DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION

Advisory Committee on 

Immunization Practices (ACIP)

Summary Report

October 28, 29, & 30 2020

Atlanta, Georgia 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Table of Contents Page

Agenda 4-6

Acronyms 7-10

 Wednesday: October 28, 2020

Welcome and Introductions 12-13

Immunization Schedules

⬧ Introduction

⬧ Introduction to Combined Immunization Schedule Work Group

⬧ Proposed Changes to 2021 Child/Adolescent Immunization Schedule

⬧ Proposed changes to 2021 Adult Immunization Schedule

13-23

Seasonal Influenza

⬧ Introduction

⬧ Efficacy of Cell-Derived Quadrivalent Influenza Vaccine (Flucelvax Quadrivalent) in Children & 

Adolescents ≥2 years to <18 Years Old

⬧ Influenza Disease Burden and Vaccine Impact Estimates, 2019-20 Season

⬧ End-of-Season Estimates of 2019–20 Seasonal Influenza Vaccine

⬧ Effectiveness against Medically Attended Influenza from Three US Networks

⬧ Updates and Work Group Considerations

24-37

Orthopoxvirus Vaccine

⬧ Introduction

⬧ Orthopoxvirus Work Group Background

⬧ JYNNEOS® (MVA-BN®) Smallpox and Monkeypox Vaccine

⬧ Variola Virus Plaque Reduction Neutralization Assay

⬧ Vaccinating against Monkeypox in the Democratic Republic of the Congo with JYNNEOS®

⬧ Next Steps 

37-56

Dengue Vaccines

⬧ Introduction

57-58

Pneumococcal Vaccines

⬧ Work Group Introduction

59-61

Cholera Vaccines

⬧ Work Group Introduction

61-62

Public Comment 62-71
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Thursday: October 29, 2020

Agency Updates 71-74

Zoster Vaccine

⬧ Introduction

⬧ Update on Post-Licensure Safety Monitoring of Recombinant Zoster Vaccine (RZV, Shingrix) in the 

Vaccine Adverse Event Reporting System (VAERS)

⬧ Vaccine Safety Datalink (VSD) Update on Post-Licensure Safety Monitoring of RZV

⬧ Risk of Guillain-Barré Syndrome Following Herpes Zoster

⬧ Summary and Planned Risk-Benefit Analysis Regarding Use of RZV in Immunocompetent Adults

⬧ Planned Risk-Benefit Analysis Regarding Use of RZV in Immunocompetent Adults

75-87

Tick-Borne Encephalitis Vaccine 

⬧ Introduction

⬧ Overview of Tick-Borne Encephalitis (TBE) and TBE Vaccine

⬧ Immunogenicity and Safety of Pfizer's TBE Vaccine

⬧ Next Steps for TBE Vaccine Work Group

87-95

Rabies Vaccines

⬧ Introduction

⬧ Minimum Acceptable Rabies Antibody Titer and Implications on ACIP Recommendations

⬧ Pertinent Fundamentals of Rabies Immunology

⬧ Pre-Exposure Prophylaxis Schedule: Grading of Recommendations Assessment, Development, and 

Evaluation (GRADE)

⬧ Evidence to Recommendation Framework (EtR)

⬧ Summary and Next Steps

96-130

 Friday: October 30, 2020

Welcome and Introductions 130-132

Coronavirus Disease 2019 (COVID-19) Vaccines

⬧ Introduction

⬧ Update from Vaccines and Related Biological Products Advisory Committee (VRBPAC) Meeting

⬧ NVX-CoV2373 Vaccine Candidate

⬧ Janssen’s SARS-CoV-2 Vaccine Program

⬧ Update on vaccine implementation planning

⬧ Vaccinate with Confidence

⬧ FDA Safety Surveillance Systems

⬧ Post-Authorization Safety Monitoring Plans

⬧ Modeling Strategies for the Initial Allocation of COVID-19 Vaccines

⬧ Updates to Immunity and Epidemiology to Inform COVID-19

⬧ Ethical Principles for Early Vaccine Allocation

⬧ Work Group Interpretation of Data

⬧ Policy questions, Evidence to Recommendation Framework, and Discussion

132-165

Certification 166

Membership Roster 167-175
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Acronyms

AAFP American Academy of Family Physicians 

AAP American Academy of Pediatrics

ACHA American College Health Association 

ACIP Advisory Committee on Immunization Practices

ACOG American College of Obstetricians and Gynecologists

ACP American College of Physicians 

AE Adverse Event

AECI Adverse Events of Clinical Interest 

AESI Adverse Events of Special Interest 

AFM Acute Flaccid Myelitis 

AGS American Geriatrics Society

AHIP America’s Health Insurance Plans

AI/AN American Indian/Alaskan Native 

aIIV Adjuvanted Inactivated Influenza Vaccine

AIM Association of Immunization Managers 

AIRA American Immunization Registry Association 

AMA American Medical Association

ANA American Nurses Association

AOA American Osteopathic Association 

APhA American Pharmacists Association 

APHL Association of Public Health Laboratories 

ARI Acute Respiratory Infection

AS American Samoa

ASA Acetylsalicylic Acid 

ASH Assistant Secretary for Health 

ASTHO Association of State and Territorial Health Officers 

BLA Biologics License Application

BSL-4 Biosafety Level 4 

CBER Center for Biologics Evaluation and Research 

ccIIV Cell Culture-Based Inactivated Influenza Vaccine

CDC Centers for Disease Control and Prevention

CEA Cost-Effectiveness Analysis 

CEF Chicken Embryo Fibroblast 

CICP Countermeasures Injury Compensation Program 

CISA Clinical Immunization Safety Assessment 

CLD Chronic Liver Disease 

CLI COVID-Like Illness 

CMS Centers for Medicare and Medicaid Services

CMV Cytomegalovirus 

CNS Central Nervous System

COI Conflict of Interest 

COU Clinical Operations Unit 

COVID-19 Coronavirus Disease 2019 

COVID-NET COVID-19-Associated Hospitalization Network 

CoVPN COVID-19 Prevention Network 

CSF Cerebrospinal Fluid

CSTE Council of State and Territorial Epidemiologists 

DFO Designated Federal Official

DNA Deoxyribonucleic Acid 

DoD Department of Defense

DRC Democratic Republic of Congo 
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DSMB Data Safety Monitoring Board 

DTaP Diphtheria and Tetanus Toxoid and Pertussis 

DVA Department of Veterans Affairs

EB Empirical Bayesian

EBV Epstein–Barr Virus

ECG Electrocardiogram 

ED Emergency Department

EHR Electronic Health Record 

EIP Emerging Infections Program 

EIS Epidemic Intelligence Service

ELISA Enzyme-Linked Immunosorbent Assay 

EMA European Medicines Agency 

EMR Electronic Medical Record 

EtR Evidence to Recommendation 

EU European Union 

EUA Emergency Use Authorization 

EV Enteroviruses 

FAQs Frequently Asked Questions 

FDA Food and Drug Administration

FFS Fee-For-Service 

FluSurv-NET Influenza Hospitalization Surveillance Network 

FQHC Federally Qualified Health Center 

FY Fiscal Year 

GBS Guillain-Barré Syndrome 

GI Gastrointestinal 

GMPs Good Manufacturing Practices 

GMT Geometric Mean Titers 

GRADE Grading of Recommendation Assessment, Development and Evaluation 

HAIVEN Hospitalized Adult Influenza Vaccine Effectiveness Network

HAN Health Alert Network 

HAV Hepatitis A Virus

HBIG Hepatitis B Immune Globulin

HCoVs Human Coronaviruses 

HCP Healthcare Personnel / Providers

HCW Healthcare Workers 

HDCV Human Diploid Cell Vaccine 

HD-IIV High-Dose Inactivated Influenza Vaccine

HepA Hepatitis A 

HepB Hepatitis B 

HHS (Department of) Health and Human Services

HI Hemagglutinin Inhibition 

Hib Haemophilus Influenzae Type B 

HIV Human Immunodeficiency Virus 

HMO Health Maintenance Organization

HPV Human Papillomavirus

HRSA Health Resources and Services Administration 

HSA Human Serum Albumin 

HZ Herpes Zoster

HZWG Herpes Zoster Work Group 

ICD International Classification of Diseases 

ICER Incremental Cost-Effectiveness Ratio 

ICU Intensive Care Unit

ID Intradermal
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IDCRP Infectious Disease Clinical Research Program 

IDSA Infectious Disease Society of America 

Ig Immunoglobulin

IHB Immunization Healthcare Branch 

IHS Indian Health Service 

IIS Immunization Information Systems 

IIV Inactivated Influenza Vaccine 

ILI Influenza-Like Illness 

ILINet Influenza-like Illness Surveillance Network 

IM Intramuscular 

IND Investigational New Drug 

IPD Invasive Pneumococcal Disease 

ISD Immunization Services Division 

ISO Immunization Safety Office

ISTM International Society for Travel Medicine 

IVIG Intravenous Immunoglobulin 

KAP Knowledge, Attitudes, and Practices 

KPSC Kaiser Permanent Southern California 

LAIV Live Attenuated Influenza Vaccine

LRN Laboratory Response Network 

MedDRA Medical Dictionary for Regulatory Activities 

MenACWY Meningococcal ACWY 

MMWR Morbidity and Mortality Weekly Report

MNT Mouse Neutralization Test 

MVA-BN Modified Vaccinia Ankara-Bavarian Nordic 

NACCHO National Association of County and City Health Officials 

NACHC National Association of Community Health Centers 

NACI National Advisory Committee on Immunization Canada

NAIIS National Adult and Influenza Immunization Summit 

NAIP National Adult Immunization Plan 

NAM National Academy of Medicine 

NAP National Action Plan 

NAPNAP National Association of Pediatric Nurse Practitioners 

NAS National Academy of Sciences 

NCEZID National Center for Emerging and Zoonotic Infectious Diseases 

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

NCHS National Center of Health Statistics 

NCIRD National Center for Immunization and Respiratory Diseases 

NEJM New England Journal of Medicine

NFID National Foundation for Infectious Diseases 

NGO Non-Governmental Organizations

NHANES National Health and Nutrition Examination Survey 

NHIRD National Health Insurance Research Database 

NHIS National Health Interview Survey 

NHSN National Healthcare Safety Network

NIAID National Institute of Allergy and Infectious Diseases 

NICU Neonatal Intensive Care Unit 

NIH National Institutes of Health

NIP National Immunization Program 

NIS National Immunization Survey 

NMA National Medical Association 

NNDSS National Notifiable Diseases Surveillance System 

NNV Number Needed to Vaccinate 
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NOS Newcastle-Ottawa Scale 

NPRM Notice of Proposed Rulemaking 

NTV Nerve Tissue Vaccine 

NVAC National Vaccine Advisory Committee 

NVP National Vaccine Plan

NVPO National Vaccine Program Office 

NVSN New Vaccine Surveillance Network 

NVSN New Vaccine Surveillance Network 

OASH Office of the Assistant Secretary for Health 

OID Office of Infectious Disease 

OIDP Office of Infectious Disease Policy and HIV/AIDS 

OMH Office of Minority Health 

PCECV Purified Chick Embryo Cell Vaccine 

PCP Primary Care Practitioner

PCR Polymerase Chain Reaction 

PCV Pneumococcal Conjugate Vaccine

PEP Post-Exposure Prophylaxis

Ph. Eur. European Pharmacopoeia 

PHAC Public Health Agency Canada 

PHN Postherpetic Neuralgia

PhRMA® Pharmaceutical Research and Manufacturers of America®

PI Principal Investigator

PICO Population, Intervention, Comparison, Outcomes 

PIDS Pediatric Infectious Disease Society 

PPE Personal Protective Equipment 

PR Puerto Rico

PrEP Pre-Exposure Prophylaxis 

PREVENT Pregnancy Influenza Vaccine Effectiveness Network 

PRNT Plaque Reduction Neutralization Test 

PRR Proportionality Reporting Ratios 

PT Pertussis Toxin

PT Preferred Terms (MedDRA)

PVRV Purified Vero Rabies Vaccine 

QALYs Quality-Adjusted Life-Years 

QC Quality Control

QI Quality Improvement 

QIV Quadrivalent Influenza Vaccine 

RCA Rapid Cycle Analysis

RCT Randomized Controlled Trial

RFFIT Rapid Fluorescent Focus Inhibition Test

RIG Rabies Immune Globulin 

RIV Recombinant Influenza Vaccine 

RN Registered Nurse

RNA Ribonucleic Acid 

ROA Route of Administration 

RR Relative Risk

rRT-PCR Real-Time Reverse Transcription Polymerase Chain Reaction 

RSV Respiratory Syncytial Virus 

RT-PCR Reverse Transcriptase Polymerase Chain Reaction

RVNA Rabies Virus Neutralizing Antibody 

RVV Rabies Virus Variants 

RZV Recombinant Zoster Vaccine

SAB Spontaneous Abortion
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SAE Serious Adverse Event 

SAGE Strategic Advisory Group of Experts on Immunization

SAHM Society for Adolescent Health and Medicine 

SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2 

sBLA Supplemental Biologics License Application

sBLA Supplemental Biologics License Application 

SCCS Self-Controlled Case Series 

SCR Seroconversion Rate

SD-IIV3 Standard Dose Inactivated Influenza Vaccine

SHEA Society for Healthcare Epidemiology of America 

SLU Saint Louis University 

SME Subject Matter Expert

TB Tuberculosis

TBE Tick-Borne Encephalitis 

TIV Trivalent Influenza Vaccine

UK United Kingdom

US United States

US Flu VE US Influenza Vaccine Effectiveness Network

USAMRIID United States Army Medical Research Institute of Infectious Diseases

USG US Government 

USPHS US Public Health Service 

UTD Up-To-Date 

VA (US Department of) Veteran’s Affairs 

VACV or VV Vaccinia Virus 

VACV-WR Vaccinia Virus Western Reserve 

VAERS Vaccine Adverse Event Reporting System

VCD Virologically Confirmed Dengue 

VE Vaccine Efficacy

VE Vaccine Effectiveness

VFC Vaccines For Children

VICP Vaccine Injury Compensation Program 

VIS Vaccine Information Statement 

VRBPAC Vaccines and Related Biological Products Advisory Committee Meeting 

VSD Vaccine Safety Datalink

VTU Vaccine Treatment Evaluation Unit 

WG Work Group

WHO World Health Organization

WPV Wild Poliovirus 
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Wednesday: October 28, 2021

José Romero, MD, FAAP

ACIP Chair

Amanda Cohn, MD

Executive Secretary, ACIP / CDC

Dr. Cohn called to order and welcomed everyone to the October 28-29, 2020 Advisory 

Committee on Immunization Practices (ACIP) meeting. She indicated that all of the meeting 

materials were available on the ACIP website, that this meeting was available by live webcast, 

and meeting participants had joined the meeting via Zoom. In addition, she indicated that the 

slides were made available through a ShareFile link for ACIP Voting, Liaison, and Ex-Officio

members; videos of the live webcast would be posted on the ACIP website approximately 4

weeks after the meeting; and that meeting minutes also would be posted on the ACIP website, 

generally within 120 days of the meeting. She noted that slides to be presented during this 

meeting could be access by all participants via the ACIP website, but were not 508-compliant

and would be taken down at the end of the meeting, made 508-compliant, and then reposted 

approximately 4 weeks following the meeting.

