tdap 

during pregnancy, 6.1% developed chorioamnionitis. Among nearly 100,000 unvaccinated 

women, only 5.5% developed chorioamnionitis. This gave an adjusted rate ratio of 1.19, with a 

95% confidence interval of 1.13 to 1.27. In contrast, the rates for delivery before 37 weeks 

gestation were lower among women who received Tdap during pregnancy, with an adjusted 

hazard ratio of 0.88 (95% CI 0.83-0.93). There were no significant differences in rates of small 

for gestational age births between vaccinated and unvaccinated women. Rates were evaluated 

for hypertensive disorders between women who received Tdap before 20 weeks gestation and 

unvaccinated women, which found an adjusted rate ratio of 1.09 (0.99-1.20). In secondary 

analyses, women who were vaccinated between 27 through 36 weeks gestation were 

evaluated, which is similar to current Tdap recommendations. Again, a very small increased 

risk was found for chorioamnionitis, with an adjusted rate ratio of 1.11 (1.03-1.21). Also found 

were reduced risk for preterm delivery and no association between Tdap vaccination and SGA 

births. 

Chorioamnionitis is thought to be an acute process due to a polymicrobial infection of the 

amnionitic fluid, fetal membranes, placenta, and/or uterus. It is usually diagnosed during the 

course of labor, and occurs in up to 8% of full-term deliveries and 30% to 40% of preterm 

deliveries. Chorioamnionitis is an important outcome as it can result in adverse consequences 

for mothers and infants, most notably as a risk for preterm birth and cerebral palsy. There are 

many known risk factors for chorioamnionitis, including prolonged labor, use of internal 

monitoring, prolonged rupture of membranes, urogenital infections, multiple exams, previous 

diagnosis, substance abuse, and obesity. 

While most prior studies of vaccination during pregnancy have not evaluated chorioamnionitis 

as an outcome, it was included in a recently published study on inactivated influenza vaccine 

during pregnancy and risks for adverse obstetric events. This study found vaccination at 20 

weeks gestation or greater to be associated with adjusted hazard rate ratio of 1.08 (1.02-1.15). 

In this study, due to multiple comparisons, a threshold was set for significance of .005 a priori so 

the observed risk was considered non-significant [Kharbanda, Elyse; Olshen MD, MPH; 

Vazquez-Benitez, Gabriela; Lipkind, Heather; MD, MPH; Naleway, Allison; Lee, Grace; MD, 

MPH; Nordin, James; MD, MPH; Obstetrics & Gynecology. 122(3):659-667, September 2013. 

DOI: 10.1097/AOG.0b013e3182a1118a]. 

In summary, receipt of Tdap during pregnancy was not associated with increased risk for 

adverse birth outcomes. The chorioamnionitis findings merit further discussion and possibly 

further investigation. First, the slight elevated risk persisted despite adjustments. For example, 

maternal age and comorbidities were both included in the propensity score and thus should 

have been well-balanced between vaccinated and unvaccinated women. However, no data 

109 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

were available to evaluate and adjust for many other chorioamnionitis-specific risk factors, such 

as urogenital infections or prior occurrence of chorioamnionitis. It is also important to note that 

the magnitude of the risk detected is small. Although due to time limitations Dr. Kharbanda did 

not present the data by year, the risk reported was primarily due to differences between 

vaccinated and unvaccinated women in their rates of chorioamnionitis in a single year (2012). 

Finally, it should be noted that chorioamnionitis is a leading cause of preterm birth. It is 

reassuring that although a small increased risk has been observed for chorioamnionitis, no 

increased risk for preterm birth was observed. 

Discussion Points 

Dr. Duchin noted that during 2010-2011 and 2011-2012, a Bordatella tsunami was striking the 

West Coast. There were huge outbreaks occurring in California and moving North to Oregon 

and Washington. He wondered how that and the associated exhortations from public health 

officials about vaccination and the press about pertussis epidemic in the community may have 

impacted the data Dr. Kharbanda shared, and what might be observed in communities not in the 

midst of large scale epidemics. 

Dr. Kharbanda indicated that the data were pulled by site for all of the VSD sites. The numbers 

were pretty small, but increased Tdap coverage rates were observed outside of California, 

Oregon, and Washington. 

Dr. Schuchat wondered whether the data had been analyzed adjusted by first pregnancy. 

Thinking about the managed care population and that half of those who were non-vaccinated 

had previously received Tdap, she wondered whether those were often second pregnancies 

and the vaccinated were first pregnancies. 

Dr. Kharbanda replied that the way the data are received, each pregnancy is a unique data 

point, and women cannot be linked to prior pregnancies. It is unknown for each pregnancy 

whether it was the first pregnancy or they were pregnancy before. A request has been made for 

additional pregnancy files within the VSD files, but this information is not currently easily 

retrievable. 

Dr. Schuchat suggested that in the future, for pregnancy-related analyses, it may be worth 

obtaining input from obstetricians about key parameters. Some of the risk factors mentioned 

are difficult to get from a medical record, but some like number of pregnancies is on every labor 

and delivery file. 

Dr. Kharbanda responded that this information is in the EHR, but is not in the standard VSD 

files. However, work is being done to expand the VSD files in order to assess some of these 

other issues. 

Dr. Kempe inquired as to whether there was any information about pregnancies that did not 

result in live deliveries. She also requested further information about the rationale for the choice 

of safety outcomes, which seemed somewhat arbitrary to her. 

Dr. Kharbanda replied that the only data available on spontaneous abortions and stillbirths was 

coverage data. Only 1.2% of women who had a pregnancy ending in spontaneous abortion, 

stillbirth, and therapeutic abortion received Tdap during pregnancy. Those numbers are not 

expected to increase much, given that the current recommendation is to vaccinate late in 

pregnancy. There have not been that many exposures. Again, with the way the data structure 

110 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

works, it is much harder to time the pregnancy for these outcomes. Most of the gestational age 

data are based on clinician assessment at delivery, which is well-validated. Within the VSD 

files, it is difficult to know whether it was a stillbirth at 20 weeks, 30 weeks, et cetera, so it is 

difficult to know when the pregnancy started or whether the Tdap was really administered when 

the woman was pregnant. The investigators do not feel comfortable doing further analyses 

using the current data files. 

Ms. Hayes (ANA/ACNM) noted that while chorioamnionitis is a link for preterm birth, the data 

were not stratified by gestational age at birth or full-term and pre-term pregnancies with 

chorioamnionitis at birth. She wondered whether this had been or could be done, and why the 

investigators selected chorioamnionitis as an outcome since it seemed like such a bizarre 

outcome to assess for vaccines. 

Dr. Kharbanda responded that while this had not yet been done, it can be and is a good 

suggestion. In terms of the selection of chorioamnionitis, in picking outcomes the investigators 

tried to focus on input and outcomes in terms of womens’ and infants’ health. These outcomes 

were also studied previously with influenza vaccine, so the investigators felt comfortable that the 

diagnoses were in the data. There has been some validation work on the outcomes. An OB 

consultant from Yale University, Dr. Heather Lipkind, has been part of the study team. She 

raised the point as well that in maternal-fetal medicine, often chorioamnionitis is on the pathway 

to preterm delivery, but is not considered an outcome in itself. They were trying to assess the 

common diagnoses that occur in pregnant women, and this is a common diagnosis. 

Dr. Campos-Outcalt noted that as time goes on, there will be increase interest in repeat 

vaccination and repeat pregnancy, so consideration must be given to that design. It was 

unclear why .005 was selected. He thought with 20 variables, most people would go to .001 in 

which case the finding would have been significant. 

Dr. Kharbanda replied that a protocol has already been written for repeat vaccination and repeat 

pregnancy, and is being led by CDC investigators. Selection of .005 was for the other study on 

influenza vaccine safety during pregnancy, for which there was a cohort of nearly 80,000 

women who received TIV during pregnancy and 300,000 who did not. There were about 20 to 

25 different comparisons, so the investigators were really worried about error if a .05 cutoff was 

used. 

Dr. Sawyer (PIDS) requested clarification about the comment that the investigators felt that the 

risk of chorioamnionitis was largely attributable to rates in differences of chorioamnionitis in 

2012, and whether they meant in the VSD population. 

Dr. Kharbanda replied that this was within the VSD data files. She presented these data last fall 

during the VSD annual meeting, and that time they only had pregnancies from 2010 and 2011. 

No increased risk was detected at that time. The 2012 data were added in January, and when 

they looked by year, it was mostly due to differences in chorioamnionitis diagnosed in 2012. 

There was a bigger differential between vaccinated and unvaccinated women just in that year. 

Dr. Riley (ACOG) said that while she hated to beat on chorioamnionitis, it was probably the 

worst diagnosis in obstetrics ever because it is a clinical diagnosis. As a practicing obstetrician, 

she could attest that if a mom gets a fever, she will receive antibiotics and a diagnosis of 

chorioamnionitis and that is what will be on the medical record. This is tough, because 

depending upon how many people receive an epidural, there will be more diagnoses of 

chorioamnionitis because 15% of women who get an epidural are going to get a fever. This is 

111 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

probably the messiest diagnosis there is, and it is very hard to make any sense out of what it 

really means. It is one of those diagnoses where all information needs to be known, and then 

there are more risk factors such as anesthesia. Therefore, she was not sure what she would do 

with this information. 

Ms. Pellegrini said she assumed that the exclusion of women who received Tdap within 7 days 

of the end of pregnancy meant regardless of when pregnancy ended, and she wondered 

whether that would capture a case in which a woman received her Tdap at 29 weeks and then 

had a preterm birth 5 days later. Could that have potentially masked a serious signal? 

Dr. Kharbanda responded that only about 300 women were excluded because their vaccine was 

within 7 days of delivery. The reasons the exclusions were done is because once a woman is in 

the hospital, all of their vaccinations may show up on the VSD records on the day they were 

admitted to the hospital even if they were really administered post-partum. This is in order to 

make the data cleaner and that it really was a pregnancy vaccine and not a post-partum 

vaccine. Very few women are thought to have received their vaccine in that window. 

Dr. Harriman wondered whether there was any biological plausibility to suggest that 

chorioamnionitis could result from either influenza or Tdap vaccine, and she suggested 

assessing different outcomes. Also of importance were the low rates of Tdap administered 

during pregnancy that were shown with these data. A survey was conducted of California birth 

hospitals during the fall in which the hospitals were to ask every woman delivering on a single 

day whether they received Tdap during pregnancy. This was not validated, but about 25% 

stated that they received Tdap. To her, that was disappointing. Anecdotally it has been said 

that if Tdap is mentioned at all, women are told to get it at the drug store. While there may be 

the best intentions, there is not follow through. ACOG has done a lot of work to educate its 

providers about this, but Tdap is not being offered as often as it should be. Certainly, there are 

some women who will not accept it, but it at least has to be offered. 

The decreased rates of preterm delivery suggested to Dr. Bennett that there was some 

uncontrolled confounding. She wondered whether that might be related to the diagnosis of 

chorioamnionitis. 

Dr. Kharbanda replied that the investigators believe that the preterm delivery and the reduced 

risk are still just bias that they are unable to eliminate in this observation cohort. Women who 

delivered at 24, 25, 26 weeks were not recommended to receive Tdap vaccine based on current 

recommendations. They will all end up in the unvaccinated group. Similarly, as they get closer, 

they just have less time. An attempt was made to adjust for that, that bias cannot be fully 

adjusted for. A lot of work has been done on this with influenza vaccine, and they just keep 

seeing that when there is a vaccination that is supposed to be given toward the end of 

pregnancy, this bias occurs in observational studies. For influenza, this was not observed for 

first and second trimester vaccinations. 

Dr. Riley (ACOG) put in a plug for OBs, because she was hopeful that 2013 would look better. 

ACOG has put a lot of time and energy into increasing the rate. She has unpublished data from 

her own institution, which assesses February 2013 through June 2013—a short period of time. 

Their vaccination rate for Tdap was 81.6%. Obviously, that is an institution where there is a 

vaccine champion. However, practicing in a very big place, this shows that with persistence 

uptake can be increased. The interesting thing they found in their data is that even though they 

got 81.6% of women, there were low rates for African American women, which was very 

disappointing. There was a high correlation with those women who were willing to take 

112 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

influenza vaccination being the same women who were willing to take Tdap vaccination. She is 

very hopeful, because their numbers did not look that great in 2012 either. 