The next regular ACIP meeting will be convened on February 24-25, 2021 and will be virtual. It 

is not clear whether the June 23-24, 2021 meeting will be in-person or virtual, but a decision will 

be made in the Spring. The Fall meeting will be October 20-21, 2021. These meeting dates do 

not include emergency ACIP meetings. CDC anticipates that as COVID-19 vaccines are brought 

to the Food and Drug Administration for consideration for Emergency Use Authorization (EUA) 

as described during prior meetings, an ACIP meeting will be convened to deliberate 

recommendations for use for any COVID-19 vaccine product immediately after an EUA is 

issued. Additional meeting dates will be announced on the ACIP website. There also is a link at 

the bottom of the ACIP page to receive email announcements. 

Dr. Cohn indicated that there would be a public comment period during this meeting. ACIP’s oral 

and written public comment processes are designed to ensure that the public has an opportunity 

to inform ACIP’s considerations for immunization recommendations. Efforts are being made to 

maximize opportunities for comments and make the public comment process more transparent 

and efficient. Those interested in making an oral comment were asked to submit a request 

online in advance of the meeting. Priority is given to these advance requests, and if more 

people request to speak than can be accommodated, a blind lottery is conducted to determine 

who will be the speakers. Speakers selected in the lottery for this meeting were notified in 

advance of the meeting. Written public comments may be made via regulations.gov using the 

Docket ID: CDC-2020-0100. Information on the written public comment process, including 

information about how to make a public comment, can be found on the ACIP website.

Call To Order, Welcome, Overview, Announcements, & Introductions 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Members of the ACIP agree to forgo participation in certain activities related to vaccines during 

their tenure on the committee. CDC has issued limited conflict of interest (COI) waivers.

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

may present to the committee on matters related to these vaccines, but are prohibited from 

participating in committee votes on issues related to those vaccines. Regarding other vaccines 

of the concerned company, a member may participate in discussions with the provision that 

he/she abstains on all votes related to the vaccines of that company. At the beginning of each 

meeting and prior to each vote, ACIP members will state any COIs.

Dr. Cohn reviewed logistics and emphasized that this would be a very long meeting, with many 

topics on various vaccine products. She expressed appreciation for everyone’s time and effort 

to make this possible by joining the meeting virtually.

Dr. Romero conducted a roll call of ACIP members during which the following COIs were 

identified:

❑ Dr. Robert Atmar is serving as the Co-Director of the Clinical Operations Unit (COU) of the 

National Institutes of Health (NIH)-funded Infectious Diseases Clinical Research Consortium

(IDCRC) that is working within the COVID-19 Prevention Network (CoVPN) to evaluate 

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) vaccine candidates in 

Phase 3 clinical trials, including those produced by Moderna, AstraZeneca, Janssen,

Novavax, and Sanofi. 

❑ Dr. Sharon Frey is employed by Saint Louis University (SLU), which has a Vaccine 

Treatment Evaluation Unit (VTU) that is part of the IDCRC. She is currently serving as the 

Site PI for the Moderna and Janssen Phase 3 COVID-19 vaccine clinical trials.

❑ Dr. Paul Hunter owns a small amount of stock in Pfizer and has received a small grant from 

Pfizer to conduct a quality improvement (QI) project on pneumococcal vaccines.

A list of Members, Ex Officio Members, and Liaison Representatives is included in the 

appendixes at the end of the full minutes for the October 28-29, 2020 ACIP meeting.

Introduction

Hank Bernstein, DO, MHCM, FAAP

Kevin Ault, MD, FACOG, FIDSA

ACIP Combined Immunization Work Group (WG) Co-Chairs

Advisory Committee on Immunization Practices

Dr. Bernstein introduced the Combined Immunization Schedule Work Group (WG), the goal of 

which is to better harmonize the child/adolescent and adult immunization schedules. These 

schedules are presented for votes every fall because ACIP’s approval is necessary prior to 

publication of the schedule in February of the following year in the Morbidity and Mortality 

Weekly Report (MMWR). ACIP approval is also necessary before the schedules are submitted 

Combined Immunization Schedule Work Group
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to the following partner professional medical organizations for approval prior to the 2021 

publications: 

❑ American College of Physicians (ACP) 

❑ American Academy of Family Physicians (AAFP) 

❑ American Academy of Pediatrics (AAP)

❑ American Academy of Physician Assistants (AAPA)

❑ American Congress of Obstetricians and Gynecologists (ACOG) 

❑ American College of Nurse Midwives (ACNM)

❑ National Association of Pediatric Nurse Practitioners (NAPNAP)

New policy is not established in the proposed child/adolescent and adult immunization 

schedules. Instead, these schedules reflect a summary of published ACIP recommendations.

Dr. Bernstein indicated that for the remainder of this session, Dr. Wodi would discuss the 

proposed edits for the 2021 child/adolescent schedule and Dr. Freedman would discuss the 

proposed edits for the 2021 adult immunization schedule. These edits are intended to 

incorporate ACIP recommendations and MMWR publications that have occurred since October 

2019 and improve readability and utility of the schedules into language that is easy to interpret 

at point of care for the busy provider. In addition to harmonization, there are proposed edits to 

Tables 1 and 2. There also are content changes for the notes sections of both schedules to be 

shared. He concluded that a discussion of the proposed edits would be followed by a vote on 

the child/adolescent and adult immunization schedules, and emphasized that the use of vaccine 

trade names was for identification purposes only and did not imply endorsement by the CDC.

2021 Child and Adolescent Immunization Schedule

Patricia Wodi, MD

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Wodi presented the proposed edits for the 2021 Child and Adolescent Immunization 

Schedule to reflect the following recommendations voted upon and published since October 

2019:

❑ Influenza vaccination published in August 2020 for the 2020–2021 influenza vaccine 

recommendations.

❑ Meningococcal A,C,W,Y vaccination published in September 2020 to reflect inclusion of 

MenACWY-TT (MenQuadfi®) as an option for preventing disease attributed to 

meningococcal serogroups A, C, W, and Y.

The table of abbreviations and trade names on the cover page has been updated to reflect 

MenQuadfi® to the list of meningococcal A,C,W,Y vaccines. Also, vaccines were added to the 

list of combination vaccines. The abbreviation for live, attenuated influenza vaccine was 

changed from LAIV to LAIV4 because only the quadrivalent formulation is currently available in 

the United States (US).
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Table 1 is the graphical presentation of the routine immunization schedule. Minor edits have 

been proposed for this table. In the Hepatitis B (HepB) row, arrows have been added to the 

second dose to clarify the recommended age range for administering the second dose. As 

noted earlier, LAIV was updated to LAIV4. Table 2 is the catch-up immunization schedule for 

children and adolescents. No edits were proposed for this table.

Table 3 is the graphical presentation of recommended immunizations based on medical 

indications. In the human papillomavirus (HPV) vaccine row, the pregnancy column has been 

changed from pink, which indicated delayed vaccination until after pregnancy, to red that 

indicates not recommended or contraindicated and that vaccine should not be administered. In 

addition, an overline text that reads “Not Recommended” with an asterisk also has been 

included in that column. The asterisk links to a descriptive text in the red box within the legend 

indicating that HPV vaccine can be given after pregnancy. Similar to the HVP row, the 

pregnancy column for measles, mumps, rubella (MMR) and varicella vaccines have been 

updated to include the overline text “Not Recommended” with an asterisk that links to the 

descriptive text in the red box in the legend indicating that vaccine can be administered after 

pregnancy. Similar to Table 1, the line for LAIV has been changed to LAIV4 and a footnote has 

been added to reflect a contraindication in children 2 to 4 years of age with asthma or wheezing. 

In terms of the edits to the “Notes” section of the schedule, the following changes have been 

made:

❑ Under “Additional Information,” the sentence on when to administer a repeat dose stating, 

“The repeat dose should be spaced after the invalid dose by the recommended 

minimum interval” has been made bold for emphasis. No changes were made to the 

language.

❑ Within the diphtheria, tetanus, and pertussis (DTaP) note, a section on “Special Situations” 

has been added with recommendations for the use of DTaP in children under 7 years of age 

that reads, “Wound management in children less than age 7 years with 3 or more doses of 

tetanus toxoid-containing vaccine: For all wounds besides clean and minor wounds, 

administer DTaP if more than 5 years since last dose of tetanus toxoid-containing vaccine. 

For detailed information, see www.cdc.gov/mmwr/volumes/67/rr/rr6702a1.htm.” 

❑ A minor edit was made to the Haemophiles influenzae type b (HIB) note for catch-up 

vaccination to include a new bullet stating that no further doses are needed for children who 

receive 1 dose of vaccine at age 15 months of age or older.

❑ A minor change was made to the notes for hepatitis A (HepA) vaccination regarding the 4-

dose series for combined HepA/HepB vaccine. This was to clarify that the 4th dose at 12 

months is a booster dose.

❑ In the notes for HepB vaccination, the sentence pertaining to infants born at ≥2,000 grams 

has been updated with additional language. The sentence now reads, “Administer 1 dose at 

chronological age 1 month or hospital discharge (whichever is earlier and even if weight is 

still <2,000 grams).” This edit was made to provide further clarification regrading when to 

vaccinate infants weighing <2,000 grams.
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❑ The notes on “Routine and Catch-Up Vaccination” for HPV vaccine was updated to include 

information on the recommendation for interrupted schedules reading, “Interrupted 

schedules. If vaccination schedule is interrupted, the series does not need to be restarted.”

❑ The influenza note was updated to specify LAIV4 and RIV4. In the section on “Special 

Situations,” the language for persons who have egg allergy with symptoms other than hives 

was revised to reflect ACIP’s recommendations for the 2020-2021 influenza season. The 

bullet now reads, “if using an influenza vaccine other than Flublok or Flucelvax, administer 

the vaccine in medical setting under supervision of health care provider who can recognize 

and manage severe allergic reactions.” New bullets on severe allergic reaction also were 

added:

➢ Severe allergic reactions to vaccines can occur even in the absence of a history of 

previous allergic reaction. All vaccine providers should be familiar with the office 

emergency plan and be certified in cardiopulmonary resuscitation.

➢ A previous severe allergic reaction to influenza vaccine is a contraindication to future 

receipt of the vaccine.

➢ LAIV4 should not be used in persons with the following conditions or situations:

• Children less than age 2 years

• Received influenza antiviral medications oseltamivir or zanamivir within the 

previous 48 hours, peramivir within the previous 5 days, or baloxavir within 

the previous 17 days

❑ Within the notes for meningococcal serogroup A, C, W, Y vaccination, MenQuadfi® was 

added to the list of vaccines in the sections on “Routine Vaccination,” “Catch-Up 

Vaccination,” and “Special situations.” The “Special Situations” section also was updated 

with language on the recommendations for the use of MenACWY-CRM (Menveo) in infants 

to receive Dose 1 at 3-6 months of age with special situations, including “Anatomic or 

functional asplenia (including sickle cell disease), HIV infection, persistent complement 

component deficiency, use of complement inhibitors (e.g., eculizumab, ravulizumab), or 

travel in countries with hyperendemic or epidemic meningococcal disease.” These updates 

were made to reflect ACIP’s current recommendations on meningococcal vaccination.

❑ Minor edits were made to the notes on pneumococcal vaccination. “High risk conditions” 

was changed to “Underlying conditions” and language was added to clarify PPSV23 should 

be administered after all recommended PCV13 doses have been completed.

❑ Similar to the DTaP note, a “Special Situations” section has been added to provide 

information on the use of tetanus, diphtheria, and pertussis (Tdap) for wound management 

in persons 7 years of age or older that reads, “Wound management in persons age 7 years 

or older with 3 or more doses of tetanus toxoid-containing vaccine: For clean and minor 

wounds, administer Tdap or Td if more than 10 years since last dose of tetanus toxoidcontaining vaccine; for all other wounds, administer Tdap or Td if more than 5 years since 

last dose of tetanus toxoid-containing vaccine. Tdap is preferred for persons age 11 years or 

older who have not previously received Tdap or whose Tdap history is unknown. If a tetanus 

toxoid-containing vaccine is indicated for a pregnant adolescent, use Tdap. For detailed 

information, see www.cdc.gov/mmwr/volumes/67/rr/rr6702a1.htm.”
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Discussion Points

Regarding Slides 18 and 19, Dr. Atmar found it confusing that some of the red cells contain 

language and some do not when the footnote basically states that it is “Not recommended/ 

contraindicated.”