Dr. Temte noted that the increase in rates of vaccine coverage during pregnancy in the other 

sites from 2% to 16% was somewhat of a tsunami of providers. That is an 8-fold increase in a 

year, which is incredible. He was curious about comments from AAFP and ANA/ACNM about 

acceptance within their organizations. 

Dr. Loehr (AAFP) replied that the family physicians who practice obstetrics are also trying to 

push Tdap vaccine. 

Carol Hayes (ANA/ACNM) indicated that ACNM has a grant from ASTHO to increase 

vaccination rates among pregnancy women, and to improve the perception about vaccines 

among nurses. 

Dr. Orenstein (NVAC) pointed out that everyone keeps lumping Tdap vaccines together, but 

there are differences in formulations, antigens, and the quantity of antigens. He wondered if 

any analyses had been done with regard to whether there are any differences between the 

available Tdap preparations. He also emphasized that NVAC is taking this on as a major effort, 

which includes the desire to have an ACIP pregnancy issue so that it makes it easier for people 

to go to one place for all of the issues pertaining to pregnant women. He presumed this could 

be distributed to everybody when it goes out for comments in March, and NVAC is trying to 

finalize the recommendations during the June meeting to cover topics such as enhancing 

communications, maximizing obstetrics provider recommendations, improving financing for 

services, linking electronic records, and dealing with issues of that nature. This is not Tdaporiented. It is vaccines ACIP recommends for pregnant women. After this is finished, the 

Maternal Immunization Working Group will take on the issue of how to incentivize development 

of more vaccines that could be used for dealing with issues that affect pregnant women or 

young newborns. 

Dr. Kharbanda replied that while analyses on various formulations have not yet been done, they 

can be. 

Dr. Temte noted that for follow-up to NVAC, Dr. Pickering sent the draft Maternal Immunization 

Working Group report out to all of the ACIP members. Pages 20-22 deals with ACIP. 

Dr. Salisbury (UK DOH) said he had an overwhelming sense of déjà vu washing over him, 

because he believed during the June 2013 ACIP meeting he presented on exactly this topic with 

20,000 pregnant women collected through a database where all health details were available. A 

specific assessment was done of stillbirth rates and prematurity and nothing was found. 

Efficacy was also analyzed, and extraordinarily high efficacy was found in women who were 

vaccinated between 28 and 38 weeks of pregnancy. Many of the questions just raised were 

answered in that presentation 8 months ago, and the report is in the ACIP meeting minutes. 

113 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

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: 

 Continued review of the investigational 9-valent HPV vaccine, which is directed against 9 

HPV types, including 5 additional high risk types that are not in the quadrivalent vaccine 

 Completion of the review and approval of the updated, combined ACIP statement, which 

includes recommendations for currently licensed bivalent and quadrivalent vaccines and for 

females and males 

To review, during the October 2103 ACIP meeting HPV session, an update was presented on 

HPV vaccination coverage in the US; the review of 9-valent HPV vaccine was begun, with a 

presentation from Merck on the clinical development program; and the draft updated ACIP 

statement was reviewed and discussed. 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. 

In terms of the overall proposed timeline for consideration of the investigational 9-valent 

vaccine, clinical trial data are to be presented during this session. In June 2014, there will be a 

presentation of additional clinical trial data, along with health economic data. GRADE will be 

discussed in October 2014, and a vote is anticipated to occur in February 2015. 

With respect to the two presentations to be given during this session regarding type attribution, 

Dr. Bocchini pointed out that understanding HPV-associated disease attributable to HPV types 

is important to assessing the potential impact and cost-effectiveness of HPV vaccines. Of note, 

detecting HPV in a cancer tissue does not necessarily indicate a causal relationship. The 

International Agency for Research on Cancer (IARC) defined some cancers to have strong 

evidence for causal etiology. These HPV-associated cancers include cervical, vaginal, vulvar, 

anal, penile, and oropharyngeal cancers. Therefore, finding HPV in these tissues is a good 

indication of causality. However, determining types responsible for HPV-associated disease 

depends on a variety of factors, including quality of the specimen, the assay used to detect 

HPV, and the algorithm to assign type attributable if multiple types are discovered in the same 

preparation. This can vary by the population sampled. 

114 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

HPV Type Attribution in Cervical Precancers 

Susan Hariri, PhD 

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

Centers for Disease Control and Prevention 

During this session, Dr. Hariri presented data on HPV type attribution in high grade cervical 

lesions in the US. She began with a brief summary of the natural history of cervical HPV 

infection and associated outcomes; reviewed the published data on the distribution of HPV 

types in non-invasive high grade cervical lesions in women from different regions of the world; 

briefly reviewed the methods used to estimate individual HPV type attribution and the reasons 

for them; and presented data from the US on HPV type attribution to high grade cervical lesions. 

Infection with genital HPV is responsible for a spectrum of cervical abnormalities. The majority 

of these abnormalities are benign and do not progress to disease. In fact, approximately 90% of 

infections become undetectable within 2 years without causing any symptoms. However, 

infection with high-risk HPV types can persist, which could lead to mild cervical abnormalities 

that tend to regress without treatment or to high grade lesions that are more likely to progress to 

invasive cervical cancer if they are not treated. Routine cervical cancer screening with Pap and 

HPV-based tests is recommended to detect and treat pre-cancerous lesions as a secondary 

cervical cancer prevention strategy. 

The focus of this presentation was on non-invasive high grade cervical lesions, specifically 

cervical intraepithelial neoplasia grade 2 and higher and adenocarcinoma in situ (CIN2+). CIN2+ 

lesions are associated with high-risk or oncogenic HPV types that are the most likely to persist 

among all genital HPV infections. About 30% of CIN2+ lesions are estimated to progress to 

cervical cancer. HPV16 is the most frequent type detected in CIN2 and 3, which are squamous 

lesions. HPV 18 is the most common in AIS lesions, which are glandular. CIN2+ lesions were 

used as the main endpoints for HPV vaccine efficacy trials, and are also used as intermediate 

endpoints to monitor post-licensure vaccine impact in some countries that have established 

screening programs. 

Using data from a meta-analysis of international studies conducted to determine HPV type 

relative contribution in non-invasive high grade cervical lesions in women around the world, 

relative contribution of groups of oncogenic HPV types were presented for 2 groups: HPV16/18 

and HPV 31/33/45/52/58 that are the 5 additional types included in the candidate 9-valent 

vaccine. There was wide variation globally in the proportion of HPV16/18 detected in high 

grade cervical lesions, from greater than 60% of lesions in women in North America, Europe, 

and South or Central America to less than 50% in lesions from women in East Asia and Africa. 

There was less variability in the distribution of the additional 5 additional types, which were 

detected in about 40% of women across all regions except in East Asia where the prevalence 

was much higher at 60% [Guan et al. Int J Ca 2012]. 

The objective of this analysis was to estimate high-risk HPV type attribution to CIN2+ lesions 

among US women aged 21 through 39 years who were diagnosed from 2008 to 2011; and to 

examine whether HPV type attribution differed by age and race and ethnicity. Data came from 

the HPV-IMPACT project, a population-based sentinel surveillance system that was established 

in 2008 to monitor HPV vaccine impact on high grade cervical lesions and HPV types 

associated with them. This project is a CDC collaboration with 5 Emerging Infections Program 

(EIP) sites and includes equally sized catchments of approximately 300,000 adult females in 

each catchment in California, Connecticut, New York, Oregon, and Tennessee. At each site, 

115 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

histopathology laboratories serving the catchments are enumerated and asked to report 

histologically confirmed CIN2+ diagnoses in adult residents of catchment 18 years of age and 

older; and to submit archived diagnostic tissue from women who were diagnosed before age 40 

years of age for HPV DNA typing. 

Depending on the number of women reported and resources available, sites request all or a 

sample of specimens from age eligible women from each reporting lab. Labs are asked to 

select tissue that is most representative of the diagnostic lesion, and to cut and process the 

tissue which is formalin fixed and paraffin embedded using a standard protocol. Processed 

specimens are sent to CDC where they are reviewed by a pathologist to ensure adequate tissue 

is present for typing. If it is, DNA is extracted and tested for 37 individual HPV types with the 

Roche Linear Array Genotyping assay. Specimens that are negative on Linear Array or fail to 

amplify control are re-tested with the Inno-Lipa genotyping assay, which represents about 10% 

of the specimens overall. 

Between 2008 through 2011, there were adequate typing results for over 5000 specimens. 

Almost all, 97%, were positive for HPV with only a single HPV type detected in 79% of 

specimens. HPV 16/18, which are the types targeted by current HPV vaccines, were detected 

in slightly more than 50%. The additional 5 types (31, 33, 45, 52, and 58) that are included in 

the candidate 9-valent vaccine were detected in 31% overall. In terms of the typing results 

broken out by severity of lesion into CIN2 (lowest histologic grade) and CIN3/AIS (highest 

grade), there were about 900 specimens in which histologic grade was not discriminated. Dr. 

Hariri did not show these, but they do represent a combination of the 2 grades. AIS was 

combined with CIN due to small numbers since AIS represented less than 2% of reported 

cases. CIN2 accounted for a bigger fraction of the lesions overall compared to higher grade 

CIN3/AIS lesions. HPV 16/18 typed were more common in CIN3/AIS compared to CIN2, 66% 

vs. 40%, whereas, the 5 additional types were more common in CIN2 than in CIN3/AIS lesions. 

In terms of prevalence of individual HPV types by histologic grade, most notably HPV 16 was by 

far the most common of any high-risk type in all grades, but a big difference was observed in 

HPV16 prevalence by grade from 35% in CIN2 to 60% in CIN3/AIS. HPV 18 was relatively 

uncommon and accounted for about 4% to 5% of lesions. In the group of the 5 types in the 

candidate 9-valent vaccine, types 31 was the most common in all histologic grades, types 52 

and 58 were next, and both were more common in CIN2 lesions. HPV types 33 and 45 were 

detected in less than 5% in all grades. With regard to oncogenic HPV types that are not 

included in any vaccine, types 35 and 51 were most common. The rest were detected in 5% or 

less of specimens across all histologic grades. 

For the purpose of HPV type attribution to cervical lesions, generally, if only a single HPV type is 

detected in a CIN2+ lesion that type is considered to be causally associated with the lesion. 

However, more than 1 HPV type is detected in about 20% of lesions and the role of each type in 

co-infected lesions is less clear. So different methods are used to quantify the degree to which 

individual types or groups of types contribute to cervical lesions with multiple HPV types, and 

individual type attribution is used to evaluate the potential impact of HPV vaccines. In this 

analysis, two methods were used that are most commonly used to determine individual type 

attribution in lesions with multiple HPV types. The first method was hierarchical and attributed a 

co-infected lesion to the most oncogenic type. For example, in a CIN3 specimen with 16 and 

31, 100% was attributed to 16. This method tends to overestimate attribution of types 16 and 

18 because they are the most oncogenic types of all of the high risk types. The second method 

assigned weights to each type that were proportional to their frequencies as single infection in a 

given histologic grade, for example, the same specimen. Here, the proportion was calculated of 

116 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

CIN3 lesions in which each type is detected as a single infection (61% for HPV16 and 9% for 

HPV31) and each by sum was divided by the proportions of both types in lesion. A less than 

2% difference was found using the two methods, so the results Dr. Hariri presented were based 

on the proportional attribution method. 

Regarding the proportional type attribution for the 3 HPV type groups by histologic grade, 38% 

of CIN2 lesions were attributable to 16/18 types, and the percentage of 16/18 attribution 

increased with severity of lesion, up to 64% in CIN3/AIS. Of CIN2, 28% and slightly less (23%) 

of higher grades were attributable to the 5 additional types in the candidate 9-valent vaccines. 

Other high risk type attribution ranged from 21% in CIN2 to less than 10% in CIN3/AIS. 

HPV16/18 accounted for the highest proportion of lesions across age groups, although there 

was a decline in 16/18 attribution in the oldest age group and an increase in the additional 5 

types. Proportional attribution of other oncogenic types was similar across age groups. With 

regard to type by race and ethnicity, the highest proportion of CIN2+ lesions were attributable to 

HPV16/18 across all racial groups. However, HPV16/18 attribution was significantly higher in 

non-Hispanic whites compared to all other race and ethnicity groups. Conversely, the additional 

5 types were more common in racial/ethnic minorities compared to non-Hispanic whites. A 

significantly higher proportion of lesions were attributable to other oncogenic or high-risk HPV 

types among non-Hispanic blacks compared to other groups. Looking at the age distribution 

within each group, the median age was similar across the groups. Breaking out the attribution 

of individual high-risk types groups by the different race and ethnic groups, HPV16 

predominated across all race and ethnic category, although to a lesser extent in black and 

Hispanic women compared to whites. There were some race differences in attribution of 

HPV45, 52, and 58 in the candidate 9-valent vaccine. There were two high-risk types (35 and 

51) with at least 5% attribution in one or more histologic grade. 

In summary, these data from a large population-based sample of women in the US showed that 

50% of CIN2+ lesions were attributable to HPV16/18 overall, and the attribution ranged from 

40% in CIN2 to >60% in CIN3/AIS lesions. An additional 25% of CIN2+ lesions were 

attributable to the 5 additional types included in the candidate 9-valent vaccine. A higher 

proportion of lesions were due to HPV16/18 in women under age 35. This is consistent with 

evidence indicating that these 2 types are stronger carcinogens compared to other high risk 

types, and are more likely to progress faster to disease. The highest proportion of CIN2+ 

lesions was attributable to HPV16/18 across all racial and ethnic groups. However, a higher 

proportion was attributable to HPV16/18 in non-Hispanic whites compared to other racial/ethnic 

groups. The reasons for racial differences are not clear, but may be due to differences in the 

underlying prevalence of HPV types in the populations or to differences in screening and 

treatment of the lesions. 

HPV-Associated Caners and Type Attribution 

Mona Saraiya, MD, MPH 

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

Centers for Disease Control and Prevention 

Dr. Saraiya first reviewed data from the Annual Report to the Nation that was published last 

year showing the incidence rate of cervical, vaginal, and vulvar cancers from 2005 through 

2009. Based on these data, black and Hispanic women have the highest rates of cervical 

cancer, and black women also have the highest rate of vaginal cancer. In terms of the rates of 

oropharyngeal and anal cancers by race, black males and females have the second highest rate 

117 

This document has been archived for historical purposes. (3/1/2014)
 

-

-

-

-

- -

-

illi , 

 f il i i t t

/ i t / t ll 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

of oropharyngeal cancer. For anal cancer, black males have the highest rate [Jemal et al, J Natl 

Cancer Inst 2013]. 

International data of archived invasive cervical cancer specimens were collected from 

convenience samples around the world and typed by one lab to determine what percentage had 

HPV 16/18, and the additional types in the candidate 9-valent HPV vaccine. The important 

issue to highlight here is that the majority of cancers, whether they are in Africa Asia, Europe, et 

cetera, usually have HPV 16/18 attribution-usually in the range of 70%. An additional 17% to 

20% are attributed to the other 5 types. Another point to note is that very few cases have been 

analyzed from North America from this comparative study, which is why the CDC study was 

conducted. The same international group in Barcelona is conducting a similar study worldwide 

for all the other HPV cancers globally [Serrano et al, Infectious Agents and Cancer, 2012]. 

The results from a summary of the literature from various US studies conducted around 2006 

that examined tissues from these cancers attributed it to HPV are shown in the following table: 

Previous Estimated Percentages of HPV 

Attribution in the U.S. 

HPV HPV 16/18 

Cancer Attributable Attributable 

% (95% CI) % (95% CI) 

Cervical 96 (95 97) 76 (NA) 

Vaginal 64 (43 82) 56 (35-76) 

Vulvar 51 (37 65) 44 (30-58) 

Anal 93 (86 97) 87 (82-91) 

Penile 36 (26 47)* 31 (22 42) 

Oropharyngeal 63 (50 75) 60 (47-72) 

G son Cancer 2008 

% Any HPV is percen tage HPV detected in a ll cancers 

*% HPV or pen e cancer s % where any oncogen c HPV ype de ected 

% HPV 16 18 s percen age HPV 16 18 de ected among a cancers 

The first column summarizes the attribution of any HPV and the second column summarizes the 

HPV 16/18 attribution. This percentage is usually combined with the number of actual cancers 

from these sites to estimate the burden of HPV-associated cancers. It is important to note here 

that the HPV DNA prevalence/HPV positivity has been considered a proxy for HPV attribution 

but it doesn’t mean that HPV caused all of these cancers as noted by Dr. Bocchini [Gillison, 

Cancer 2008]. 

The objectives of the CDC analysis were to establish a systematic population-based approach 

to monitoring HPV types in cervical cancer and other HPV-associated cancers in the US; 

determine attribution of HPV 16/18 and additional types in candidate 9-valent vaccines; and 

determine HPV type attribution by race/ethnicity. For the study design, cancer registries were 

used to collect data, most of which were collected from 2004 through 2005 right before the HPV 

vaccines were licensed, to help establish a baseline. The registries have information about the 

cancer diagnoses, but in order to get the actual tissue specimens, four cancer registries went to 

pathology labs to get the most representative specimens, and three cancer registries used 

existing biorepositories. Most of the cancers that were collected were invasive cancers, but 

there were a few in situ cancers because the registries had legal authority to collect these data. 

The HPV genotyping was done by the CDC lab-as described by Dr. Hariri and the attribution 

method was the same. HPV cancers were grouped into the following categories: HPV 16/18, 

additional 5 types other HPV (which includes low risk), and HPV negative. The denominator 

included all cancers. 

118 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Four cancer registries (Michigan, Louisiana, 3 Florida counties, Kentucky) generated a list of all 

eligible cervical cancer/precancer cases, sampled randomly, and then requested the local 

hospital or pathology lab with the tissue specimen to prepare and send the tissue to the CDC 

HPV lab for genotyping analysis. Three cancer registries (Hawaii, Iowa, Los Angeles) had 

Residual Tissue Repositories which store their own tissue specimens, and here eligible cases 

were identified in-house and sent directly to the CDC HPV Lab. In all states, tissue specimens 

were prepared according to a common protocol. Complete genotyping results were then linked 

with demographic information collected by each cancer registry, and results were shared with 

each cancer registry. While 3017 tissue samples were submitted to the CDC HPV lab, due to 

specimen inadequacy and other issues the final sample size was 2670 cancers. 

Assessing the percentage of any HPV detection by cancer site, HPV DNA was detected in 91% 

of cervical cancers, 99% of in situ cervical cancers, 69% of vulvar cancers, 75% of vaginal 

cancers, 91% of anal cancers, 63% of penile cancers, and 70% of oropharyngeal cancers 

[Saraiya et al, presented at International Papillomavirus Conference 2012, Puerto Rico]. 

In terms of the top 5 cancer-causing types in these select cancers, the theme is that HPV 16 is 

the most common in all cancers. Regarding the attribution by the 4 HPV groups, for cervical 

cancer 66.2% had 16/18 detected compared to 14.7% for the additional 5 types. Anal cancer 

had the higher proportion of 16/18 detected. The cancer with highest attribution due to the 5 

types were in situ cervical cancer, vaginal cancer, and vulvar cancer. Regarding the general 

findings of a number of analyses that were conducted for this study, by age there was definitely 

a higher proportion of cancers in younger age groups attributable to HPV 16/18. By 

race/ethnicity, there were no differences for cancers except for in situ cervical cancers and 

oropharyngeal cancers. By gender, there were no differences for cancers except oropharyngeal 

cancers. With respect to the racial differences for in situ versus invasive cervical cancer, there 

was a lower proportion of in situ cancers that had HPV 16/18 detected among Black and 

Hispanic populations. But it should be noted that for in situ cervical cancers, the numbers are 

quite small. In contrast, when the invasive cancers were examined when there was a good 

sample size for each racial group, the proportion of HPV negative cancers were lower among 

blacks and Hispanics than Whites. More importantly, there were no significant differences in the 

proportion of 16/18: White Non-Hispanic 67%, Black Non-Hispanic 68%, and Hispanic 64% 

[Saraiya et al, presented at AACR Health Disparities in Cancer, 2013]. 

This raises the question, “How can cervical cancers be negative?” The classic study by 

Wallboomers/Bosch et al found that 99.7% of cervical cancers were HPV positive. However, it 

is important to keep in mind that that study was based on multiple HPV assays and cancers that 

met select criteria. The Saraiya et al study is based on a population-based surveillance study. 

There may be misclassification of the actual anatomic site in that lower segment uterine cancers 

are not distinguishable from upper segment cervical cancers. There may be false negatives in 

that there may be HPV that could not be detected with the current assays or the 

specimen/tissue is not well-preserved. There may be true HPV negative cervical cancers, albeit 

these are rare histologies and represent perhaps 1% to 2% at the most of all cervical cancers. 

For anal cancer, there were few differences by race/ethnicity. About 80% of anal cancers were 

attributed to types 16/18. There were also no difference by gender, with 79% of HPV 16/18 

among males compared to 80% of HPV 16/18 among females. Although it appeared that 

females had a higher percentage of additional HPV types in the candidate 9-valent vaccine, this 

difference was not significant. Regarding oropharyngeal cancer and HPV attribution by 

race/ethnicity and gender, a higher proportion (50%) of HPV negative cancers was observed 

among blacks compared to 25% among whites and 27% among Hispanics. A lower proportion 

was observed of 16/18 cancers overall among blacks, even though the cancers were limited to 

119 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

HPV positive cancers. By gender, there was also a higher proportion of HPV negative cancers 

among females, and a lower proportion of HPV 16/18 cancers as well. 

Using the data from this particular study to revise the estimated percentages of cancers 

attributed to HPV in the US, it can definitely be said with more authority using population-based 

and consistent assays that the prevalence of HPV positivity would be slightly revised. For 

example, for cervical cancer 91% were attributable to HPV, 66% were attributable to 16/18, and 

15% were attributable to the additional 5 types in the candidate 9-valent vaccine. Also 

important to note for oropharyngeal cases for males is that 72% were HPV-attributable, which is 

much higher than the previous estimates; 63% had 16/18; and 4% had the additional 5 types in 

the candidate 9-valent vaccine. 

In summary, 62% of invasive cancers were attributable to HPV 16/18. This was a range from 

48% of penile cancers to 79% of anal cancers. Among females, approximately 62% of cancers 

were attributable to HPV 16/18 compared to 63% for males. This translates overall to 

approximately 25,500 cases annually. Of the invasive cancers, 11% were attributable to the 5 

additional types in the candidate 9-valent vaccine. Based on the cancer type, this is a range 

from 6% for oropharyngeal cases to a high of 18% for vaginal cancers. There was also a 

difference by gender, with 14% of female cancers being attributable to the additional 5 types in 

the candidate 9-valent vaccine compared to 5% of male cancers. Overall, this translates to 

4000 cases annually. In terms of racial ethnic differences, HPV 16/18 attribution did not differ 

for invasive cancers except oropharyngeal cancers. A lower percentage of oropharyngeal 

cancers was attributable to HPV positive (or HPV 16/18) among blacks. These data will be 

useful in estimating the impact of candidate 9-valent vaccine on cancers and for cost-effective 

analyses. 

Discussion Points 

Given that the cases assessed spanned a time range from before and after HPV vaccine use, 

as well as what is known about fairly low coverage and latency, Dr. Reingold wondered whether 

the amount attributable to 16/18 may be underestimated. 

Dr. Hariri responded that this is possible. An attempt is made to collect HPV vaccination history 

on all of the cases reported to the HPV-IMPACT project, but sometimes vaccination history 

cannot be found for everybody. However, vaccination history was collected on about 50% of 

the cases. Among those, a fairly sizeable proportion of 18 through 20 year old females with 

CIN2+ were vaccinated. Fewer 21 through 29 year olds were vaccinated. However, excluding 

cases with known receipt of at least 1 dose from the analyses did not significantly change the 

results. It is possible that there is some impact, but because there is no vaccination history for 

50% of the cases, it is very difficult to tease that apart. 

Dr. Karron requested a reminder about cross protection against non-16/18 serotypes from the 

vaccines in terms of which serotypes there may be protection against, and whether the vaccines 

differ in their ability to do that. 

Dr. Hariri replied that some cross protection has been shown for both vaccines, mostly in types 

31, 33, and 45. Cross protection has been somewhat stronger for the bivalent vaccine, 

although it is really difficult to compare the two vaccines head-to-head. Though some cross 

protection has been demonstrated, the duration of protection is unknown. 

120 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Regarding Dr. Hariri’s slides 11 and 17, Carol Hayes (ANA/ACMN) said that when she looked at 

the data, there appeared to be two strains of HPV that seemed to be higher than those used in 

the new 9-valent vaccine. She was confused by that. For those on the right, 51 and 35 were 

higher than 33 and 45. It was unclear why 35 and 51 were not included in the vaccine and why 

were 33 and 45 included. 