Dr. Wodi indicated that for the pregnancy column, the overline text was added because they 

wanted to indicate that some vaccines could be used after pregnancy. An option would be to 

include the asterisk and leave the overline text off. In addition, there was an effort to try to 

harmonize the adult and child/adolescent schedules. The adult scheduled includes “Not 

Recommended” in some of the boxes as well.

Referring to Slide 31 under “Routine Vaccination,” Dr. Hayes (ACNM) suggested combining the 

2 bullets pertaining to pregnancy into one bullet with the 2 sentences since both pertain to 

pregnancy.

2021 Adult Immunization Schedule

Dr. Mark Freedman

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Freedman indicated that the 2021 Adult Immunization Schedule was updated to reflect 

recommendations published or voted upon since the October 2019 meeting and editorial 

changes to clarify notes or harmonize the adult schedule with the child/adolescent schedule in 

the following areas:

Changes to Tables

❑ Cover Page

❑ Table 1

❑ Table 2

Changes to Notes

❑ Hepatitis A

❑ Hepatitis B

❑ Human Papillomavirus

❑ Influenza

❑ Meningococcal ACWY

❑ Meningococcal B

❑ Pneumococcal

❑ Tetanus, diphtheria and pertussis

❑ Zoster

Minor changes were made to the cover page. First, the abbreviations for LAIV and RIV were 

updated to reflect that those are both available as quadrivalent vaccines, LAIV4 and RIV4. 

MenQuadfi® was added to the list of MenACWY vaccines and abbreviations were added for all 3 

types of meningococcal ACWY vaccines. Zoster vaccine live (ZVL) was removed from the table 

and the injury claims section since it is no longer available on the market. Under the “Helpful 

Information” section, a link was added to frequently asked questions (FAQs) regarding shared 

clinical decision-making recommendations. These FAQs were not available when the schedule 

was published last year, so they are now easily referenced for providers.
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In terms of changes to Table 1, which is the recommended adult immunization schedule, LAIV 

and RIV are now LAIV4 and RIV4 in the influenza row to reflect the availability of quadrivalent 

vaccine only. The Tdap row was split into two rows with the upper half colored purple to indicate 

vaccination is recommended for adults with an initial risk factor such as pregnancy and wound 

management. The lower half remained yellow to indicate that vaccination is recommended for 

adults. In addition, text overlay was added to the purple half of the row that states, “1 dose Tdap 

each pregnancy: 1 dose Td/Tdap for wound management (see notes).” In the MMR row, the 

yellow color was extended to the 50-64 years age column to reflect the age of persons born in 

1957 or later. In the varicella row, the line between the yellow color and the purple color was 

shifted to the left to reflect the age of persons born in 1980 or later. In the zoster row, the row 

that referenced ZVL (Zostavax) was removed since it is no longer available on the market. In 

addition, the language was removed that said RZV was preferred since that is now the only 

vaccine available for zoster. In the column for ≥65 years in the pneumococcal row for PCV13, 

the text overlay in the blue box was changed from “≥65 years” to “1 dose” to be consistent with 

the other overlays in this table that reference doses and not ages.

Regarding edits to Table 2, the medical indications table, LAIV and RIV were changed to LAIV4 

and RIV4. In the MMR row in the pregnancy column, an asterisk was added after the “Not 

Recommended” text overlay to indicate that MMR vaccine should be administered after 

pregnancy. In addition, a line was added between the pregnancy column and the 

immunocompromised column to clearly separate them. In the varicella row also in the 

pregnancy column, an asterisk was added to the text overlay to indicate that varicella vaccine 

should be administered after pregnancy. A line was added between the pregnancy and 

immunocompromised columns to clearly separate them. In the column for HIV infection with 

CD4 counts ≥200 cells per cubic millimeter, the color was changed to blue to indicate that 

vaccination should be based on shared clinical decision-making. This reflects the 

recommendation that vaccination “may” be considered for this group. If it is considered, it would 

be 2 doses administered 3 months apart. In the zoster row, references to ZVL (Zostavax) and 

the text stating that is was preferred were removed. In the pregnancy column for the zoster row, 

the pink color for delay until after pregnancy was replaced with the red color with the text 

overlay “Not Recommended” with an asterisk to indicate that it can be given after pregnancy. In 

the HPV row in the pregnancy column, the pink color was replaced with the red color and the 

text overlay “Not Recommended” was added with an asterisk to indicate that it can be given 

after pregnancy. For the asplenia, complement deficiencies column through men who have sex 

with men (MSM), the text overlay was modified to state, “2 or 3 doses through age 26 years 

depending on age at initial vaccination or condition.” For the HepB row, the text overlay in the 

asplenia through chronic liver disease (CLD) now reads “2, 3, or 4 doses depending on vaccine 

or condition.” This accounts for the accelerated Twinrix schedule and dosing HepB vaccine for 

persons undergoing dialysis. In the diabetes column, the cell was split into a top half of yellow 

for those <60 years of age and a bottom half of blue to indicate that shared clinical decisionmaking should be used for vaccinating persons ≥60 years of age who have diabetes.

In terms of the edits to the “Notes” section of the schedule, the following changes have been 

made:

❑ Within the HepA note under “Travel in countries with high or intermediate endemic HepA, 

text was added for the accelerated Twinrix schedule reading, “(HepA-HepB [Twinrix] may be 

administered on an accelerated schedule of 3 doses at 0, 7, and 21–30 days, followed by a 

booster dose at 12 months).
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❑ With the HepB note under “Special Situations,” a note was added reading, “Percutaneous or 

mucosal risk for exposure to blood e.g., Diabetes: hepB vaccination using shared clinical 

decision-making for persons age 60 years or older.”

❑ Minor wording changes were made in the HPV vaccine note:

➢ In the first bullet, HPV vaccination is now recommended for all persons through age 

26 years; whereas, last year it was recommended for adults through age 26 years.

➢ Under “Routine Vaccination” the first bullet about 15 years of age or older was 

reformatted to match the language in the child/adolescent schedule, given that the 

previous wording was confusing. 

➢ A bullet was added to state that “No additional dose recommended after completing 

series with recommended dosing intervals using any HPV vaccine.”

➢ In the “Shared Clinical Decision-Making” section, the text was modified slightly to 

state that “Some adults age 27-45 years” instead of “Adults.” That was to clarify and 

more accurately reflect the recommendations.

➢ Two bullets were added under “Special Situations” reading as follows:

• Age ranges recommended above for routine and catch-up vaccination or 

shared clinical decision-making also apply in special situations.

• Immunocompromising conditions, including HIV infection: 3-dose series as 

above, regardless of age at initial vaccination.

❑ In the influenza vaccine section, the following changes were made to the “Special 

Situations” section: 

➢ Regarding egg allergy: New language was added to the second sentence in the 

second bullet such that the second sentence now reads, “Egg allergy more severe 

than hives: If using an influenza vaccine other than Flublok or Flucelvax, administer 

in medical setting under supervision of health care provider who can recognize and 

manage severe allergic reactions.” Two new bullets were added that read as follows:

• Severe allergic reactions to vaccines can occur even in the absence of a 

history of previous allergic reaction. All vaccination providers should be 

familiar with the office emergency plan and certified in cardiopulmonary 

resuscitation.

• A previous severe allergic reaction to influenza vaccine is a contraindication 

to future receipt of the vaccine.

➢ A bullet was added to the “LAIV4 should not be used section” that reads, “Received 

influenza antiviral medications oseltamivir or zanamivir within the previous 48 hours, 

peramivir within the previous 5 days, or baloxavir within the previous 17 days.”

❑ The following edits were made to the meningococcal vaccines section:

➢ MenQuadfi (MenACWY-TT) was added in all sections as a potential meningococcal 

vaccine.

➢ Language was added under “Special Situations” regarding booster doses for 

MenACWY and MenB reading, “Booster dose recommendations for groups listed 

under “Special Situations” and in an outbreak setting (e.g., in community or 

organizational settings, and among men who have sex with men) and additional 

meningococcal vaccine, see https://www.cdc.gov/mmwr/volumes/69/rr/rr6909a1.htm
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❑ In the pneumococcal vaccination notes:

➢ The link was updated for routine vaccination in persons age 65 years or older to 

reference a new publication: 

www.cdc.gov/mmwr/volumes/68/wr/mm6846a5.htm?_cid=mm6846a5+w

➢ Under “Shared Clinical Decision-Making,” the order of the bullets was changed 

though the language in the bullets did not change. The order is now:

• If both PCV13 and PPSV23 are to be administered, PCV13 should be 

administered first

• PCV13 and PPSV23 should be administered at least 1 year apart

• PCV13 and PPSV23 should not be administered during the same visit

❑ In the Tdap notes, information was updated for wound management based on the most 

recent publication. The language states, “Persons with 3 or more doses of tetanus toxoidcontaining vaccine: For clean and minor wounds, administer Tdap or Td if more than 10 

years since last dose of tetanus toxoid-containing vaccine; for all other wounds, administer 

Tdap or Td if more than 5 years since last dose of tetanus toxoid-containing vaccine. Tdap 

is preferred for persons who have not previously received Tdap or whose Tdap history is 

unknown. If a tetanus toxoid-containing vaccine is indicated for a pregnant woman, use 

Tdap For detailed information, see 

https://www.cdc.gov/mmwr/volumes/69/wr/mm6903a5.htm” 

❑ In the zoster notes, references to prior ZVL dosing were removed for routine vaccination of 

persons ≥50 years old with RZV and the bullet was deleted that explained ZVL dosing for 

persons ≥60 years since ZVL is no longer available.

Discussion Points

Regarding pneumococcal vaccine, Dr. Poehling suggested that the third bullet did not seem 

necessary since the second bullet states that “PCV13 and PPSV23 should be administered at 

least 1 year apart.”

Dr. Freedman said that while he understood the point, he thought it was important to emphasize 

that they should not be administered during the same visit based on some questions CDC 

receives through the vaccine questions email and instances in which they have been coadministered.

To contrast the pediatric versus adult schedules, Dr. Atmar observed that “Not Recommended” 

is in all of the cells on the adult schedule. For the pediatric schedule, that could be a problem 

because there are a couple of cells in which there is language to identify a specific 

subpopulation within a group that would make putting “Not Recommended” problematic. As an 

adult physician, he finds the text overlay on the adult schedule to be useful and would not 

propose changing that. Perhaps the question for the pediatric schedule regarded how to have 

the asterisks in the pregnancy column stand out.

Dr. Freedman indicated that historically, the adult schedule has always had the text overlay and 

the child schedule has not. In general, the table by medical condition for the adult schedule has 

a lot more text overlay. The suggestion from the Combined Immunization WG was to get rid of 

the pink color because it caused additional confusion. Because red now indicates not 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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recommended/contraindicated, the addition of the asterisk could address dosing for pregnancy. 

The WG is open for suggestion.

Dr. Wodi suggested that a possible option would be to remove the “Not Recommended” text 

and just have an asterisk on the child/adolescent schedule. 

Dr. Bernstein suggested changing the line spacing under the red box so that the asterisk stands 

out more in terms of vaccinating after pregnancy. In terms of the routine vaccination for Tdap 

that was proposed in the child/adolescent schedule, that level of information is not included in 

the adult schedule. Perhaps the suggestion to administer Tdap regardless of the interval applies 

more broadly than just during pregnancy.

Dr. Goldman (ACP) said that as a practicing internist, he found the text overlay to be helpful. 

One thing that needs to be emphasized for practicing clinicians is the importance of reading the 

notes section. While the comprehensive, color-coded text overlay guide is very useful for a 

quick glance, it does not really encompass the full depth of recommendations within it.

Dr. Freedman pointed out that the cover pages in both schedules include a box that describes 

how to use the schedule and emphasizes that all of the tables and notes should be used.

Revisions to the 2021 Immunization Schedules

Dr. Mark Freedman

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Freedman indicated that the WG took into consideration the ACIP members’ input and 

presented the following revisions that were made based on that input:

❑ Table 3, Child/Adolescent Schedule: “Not Recommended” was removed and the asterisk 

remained.

❑ Table 2, Adult Schedule: “Not Recommended” was removed from HPV during pregnancy 

and an asterisk remained in order to indicate that HPV vaccine should be given after 

pregnancy.

❑ Regarding recombinant zoster vaccine in pregnancy, the WG proposed making the box gray 

with no asterisk instead of red with an asterisk because the actual note from the policy 

states that, “There are no available data to establish whether RZV is safe in pregnant or 

lactating women and there is currently no ACIP recommendation for RZV use in this 

population. Consider delaying vaccination with RZV in such circumstances.” The gray color 

indicates that there is no ACIP recommendation. The red color was left over from when ZVL 

live was still available, which was contraindicated in pregnancy. 
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Discussion Points

Dr. Poehling asked whether the same approach with the red box with an asterisk should be 

used for MMR and varicella vaccine on the adult schedule as on the child schedule.

Dr. Freedman indicated that those are true contraindications because they are live vaccines. 

Historically, there has always been more text overlay on the adult schedule. However, he 

emphasize that if ACIP felt strongly, the WG would consider changing that one as well.

Dr. Fryhofer (AMA) thought it would be helpful to keep the “Not Recommended” as a reminder 

that these are live virus vaccines. Although pediatricians are wonderful at giving immunizations, 

those who immunize adults are still trying to rise to the occasion to meet the bar pediatricians 

have set for them. The overlays are very helpful, especially in terms of indicating which vaccines 

are live and which ones definitely should not be given because of the subsets listed on the 

medical conditions. She suggested that perhaps for the live virus vaccines (MMR, varicella, 

LAIV) the overlay could say “Contraindicated” and for HPV could say “Not Recommended.”

Dr. Rockwell (AAFP) thought it should be all or nothing in terms of whether there is text overlay. 

Red means “no.” It is more confusing to remove the text only in one box but leave it in the 

others. “Not Recommended” is different from “Contraindicated.” Perhaps extra verbiage is 

needed with “Contraindicated” to ensure that people understand not to give the vaccine. It 

seemed like they were now making subsets within the red, which would be more confusing.