Dr. Hariri pointed out that the prevalence was very low compared to type 16 across the board 

for all of the types. While it was correct that 35 and 51 were more common, that was mostly in 

the CIN2 lesions which are a lower histologic grade and are probably not the true precancers. 

The prevalence is significant lower in the CIN3 and AIS lesions that are most likely to progress 

to invasive cancer. She said she could not really speak to the decision about which types were 

included in the vaccine. 

Dr. Markowitz clarified that these were precancers, and most decisions were made based on 

the types in the cancers. Many of these, even if they are oncogenic types, are less likely to 

progress to cancers than 16/18. 

Barbara Kuter (Merck) indicated that the decision Merck made in terms of what additional types 

would go into the vaccine was based on their global data that assessed the prevalence of all of 

these types around the world. The decision was based primarily on the oncogenic cancer 

types, which is why 31, 33, 45, 52, and 58 are in the current vaccine. There is some difference 

in the epidemiology between the US data shown during this session and the global rates. 

Dr. Bennett said she was very interested in the racial differences shown in Dr. Hariri’s data, and 

requested a reminder regarding what was shown in the carriage data from National Health and 

Nutrition Examination Survey (NHANES) and whether there were racial differences in those 

data as well. 

Dr. Hariri responded that HPV prevalence is being monitored in the US population in the 

NHANES. HPV type prevalence in NHANES over time has been assessed, and it is true that 

there are racial differences. However, there is a higher prevalence of all types in non-Hispanic 

blacks compared to non-Hispanic whites. Though a closer assessment of the data is underway, 

there does not seem to be a differential increase or decrease in the prevalence of the oncogenic 

types. 

Dr. Bennett inquired as to whether there were any thoughts about why that pattern would be 

found in the early lesions and not in the invasive cancers or NHANES data either for 16/18 

differences. 

Dr. Hariri replied that 16/18 have more oncogenic potential than the other oncogenic types. As 

shown in Dr. Saraiya’s presentation, no differences are seen by race in terms of the invasive 

lesions. It is not clear what to attribute the racial differences to, but it could have something to 

do with the prevalence combined with the differential oncogenic potential of the types. Again, 

that needs further investigation. 

121 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

9-Valent HPV Vaccine Clinical Trial Data 

Alain Luxembourg, MD, PhD

Director, Clinical Research 

Merck & Company, Inc. 

Dr. Luxembourg reminded everyone that a presentation regarding program design was given to 

ACIP during the October 2013 meeting. During this session, he discussed some of the key data 

from the clinical program for the 9-valent vaccine. He explained that 9vHPV vaccine is the 

investigational 9-valent HPV vaccine, while qHPV vaccine is the licensed quadrivalent vaccine 

Gardasil®. 

In terms of the relative contribution of HPV types worldwide, the existing qHPV vaccine covers 

types 16/18, which cause approximately 70% of cervical cancers worldwide. By adding the 5 

next most frequent HPV types in cervical cancers, there is a potential to reach approximately 

90% cervical cancer prevention. To answer the question that was asked following the previous 

presentation, the selection of the 5 additional HPV types was based on the frequency in cancer 

worldwide—not in precancer or dysplasia. The 5 high-risk HPV types that were not included in 

the vaccine represent 5% to 6% of cervical cancer cases worldwide. Looking at precancers 

worldwide, there is also a potential for additional coverage with the additional HPV types. With 

CIN2/3 lesions, there is a potential to increase protection from 50% with the existing vaccine to 

80% with the 9vHPV vaccine, which would exceed the best cervical cancer screening programs. 

This is an exciting possibility. The contribution of the additional HPV types in cancer is slightly 

lower than in precancer, which most likely reflects a generally faster progression to cancer with 

HPV types 16/18 than with HPV types 31/33/45/52/58. Overall, the potential benefit with the 

9vHPV vaccine is not only a substantial increase in prevention of cervical cancer worldwide, but 

also for the prevention of precancerous cervical lesions. This means that in countries with 

cervical cancer screening programs there will be a lower need for invasive procedures, because 

precancers are treated by surgery, and lower costs, better quality of life, and lower risks. A wide 

range of benefits could be estimated from the 9vHPV vaccine. 

The qHPV vaccine is a virus-like particle (VLP)-based vaccine that contains L1 VLPs for HPV 

types 6, 11, 16, and 18. Types 6 and 11 are responsible for 90% of genital warts, and are 

generally responsible for benign lesions. Types 16 and 18 are responsible for most cervical 

cancers. The 9vHPV vaccine contains these same 4 types plus the 5 additional high-risk HPV 

types (31, 33, 45, 52, and 58). The aluminum-based adjuvant is the same in both vaccines, but 

the amount of adjuvant has been increased in the 9vHPV vaccine to keep the adjuvant to 

antigen ratio the same as in the qHPV vaccine. The amount of antigen for the original types has 

also been increased to preserve immunogenicity compared with the qHPV vaccine. Thus, the 

dose selection process was data-driven. 

The aim is to transition from the clinical program was designed to support full transition from the 

qHPV vaccine to the 9vHPV vaccine. One goal of the program is to show that for the original 4 

types, the two vaccines perform the same. A second goal is to demonstrate that the new 

vaccine is highly protective against infection and disease due to the additional types. A third 

goal pertains to adolescent populations. HPV vaccine efficacy cannot be assessed in 

adolescents because they are not frequently exposed to HPV. Therefore, similar to what was 

done in the qHPV vaccine program, the efficacy findings in young women exposed to HPV will 

be extended to adolescents based on similar immunogenicity. So the program is designed to 

demonstrate non-inferior immunogenicity in adolescents versus young women (e.g., 

immunobridging). A fourth goal is to demonstrate is that the safety profile for the 9vHPV 

122 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

vaccine is acceptable. If these 4 goals can be demonstrated, it will show value for the new 

vaccine. 

Six Phase 3 studies have been conducted and were included in the initial filing. Three pivotal 

studies support the key indications. Protocol 001 is the only efficacy study. It was conducted in 

young women ages 16 through 26, and has been completed. A long-term extension of this 

study is ongoing to assess long-term effectiveness and long-term immunogenicity. There were 

two immunobridging studies in adolescents. Protocol 002 provided adult-to-adolescent 

immunobridging. This study is completed and an extension is ongoing to assess long-term 

effectiveness and immunogenicity up to 10 years post-dose 3. The purpose of protocol 009 was 

to assess whether the qHPV and 9vHPV vaccines induce the same immunogenicity in 

adolescents. Three additional studies were included in the initial filing, and the data regarding 

these studies will be presented during the next ACIP meeting. Two of these were concomitant 

use studies to assess vaccines commonly used in adolescents, co-administered with the 9vHPV 

vaccine. Protocol 005 assessed Menactra® (meningococcal vaccine) and Adacel® (Tdap 

vaccine). two vaccines commonly used in the Americas, and Protocol 007 assessed Repevax® 

(Tdap-IPV vaccine), a vaccine commonly used in the European Union. These two studies have 

been completed. Protocol 006 was a study conducted to assess the 9vHPV vaccine in prior 

qHPV vaccine recipients. Recognizing that millions of individuals have been vaccinated with 

qHPV vaccine, and that even if among them a small fraction is interested in a fuller vaccination 

with 9-valent, Merck feels obliged to provide data to help providers and individuals make those 

choices. Though no indication was sought in this case, Merck believes this will be an important 

study to discuss. The initial filing was in boys 9 through 15 years of age and girls and young 

women 9 through 26 years of age. Protocol 003, the young men study, is ongoing. It started a 

little later than the other phase 3 studies and the results will be available later in 2014. 

These are not the only studies ongoing for the 9vHPV vaccine, but for the sake of time, 

everything could not be presented. Of potential interest to ACIP, Merck recently started an 

evaluation of a 2-dose regimen for the 9-valent vaccine. A full transition from the qHPV to the 

9vHPV vaccine is expected to be very rapid in the US, so the focus for the 2-dose study is on 

the 9vHPV vaccine. An initial immunogenicity study was begun to evaluate the question of 

feasibility and value. Merck recognizes that long-term effectiveness information will be needed 

as well. 

During this session, Dr. Luxembourg discussed study results data for the following studies: 

 Evaluation in young women (16 through 26 years of age) 

 Protocol 001 (pivotal efficacy study) 

 Efficacy and immunogenicity 

 Safety 

 Evaluation in adolescents (girls/boys, 9 through 15 years of age) 

 Protocol 002 (adult-adolescent immunobridging) 

 Immunogenicity 

 Safety 

 Protocol 009 (qHPV-9vHPV immunobridging) 

 Immunogenicity 

 Safety 

123 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Protocol 001 is a large international study comprised of more than 14,000 young women ages 

16 through 26. It is a double-blinded study in which young women were randomized to 9vHPV 

or qHPV vaccine. Placebo was not used for ethical reasons: the qHPV vaccine is widely 

recommended and widely available, and it would not be acceptable to let study participants 

develop precancers that can be prevented by the licensed qHPV vaccine. The study was 

started in 2007 one year after qHPV vaccine was licensed as a 3-dose regimen vaccine. Since 

the goal was to bridge from qHPV to the 9vHPV vaccine, both vaccines were administered as a 

3-dose regimen. A key goal of the study is to assess 9vHPV vaccine efficacy. Women are 

followed by genital gynecological examinations. Every 6 months, genital swabs are used to 

assess for the presence of HPV and a Pap test is done. For any subject with an abnormal Pap 

test, there is a protocol-mandated triage to assess for disease endpoints. Immunogenicity is 

also assessed Day 1 and Month 7 for antibody titers for all 9 vaccine HPV types. Safety is also 

assessed through standard methods. 

This large efficacy trial has been underway for almost 6 years. Subjects have had follow-up for 

up to 4 years post-vaccination. The intensive screening (every 6 months) ensures that no 

lesions are missed, so the data package is very high quality. Again, there is no placebo control. 

The control is the licensed qHPV vaccine, which is highly efficacious. For this reason, no 

disease endpoints are expected for the original types in the qHPV vaccine group. If the 9-valent 

vaccine is successful, very few to no disease endpoints are expected for the original types in the 

9vHPV vaccine group as well. This means a head-to-head comparison based on efficacy 

endpoints is not feasible, because there will be too few disease endpoints to conduct a 

statistical comparison. Given that, the primary demonstration of efficacy for the original types is 

based on the demonstration of non-inferior immunogenicity. The goal is to bridge the efficacy 

findings with the qHPV vaccine to the 9vHPV vaccine based on non-inferior immunogenicity. 

For the additional types, a difference is expected between the two vaccines in terms of these 

endpoints. As mentioned, there is some cross-reactivity and some cross-protection, though this 

is still insufficient to cover all of the types. So the qHPV vaccine cohort will be assimilated to an 

unvaccinated cohort for the additional types. If anything, this would mean an underestimation of 

the true efficacy of 9vHPV vaccine. 

Two different primary objectives are being followed for the original and additional types. The 

primary analysis population for efficacy is the susceptible population, consisting of women who 

are seronegative for the relevant HPV type at Day 1 and PCR negative for the relevant HPV 

type on all swabs/biopsies from Day 1 through Month 7. This definition is similar to the one 

used previously in the qHPV vaccine clinical program. In addition subjects in the primary 

analysis population received all 3 vaccinations within 1 year, and had no protocol violations. 

The primary analysis population for immunogenicity has a similar definition. 

Compliance was very good. Most subjects received 3 doses and most of them stayed in the 

study. There was no difference between the two vaccine cohorts. Over 96% of subjects 

continued in the efficacy evaluation phase. Month 7 antibody titers were measured by the 9­

valent HPV competitive Luminex Immunoassay (HPV-9 cLIA), which is based on the same 

principle as the HPV-4 cLIA, the immunoassay which was used previously in the qHPV vaccine 

program. Non-inferiority was demonstrated for all 4 types with GMT ratios with a p value 

<0.001. Seroconversion rates were also comparable between the two vaccine groups. Based 

on these results efficacy with respect to HPV types 6, 11, 16, and 18 is inferred. 