In terms of the adult schedule, there was considerable support for either returning the text 

overlay to all of the red boxes or leaving it out of all of them.

Dr. Hayes (ACNM) reminded everyone that there is a major difference in pregnancy between 

“Not Recommended” and “Contraindicated.” Some of these vaccines can be given during 

pregnancy if there is a clinical indication and the vaccine is not live. Not only is a live vaccine not 

recommended, but also it is contraindicated. The red bar is different from the orange bar. 

Perhaps if “Not Recommended” is to be used and it is a dead vaccine, the orange bar should be 

used.

Dr. Atmar pointed out that while the two are different, in fact they are combined in the color 

coding legend. Red with an asterisk is probably appropriate. Perhaps the text language in the 

supporting document can address the differences. 

Dr. Lee pointed out that the immunocompromised category is increasingly complex and that 

there is newer guidance from transplant societies in terms of considering live viral vaccines in 

certain sub-populations where sufficient data are available about the importance of its use. The 

red box will become messy pretty quickly. For the future, it might make sense to explore this 

further.

Dr. Maldonado (AAP) suggested leaving the pediatric schedule as it is now, given that AAP has 

not had time to think about it. AAP harmonizes closely with everything CDC does pertaining to 

the schedule. Since it was not under consideration at the outset, this should be taken up 

separately in order to give careful consideration to how this would impact pediatric providers’ 

approach to the schedule.

Dr. Romero indicated that the meeting would adjourn at this time and the schedules and vote 

would be revisited the next morning.
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Vote: 2021 Immunization Schedules

Dr. Mark Freedman

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

During the second day of the meeting, Dr. Freedman reviewed the pending issues and 

presented the revisions before the vote. The first issue that arose regarded the wording under 

the child/adolescent schedule in terms of the notes for Tdap vaccination. There was a comment 

about combining the second and third bullet. The WG wanted to emphasize that Tdap may be 

administered regardless of the interval since the last tetanus Tdap vaccine. It does apply to 

pregnancy, so there was a request to combine the two bullets. However, it also applies to some 

other situations. For example, if a child inadvertently was given Tdap between 7 to 9 years of 

age, they would still be recommended to receive a Tdap booster at 11 to 12 years of age. 

Therefore, the WG opted to keep the bullets separate.

Regarding Table 1 of the child/adolescent schedule, the asterisks alone were used without any 

text overlay in preparation for Table 3 comment from the previous day. “Not Recommended” 

was removed from the pregnancy column in Table 3 for MMR, varicella, and HPV. The asterisks 

remain and the key for the red color will explain that the asterisk indicates to vaccinate after 

pregnancy. A line space will be added between the word “administered” and *Vaccinate after 

pregnancy so that it stands out more.

On Table 2 in the adult schedule, “Not Recommended” with an asterisk will be left for MMR, 

VAR, and HPV because the adult schedule traditionally has used more text overlay. For the 

pregnancy column, zoster vaccine was changed from red with “Not Recommended” text overlay 

and an asterisk to gray, which means there is no recommendation. That means that there is no 

recommendation for pregnancy, immunocompromised, or HIV infection because that reflects the 

currently published guidance.

Dr. Freedman concluded that the language for the vote was to “Recommend the proposed edits 

to both the 2021 adult and child/adolescent immunization schedules.” 

Motion/Vote: Adult and Child/Adolescent Immunization Schedules 

Dr. Atmar made a motion to accept the Adult and Child/Adolescent Immunization Schedules as 

revised and presented. Dr. Poehling seconded the motion. No COIs were declared. The motion 

carried unanimously with 14 affirmative votes, 0 negative votes, and 0 abstentions. The 

disposition of the vote was as follows:

14 Favored: Atmar, Ault, Bahta, Bell, Bernstein, Frey, Hunter, Lee, McNally, Poehling, 

Romero, Sanchez, Szilagyi, Talbot 

 0 Opposed: N/A

 0 Abstained: N/A
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Introduction

H. Keipp Talbot, MD, MPH

Chair, Influenza Work Group

Associate Professor of Medicine

Vanderbilt University

Dr. Talbot reminded everyone that during the June 2020 ACIP meeting, there were 

presentations on 2019-2020 influenza activity, vaccine effectiveness (VE), safety updates, and 

WG considerations and proposed 2020-2021 recommendations.

WG activities since June 2020 have included finalization of the publication of the 2020-2021 

ACIP Influenza Statement that was published in the MMWR on August 20, 2020; review and 

discussion of 2019-2020 estimates of influenza VE, influenza disease burden, and burden 

averted through vaccination; and discussion of data from a randomized controlled trial (RCT) of 

cell culture-based influenza vaccine, FLUCELVAX® Quadrivalent, among children aged ≥2 

through <18 years.

The agenda for this session included the following presentations:

❑ Efficacy Results of FLUCELVAX® Quadrivalent Cell Culture-Based Inactivated Influenza 

Vaccine (ccIIV4) in Subjects Aged ≥2 to <18 Years

❑ Influenza Disease Burden and Vaccine Impact Estimates, 2019-2020 Season

❑ End-of-Season Estimates of 2019–2020 Seasonal Influenza Vaccine Effectiveness against 

Medically Attended Influenza from Three US Networks

❑ Updates and WG Considerations

Efficacy of Cell-Derived Quadrivalent Influenza Vaccine (Flucelvax

Quadrivalent) in Children & Adolescents ≥2 Years to <18 Years Old

Gregg C. Sylvester, MD, MPH

Chief Medical Officer

SeqirusTM A CSL Company

Dr. Sylvester presented the results of a recently completed SeqirusTM study in a pediatric 

population for its ccIIV4, FLUCELVAX®, including a brief background on the merits of cell-based 

manufacturing, an understanding of the objectives and design of this RCT, and the results and 

conclusions. While there was a subset of participants who were part of an immunogenicity study 

during the second and third season, he did not present those data during this session due to 

time. This immunogenicity data was presented to and discussed with the Influenza WG prior to 

this presentation. The presentation during this session focused on the efficacy and safety data.

FLUCELVAX® is a cell-based influenza vaccine that is manufactured in a mammalian cell line 

instead of in chicken eggs. This process avoids the possibility of egg adaptation, which can 

occur in egg-based manufacturing. The cell-based vaccine is a closer match to the FDAselected strains, and it has the potential for improved effectiveness compared to egg-based 

Influenza
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vaccines. FLUCELVAX® is the only cell-based inactivated vaccine licensed by the FDA1. The 

original licensure occurred in 2012 for adults. In 2016, SeqirusTM was granted a new indication 

for ≥4 years of age based on immunogenicity and safety data. This is the first efficacy study with 

a quadrivalent cell-based influenza vaccine in a pediatric population, and it is a post-approval 

requirement by the FDA [

1Pérez Rubio A & Eiros JM. Hum Vaccin Immunother. 2018;14:1874–

1882].

The primary objective was to demonstrate VE of ccIIV4 in preventing polymerase chain reaction 

(PCR)-confirmed influenza versus non-influenza in a pediatric population. Given that this is an 

absolute efficacy study, FLUCELVAX® was compared to a non-influenza vaccine. The study 

would be deemed a success if a pre-defined criterion was met. The study was designed and 

powered to assess the lower limit of a 2-sided 95% confidence interval for VE to be above 20%. 

This was negotiated with the FDA prior to the start of the study. The secondary objective was to 

demonstrate VE of ccIIV4 in preventing culture-confirmed influenza due to any and vaccinematched strains as well as vaccine-matched strains. As mentioned earlier, a subject participated 

in an immunogenicity study and FLUCELVAX® demonstrated a robust immune response 

against all 4 strains over the 2 seasons as assessed by seroconversion rates. The safety and 

tolerability of FLUCELVAX® also was evaluated in this population.

This study was a double blinded placebo controlled randomized clinical trial with randomization 

occurring in a 1:1 fashion. The study occurred over 3 influenza seasons. The study vaccine was 

manufactured containing the 4 influenza strains selected by the World Health Organization 

(WHO) for each one of those seasons. Menveo® was selected as a comparator vaccine. 

Menveo® is a conjugated meningococcal ACWY (MenACWY) vaccine. This comparator was 

chosen because it was licensed for children ≥2 years of age, it has a dosing regimen 

comparable to FLUCELVAX® and does not interfere with existing national immunization 

programs in the participating countries or the sites within those countries. Standard vaccine 

protocol inclusion and exclusion criteria were used during the enrollment phase and 2 cohorts 

were studied. Participants were divided into a previously vaccinated group and a previously not 

vaccinated group. Approximately two-thirds (N=3000) subjects were considered previously 

vaccinated. This meant that any subject ≥9 years of age or any subject younger than 9 years of 

age who had received 2 or more influenza vaccines prior to enrollment were considered 

previously vaccinated. Approximately 1500 were categorized as previously not vaccinated. 

These subjects were 2 to 9 years of age who had not receive 2 or more doses of influenza 

vaccine. This cohort received 2 doses of vaccine at least 28 days apart. All study participants 

received a 0.5 mL of FLUCELVAX® or a non-influenza comparator.

There were 39 clinical sites located in 8 participating countries, with a total of 4514 participants. 

There are no sites in the US because of the trial design. The ACIP has recommended a routine 

annual influenza vaccine for all persons ≥6 months of age who do not have a contraindication. 

However, the study sites did not enroll subjects with similar race demographics to the US 

population. Both study groups are similar in age, gender, race, prior vaccine status, and season 

in which the study participants were enrolled. The participants were Asian and White. Diversity 

and inclusion is important in clinical trials. SeqirusTM is currently finishing a US immunogenicity 

trial with FLUCELVAX® in infants and young children. In that study, African Americans and 

Hispanics comprise more than 25% of the study population. Dr. Sylvester said that he would be 

happy to present those results during a future ACIP meeting.
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In terms of the results of the primary efficacy objective, there were 175 subjects with confirmed 

influenza by PCR in the FLUCELVAX® and 364 subjects with PCR-confirmed influenza in the 

control group. This calculates to a VE point estimate of 54.5% with 95% confidence intervals of 

46% to 62%. The lower bound of the confidence interval is well above the pre-specified 

endpoint of 20% and thus, the success criterion was met. To summarize the secondary efficacy 

results for FLUCELVAX® against culture-confirmed influenza, efficacy for FLUCELVAX® to 

prevent culture-confirmed influenza due to any A or B type of influenza strain regardless of 

antigenic shift was nearly 61%. The highest efficacy was against influenza A/H1N1 followed by 

any B influenza strain and then influenza A/H3N1. The efficacy against matched strains was 

slightly higher, with the majority of H1N1 and B/Yamagata strains being matched.

Regarding the percentage of study participants reporting at least one solicited local or systemic 

AE, solicited AEs are reported from 6 hours after vaccination all the way through Day 7. 

Unsolicited local and systemic AEs were collected from Day 8 all the way to 180 days or to the 

end of the influenza season, whichever period was longer. The most commonly reported 

solicited local AE in both the FLUCELVAX® and the comparator vaccine groups was tenderness 

at 28.7% and 25.4%, respectively. Pain was 23.8% in the FLUCELVAX® group and 19% in the 

comparator group, and erythema was 19.3% in the FLUCELVAX® group and 21.2% in the 

comparator group. Except for a slightly higher rate of pain and tenderness in the FLUCELVAX®

group, no notable differences in rate of solicited local AEs were observed between the two 

groups.

Severe solicited local AEs were uncommon at ≤1.4% in both vaccine groups. The majority of 

solicited local AEs resolved spontaneously within a few days after vaccination. Headache and 

fatigue were the most common solicited AEs. These 2 symptoms were collected from study 

participants who were ≥6 years of age. The symptoms of sleepiness and irritability were 

collected from parent diaries for children up to 6 years of age. Severe solicited systemic AEs 

were uncommon and generally less than 1%. There was 1 death that occurred within the control 

group. The child died of cerebral edema caused by diabetic ketoacidosis. This death was 

carefully reviewed and deemed not related to the vaccine in the control group. The reported 

unsolicited AEs for local and systemic were also similar amongst the two groups. This study’s 

safety profile is similar to the previous SeqirusTM immunogenicity FLUCELVAX® in children ≥4 

years of age.

In conclusion, this is the first efficacy study in a pediatric and adolescent population with a cellculture-based quadrivalent influenza vaccine. The overall VE was 54.6% with high confidence 

intervals (95% CI 45.7, 62.1). FLUCELVAX® was well-tolerated, with similar rates of solicited 

and unsolicited AEs the two vaccination groups.

Discussion Points

Dr. Szilagyi asked whether Dr. Sylvester could provide information about VE across influenza 

seasons, and whether any subgroup analyses were done by smaller age groups.

Dr. Sylvester referred to back-up slide 13 of absolute VE by season. Season 1 is the Southern 

Hemisphere 2017, Season 2 is the Northern Hemisphere 2017-2018, and Season 3 is the 

Northern Hemisphere 2018-2019. Season 1 was 56.5% for any strain, for Season 2 was 44%, 

and Season 3 was 59%. These data are also broken down by whether the strain was H1N1, 

H3N2, or one of the B strains. Subgroup analyses were done by age and they looked to see 

whether there was a difference between the previously vaccinated and non-previously 

vaccinated groups, and no difference was seen.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Dr. Kimberlin (AAP Redbook) asked whether this was a stratified study in that the randomization 

within each of the two-thirds vaccinated and one-third not vaccinated was evenly spaced 

between active influenza recipients and placebo recipients.

Dr. Sylvester indicated that the previously vaccinated group of about 3000 participants were 

relegated to receive either the comparator or FLUCELVAX®. Within the 1500 not vaccinated 

group, 750 received FLUCELVAX® and the rest received the comparator.

Dr. Whitley-Williams (NMA) asked when data would be available for the ACIP to review from the 

US immunogenicity trial with FLUCELVAX® in infants and young children that includes over 

25% African American and Hispanic participants.

Dr. Sylvester indicated that the trial he just shared has been submitted to the FDA under a 

supplemental biologics license application (sBLA) down to ≥2 years of age, with the hope that 

they will hear from the FDA whether this trial is approved by January 2021. In terms of the data 

he referenced, the hope is to submit the sBLA in March 2021. Once that is submitted, he would 

be happy to share the data with the WG prior to June and then in June 2021 to present the data 

to the entire ACIP. That age range is ≥6 months of age up to ≥4 years of age and it is an 

immunogenicity study.

Dr. Poehling asked whether the 2 doses 1 month apart was used for the previously not 

vaccinated group of children.

Dr. Sylvester clarified that the previously non-vaccinated group received 2 doses of the 0.5 mL

vaccine on Day 1 and again on Day 28. If they were in the non-comparator, they received 

Menveo® as their first vaccine and then a saline solution placebo for their second vaccine.

Influenza Disease Burden and Vaccine Impact Estimates, 2019-2020 Season

Carrie Reed, DSc, MPH

Lead, Applied Research and Modeling Team

Influenza Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Reed reminded everyone that CDC tracks influenza activity in the US in collaboration with 

state and local health departments using multiple surveillance systems in different surveillance 

categories. Together, these systems are designed to provide a national picture of influenza 

activity, including how much influenza-like illness (ILI) there is; determine the distribution of the 

virus types and subtypes circulating; and measure trends in influenza-related outpatient illness, 

hospitalizations, and deaths.

To provide context to the rest of the presentation, Dr. Reed shared data from influenza testing in 

clinical laboratories for the 2019-2020 influenza season. Influenza began to increase in early 

November of 2019, peaked in Week 6 in February 2020, and then declined rapidly in March 

2020 similar to recent seasons. Stratifying by positivity for influenza A and influenza B viruses 

separately illustrates that the early season activity was influenza B and later season activity 

experienced increases in influenzas A activity. Comparing influenza types for the 2019-2020 

season to recent prior seasons based on influenza testing done and reported to CDC by public 

health laboratories, the 2019-2020 season was predominated by influenza A/H1N1 and 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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influenza B/Victoria viruses and there was very little H3N2 virus activity 

[https://www.cdc.gov/flu/weekly/fluviewinteractive.htm].

For a number of reasons, these surveillance systems that CDC uses to monitor influenza 

activity do not capture every influenza-related illness, medical visit, hospitalization, or death in 

the US. CDC feels like it is important to convey the full burden of seasonal influenza and the 

reductions in disease burden that occur because influenza vaccination in the US. Therefore, Dr. 

Reed presented on two additional activities that use the surveillance data collected through 

CDC’s routine systems and other key influenza platforms to answer some key questions about 

influenza disease burden and the impact of vaccination in the population.

One of the key questions that is not measured directly in surveillance is, “How do people get 

influenza every year?” and by extension, “How many people are hospitalized and how many 

people die?” Measuring this directly in surveillance presents major challenges and cases, 

hospitalizations, and deaths are considered that are confirmed to be influenza and reported to 

public health agencies and CDC to be the “tip of the iceberg.” This can be for a number of 

reasons, some of which include the following:

❑ Not all people seek medical attention for their illness

❑ Symptoms can be similar among respiratory pathogens

❑ Illnesses often are not confirmed with laboratory testing

❑ Many adults are no longer shedding virus by the time that they are tested

❑ Complications may be broader than respiratory illness and not thought to be influenza and 

not tested

❑ Even when confirmed, influenza many not be recorded on a death certificate

❑ Surveillance is not conducted everywhere

Thinking about why not all cases are detected and how that impacts what is known, someone 

who is hospitalized with influenza may or may not be tested for influenza when they present for 

care. If someone is tested for influenza, there are a variety of tests that could be used and there 

is a variation in the sensitivity between tests. Some people who are tested may test positive, but 

there may be some people who are falsely negative on their test results. What is know about in 

the surveillance systems are the positive influenza tests. In order to know total number of 

hospitalizations, CDC collects information on some additional factors such as test sensitivity, 

distribution of test types that are used, and the percent of patients in settings such as hospitals 

that test for influenza. Using these additional pieces of information, it is possible to map out and 

work back to the total number of influenza hospitalizations.

The method used to estimate the disease burden of illness, hospitalizations, and deaths 

observed during an influenza season was developed originally during the 2009 pandemic. This 

model has been refined over the last several years to be able to monitor the disease burden 

during a season based on routine surveillance. The key system in this process is the Influenza 

Hospitalization Surveillance Network (FluSurv-NET), with several other steps utilized to 

extrapolate this to the US population and estimate illness, deaths, and medical 

visits/hospitalizations as depicted in this illustration:
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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 Figure 1: Illustration of Influenza Burden Estimates Model

To correct for under-detection, data are collected on influenza testing in hospitals. To calculate 

deaths, the risk of dying in a hospital setting from influenza is monitored in FluSurv-NET. 

Because some people die outside of the hospital, additional information is collected from death 

certificates on the proportion of deaths that have occurred outside of the hospital to capture the 

full number of deaths inside/outside of the hospital. To calculate illness, CDC has data from 

previous studies on the risk of hospitalizations to estimate how many symptomatic illnesses 

were in the population given the estimates of hospitalization and then some additional 

information on medical care seeking behaviors to estimate medical visits. As mentioned, these 

methods have been refined over time and have been published in the scientific literature [Reed 

et al. PLoS One. 2015; Rolfes et al. IoRV. 2018].

Following that methodology, the estimates overall for all ages for the 2019-2020 influenza 

season are 38.2 million Illnesses, 17.5 million medical visits, 400,000 hospitalizations, and 

22,000 deaths. This also is estimated by 5 age groups: 0-4, 5-17, 18-49, 50-64, 65+ years. The 

detailed estimates for this past season as well as estimates for all seasons since 2010-2011 can 

be found at https://www.cdc.gov/flu/about/burden/index.html. Of note, these estimates are 

considered to be preliminary because some of the data inputs mentioned with respect to the 

model can be lagged in time. Data are used from previous seasons until those can be finalized 

and estimates can be updated when more complete data are available. The website was 

updated a few years ago to present a lot more information. High-level information is included on 

how/why CDC estimates burden, a link is provided to the tables with the detailed estimates by 

age group and by season for all past seasons, and there is a link to the preliminary in-season 

estimates that are updated weekly throughout the influenza season.

The second question that is not directly estimated in any of CDC’s platforms is, “what impact 

can our interventions have, specifically vaccination, in terms of reducing disease burden in the 

population?” Influenza vaccination is the primary strategy available to prevent influenza illness 

and its complications. Vaccine coverage, VE, and rates of influenza can all vary between 

seasons, between age groups, and between different types and subtypes of influenza viruses. A 

few years ago, CDC began a process to use the data available on those factors from that

season to estimate the burden of influenza prevented by vaccination to better describe the

population impact of influenza vaccination [Tokars et al. Vaccine. 2018; Rolfes et al. CID. 2019; 

Chung et al. CID. 2020].
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For the 2019-2020 season, the components that went into that analysis included: 1) disease 

burden (38 million illnesses; 22,000 deaths; 400,000 hospitalizations) estimated by age group 

and influenza type/subtype; 2) vaccine coverage (38% to 75%, varying by age group) from 

CDC’s FluVaxView; and 3) VE (22% to 57%, varying by age group and influenza type) from the 

US Flu VE Network. Assembling those pieces of information, the estimated influenza averted 

burden from the 2019-2020 influenza season is illustrated in this infographic:

A few years ago, CDC’s Communications Group started using analogies such as those 

presented in the infographic above to try to communicate the magnitude of these estimates. In 

addition to influenza illness estimates, CDC also calculates the prevented fraction or proportion 

of potential influenza cases that were prevented because of vaccination. For example in this 

case, it was estimated that 21% (N=105,000) of all influenza hospitalizations were prevented or 

1 in 5 influenza hospitalizations did not occur because vaccination. This fraction was highest 

this year for children 6 months to 4 years of age, with 28% or over one-fourth of hospitalizations 

prevented by influenza vaccine.

To summarize, during the 2019–2020 season an estimated 38 million people were sick with 

influenza. This resulted in 18 million visits to a health care provider; 400,000 hospitalizations; 

and 22,000 deaths. The estimated influenza illnesses, hospitalizations, and deaths were lower 

than some recent seasons and similar to other seasons where influenza A(H1N1)pdm09 viruses 

dominated. Persons aged <50 years had rates of illnesses, hospitalizations, and deaths similar 

to or greater than during the 2017-2018 season, a recent season with high severity. Vaccination

prevented the greatest proportion of outcomes among children aged 6 months to 4 years of age,

an age group with high vaccine uptake and the greatest vaccine effectiveness.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Discussion Points

Dr. Szilagyi noted that he has been pointing out for several years that it would be great to show 

data about disease averted by vaccine, and found this to be a wonderful way to do this. He did 

not think the analysis accounted for herd immunity and wondered whether there may be some 

additional analyses that could account for this. With FluVENET, the Hospitalized Adult Influenza 

Vaccine Effectiveness Network (HAIVEN), and New Vaccine Surveillance Network (NVSN) it 

may be good to hone in on the actual VE that are specific to outpatients, emergency 

departments (EDs), or hospitalizations from these 3 networks that are now available. Assessing 

ED visits would be very good.

Dr. Reed confirmed that this analysis did not include any indirect effects, or herd immunity, from 

reduced susceptibility in the population. This is directly from people being vaccinated and not 

from herd protection in the population, thought this is a question that they are examining with 

some modeling colleagues with the hope of refining the analysis to include the additional 

benefits. In terms of the comment regarding VE, a single VE is included from the US Flu VE 

Network. The assumption in the analysis is that if influenza is prevented, downstream 

consequences from influenza are prevented. They do not have separate VE for hospitalizations 

or deaths. However, there is additional attenuation from vaccine that could be included in the 

future and they have discussed examination of ED visits as well.

Dr. Frey asked Dr. Reed to share her thoughts about the effect that COVID-19 infection and 

mask wearing may have for the 2020-2021 influenza season on the ability to effectively estimate 

influenza burden.

Dr. Reed indicated that there have been discussions about this and observed that at the end of 

last season, influenza activity decreased faster than it had in previous seasons likely in part due 

to COVID-19 interventions and restrictions that were in place in March. There has been 

discussion about how to monitor influenza burden this season. The plan is to continue to rely on 

the hospitalization platform and continuing to do case finding for influenza this season. One of 

the key factors will be how influenza testing in the clinical setting is influenced and whether 

influenza is being detected at the same rate as usual. There is some ongoing work to better 

monitor how influenza rates, hospitalizations, testing practices, and detection of influenza is 

changing during this coming season. It is likely to be a challenge, but efforts are being made to 

assess influenza detection.

Dr. Romero asked whether the availability of combined COVID-19 and influenza testing would 

offer a better idea or confound the evaluation in the coming season.

Dr. Reed said that through various platforms, they are trying to collect information about 

influenza testing overall and COVID-19 testing rates overall, and combined testing and whether 

these are more likely to be positive for one or the other and the factors associated with that.

Dr. Bernstein asked whether the model which has been published is used by other countries, 

particularly in the Southern Hemisphere where SARS-CoV-2 and influenza have already cocirculated. This could be beneficial given the current pandemic.

Dr. Reed indicated that CDC has worked closely with its international colleagues in the past on 

applying the averted burden model. Many colleagues in the Southern Hemisphere have been 

using similar methods to estimate averted burden for influenza. They have not worked with them 

specifically during this past influenza season. In many parts of the world and the Southern 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Hemisphere, influenza activity was relatively low during this season, but this method has been 

used elsewhere in past seasons.

Dr. Lee was glad to see the information presented this way in terms of disease burden and 

preventable burden, and expressed her hope that the same could be done for COVID-19 

vaccines. Given that the estimates on detection are dependent upon people getting tested, she 

wondered whether consideration had been given to ways to account for disparities in testing 

and vaccination and how that might impact disparities in the estimates for disease burden. A lot 

is being learned from COVID-19 and thinking about how to account for that might be very 

important. It also would be extremely helpful to understand the burden of disease and the 

preventable burden in pregnant women through vaccines. She encouraged the team to try to 

capture those estimates for influenza vaccine and potential future COVID-19 vaccines.

Dr. Reed indicated that they have an analysis to the one she presented for pregnant women 

specifically. Though this was sidelined somewhat due to the COVID-19 response began, it is in 

progress and the hope is to have it out soon. They do recognize the disparities in COVID-19 

burden estimates, especially racial and ethnic disparities. They have stratified the hospitalization 

rates she mentioned by race and ethnicity and are thinking about what other inputs would be 

needed to better understand, especially in terms of how race/ethnicity testing practices could 

help to better understand disparities in burden.

Ms. Bahta noted that the data Dr. Reed shared are used at the state level for messaging about 

the importance of influenza, and agreed that the same type of messaging would be helpful in 

terms of how vaccination could help mitigate COVID-19.

Dr. Ault asked whether the proposed modeling for pregnancy would include pre-term delivery 

and other obstetrical complications of influenza infection in pregnant women.

Dr. Reed indicated that while they have had these discussions, right now it is similar to what she 

presented earlier in terms of illnesses, medical visits, hospitalizations, and deaths in pregnant 

women and their infants who potentially would have residual protection from vaccination. They 

have not yet gotten into some of the other specific pregnancy outcomes.

Given the situation in clinical practice with the current influenza season of differentiating 

between COVID-19 and influenza, Dr. Hunter asked if there would be a recommendation or 

guidance on a national level to perform more influenza testing this year than would be done in 

most years and if so, how that would tie into the availability of supplies since influenza testing 

would use similar reagents as COVID-19 testing.

Dr. Reed said they have heard comments from surveillance sites that are having similar 

questions about how to prioritize testing since supplies are currently limited. While she could not 

speak to the current status of discussions about recommendations, but perhaps others could 

report back to ACIP on that.