124 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

To evaluate efficacy with respect to the additional types, composite endpoints were assessed 

for disease or infection caused by any of the 5 additional types. The key endpoints were (1) 

high-grade cervical, vulvar, and vaginal disease due to any of the additional types,(2) cervical, 

vulvar, and vaginal disease of any grade due to any of the additional types, and (3) 6-month 

persistent infection due to any of the additional types. What is remarkable is that the efficacy is 

very high at greater than 96%, and is very consistent across all endpoints. This demonstrates 

that the vaccine is highly efficacious in reducing the risk of disease and infection due to the 

additional types. In addition, these very high numbers are reminiscent of the numbers for 

efficacy found in the qHPV vaccine program where the efficacies were in the high 90s. Now 

there are two vaccines based on the same technology, VLP, that in two different clinical 

programs were shown to be highly efficacious. 

Looking at cervical and vulvar disease separately, the study results show that 9vHPV vaccine is 

highly efficacious for high-grade cervical, cervical disease of any grade, high-grade vulvar and 

vaginal disease, and vulvar and vaginal disease of any grade. There was one case of high 

grade cervical disease in the 9-valent group. This case was co-infected with a non-vaccine 

high-risk HPV type, type 56. Most likely, type 56 is the causal virus because this subject was 

infected by Type 56 from Day 1 and through at least the first two years of the study; whereas, 

type 58 was found only at the time biopsy was done. Type 58 was mostly likely a transient 

infection. In terms of invasive procedures related to the additional types, the risk of biopsies 

and definitive therapies was substantially decreased. This suggests that not only does the 

vaccine have the potential to prevent a lot of disease types, but also the potential to prevent a 

lot of procedures. 

Regarding safety for Protocol 001, Dr. Luxembourg showed a summary of the vaccine-related 

experiences comparing two vaccines. Essentially the profiles were similar, with very few 

vaccine-related SAEs on days 1 through 15 following vaccination. There were no vaccinerelated deaths and very few discontinuations. The only difference was a higher frequency of 

injection site SAEs among 9vHPV recipients. This was not a surprise, given that there are more 

adjuvant and more antigen in the 9vHPV vaccine than in the 4vHPV vaccine. Looking more 

closely at the injection-site adverse experiences from Days 1 through 5 following each dose of 

vaccination in the safety set, it is clear that there was a difference for all three types of injection 

site adverse events (erythema, pain, swelling) and that the difference was statistically 

significant. Due to the very high numbers of subjects, the difference can be demonstrated. 

From a clinical standpoint, most injection site adverse events were of mild or moderate intensity 

in both vaccine groups. Thus, it is anticipated that the clinical significance of this difference will 

be minimal. 

Looking at systemic vaccine-related adverse events with an incidence of more than 2%, there 

were only 5 types of events (headache, pyrexia, nausea, dizziness, fatigue) within a study of 

14,000 subjects. All of these events are everyday life events that are commonly used in vaccine 

studies. There was no substantial difference between the two vaccines. Four serious vaccinerelated adverse events were observed, 2 in the 9-valent group and 2 in the qHPV vaccine 

group. None of these required hospitalization except for one day for the event of headache in 

the qHPV vaccine group. The adverse event terms were seen previously in the 4-valent clinical 

program, and all events were promptly resolved. 

In conclusion of Protocol 001, non-inferior immune responses were demonstrated for the 

original types. An approximately 97% reduction in disease was demonstrated for the additional 

types. Regarding safety, the 9vHPV vaccine was generally well-tolerated in more than 7,000 

young women. The adverse experiences profile was generally comparable between 9vHPV 

125 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

vaccine and qHPV vaccine. A higher frequency was noted of injection-site adverse events with 

9vHPV vaccine, but most were of mild or moderate intensity. 

Turning to Protocol 002, the international adult-adolescent immunobridging study, the 

immunogenicity goal was to demonstrate non-inferior immunogenicity of 9vHPV vaccine in 

adolescents 9 through 15 years of age versus young women 16 through 26 years of age. The 

safety goal was to evaluate the safety and tolerability of the 9vHPV vaccine in adolescent boys 

and girls and young women. The study population was comprised of 1800 girls, 600 boys, and 

400 young women. This was an open-label study in which subjects received a 3-dose regimen 

of 9-valent vaccine. Immunogencity was assessed at Day 1 and Month 7, while safety was 

assessed at Day 1 through Month 12. 

In terms of GMTs in girls versus young women, non-inferiority was met in that the GMTs were 

higher in girls compared to young women. This is reminiscent of what was seen in the 4-valent 

program where a similar comparison was made for the 4 original types, and the GMT ratio was 

about 2. Once again, there was similarity between the two vaccines. Regarding 

seroconversion rates, most subjects became seropositive for 9 types after a 3-dose regimen 

both in the girls and young women cohorts. Like the comparison between the girls and the 

young women, the boys had a higher immunogenicity and GMT ratios of approximately 2 and 

close to 3 for some types. There was clearly superior immunogenicity in this group as well. 

Seroconverstion rates were very good in male subjects, all of whom converted to all 9 types. 

With regard to safety during Days 1 to 15 following any vaccination, the safety profile was 

similar between the three demographic groups. Safety may even look slightly more favorable 

for the boys, which is similar to what was observed in the 4-valent vaccine clinical program. 

In conclusion for Protocol 002, non-inferior immunogenicity was demonstrated in adolescents 

compared to adults. This supports bridging of efficacy findings in young women to the 

adolescent population. Immunogenicity was comparable in boys versus girls. In terms of 

safety, 9-valent vaccine was generally well-tolerated in all 3 demographic groups. 

Moving to Protocol 009 (qHPV-to-9vHPV immunobridging), the immunogenicity objective was to 

compare anti-HPV 6, 11, 16 and 18 GMTs in adolescent girls who received qHPV vaccine 

compared to adolescent girls who received 9vHPV vaccine. The safety objective was to 

evaluate the safety and tolerability of the qHPV and 9vHPV vaccines in adolescent girls. 

Protocol 009 was a double-blinded study in which subjects receives 9vHPV or qHPV vaccine. 

The study was comprised of 600 girls who were equally randomized to 9vHPV vaccine or qHPV 

vaccine. The key endpoints included immunogenicity at Day 1 and Month 7, and safety for Day 

1 through Month 7. Compliance was very good. Most subjects who completed the study 

received the 3-dose regimen. Non-inferiority of GMTs was demonstrated. The immunogenicity 

was comparable between the two vaccines for the two oncogenic Types 16 and 18. This 

mirrors the data in young women, and adds confidence that the two vaccines have the same 

profile. There was similar immunogenicity for Types 6 and 11, the non-oncogenic genital wart 

causing types. Of the subjects, 100% seroconverted after a 3-dose regimen in both vaccine 

groups, which shows that the vaccine was highly immunogenic. 

In conclusion for Protocol 009, for the immunogenicity endpoint, anti-HPV 6/11/16/18 GMTs 

were comparable in adolescent girls who received 9vHPV vaccine compared to adolescent girls 

who received qHPV vaccine. This supports the bridging of efficacy findings with qHPV vaccine 

to 9vHPV vaccine. The safety profile was comparable between 9vHPV vaccine and qHPV 

vaccine, with most injection-site reactions being of mild or moderate intensity with both 

vaccines. 

126 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

With respect to the overall conclusions, the 9-valent clinical development program is believed to 

be successful. All efficacy and immunogenicity objectives were met for the key pivotal studies. 

Non-inferior immunogenicity was demonstrated for anti-HPV 6, 11, 16, 18 responses compared 

to qHPV vaccine. Approximately 97% protection was demonstrated against disease caused by 

the additional types (HPV 31, 33, 45, 52, 58). Non-inferior immunogenicity was demonstrated in 

adolescents versus adults. The 9-valent vaccine is generally well-tolerated. There were over 

10,000 subjects in protocols 001, 002, 009. The adverse event profile was generally similar to 

that of qHPV vaccine. Additional information to be presented during future ACIP meetings 

includes data on concomitant use; prior qHPV vaccine recipients; and young men 16 through 26 

years of age. Presently, the 9-valent vaccine is still an investigational product even though the 

studies have completed. The product is currently under standard FDA review, and regulatory 

action is expected within the next few months. 

Discussion Points 

In terms of adverse events, Dr. Jenkins noted that for the 4-valent vaccine recipients 

experienced syncope following vaccination. She did not hear that mentioned in terms of these 

studies. 

Dr. Luxembourg replied that Merck monitored all systemic adverse events, but he showed only 

the most frequent events. Syncope and syncope with fall was monitored, and there was no 

event of syncope with fall during the study. Precautions were also taken to observe subjects 

during the study, and there were no events like that. There was one event of syncope prior to 

vaccination. 

Dr. Riley (ACOG) inquired as to what this looked like in HIV-positive women. 

Dr. Luxembourg responded that HIV-positive women have not been studied. All of the studies 

were conducted in healthy subjects, as is common in vaccine studies. An academic study was 

conducted in HIV-positive children 7 through 12 years of age for the 4-valent vaccine. Given 

that the immunogenicity profiles of the two vaccines are very similar and consistent, the same 

safety and immunogenicity profile would be expected in that population as when 4-valent was 

administered to that subgroup. 

Dr. Temte asked whether there were any differences in side-effects between the first, second, 

and third doses in terms of the profile. 

Dr. Luxembourg indicated that there were differences. The main difference was in terms of 

frequency of injection site swelling and injection site erythema. The frequency increases by 

dose, and it is similar to what has been observed previously with the 4-valent vaccine. 

Dr. Pickering asked whether there were any data on women who may have received 3 doses of 

HPV 4-valent with regard to injection site reactions in these women if they received HPV 9­

valent. 

Dr. Luxembourg responded that Merck has conducted one study, Protocol 006, with one of the 

primary goals being to assess 3 + 3. The safety profile was found to be acceptable, and there 

was no major increase in terms of injection site adverse experiences. 

127 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dr. Neuzil (IDSA) noted that there was a press release earlier in the day that reported that 

Gardasil® received a favorable opinion from the EMA for a 2-dose schedule. She wondered 

what Merck’s clinical development plans were for the 9-valent 2-dose schedule. 

Dr. Luxembourg indicted that Merck is interested in and recognizes the importance of this topic. 

A 2-dose study has been initiated for the 9-valent vaccine. Merck first wants to demonstrate the 

feasibility, value, and immunobridging of the 9-valent vaccine. Merck also recognizes that 

follow-up is important with regard to long-term effectiveness and duration of protection conferred 

by 2 doses versus 3 doses. It is a somewhat premature to discuss more about the plans at this 

stage, but an immunogenicity study has been started. 

Dr. Sawyer (PIDS) inquired as to how long Merck’s long-term follow-up of the quadrivalent 2­

dose series has been and, therefore, what could be expected for the 9-valent. 

Dr. Luxembourg responded that Merck has long-term follow-up for a 3-dose regimen for the 4­

valent vaccine. At this time, there is no evaluation of long-term effectiveness for a 2-dose 

regimen. 

Summary and Next Steps 

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 began with a brief summary of some of the data presented during this session 

about HPV type attribution. Of the CIN2+ lesions, about 50% are attributable to HPV16/18 and 

about 25% are attributable to 5 additional types in investigational 9-valent vaccine. The largest 

percentage of lesions in all racial/ethnic groups is attributable to HPV16/18. A larger 

percentage of lesions is attributable to HPV16/18 among non-Hispanic white compared with 

non-Hispanic black and Hispanic women. For HPV-associated cancers, approximately 62% 

(range, 48% penile - 79% anal) are attributable to HPV16/18, and 11% (range, 8% anal - 18% 

vaginal) are attributable to the 5 additional types. The largest percentage of HPV-associated 

cancers in all racial/ethnic groups is attributable to HPV16/18. No differences have been 

observed by race for cervical, vaginal, vulvar, penile or anal cancers. A smaller percentage of 

oropharyngeal cancers are attributable to HPV among non-Hispanic blacks. Among HPV 

positive oropharyngeal cancers, a smaller percentage is attributable to HPV16/18. The Pivotal 

efficacy study among females aged 16 through 26 years of age found non-inferior HPV 

6/11/16/18 immunogenicity versus HPV4, and approximately 97% protection against HPV 

31/33/45/52/58-related disease. The immunobridging studies in adolescents demonstrated noninferior immunogenicity in adolescents versus adults. 

As a reminder about the HPV WG timeline, further trial data will be presented to ACIP during the 

June 2014 meeting, specifically data from concomitant administration and 9-valent vaccine 

among prior HPV4 recipients. There are also plans to discuss health economics at that time. In 

October 2014, GRADE results will be presented and recommendation options will be discussed. 