Ms. Stinchfield (NAPNAP) indicated that testing of COVID-19 to date has mostly been single 

antigen tests, which will be going away in her area in a couple of weeks when they begin using 

a 4-plex test that includes influenza A, influenza B, respiratory syncytial virus (RSV), and 

COVID. They are certainly planning to have more data than usually because of the need to rule 

out COVID versus influenza in children. They will be happy to share this information later.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Dr. Goldman (ACP) asked whether there are any modeling data or studies suggesting VE in 

preventing disease and the timing of when the vaccine is administered, early or late, in the 

season.

Dr. Reed indicated that their group recently published an analysis by Ferdinands et al that 

assessed this to some extent and there is ongoing interest in refining models related to that as 

well.

Dr. Schaffner (NFID) commented that due to the increasing number of COVID-19 cases, the 

2020-2021 influenza season is likely to be very challenging. Many of the same individuals who 

are most vulnerable to serious complications of COVID-19 (e.g., older adults, members of 

minority groups, and those with certain chronic health conditions) also are at greater risk for the 

complications from influenza. To address this public health issue, NFID convened a 

multidisciplinary round table to explore the potential impact of influenza and COVID-19 on adults 

with chronic health conditions. Outcomes from the round table are summarized in the NFID “Call 

to Action: The Dangers of Influenza and COVID-19 in Adults with Chronic Health Conditions 

(October 2020),” which is available on the NFID website at https://www.nfid.org/wpcontent/uploads/2020/10/NFID-Call-to-Action-Dangers-of-Influenza-and-COVID-19-in-Adultswith-Chronic-Health-Conditions.pdf. All healthcare professionals are encouraged to use the 

strategies in this publication to save lives, decrease hospitalizations, and reduce the overall 

burden on the healthcare system. Let’s just vaccinate!

End-of-Season Estimates of 2019–2020 Seasonal Influenza VE 

Against Medically Attended Influenza from Three US Networks

Lisa Grohskopf, MD, MPH

Influenza Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Grohskopf reported preliminary results from three networks (US Flu VE, HAIVEN, and 

NVSN) to evaluate VE against laboratory-confirmed, medically-attended influenza in a variety of 

settings and for a variety of ages. The US Flu VE enrolls children and adults ages ≥6 months

from ambulatory settings with acute respiratory illness (ARI), including cough. This network 

consists of sites located in Washington (Mike Jackson, Lisa Jackson), Wisconsin (Ed Belongia, 

Huong McClean), Michigan (Arnold Monto, Emily Martin), Pennsylvania (Rick Zimmerman, 

Tricia Nowalk), and Texas (Manju Gaglani) with the Principal Investigators (PIs) shown in 

parentheses. The HAIVEN sites enroll adults ≥18 years of age with ARI, including cough or 

worsening cough or sputum production, from inpatient settings. This network consists of sties in 

Michigan (Arnold Monto, Emily Martin), Pennsylvania (Rick Zimmerman, Donald Middleton, 

Fernanda Silveira), Tennessee (H. Keipp Talbot), and Texas (Manju Gaglani). Three of these 

sites overlap with the US Flu VE sites. The NSVN enrolls children aged 6 months–17 years in 

inpatient settings. This network consists of sites in Washington (Janet Englund, Eileen Klein), 

New York (Geoffrey Weinberg, Peter Szilagyi), Ohio (Mary Staat), Pennsylvania (John Williams, 

Marian Michaels), and Texas (Julie Boom).

The methods overall for these networks are similar. They use a test-negative study design to 

estimate VE by comparing the odds of influenza vaccination among patients with laboratoryconfirmed influenza by reverse transcriptase polymerase chain reaction (RT-PCR) vs. patients 

testing influenza-negative who serve as the test-negative controls. Vaccination status is defined 

by receipt of any licensed 2019–2020 seasonal influenza vaccine at least 14 days prior to illness 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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onset. Vaccination status was ascertained using a variety of sources, including medical records, 

immunization registries, and/or self-report. VE is estimated as 1 – adjusted odds ratio of receipt 

of current seasonal influenza vaccination in cases compared to controls x 100%. These 

analyses are adjusted for a number of potential confounders such as study site, age, calendar 

time, and baseline health status.

The US Flu VE Network enrolled 8845 patients between November 2019 and March 2020, with 

31% testing positive for influenza. HAIVEN enrolled 3116 patients between October 2019 and 

March 2020, with 18% testing positive for influenza, NVSN-Hospital enrolled 2029 patients 

between September 2019 and May 2020, with 17% testing positive for influenza. NVSN-ED 

enrolled 2102 patients between September 2019 and May 2020, with 32% testing positive for 

influenza.

In terms of the relative distributions of the different types and subtypes of influenza viruses in 

the networks, the VE analysis included participants enrolled during each site’s specific influenza 

season. The season was defined as the dates of the first through the last influenza-positive 

case among the enrolled patients at each site. The season for NVSN was characterized by early 

circulation of B/Victoria viruses and A(H1N1)pdm09 viruses that came to a peak later and 

circulating throughout the season. For HAIVEN, there were relatively few influenza B cases. 

This is typical of disease patterns in adults and most of the B cases were observed early in the 

season. A(H1N1)pdm09 viruses represented the overall majority of infections in this network. In 

NSVN, which includes both children and adults, most early season influenza cases were from 

B/Victoria viruses, followed by a predominance of A(H1N1)pdm09 viruses during the second 

half of the season. Of note, there was very little A(H3N2) activity observed in any of the VE 

networks for this season.

In terms of VE results for the US Flu VE Network, preliminary estimates were initially presented 

during the ACIP meeting in June 2020. Final end-of-season estimates are pretty similar to these 

previous estimates. Overall VE against medically-attended A and B influenza viruses was 39%, 

with B slightly lower than expected. A/H1N1pdm09 was 30% and B/Victoria was slightly higher 

than expected at 45%, particularly since most of the B viruses were antigenically drifted from the 

vaccine components. For VE by age group, point estimates overall were fairly similar across 

age groups, with overlapping confidence intervals. For A/H1N1pdm09 viruses, VE was relatively 

low across all age groups compared with prior seasons. There was some suggestion of some 

variability between different age groups, with VE ranging from 22% to 42% and being the lowest 

in children. Again, confidence intervals overlap.

For NVSN, VE in children by virus type and further stratified by inpatient versus ED setting, 

overall VE in children was relatively high at 62% against hospitalized influenza-associated 

illness and 56% against medically-attended illness in the ED setting. For A/H1N1pdm09 viruses, 

this was 64% against hospitalized illness and 53% in the ED setting. Estimates were similar for 

B/Victoria viruses in inpatient and ED settings at 54% and 55%, respectively. Comparing VE 

estimates from children from the ambulatory US Flu VE Network to the inpatient and ED 

estimates for NVSN. Higher VE was observed in the inpatient and ED settings compared with 

the ambulatory settings, which was most noticeable for A/H1N1pdm09 viruses. The group plans 

to assess geographically overlapping sites to see if they can still observe the same trends 

restricted to similar geographic areas. In terms of further inpatient, ED, and outpatient estimates 

for children within the more restricted pediatric age categories (6 months to 16 years, 6 months 

to 4 years, and 5 to 17 years) similar trends were observed, with overall lower VE seen in the 

ambulatory network.
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For VE against hospitalization by virus type in HAIVEN compared to Flu VE, estimates were 

similar between the inpatient and ambulatory networks. In hospitalized adults, an overall VE of 

41% was seen for A and B viruses. VE for A/H1N1pdm09 was 40% and VE for B viruses was 

33%, but with wide confidence intervals due to the small number of B cases among hospitalized 

adults. For VE against influenza hospitalized and outpatient visits in HAIVEN and US Flu VE 

respectively among adults 3 non-overlapping age groups, within each age group, confidence 

intervals for VE estimates in the inpatient and ambulatory settings overlapped. For hospitalized 

adults, VE surprisingly was highest among adults ≥65 years of age with a point estimate of 54% 

and lowest and not significant in young adults 18 to 49 years of age with a non-significant VE of 

16%.

VE networks are subject to a number of limitations. In particular, networks are limited in their 

ability to assess estimates of VE by specific vaccine types and there were a number of them for 

the 2019-2020 season. Notably, there was limited use of LAIV4 among children as well as the 

existence of site-specific difference in use of vaccine types offered to patients when the different 

sites are compared. Some results, including VE for partial versus full vaccination status among 

children under 9 years of age is pending confirmation of final vaccine receipt data.

In summary, 2019–2020 influenza vaccination significantly reduced laboratory-confirmed

medically-attended influenza across all VE networks as followed: 

❑ 39% (95%CI: 32, 44) against outpatient illness aged ≥6 months (Flu VE)

❑ 62% (95%CI: 52, 71) against pediatric hospitalizations (NVSN)

❑ 56% (95%CI: 46, 65) against pediatric ED visits (NVSN)

❑ 41% (95%CI: 27, 52) against adult hospitalizations (HAIVEN)

Despite vaccine mismatch, vaccination offered important protection against B viruses in children 

for whom B viruses tend to be associated with severe disease. In children, VE trended lower for 

ambulatory compared to inpatients and ED settings, which warrants additional analysis. For 

adults, outpatient and inpatient VE were similar.

Discussion Points

Dr. Kimberlin (AAP Red Book) noted that several slides had “NVSN/Flu VE” and requested 

clarity regarding whether that was the Flu VE Network or influenza VE from the NVSN.

Dr. Grohskopf clarified that these were comparisons between the two networks, NVSN and US 

Flu VE Network, to compare hospitalized/ED within NVSN to outpatients in the US Flu VE 

Network.

Dr. Lee asked whether any information could be provided about background rates of community 

vaccination in the communities in which these individuals are coming from, and whether there 

are any differences in distribution of communities by outpatient versus hospitalized ED status. 

This relates to the question from the prior presentation about how much herd immunity can be 

accounted for, realizing that these studies are focused on direct protection.

Dr. Flannery indicated that in the US Flu VE Network, many of the sites have a population that 

is enrolled in a health system who are likely to be more vaccinated than the general population 

in those areas. That is also true because of the overlapping sites with the inpatient adult 

network. The NVSN network enrolls in children’s hospitals where not all of them are drawing 

from source populations and may be more reflective of vaccine coverage in children. When the 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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US Flu VE Network is compared to some of the other network data in the control group, or 

influenza-negative group, vaccination coverage in the US Flu VE Network tends to be higher 

than survey-based estimates for those areas. However, that may not be the case with the NVSN 

hospital and ED networks and they will have to look into this further with that group.

From the consumer perspective, Ms. McNally asked whether there has been any discussion 

regarding potential ways to evaluate VE for LAIV4.

Dr. Grohskopf indicated that uptake of LAIV4 has not been terribly high in the last couple of 

seasons, which does somewhat limit the ability to detect VE.

Dr. Flannery added that CDC is tracking VE from other networks. The best are from the UK. 

Several years ago when comparisons were done between the US and UK, data showed 

discordant results. CDC does not have data from other networks at this point for LAIV 

effectiveness against H1N1. As Dr. Grohskopf indicated, intake has been low in both the NVSN 

and the US Flu VE network, so it has not been positive to have an estimate for LIAV either 

overall or for H1N1.

Dr. Hunter if an influenza vaccine is preventing hospitalization more than all medically-attended 

infections, it meant that some vaccinated people having mild symptoms might be continuing 

their social interactions that result in some transmission. If so, he wondered what the role of 

physical distancing and masking might be in future influenza seasons.

Dr. Grohskopf said that while she did not have a specific answer to that, it is conceivable that 

people may have relatively milder sub-clinical illness. Some people do get infected with 

influenza and do not have many symptoms at all; however, that does not mean that they are not 

contagious. It remains to be seen what sort of effect the current measures being applied to 

mitigate the spread of COVID-19 will have on influenza as well. It is difficult to speculate on 

whether it would be desirable to apply those measures specifically to prevent transmission of 

influenza at this point.

Ms. Hayes (ACNM) said that anecdotally, she knows a couple of people who had a prescription 

called in for treatment for influenza without ever getting testing. This made her curious as to 

whether CDC is monitoring prescriptions in addition to monitoring testing.

Dr. Grohskopf said that at least within this activity, they are not monitoring prescriptions. The 

recommendations for the use of antivirals for influenza generally state that if the clinician 

believes that it is influenza and the person falls into a category for which the antiviral would be 

indicated (e.g., people who are at high risk of severe illness), testing is not required or the 

clinician does not have to wait for positive test results before prescribing antivirals. She was not 

aware of the proportion of individuals who do not get tested but receive a prescription. While 

she was not aware of whether CDC is actively monitoring the sale and number of anti-influenza 

medications as a way of monitoring the cases.

Dr. Cohn added that CDC does monitor prescription medications, but more so from the 

perspective of monitoring them for potential shortages. They have not used that as a way to 

assess potential influenza disease. They definitely can take this into further consideration.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Updates and WG Considerations

Lisa Grohskopf, MD, MPH

Influenza Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Grohskopf expressed gratitude to Dr. Atmar for his leadership as Chair of the Influenza WG 

during this demanding period of time and welcomed Dr. Talbot.

She reported that there have not been any policy changes. For pertinent updates, it is projected 

that approximately 194 to 198 million doses of influenza vaccine will be distributed this seasons. 

Approximately 154.6 doses had been distributed as of October 16, 2020. Influenza activity in the 

US is currently low. Based on the virologic surveillance results from FluView, the percent of 

specimens positive is about 0.3%. Data from the Influenza-like Illness Surveillance Network

(ILINet) as of Week 42 ending October 17, 2020 show very little ILI activity being reported 

through this network even relative to other recent seasons.

Regarding WG discussions and considerations, the Influenza WG had the opportunity to hear 

and discuss the presentations of burden, averted burden, and VE that were presented during 

this session. In addition, they heard the data for the trial of FLUCELVAX® Quadrivalent vaccine 

among children ≥2 through <18 years of age. While some clarifying questions were raised 

during the discussion about the design of the study population, no specific concerns were raised 

by the WG.

Discussion Points

Dr. Hunter said his impression was that if the very low rates of influenza currently occurring are 

representative of what is occurring in clinical practice, there is not a strong reason for clinicians, 

health systems, and public health to spend a lot of resources for influenza testing or diverting 

resources from COVID-19 testing to influenza at this point.

Dr. Grohskopf said that with influenza, it is known that one thing that can be anticipated is being 

surprised and not necessarily being able to predict. It is unknown what will happen with the 

remainder of the season.

Introduction

Beth Bell, MD, MPH 

ACIP, Orthopoxvirus Vaccine WG Chair

Clinical Professor, Department of Global Health

School of Public Health, University of Washington 

Dr. Bell explained that the purpose of the Orthopoxvirus WG is to update the ACIP

recommendations to include the use of JYNNEOS® to prevent orthopoxviruses in persons at risk 

for occupational exposure. WG activities have been to: 1) review and evaluate available data 

Orthopoxvirus Vaccine 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

38

about the safety and effectiveness of the newly licensed vaccine JYNNEOS®; 2) consider 

consolidating US recommendations for vaccination of persons who may have occupational 

exposures to orthopoxviruses; and 3) identify areas in need of further research for informing 

future vaccine recommendations to prevent Orthopoxvirus infection.

In terms of WG accomplishments since announcing its formation during the October 2019 ACIP 

meeting, the WG began meeting in February 2020. The WG has heard 3 background 

presentations and assessed the scope of work, and has deliberated data about use of the newly 

licensed orthopoxvirus vaccine, JYNNEOS® (also known as MVA-BN®, IMVAMUNE®, and 

IMVANEX®) for persons at risk for occupational exposure to orthopoxviruses. They reviewed the 

ACIP recommendations published over the last approximately 20 years about orthopoxviruses. 

They heard a presentation by the manufacturer about data that contributed to licensure of 

JYNNEOS® and evaluated data presented by CDC about variola plaque reduction neutralization 

test (PRNT) data and preliminary immunogenicity data from a monkeypox vaccine study in the

Democratic Republic of Congo (DRC) using JYNNEOS®.

In addition, the WG drafted PICO (Population, Intervention, Comparison, Outcomes) questions

after reviewing examples from previous ACIP WGs and identified outcomes that were 

considered “critical” or “important” and which should therefore be included in the GRADE

(Grading of Recommendation Assessment, Development and Evaluation) and the Evidence to 

Recommendation (EtR) Framework. The WG also confirmed that considerations will be limited 

to those at occupational risk pre-event and began discussions about which occupations (e.g., 

laboratorians) should be included in this update. Previous recommendations have included 

broad occupational groups. Finally, the WG determined search terms for a systematic review of 

the published literature and began that review. The goal for this session is to begin detailed 

presentations to ACIP, provide background information and the proposed PICO question in 

preparation for GRADE and EtR presentations during the next meeting, and answer questions 

about the WG’s progress and the day’s presentations. The presentations for this session 

included the following:

❑ Background

❑ Variola Virus PRNT Assay for the Assessment of JYNNEOS® Vaccinee Sera

❑ JYNNEOS® (MVA-BN) Smallpox and Monkeypox Vaccine

❑ Vaccinating Against Monkeypox in the DRC with JYNNEOS®

❑ Summary and Next Steps

Background

Brett Petersen, MD, MPH

Orthopoxvirus WG Team Lead

United States Public Health Service

Epidemiology Team Lead, Poxvirus and Rabies Branch 

NCEZID National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Dr. Petersen provided background on the orthopoxviruses, introduced the currently licensed 

orthopoxvirus vaccine, and provided a brief overview of the current ACIP recommendations.

The poxviridae are a family of deoxyribonucleic Acid (DNA) viruses that infect a broad range of 

hosts. The orthopoxvirus genus within this family includes several species that cause disease in 

humans that can lead to isolated lesions to systemic rash illness. Variola virus is the most 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

39

commonly known orthopox virus. It is the causative agent of smallpox. Vaccinia virus is the 

principal source of smallpox vaccine, causes zoonotic infections in South America, and is used 

fairly widely in biological research. Monkeypox virus causes both endemic and epidemic 

disease in Africa as well as imported cases to other countries, including the US. Cowpox virus is 

endemic in Europe. There are even newly discovered species orthopoxvirus species, including 

Akhmeta virus that was discovered in the Country of Georgia and Alaskapox virus that has 

occurred in the US.

It is the ability of orthopoxviruses to induce cross-protective immunity that has led to the use of 

vaccinia virus (VACV or VV) as a smallpox vaccine. The traditional smallpox vaccines contain 

live virus and they are replication competent. They are administered in a single dose via multiple 

puncture technique using a bifurcated needle. This produces a major cutaneous reaction or 

“take” that is actually evidence of a successful vaccination. However, these vaccine site lesions 

are infectious and can be spread to other parts of the body of the vaccinee and to other persons 

through inadvertent inoculation.

ACAM2000® is the currently available smallpox vaccine. It was licensed by FDA in August 2007. 

It replaced the previous smallpox vaccine, Dryvax®. The Dryvax® license was withdrawn by the 

manufacturer and remaining vaccine destroyed. ACAM2000® is indicated for active 

immunization against smallpox disease for persons determined to be at high-risk for smallpox 

infection [https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5708a6.htm; 

https://www.fda.gov/media/75792/download].

The ACAM2000® package insert does have contraindications and recommends that individuals 

with severe immunodeficiency who are not expected to benefit from the vaccine should not 

receive ACAM2000®. It further describes these individuals as those who are undergoing bone 

marrow transplantation or individuals with primary or acquired immunodeficiency who require 

isolation. The package insert also includes a number of warnings and precautions, including a 

“black box warning” for a series of AEs, including: myocarditis and pericarditis (suspect cases 

observed at a rate of 5.7 per 1000 primary vaccinees (95% CI: 1.9-13.3)), encephalitis, 

encephalomyelitis, encephalopathy, progressive vaccinia, generalized vaccinia, severe vaccinial 

skin infections, erythema multiforme major (including Stephanes-Johnson Syndrome), eczema 

vaccinatum resulting in permanent sequelae or death, ocular complications, blindness and fetal 

death that have occurred following either primary vaccination or revaccination with live vaccinia 

virus smallpox vaccines. The label notes that these risks are increased in certain individuals and 

may result in severe disability, permanent neurological sequelae, and/or death. However, it 

does go on to further note that persons at greatest risk of experiencing serious vaccination 

complications are often those at greatest risk for death from smallpox or other orthopoxvirus 

infections. Consequently, the risk for experiencing serious vaccination complications must be 

weighed against the risks for experiencing a potentially fatal smallpox or other orthopoxvirus

infection [https://www.fda.gov/media/75792/download].

Examples of severe vaccinia virus complications are illustrated in the following images:
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Progressive vaccinia is seen in the first image. This is a complication that occurs in persons with 

immunosuppression and leads to uncontrolled replication of the virus and often death. Eczema 

vaccinatum is seen in the second image is another complication resulting in uncontrolled 

replication of the virus, which is often seen in persons with atopic dermatitis. This also can have 

high mortality. Postvaccinial encephalitis occurs most commonly in the pediatric population. 

Fetal vaccinia has been observed with vaccinia virus vaccines in which there is vertical 

transmission of the virus to the fetus, resulting in fetal loss. Autoinoculation and inadvertent

transmission can be significant problems when the virus is spread to areas on the body with 

high risk of severe sequelae, including ocular infections that often result in blindness. 

Myopericarditis is also associated with ACAM2000®. Although the mechanism of action of the 

AE is not completely understood, it continues to be a problem. 

In an effort to improve smallpox vaccine, there have been many advances made in vaccine 

technology. The first generation vaccines were those used in the smallpox eradication campaign 

that were propagated in animals, most commonly calf skin. The second generation vaccines are 

now propagated in tissue culture and produced using modern Good Manufacturing Practices

(GMPs). However, they are almost equivalent as they are clonally derived from the first 

generation vaccines and are expected to have similar efficacy and safety. In contrast, the third 

generation vaccines are those that have been attenuated through propagation in tissue culture. 

However, these also are still produced using modern GMPs. Fourth generation vaccines also 

have been developed (e.g., protein subunit vaccines, DNA vaccines), but they are still 

experimental and not yet available.

JYNNEOS® is an example of the third generation vaccines. It is a live vaccine produced from 

the strain Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN®). It is an attenuated, nonreplicating orthopoxvirus that has a number of other names as Dr. Bell mentioned 

(IMVAMUNE®, IMVANEX®, MVA®). MVA-BN is grown in primary chicken embryo fibroblast 

(CEF) cells. Its multiple passages through these cells leaves it unable to replicate in mammalian 

cells. This vaccine was approved by the FDA in September 2019. JYNNEOS® is indicated for 

the prevention of smallpox and monkeypox disease in adults ≥18 years of age determined to be 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 8
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

41

at high-risk for smallpox or monkeypox infection. It is administered via subcutaneous injection

and is given in two doses (0.5 mL each) 4 weeks apart. Each dose (0.5 mL) is supplied in a 

single-dose vial.

The rates of solicited adverse reactions, including injection site reactions, and systemic AEs are 

similar to other modern vaccines. Of note, this vaccine has been studied in populations at highrisk for severe vaccine complications, including persons with HIV infection and adults with atopic 

dermatitis. None of the severe vaccine complications described earlier were seen in these 

populations. The frequency of AEs also were similar to those observed in healthy adults. 

Overall, the 4 SAEs for which a causal relationship to JYNNEOS® could not be excluded were 

not fatal. The 6 cases of cardiac adverse events of special interest (AESI) were considered to 

be causally related to JYNNEOS® vaccination, though none were considered serious and no 

cases of myopericarditis were identified. VE against smallpox was inferred by comparing the 

immunogenicity of JYNNEOS® to the currently licensed ACAM2000

® smallpox vaccine using a 

Plaque Reduction Neutralization Test (PRNT) and also was supported by efficacy data from 

animal challenge studies. Similarly, the VE against monkeypox also was inferred from 

immunogenicity and efficacy data from animal challenge studies [https://www.fda.gov/vaccinesblood-biologics/jynneos]. Solicited AEs, severe AEs, cardiac AEs of special interest, and VE are 

listed on the package insert as follows:

Solicited Adverse Reactions

▪ In smallpox vaccine-naïve healthy adults, the most common (> 10%) solicited injection 

site reactions were pain (84.9%), redness (60.8%), swelling (51.6%), induration (45.4%), 

and itching (43.1%); the most common solicited systemic adverse reactions were muscle 

pain (42.8%), headache (34.8%), fatigue (30.4%), nausea (17.3%) and chills (10.4%)

▪ In healthy adults previously vaccinated with a smallpox vaccine, the most common (> 

10%) solicited injection site reactions were redness (80.9%), pain (79.5%), induration 

(70.4%), swelling (67.2%), and itching (32.0%); the most common solicited systemic 

adverse reactions were fatigue (33.5%), headache (27.6%), and muscle pain (21.5%)

▪ The frequencies of solicited local and systemic adverse reactions among adults with 

HIV-infection and adults with atopic dermatitis were generally similar to those observed 

in healthy adults

Severe Adverse Events

▪ Across all studies, a causal relationship to JYNNEOS could not be excluded for 4 SAEs, 

all non-fatal, which included Crohn’s disease, sarcoidosis, extraocular muscle paresis 

and throat tightness

▪ Cardiac Adverse Events of Special Interest

▪ Among the cardiac AESIs reported, 6 cases (0.08%) were considered to be causally 

related to JYNNEOS vaccination and included tachycardia, electrocardiogram T wave 

inversion, electrocardiogram abnormal, electrocardiogram ST segment elevation, 

electrocardiogram T wave abnormal, and palpitations

• None of the cardiac AESIs considered causally related to study vaccination were 

considered serious

• No myopericarditis
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Cardiac Adverse Events of Special Interest

▪ Among the cardiac AESIs reported, 6 cases (0.08%) were considered to be causally 

related to JYNNEOS vaccination and included tachycardia, electrocardiogram T wave 

inversion, electrocardiogram abnormal, electrocardiogram ST segment elevation, 

electrocardiogram T wave abnormal, and palpitations

• None of the cardiac AESIs considered causally related to study vaccination were 

considered serious

• No myopericarditis

Vaccine Effectiveness

▪ Vaccine effectiveness against smallpox was inferred by comparing the immunogenicity 

of JYNNEOS to a licensed smallpox vaccine (ACAM2000) based on a PRNT using the 

Western Reserve strain of vaccinia virus and was supported by efficacy data from 

animal challenge studies

▪ Vaccine effectiveness against monkeypox was inferred from the immunogenicity of 

JYNNEOS in a clinical study and from efficacy data from animal challenge studies

Moving on to describe the current ACIP recommendations for orthopoxviruses, the latest 

recommendations are from 2015 and describe the use of vaccinia virus smallpox vaccine in the 

laboratory and HCP at risk for occupational exposure to orthopoxviruses. As mentioned 

previously, vaccinia virus is used as a tool in biological research, as well as a viral vector for 

recombinant vaccine. Laboratory exposures and resulting infections do occur in this population. 

To prevent these infections, ACIP does recommend routine vaccination with ACAM2000® for 

laboratory workers who directly handle a) cultures or b) animals contaminated or infected with 

replication-competent vaccinia virus, recombinant vaccinia viruses derived from replicationcompetent vaccinia strains, or other orthopoxviruses that infect humans (e.g., monkeypox, 

cowpox, and variola).