If data are available from the ongoing immunogenicity trial in males 15 through 26 years, those 

data will also be reviewed during the October ACIP meeting. If 9-valent vaccine is licensed, a 

vote can be anticipated on the recommendations during the February 2015 ACIP meeting. 

128 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

A variety of issues will be considered by the HPV vaccine WG with regard to 9-valent vaccine 

including the following: 

 Routine vaccination of females and males at age 11 through 12 years of age 

 Vaccination of older females and males who were not vaccinated at the recommended age; 

the timing for consideration of males age 16 through 26 years will be discussed by the work 

group, because it is anticipated that the vaccine will not be licensed in this age group at the 

time of first licensure 

 Vaccination of persons fully or partially vaccinated with HPV4 

While the ACIP HPV vaccine WG is focusing on review of data relevant to the investigational 9­

valent vaccine, other issues are being considered. As always, there is ongoing review of postlicensure safety and coverage data. The WG is also keeping abreast of data on reduced dose 

schedules for HPV vaccination and plans for a future review of these data. With regard to the 

issues related to a reduced number of doses or simplified schedules, there is global interest in 

simplified schedules for HPV vaccine. This would reduce logistical challenges for delivery and 

decrease resources and costs. There are available data on 2-dose schedules for the bivalent 

and the quadrivalent vaccines. These are primarily immunogenicity studies, but there are posthoc evaluation of data from the efficacy trial for the bivalent vaccine, and post-licensure 

effectiveness data for the quadivalent vaccine. Some jurisdictions are using 2-dose schedules 

in their national or provincial immunization programs around the world. The EMEA granted 

marketing authorization for Cervarix®, the bivalent vaccine produced by GSK, as a 2-dose 

schedule given at 0 and 6 months for girls aged 9 through 14 years in December 2013. Merck 

has submitted an application to the EMEA for a 2-dose schedule as well. The 9-valent vaccine 

is currently in immunogenicity trials. The HPV Work Group will be keeping abreast of these 

data, and can report back to ACIP. 

Updated ACIP Statement for Bivalent & Quadrivalent Vaccines 

Lauri Markowitz, MD 

HPV Vaccine Working Group 

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

Centers for Disease Control and Prevention 

Regarding the updated HPV vaccine ACIP statement, Dr. Markowitz reminded everyone that 

the first recommendation was in 2006 and the most recent for routine vaccination of males in 

late 2011. Because of the evolving recommendations, after the original 2007 ACIP statement, 

short Policy Notes were published with updated recommendations. The 2011 Policy Note was 

published for the recommendation for routine vaccination of males. This last recommendation 

was the only one in which GRADE was used, as this was after GRADE adoption by ACIP. To 

review, the following are published ACIP recommendations for HPV vaccines: 

 2007 ACIP Statement [MMWR Recomm Rep 2007;56:1-24] 

 Recommendation for routine vaccination of females at age 11 or 12 years with 

quadrivalent HPV vaccine 

 2010 Policy Note [MMWR 2010;59:626-9] 

 Recommendation for routine vaccination of females with bivalent or quadrivalent 

HPV vaccine 

129 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

 2010 Policy Note [MMWR 2010;59:630-2] 

 Quadrivalent HPV vaccine may be given to males 9 through 26 years 

 2011 Policy Note [MMWR 2011;60:1705-8] 

 Recommendation for routine vaccination of males at age 11 or 12 years with 

quadrivalent HPV vaccine 

 This was the only recommendation for which GRADE was used, because GRADE 

had just been adopted by ACIP before that time 

The objectives of the updated HPV vaccine statement are to consolidate recommendations for 

females and males; consolidate information and recommendations for bivalent and quadrivalent 

vaccines; harmonize wording that differ in policy notes and the statement; and update 

background information and data regarding efficacy, safety, immunogenicity, impact monitoring, 

et cetera. This overlaps with consideration of the 9-valent vaccine, but the work group believes 

that the updated ACIP statement will facilitate efforts for development of future policy. All 

members have reviewed the statement. 

The new statement has many of the same sections as the 2007 document. These include: 

 Background on biology, immunology, epidemiology, and natural history 

 Clinical sequelae 

 Cancers 

 Anogenital warts 

 Recurrent respiratory papillomatosis (RRP) 

 Prevention, treatment, and cervical cancer screening 

 Prevention of sexual transmission of HPV, non-vaccine 

 Cervical cancer screening 

 Treatment of HPV related disease 

 Selected health care and research laboratory workers (non-vaccine prevention 

measures) 

The updated ACIP statement sections include the following: 

 Vaccines 

 Clinical trial data for quadrivalent and bivalent vaccines 

 Post licensure safety data 

 Economic burden of HPV disease and cost-effectiveness 

 HPV vaccination program in the US 

 Summary of rationale for HPV vaccination recommendations 

 Recommendations 

 Routine 

 Administration: intervals, concomitant administration, interchangeability 

 Special populations 

 Precautions and contraindications 

130 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

In the first updated draft statement discussed during the October 2013 ACIP meeting, the 

recommendation section was divided into recommendations for females and males. In the 

current version, the female and male recommendations are combined as follows: 

 ACIP recommends routine vaccination at age 11 or 12 years with HPV4 or HPV2 for 

females and with HPV4 for males (male GRADE recommendation category: A, evidence 

type: 2). The vaccination series can be started beginning at age 9 years. 

 HPV4 and HPV2 are each administered in a 3-dose schedule. The second dose should be 

administered 1-2 months after the first dose; the third dose 6 months after the first dose. 

 Vaccination also is recommended for females aged 13 through 26 years and for males aged 

13 through 21 years who have not been previously vaccinated or who have not completed 

the 3-dose series. Males aged 22 through 26 years may be vaccinated. 

There are also recommendations for special populations and precautions and contraindications, 

which are as follows: 

Special Populations 

 Persons with abnormal Pap, genital warts, et cetera 

 Immunocompromised persons 

 Men who have sex with men (MSM) 

 Lactating women 

 Children with history of sexual abuse or assault (new in this statement; discussed several 

times with ACIP) 

Precautions and Contraindications 

 Hypersensitivity or allergy 

 Acute illness 

 Preventing syncope 

 Pregnancy 

The language in the updated HPV vaccine ACIP statement for special populations is as follows: 

Immunocompromised Persons 

“ACIP recommends routine vaccination at 11 or 12 years with HPV2 or HPV4 for females and 

with HPV4 for males. Vaccination is recommended through age 26 years for 

immunocompromised persons who have not been vaccinated previously or who have not 

completed the 3-dose series.” 

Men who have Sex with Men (MSM) 

“For MSM, ACIP recommends routine vaccination with HPV4, as for all males, and vaccination 

through age 26 years for those who have not been vaccinated previously or who have not 

completed the 3-dose series.”
 

History of Sexual Abuse or Assault 

“While HPV vaccination will not promote viral clearance or protect against disease progression 

due to types already acquired, vaccination would protect against vaccine-preventable types not 

yet acquired. ACIP recommends HPV vaccination beginning at age 9 years for children and 

youth with any history of sexual abuse or assault who have not initiated or completed the 3-dose 

131 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

series. Adults through age 26 years who are victims of sexual abuse or assault should receive 

HPV vaccine if they have not already been vaccinated.” 

Hypersensitivity or Allergy to Vaccine Components 

“HPV vaccines are contraindicated for persons with a history of immediate hypersensitivity to 

any vaccine component. HPV4 is produced in Saccharomyces cerevisiae (baker’s yeast) and is 

contraindicated for persons with a history of immediate hypersensitivity to yeast. Prefilled 

syringes of HPV2 have latex in the rubber stopper and should not be used in persons with 

anaphylactic latex allergy. HPV2 single dose vials contain no latex 

The language in the updated HPV vaccine ACIP statement for precautions and 

contraindications is as follows: 

Pregnancy 

“HPV vaccines are not recommended for use in pregnant women. The vaccines have not been 

causally associated with adverse outcomes of pregnancy or adverse events in the developing 

fetus. However, if a women is found to be pregnant after initiating the vaccination series, the 

remainder of the 3-dose series should be delayed until completion of pregnancy . . .” 

Finally, there are sections on monitoring impact of vaccination and areas for ongoing research 

and future priority activities. A variety of issues are very briefly mentioned here, including the 

investigational 9-valent vaccine and reduced dose schedules. 

A variety of helpful comments were received from ACIP members and other reviewers. These 

included requests for edits and clarifications and requests for additional data on post-licensure 

safety evaluations. In the recommendation section, suggestions were received for rewording of 

the sexual abuse section, as well as other minor wording changes. 

The following table is included in the document. It reviews post-licensure safety evaluation in 

the US and other countries. This was in the last version ACIP members reviewed, but text was 

added to mention briefly each of these studies, which have all shown reassuring safety profiles: 

132 

23

Table 8. Observational, population-based, post-licensure quadrivalent HPV (HPV4) vaccine 

safety studies among females aged 9–26 years — USA and other countries

System or review and

Country

Doses

evaluated Description Methods Findings

Vaccine Safety Datalink

(VSD)a

USA

600,559 Large data base used for active

surveillance and research. Safety

assessment of 7 pre‐specified

health outcomes among HPV4

female recipients.

Cohort design with

weekly sequential

analyses of electronic

medical data

No statistically significant

increase in risk for the outcomes

monitored.

Post‐marketing

commitment (to US FDA)b

USA

346,972 General study assessment of

HPV4 following routine

administration at two large

managed care organizations.  

Self‐controlled risk

interval design

supplemented with

medical record review

HPV4 associated with syncope

on the day of vaccination and

skin infections in the two weeks

after vaccination.§ No other

vaccine safety signals were

detected.

Post‐marketing

commitment (to US FDA)c

USA

346,972 Assessment of 16 pre‐specified

autoimmune conditions

following routine use of HPV4 at

two large managed care

organizations.

Retrospective cohort

using electronic medical

data, supplemented with

medical record review

No confirmed safety signals for

monitored conditions.

Register based cohort

studyd

Denmark and Sweden

696,240 Assessment of 23 different

autoimmune, 5 neurologic

conditions and VTE following

HPV4 among females aged 10‐17

years.

Retrospective cohort

using national patient

registers

No consistent evidence of causal

associations between HPV4 and

the events monitored.

Pharmacoepidiemiologic

General Research

Extensione

France

Assessment of 6 different

autoimmune outcomes among

211 cases and 875 controls aged

14‐26 years.

Case control study with

recruitment of cases and

controls through

registries

No increased risk of combined

endpoint of 6 autoimmune

disorders.

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

In summary, the draft statement updates background information and clinical trial data; 

consolidates and clarifies existing recommendations; and includes a variety of new sections, 

including a substantial amount of post-licensure safety data. This still has to finish going 

through editorial clearance, so there are likely to be a number of additional changes. The hope 

is that it will be published in the spring. The WG realizes that substantial new data will become 

available, and understands that recommendations will be updated in the future as more data 

become available. 

Discussion Points 

Dr. Temte reminded everyone that it is the goal of ACIP to renew, revise, or retire statements 

about every 5 years, so this is very timely considering everything that has occurred. The ACIP 

members received and reviewed this document, and submitted comments on it previously. He 

asked Dr. Markowitz whether there were any comments from the WG regarding the next steps. 

He said he was reflecting on the discussion the previous day about how difficult it is to consider 

making a change for a well-established, very successful vaccine program in terms of trying to 

reduce doses. 

Dr. Markowitz replied that the WG has been closely following the discussions for the 

pneumococcal vaccine. Currently, the WG does not have plans to bring anything forward to the 

ACIP. The group is keeping abreast of the data, reviewing what is occurring, and is aware that 

there is a lot of interest in this area. More information will be available from ongoing studies, 

and while the work group is happy to present the data, they are considering a motion or 

consideration by ACIP at this time. 

Dr. Tan (IAC) thanked ACIP for consolidating the recommendations. As everyone knows, 

having consolidated guidance will be very useful to providers to strongly recommend this 

vaccine. He called attention to a letter and press release provided to ACIP members essentially 

urging providers to not just give a recommendation for HPV vaccination, but to make the 

recommendation very strong. The tag line for this “Dear Colleague” letter essentially is “What 

you say matters, but how you say it matters even more.” Dr. Tan said it had been a delight to 

collaborate with AAP, AAFP, ACOG, ACP, and CDC to create this “Dear Colleague” letter, 

which was launched two days after the President’s Cancer Panel and it is fortunate to be able to 

collaborate with the President’s Cancer Panel to market this letter with their report. This letter 

has been very favorably received by the media. Any questions can be directed to Dr. Tan. 

Dr. Jean Smith (ACIP Medical Officer) noted that in the last two days they had heard mention of 

two anniversaries, the 50-year anniversary of ACIP and the 20-year anniversary of the 

implementation of VFC. She informed the audience that this also marked the 10-year 

anniversary of Dr. Markowitz serving as the WG lead. She has worked with several ACIP 

members serving as WG chair. Dr. Smith said she could personally say that she was 

astonished at Dr. Markowitz’s fortitude as problems and issues are thrown out repeatedly. She 

always marches forward with absolute calm. 

133 

This document has been archived for historical purposes. (3/1/2014)
 

0 Abstained: N/A

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Vote: Updated HPV ACIP Statement 

Dr. Coyne-Beasley made a motion to accept the recommendations as proposed. Dr. Rubin 

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 

0 Opposed: N/A 

Smallpox Vaccine 

Lee Harrison, MD 

ACIP, Work Group Chair 

Dr. Harrison noted that numerous occurences of laboratory-acquired orthopoxviruses infections 

have been reported. Smallpox vaccine provides cross-protection against all orthopoxviruses 

(e.g., smallpox, monkeypox, vaccinia, and cowpox). Smallpox vaccine is used to protect clinical 

and research laboratory workers against these viruses. Dr. Harrison shared several images of 

ocular, ear, and needlestick vaccinia virus transmissions in laboratory workers. 

In terms of background, ACIP recommendations for smallpox vaccination of laboratory workers 

have not been updated since 2003. A new smallpox vaccine, ACAM2000, was licensed in 2007 

and has replaced the previously used smallpox vaccine, Dryvax. The Smallpox Vaccine Work 

group was established in March 2013, and monthly meetings have been held since that time. 

The work group’s terms of reference are as follows: 

1. Review recommendations for smallpox vaccination for lab workers in 2001 statement (and 

supplements from 2003): 

a. Review Biosafety in Microbiological and Biomedical Laboratories (BMBL) 

requirements for work with orthopoxviruses 

b. Review orthopoxvirus laboratory exposure cases and reports 

2. Review data on smallpox vaccine: 

a. ACAM2000 

•	 Safety and immunogenicity data 

•	 Adverse event rates with current stringent prescreening program 

b. Dryvax: Publications on 2002 through 2004 pre-event smallpox vaccination program 

3. Review human safety and animal model efficacy data for attenuated smallpox vaccine 

IMVAMUNE stored in Strategic National Stockpile and potential role in smallpox vaccination 

for lab workers (unlicensed product and therefore informational) 

134 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

4. Review data on recombinant vaccinia viruses in development or under investigation in 

clinical trials to provide guidance on need for smallpox vaccination in healthcare and/or 

laboratory personnel working with these viruses 

5. Revise existing statement and supplements for smallpox vaccination of laboratory workers 

into single ACIP Policy Note document 

Use of ACAM2000 Smallpox Vaccine in Laboratory Personnel 

Brett W. Petersen, MD, MPH 

CDC Lead, Smallpox Work Group 

Medical Officer, Poxvirus and Rabies Branch, CDC 

Lieutenant Commander, U.S. Public Health Service 

Dr. Petersen indicated that the goal of his presentation was to provide a general overview of 

some of the topics and issues that the Smallpox Work Group has discussed to date, as well as 

some of the data that the WG has reviewed and assessed. The hope is that this information will 

serve as a foundation for revising and updating the smallpox vaccine recommendations for 

laboratory workers. 

With regard to background, orthopoxviruses are a group of large double-stranded DNA viruses 

within the family Poxviridae. There are four known species that infect humans: Variola 

(Smallpox), Vaccinia (Smallpox Vaccine), Monkeypox, and Cowpox. Orthopoxvirus virus 

infection provides cross protection across species. It is this property that has allowed the 

development of vaccinia as a vaccine for smallpox and other orthopoxviruses and has ultimately 

resulted in eradication of smallpox as a human disease. However, orthopoxviruses remain an 

active subject of research. 

In particular, vaccinia virus is commonly used in laboratory research. There are many historic 

vaccine seed stocks and derivatives including the following: New York City Board of Health 

(NYCBH), Lister, Modified Vaccinia Ankara (MVA), Western Reserve, LC16M8, Copenhagen, 

among others. Different vaccinia viruses demonstrated varying degrees of attenuation and 

safety profiles. Recombinant vaccinia viruses are being used increasingly in the laboratory 

setting as a viral vector for expression of foreign genes using gene therapy or genetic 

engineering, and are also under investigation as potential recombinant vaccines and as 

oncolytic or immunotherapy for cancer. 

Given the risks to laboratory workers using these viruses, ACIP produced recommendations for 

vaccinia vaccine in 2001. ACIP recommended vacinia vaccine for laboratory workers who 

directly handle cultures or animals contaminated or infected with non-highly attenuated vaccinia 

virus, recombinant vaccinia viruses derived from non-highly attenuated vaccinia strains, or other 

orthopoxviruses that infect humans (e.g., monkeypox, cowpox, vaccinia, and variola). 

Vaccination can be offered to healthcare workers with direct contact with dressings or other 

infectious material from volunteers in clinical studies where non-highly attenuated vaccinia 

viruses or recombinant viruses derived from these strains are used. Persons working with 

vaccinia virus, recombinant vaccinia viruses, or other non-variola Orthopoxviruses should be 

revaccinated at least every 10 years. Revaccination every 3 years can be considered for 

persons working with more virulent non-variola Orthopoxviruses (e.g., monkeypox). 

135 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Laboratory and healthcare personnel working with highly attenuated poxvirus strains do not 

require routine vaccinia vaccination. Highly attenuated poxvirus strains include the following: 

 MVA: Derived from vaccinia virus Ankara 

 NYVAC: Derived from vaccinia virus Copenhagen 

 TROVAC: Derived from fowlpox virus 

 ALVAC: Derived from canarypox virus 

The population at risk is difficult to estimate, given that there is no registry of persons who work 

with orthopoxviruses. Indirect measures that offer some sense of the size of this population 

include the following: 

 A simple PubMed search revealed that 431 orthopoxvirus-related publications were 

released in 2013 

 A search of the NIH Research Portfolio Online Reporting Tools revealed that there are 185 

active projects listed relating to vaccinia virus work (http://projectreporter.nih.gov/) 

 Clinicaltrials.gov lists 25 open clinical trials involving vaccinia virus 

 As of 2013, 31 different sites received 80 shipments of smallpox vaccine from the CDC 

stockpile in 2013 and over the last 5 years, 96 different sites received 523 shipments 

The risk of orthopoxviral disease is difficult to estimate as well, given that surveillance is not 

ideal and the true burden of disease is not known. Vaccinia and cowpox infections are not 

reportable conditions, so there is not a comprehensive list of all potential infections. Similarly, 

orthopoxvirus exposures are not always reported. In addition, the pathogenicity and virulence of 

the virus may not be well-characterized, particularly with regard to recombinant viruses. 

However, CDC has maintained a database of laboratory-related orthopoxvirus exposures and 

infections that have been reported since 2004. Of the 26 exposure incidents reported, 18 (69%) 

involved recombinant viruses and 14 (54%) resulted in infections. Of those 14, 12 (86%) 

involved recombinant viruses, 12 (86%) involved vaccinia infections, 2 (14%) involved cowpox 

infections, 4 (29%) required hospitalization, and 4 (29%) involved infection with a strain other 

than that with which they were working (or thought they were working). Of the 26 exposure 

incidents reported, 7 (27%) met ACIP vaccination recommendations, and 1 of those 7 (14%) 

resulted in infection. One other infection occurred in an individual vaccinated over 10 years 

prior, which did not meet the ACIP vaccine recommendations [Adapted from MacNeil A, 

Reynolds MG, Damon IK. Risks associated with vaccinia virus in the laboratory. Virology. 2009 

Mar 1;385(1):1-4 and CDC records]. 

ACAM2000 is currently the only smallpox vaccine licensed and available in the US. It was 

licensed in 2007 and replaced the previously used smallpox vaccine, Dryvax, which is no longer 

available. ACAM2000 has been used in laboratory and healthcare workers and select DoD 

personnel. It is a live vaccinia virus vaccine that is produced in vero cells. It is derived from a 

clonal isolate of Dryvax, a New York City Board of Health strain used during the smallpox 

eradication campaign. ACAM2000 is administered in a single dose percutaneously via multiple 

puncture with a bifurcated needle. Following vaccine administration, a lesion develops at the 

site of vaccination. During this time, the lesion does contain infectious virus that can be 

transmitted to others via inadvertent inoculation or to other sites of the body via auto-inoculation. 

However, this cutaneous response is also referred to as a “take” and is considered a marker of 

successful vaccination. 

136 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Historically, smallpox vaccines have been associated with a number of adverse events, some of 

which can be severe and life-threatening. Some of those include eczema vaccinatum, 

progressive vaccinia, and postvaccinial encephalitis. Based on data from primary vaccination 

with Dryvax from a study conducted in 1968 during the time of routine immunization with 

smallpox vaccine, the rates ranged from 1.5 cases/million vaccinations to 38.5 cases/million 

vaccinations. Overall rates for deaths were also reported as approximately 1 death/million 

vaccinations. The rates for revaccination were much lower than those for primary vaccination 

[Adapted from Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 

1968: results of ten statewide surveys, J Infect Dis. 1970 Oct;122(4):303-9 and ACAM2000 

package insert]. 

Based on data from a more recent study evaluating the adverse event rates observed during the 

DoD and HHS vaccination programs during 2002 and 2005, of note was the absence of any 

observed eczema vaccinatum or progressive vaccinia cases. This was likely due to the intense 

screening of persons for risk factors for these adverse events. Also of note was the incidence of 

myo/pericarditis, which had not previously been recognized as a significant adverse event 

related to smallpox vaccine [Adapted from Poland GA, Grabenstein JD, Neff JM. The US 

smallpox vaccination program: a review of a large modern era smallpox vaccination 

implementation program. Vaccine 2005, Mar 18;23(17-18):2078-81 and ACAM2000 package 

insert]. 

Using this background, the GRADE method was used to assess the ACAM2000 in laboratory 

workers utilizing the following steps: 

 Development of a policy question 

 Identification and assessment of the importance of outcomes 

 Review of the literature 

 Summarization of the evidence for critical outcomes 

 Evaluation of the quality of evidence for outcomes 

The policy question formulated by the WG was, “Should administration of ACAM2000 be 

recommended routinely to persons at risk for orthopoxviral disease?” The population of interest 

was persons at risk for exposure to orthopoxviruses. The intervention was vaccination with 

ACAM2000, the currently available vaccine, and the comparison was vaccination with the 

previously recommended vaccine, Dryvax. A modified Delphi method was used to solicit 

outcomes assessments from the work group members. The outcomes identified included 

benefits and harms. Among the benefits were vaccine efficacy to prevent orthopoxviral disease, 

cutaneous response or take, and neutralizing antibody response. Among the harms were 

serious adverse events, myo/pericarditis resolved with sequelae, myo/pericarditis resolved 

without sequelae, inadvertent inoculation, and mild adverse events. Outcomes deemed to be 

critical were vaccine efficacy to prevent orthopoxviral disease, serious adverse events, and 

myo/pericarditis resolved with sequelae. All of the outcomes were included in the evidence 

profile, though data were not available for vaccine efficacy to prevent orthopoxviral disease. 

Therefore, cutaneous response and neutralizing antibody response were used as surrogates for 

this benefit outcome. 

A systematic literature review was performed to identify studies that met the criteria and 

addressed the outcomes identified by the work group. A total of 5 RCTs were identified that 

addressed the benefits outcomes, 4 of which also addressed the harms outcomes. Cutaneous 

response was best assessed in two studies evaluating this outcome in vaccinia-naïve and 

previously vaccinated subjects who were vaccinated with both ACAM2000 and the comparator 

137 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Dryvax. Of vaccinia-naïve subjects receiving ACAM2000, 96% demonstrated vaccination 

success. ACAM2000 was found to be non-inferior to the comparator, Dryvax, among this 

population. Of the previously vaccinated subjects receiving ACAM2000, 84% demonstrated 

vaccination success by cutaneous response as compared to 98% of Dryvax subjects. A 

statistical analysis revealed that ACAM2000 did not meet the predefined criteria for noninferiority to Dryvax among this population. In terms of the neutralizing antibody response, 

these same studies evaluated the response in both vaccine-naïve and previously vaccinated 

subjects. Among vaccinia-naïve subjects, the geometric mean neutralizing antibody titer and 

the Log10 mean were comparable to the comparator, Dryvax, although by the slightest of 

margins ACAM2000 did not meet the criteria for non-inferiority to the comparator vaccine. In 

contrast, among the previously vaccinated subjects, the neutralizing antibody titers were again 

similar and in this instance did meet the criteria for non-inferiority. 

Regarding the critical harms outcomes, no serious adverse events were reported in the RCTs 

reviewed (e.g., death, eczema vaccinatum, progressive vaccinia, or postvaccinial encephalitis). 

There were 7 cases of suspected myo/pericarditis reported among the 2983 clinical trial 

participants who received ACAM2000. The best estimate of risk based on detection of 5 cases 

among 873 vacinees during Phase 3 clinical trials incorporating active monitoring for 

myocarditis and pericarditis is 5.7 cases/1000 vaccinees. One case among those reporting 

myo/pericarditis demonstrated sequelae (e.g., persistent abnormal echocardiogram at one 

year). 

Using the GRADE methodology to assess the evidence, the WG had no concerns for risk of 

bias or inconsistency for any of the outcomes. However, there were concerns about 

indirectness in the cutaneous response, neutralizing antibody, and myo/pericarditis resolved 

without sequelea outcomes. With respect to imprecision, there were concerns regarding the 

serious adverse events and inadvertent inoculation outcomes. Given these concerns, the 

evidence type was downgraded for those outcomes. In terms of indirectness, there was 

concern that the outcomes that were assessed in the RCTs may have differed from those of 

primary interest. With regard to the benefits outcomes, the cutaneous response and 

neutralizing antibody response were surrogates for the outcome of primary interest (i.e., vaccine 

efficacy to prevent orthopoxviral disease). With regard to harms outcomes, the true clinical 

significance of myo/pericarditis that resolved without sequelae is unclear. Many of these cases 

represented asymptomatic disease that were only detected due to the intensive cardiac 

monitoring that was performed during these trials. These included monitoring of EKGs as well 

as cardiac enzymes. Some of the suspected cases were only transient EKG changes or 

elevations of cardiac enzymes that had no symptoms whatsoever. Thus, myo/pericarditis that 

resolved with sequelae was felt to better represent the outcome of primary interest. Regarding 

imprecision, the work group found that the clinical trials were not adequately powered to detect 

serious adverse events (e.g., death, eczema vaccinatum, progressive vaccinia, or postvaccinial 

encephalitis), and was also not powered to detect inadvertent inoculation. Calculations of the 

probability that these adverse events would not be observed based on the number of 

participants in the clinical trials, as well as the sample size that would be needed to detect these 

events certainly support the assessment of imprecision in these cases. Based on this GRADE 

assessment, the overall level of evidence was determined to be 2. Although the studies 

evaluated were all RCTs, they did have important limitations. 

Regarding next steps, the work group will begin updating and revising the recommendations 

using the date reviewed and discussed to date. The hope is to present these recommendations 

to ACIP during a future meeting, and ultimately to publish these recommendations in at least an 

ACIP Policy Note. 

138 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Discussion Points 

With respect to nomenclature, Dr. Temte inquired as to whether this should be referred to as an 

orthopoxvirus vaccine as opposed to smallpox vaccine. 

Regarding the serious sequelae shown on Slide 24, Dr. Kempe noted that the comparator was 

not given for Dryvax and she wondered what those were. 

Dr. Petersen replied that the rate of myo/pericarditis in the ACAM2000 group was lower, with 7 

cases reported among the ACAM2000 group (5.73 events per thousand vaccinations) and 3 

cases among the Dryvax group (10.38 events per thousand vaccinations). 

Dr. Campos-Outcalt noted that this was a pretty high rate of myo/pericarditis at about 1/180. He 

was interested in knowing the rate of autoinoculation and other complications among laboratory 

workers who have exposures, given that the harms and benefits must be weighed of offering it 

to someone. He would like to see a comparison the rate of 1/180 to the rates of autoinoculation 

and other complications from vaccinia exposure in the lab. 

Dr. Petersen responded that this could certainly be investigated to see if the rate of 

autoinoculation among laboratory workers with lab-acquired infections can be determined. 

It remained unclear to Dr. Kempe why the GRADE comparison was not being done against 

nothing versus Dryvax. 

Dr. Petersen replied that the previous vaccine was Dryvax, so that was how the WG 

approached the GRADE assessment. There are no RCTs and there are very little data with 

which to evaluate the question of a comparison with nothing. Since smallpox vaccine was the 

first vaccine invented and in some sense has been grandfathered in, there have not been any 

robust studies to evaluate its actual efficacy against orthopoxviruses. 

Dr. Harriman in the 2003 pre-event Dryvax vaccination program, people who got 

myo/pericarditis were older and often male. She wondered whether there was indication that 

certain types of people would be more likely to get myo/pericarditis in the ACAM2000 group. 

Dr. Petersen indicated that it was correct that persons who experienced myo/pericarditis in 

recent vaccination campaigns were older. However, overall the population being vaccinated 

was older as well. In analyses of myo/pericarditis, no significant risk factors have been 

identified among the population that might predict who would be at higher risk of suffering this 

adverse event. 

Dr. Decker (Sanofi Pasteur) offered some insight on most of the question posed thus far by 

reporting briefly on one of the post-marketing trials that Sanofi Pasteur is conducting as the 

licensed holder for ACAM2000 vaccine. When it was licensed as a national imperative at the 

time, ACAM2000 was licensed in recognition of the data Dr. Petersen described and in 

association with a family of coordinated post-marketing commitment trials designed to further 

assess the safety of the vaccine—all but one of which are still underway. One study has been 

completed and the report is in preparation. All of the studies are being conducted within the 

DoD, which is where people are receiving this vaccine. Study 004 is being conducted among 

troops who receive ACAM2000 while being processed to deploy oversees. There are study 

sites at 6 major military bases in the US that solicit participation of deploying troops into the 

139 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

study. To date, approximately 130,000 deploying troops have been solicited and about 15,000 

have agreed to participate. Of those, approximately 12,000 received ACAM2000 and remainder 

did not receive it either because they did not need another smallpox vaccination or because 

they had some type of contraindication such as a close contact who is pregnant. This study 

population obviously differs from the study population of laboratorians in that these are generally 

more fit people, and they receive their vaccinations in a highly structured or organized DoD 

program that has a rigorous list of contraindications. That list of contraindications is, in and of 

itself, a list issues that put one at higher risk if receiving the vaccination. For example, anyone 

with more than four signal cardiac risks or cardio-respiratory conditions is not offered 

vaccination. CDC also operates off of a similar list in giving guidance to who is vaccinated 

through the civilian program. The study is still underway; therefore, Dr. Decker did not have the 

detailed results. However, from the administrative management of the study, he was able to 

say that approximately 3/1000 vacinees develop signs or symptoms suggesting possible 

myo/pericarditis that warrants their referral to an independent expert committee that adjudicates 

based on the complete and available medical data, regardless of whether they have definite, 

probable, possible, or no myo/pericarditis. Based on that, about 30 so far out of approximately 

10,500 have been adjudicated as possible, probable, or definite myo/pericarditis. That is 

typically based on elevated troponin or abnormal EKG. Virtually none of these people have 

been symptomatic. There is also an attempt to follow the long-term clinical course, and almost 

no one solicited has been willing to participate in the study, which perhaps suggests that they do 

not feel any personal benefit of the study because they do not feel that they have any personal 

medical problems. However, that is just conjecture. 

Day 2: Public Comment 

No public comments were offered during this session. 

140 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Certification 

Upon reviewing the foregoing version of the February 26-27, 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. 

141 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 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 

142 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 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 

143 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 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 

RUBIN, Lorry, MD 

Director 

Pediatric Infectious Diseases 

Steven and Alexandra Cohen Children’s Medical Center of New York 

North Shore-Long Island Jewish Health System 

New Hyde Park, NY 

Professor of Pediatrics, Hofstra-North Shore LIJ School of Medicine 

Hempstead, NY 

Term: 07/01/2012 – 06/30/2016 

VÁZQUEZ, Marietta, MD 

Associate Professor of Pediatrics 

Department of Pediatrics 

Yale University School of Medicine 

New Haven, CT 

Term: 07/01/2011-06/30/2015 

EX OFFICIO MEMBERS 

Centers for Medicare and Medicaid Services (CMS) 

HANCE, Mary Beth 

Senior Policy Advisor 

Division of Quality, Evaluations and Health Outcomes 

Children and Adults Health Programs Group 

Center for Medicaid, CHIP and Survey & Certification 

Centers for Medicare and Medicaid Services 

Baltimore, MD 

Department of Defense (DoD) 

GEIBE, Jesse, MD, MPH, MBA 

CDR, Medical Corps 

Defense Department Liaison Officer 

Centers for Disease Control and Prevention 

Atlanta, GA 

144 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 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) 

CASERTA, Vito, MD, MPH 

Acting Director 

Division of Vaccine Injury Compensation 

Director, Countermeasures Injury Compensation Program 

Healthcare Systems Bureau 

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 

145 

This document has been archived for historical purposes. (3/1/2014)
 

 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 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 

American College of Physicians (ACP) (alternate) 

POLAND, Gregory A., MD 

Mary Lowell Professor of Medicine and Infectious Diseases 

Mayo Clinic 

Rochester, MN 

146 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 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 

American Nurses Association (ANA) (alternate) 

HAYES, Carol E., CNM, MN, MPH 

Advanced Practice Nurse 

American Nurses Association 

American College of Nurse Midwives 

DeKalb Board of Health 

Decatur, GA 

American Osteopathic Association (AOA) 

GROGG, Stanley E., DO, FACOP 

Associate Dean/Professor of Pediatrics 

Oklahoma State University-Center for Health Sciences 

Tulsa, OK 

American Pharmacists Association (APhA) 

FOSTER, Stephan L., PharMD, FAPhA 

Professor and Vice Chair, Department of Clinical Pharmacy 

University of Tennessee Health Sciences Center, College of Pharmacy 

Memphis, TN 

Association of Immunization Managers (AIM) 

MOORE, Kelly, MD, MPH 

Medical Director, State Immunization Program 

Tennessee Department of Health 

Nashville, TN 

147 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

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 

Department of Health, United Kingdom 

SALISBURY, David M., CB, FRCP, FRCPCH, FFPH 

Director of Immunisation 

Department of Health, London 

London, England, U.K. 

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 

148 

This document has been archived for historical purposes. (3/1/2014)
 

 

Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

Infectious Diseases Society of America (IDSA) (alternate) 

BAKER, Carol J., MD 

Professor of Pediatrics 

Molecular Virology and Microbiology 

Baylor College of Medicine 

Houston, TX 

National Association of County and City Health Officials (NACCHO) 

ZAHN, Matthew, MD 

Medical Director, Epidemiology 

Orange County Health Care Agency 

Santa Ana, CA 

National Association of Pediatric Nurse Practitioners (NAPNAP) 

STINCHFIELD, Patricia A., RN, MS, CPNP 

Director 

Infectious Disease/Immunology/Infection Control 

Children's Hospitals and Clinics of Minnesota 

St. Paul, MN 

National Foundation for Infectious Diseases (NFID) 

SCHAFFNER, William, MD 

Chairman, Department of Preventive Medicine 

Vanderbilt University School of Medicine 

Nashville, TN 

National Immunization Council and Child Health Program, Mexico 

VILLASEÑOR RUIZ, Ignacio 

Directora del Programa de Atencion da la Salud de la Infancia y la Adolescencia / Director 

General, Child and Adolescent Health 

Centro Nacional Para la Salud de la Infancia Y La Adolescencia / National Center for Child and 

Adolescent Health 

Ministry of Health / Secretaría de Salud 

Mexico 

National Medical Association (NMA) 

WHITLEY-WILLIAMS, Patricia, MD 

Professor and Chair 

University of Medicine and Dentistry of New Jersey 

Robert Wood Johnson Medical School 

New Brunswick, NJ 

National Vaccine Advisory Committee (NVAC) 

ORENSTEIN, Walt, MD 

Chair, NVAC 

Associate Director, Emory Vaccine Center 

Emory University 

Atlanta, GA 

149 

This document has been archived for historical purposes. (3/1/2014)
Advisory Committee on Immunization Practices (ACIP) Summary Report February 26-27, 2014 

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 

150 

This document has been archived for historical purposes. (3/1/2014)