The recommendation goes on to define replication-competent vaccinia viruses that are capable 

of causing clinical infection and producing infectious virus in humans. Vaccination with 

ACAM2000® is not recommended for persons who work only with replication-deficient strains of 

vaccinia virus (e.g., MVA, NYVAC, TROVAC, and ALVAC). MVA is the strain used for 

JYNNEOS®. In terms of healthcare workers, those whose contact with replication-competent 

vaccinia viruses is limited to contaminated materials (e.g., dressings) and persons administering 

ACAM2000® smallpox vaccine who adhere to appropriate infection prevention measures can be 

offered vaccination with ACAM2000®.

ACIP lists a number of contraindications in order to prevent severe vaccine complications. The 

high-risk populations that are contraindicated are listed in the following table. Of note, even 

potential vaccinees who have household contacts among these several high-risk populations 

also are contraindicated:
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/smallpox.html

* Household contacts include persons with prolonged intimate contact with the potential vaccinee (e.g., sexual contacts) and others who 

might have direct contact with the vaccination site or with potentially contaminated materials (e.g., dressings or clothing).

† Conditions include eczema, burns, impetigo, varicella zoster, herpes, severe acne, severe diaper dermatitis with extensive areas of 

denuded skin, psoriasis, or Darier disease (keratosis follicularis).

§ Conditions include human immunodeficiency virus/acquired immune deficiency syndrome infection, leukemia, lymphoma, generalized 

malignancy, solid organ transplantation, therapy with alkylating agents, antimetabolites, radiation, tumor necrosis factor inhibitors, highdose corticosteroids, being a recipient with hematopoietic stem cell transplant <24 months post-transplant or ≥24 months but with graftversus-host disease or disease relapse, or having autoimmune disease with immunodeficiency as a clinical component.

¶ Vaccination of infants aged <1 year is contraindicated. Additionally, the Advisory Committee on Immunization Practices does not 

recommend vaccinating children and adolescents aged <18 years.

** Major cardiac risk factors include hypertension, diabetes, hypercholesterolemia, heart disease at age 50 years in a first-degree 

relative, and smoking.

ACIP also has recommendations for revaccination of laboratory and HCP. For those individuals 

working with vaccinia viruses, the recommendation is that they be revaccinated at least every 

10 years. Those working with more virulent orthopoxviruses like variole or monkeypox should be 

vaccinated every 3 years. 

There also is a 20031recommendation document describing the use of smallpox vaccine in a 

pre-event vaccination program. These recommendations do recommend smallpox vaccination 

for both Smallpox Response Teams and Smallpox Health-Care Teams with a goal of having a 

cadre of vaccinated individuals who are able to investigate in the event of a possible smallpox 

outbreak and to provide care for any initial smallpox cases. The 2003 recommendations do not 

provide recommendations, advice, or guidance for revaccination. A memo was produced in 

October 2008 to address this issue2. In this memo, it was recommended that individuals 

vaccinated under this pre-event smallpox program would only be re-vaccinated on an “as 

needed” or “out-the-door basis” in the event of an emergency 

[

1https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/smallpox.html; 

2https://www.cdc.gov/smallpox/pdfs/revaccination-memo.pdf].

 

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Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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With respect to how much vaccine is actually being distributed, all of the ACAM2000® is 

provided by CDC’s Drug Services. They receive approximately 100 requests for ACAM2000®

per year. Vaccine is distributed as 100-dose vials. This number of requests is believed to 

represent approximately 100 to 200 individual vaccinated per year. Of these requests, about 5 

are for Smallpox Response Teams, which may represent 5 to 10 individuals per year. The vast 

majority of vaccine that is currently being administered is for laboratory and healthcare worker 

populations.

Discussion Points

Dr. Lee asked whether other than nurses and physicians there are HCP who might be exposed 

to potentially contaminated materials who would be important to consider as well. For example, 

is there any concern about environmental service workers handling contaminated dressings 

from wound care.

For ACAM2000®, Dr. Petersen indicated that those who they expect may be exposed would be 

those who are administering ACAM2000®, those making follow-up visits to evaluate vaccine site 

lesions, or those who are taking care of people who are receiving experimental recombinant 

vaccinia virus vaccine. It is not a large population and is anticipated to be comprised largely of 

nurses or physicians. That is who the HCP recommendation is really directed toward. If 

contaminated dressings are taken care of according to recommendations, they should be 

placed in biohazard bags with the addition of bleach or another viricidal agent. If those 

precautions are being followed, there is very little risk that there would be any potential 

exposures to others in environmental services or other sectors.

JYNNEOS®(MVA-BN®) Smallpox and Monkeypox Vaccine

Heinz Weidenthaler, MD

Vice President, Clinical Strategy

Bavarian Nordic

Dr. Weidenthaler provided: 1) background on smallpox orthopoxvirus vaccines and JYNNEOS®

(MVA-BN®); 2) a summary of the safety data and FDA approved label of JYNNEOS®; and 3) an 

overview of clinical data supporting JYNNEOS® approval in terms of the Phase 3 non-inferiority 

trial versus replicating smallpox vaccine, immunocompromised subjects, and durability data.

In terms of why Bavarian Nordic developed a vaccine knowing that smallpox has been 

eradicated since the late 1970s, smallpox may remain a biosecurity threat especially taking into 

account that de novo synthesis of orthopoxviruses is technically feasible. In 2018, Noyce et al 

reported on an infectious horsepox virus from commercially available DNA fragments. There is 

waning population immunity after cessation of smallpox vaccinations. Given that there are no 

longer routine vaccinations, the younger half of the population has never received a poxvirusbased vaccine. This makes the population a lot more vulnerable to poxvirus infections. Natural 

disease remains including monkeypox, camelpox, and other animal reservoirs for orthoxpoxes. 

There also is the potential for accidental releases of othropoxviruses in laboratories or research, 

or resurface of old samples. In 2014, live smallpox was discovered in storage in the US.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Monkeypox is a global threat beyond the African-endemic countries. Some recent cases of 

travelers who have brought infection into other countries, including secondary transmissions to 

healthcare workers in the UK. The complications of replicating smallpox vaccines also can be 

an issue. The more recent complication identified was myopericarditis, which was identified only 

after a smallpox eradication campaign when the vaccines were used in the post-911 setting in a 

large-scale vaccination campaign. Based on that experience, there has been a very close focus 

on cardiac adverse events during the development program of JYNNEOS®. This product was 

finaly developed as a safe alternative smallpox vaccine to the previous replicating vaccines. 

They also had in mind that there ware a number of populations who cannot receive replicating 

smallpox vaccines, so Bavarian Nordic wanted to create someting that is suitable for all 

populations.

JYNNEOS® is a live, attenuated, non-replicating strain of Modified Vaccinia Ankara (MVA), 

indicated for prevention of smallpox and monkeypox disease. It has been FDA-approved since 

September 24, 2019 for adults ≥18 years of age determined to be at high-risk for smallpox or 

monkeypox infection. In terms of the safety profile, it is important to note that there has been no 

signal of inflammatory cardiac disorders. It is suitable for all populations, including immunocompromised persons. The standard dose regimen per the approved label is subcutaneous 

injection of 2 doses 4 weeks apart.

This table offers a high-level overview of the development program Bavarian Nordic has been 

running over the past 2 decades, which has included the enrollment of a variety of populations 

(e.g., healthy, atopic dermatitis, immunocompromised, elderly, vaccinia-naïve, or vacciniaexperienced populations):

 

 

 

 

 

  

  

 

 

 

 

 

 

 

 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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To summarize the safety data based on these 22 completed trials with 7871 subjects, the vast 

majority of AEs have been local injection site reactions that were mild to moderate and resolved 

rapidly without intervention. No trends or clusters have been observed for unexpected or serious 

adverse reactions. There were 6 cases of cardiac AESIs (0.08%) that were considered to be 

causally related to vaccination. None of these were considered serious and there have been no 

signals for cardiac inflammatory disorders in any MVA-BN clinical trial or in the development 

program as a whole. There is no clinically relevant difference between vaccinia-naïve and 

experienced populations or healthy and at-risk populations, including subjects with atopic 

dermatitis and HIV. The safety profile of MVA-BN has been confirmed in approximately 40,000 

subjects exposed to MVA-BN-Filo as part of Janssen’s heterologous Ebola vaccination regimen 

[References: JYNNEOS® Prescribing Information, Janssen MVA-BN-Filo data on file Volkmann 

(2020), Vaccine. 2020 Oct 17;S0264-410X(20)31091-4. doi: 10.1016/j.vaccine.2020.08.050].

Because of the experience with the replication vaccines in terms of myopericarditis, the 

development program included active cardiac monitoring of all subjects that included targeted 

physical examinations, electrocardiograms (ECGs), and Troponin testing. The inclusion criteria 

included Troponin <2xULN, ECG without clinically significant findings, and no previous cardiac 

diseases history. Among the cardiac AESIs reported, 6 cases (0.08%) were considered to be 

causally related to JYNNEOS® vaccination and included tachycardia, electrocardiogram T wave 

inversion, electrocardiogram abnormal, electrocardiogram ST segment elevation,

electrocardiogram T wave abnormal, and palpitations. None of the cardiac AESIs considered 

causally related to the study vaccination were considered serious. There were no cases of 

myocarditis in in over 7800 vaccinated subjects [JYNNEOS Prescribing Information ZitzmannRoth (2015), PLoS One, 16-Apr-2015, DOI:10.1371/journal.pone.0122653 Elizaga (2013), PLoS 

One, 17-Jan-2013, DOI:10.1371/journal.pone.0054407 Volkmann (2020), Vaccine. 2020 Oct 

17;S0264-410X(20)31091-4. doi: 10.1016/j.vaccine.2020.08.050].

In terms of special populations, the cardiac safety of JYNNEOS® also was investigated in HIVpositive (n=696), atopic dermatitis (n=381), and elderly (n=120) subjects. Elderly subjects in the 

trial had less stringent inclusion/exclusion criteria. This allowed for a previous history of 

myocardial infarction >2 year previously; up to a 25% risk of major cardiac events using cardiac 

risk calculator; allowing subjects on chronic, stable medication such as low-dose acetylsalicylic 

acid (ASA) to participate. The trial with older subjects using MVA-BN was in 120 subjects aged 

56+ among whom 42 subjects were aged 65+. No differences were observed in the cardiac 

safety profile as compared to healthy populations, and there were no cases of ischemic or 

inflammatory cardiac disorders in special, vulnerable populations [Elderly: Greenberg (2016). 

PLoS One. 2016 Jun 21;11(6):e0157335. doi: 10.1371/journal.pone.0157335. HIV-positive: 

Greenberg (2013). J Infect Dis. 2013 Mar 1;207(5):749-58. doi: 10.1093/infdis/jis753 Overton 

(2015). Open Forum Infect Dis. 2015 May 5;2(2):ofv040. doi:0.1093/ofid/ofv040 Overton (2020). 

Vaccine. 2020 Mar 4;38(11):2600-2607. doi: 10.1016/j.vaccine.2020.01.058. Atopic dermatitis: 

von Sonnenburg (2014). Vaccine. 2014 Sep 29;32(43):5696-702. doi:10.1016/j.vaccine. 

2014.08.022 Greenberg (2015). PLoS One. 2015 Oct 6;10(10):e0138348. doi: 10.1371/journal. 

pone.0138348].
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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This table summarizes the comparison of the traditional smallpox vaccine to the JYNNEOS®

(MVA-BN) vaccine:

Replicating Smallpox Vaccines Non-Replicating JYNNEOS® (MVA-BN)

❑ Based on replicating virus strains

❑ Single dose by scarification using a 

special bifurcated needle

❑ Cause a major cutaneous reaction 

(“take”); only historical measure of 

efficacy (protection)

❑ Vaccines associated with autoinoculation 

and accidental infection of others

❑ Not suitable for immune compromised or 

people in close contact with risk 

populations

❑ Myocarditis in up to 1 in 200 vaccinees

❑ Non-replicating in human cells

❑ Administered subcutaneously, 2 doses 4 

weeks apart

❑ No vaccine take is induced

❑ Cannot cause transmission to self or 

others

❑ Designed for the general population 

including immune compromised

❑ No myocarditis cases in >10,000 

subjects dosed (>50,000 with the MVABN vector platform)

To summarize the clinical data, the co-primary objectives of the JYNNEOS® (MVA-BN) Phase 3

head-to-head non-inferiority trial vs. ACAM2000® were immunogenicity and efficacy:

Immunogenicity 

Non-inferiority of JYNNEOS® (MVA-BN) compared to ACAM2000® in terms of vaccinia specific 

PRNT antibody response at the Peak Visits (Day 42 for Group 1 and Day 28 for Group 2). 

Endpoint: PRNT GMT at the Peak Visits.

Efficacy

Showing that vaccination with JYNNEOS® (MVA-BN) prior to administration of ACAM2000®

results in an attenuation of take in terms of Maximum Lesion Area (MLA). Endpoint: MLA in mm2

after scarification with ACAM2000®.

The conclusions from this Phase 3 trial were that the Peak Visit antibody responses (based on 

PRNT and ELISA GMTs) induced by JYNNEOS® are non‐inferior to those elicited by the 

licensed replicating smallpox vaccine ACAM2000®, which are considered protective. The 

attenuated “take” and accelerated healing time observed in subjects who received JYNNEOS®

prior to scarification with ACAM2000® shows that JYNNEOS® is able to suppress the viral

replication induced by ACAM2000®. JYNNEOS® is safe and well-tolerated in vaccinia‐naïve 

healthy subjects. JYNNEOS® shows significantly better tolerability as compared to the standard 

single‐dose ACAM2000® vaccination regimen. JYNNEOS® shows equal induction of neutralizing 

antibodies compared to ACAM2000® post a single vaccination, at a time when ACAM2000® is 

considered efficacious based on “take.”

To summarize the Phase 2 data in immunocompromised subjects, increasing either the dose or 

the number of JYNNEOS® vaccinations shown to be safe and well-tolerated when compared to 

the standard 2‐dose regimen. No clinically relevant differences were observed between the 

different doses/schedules. This study confirmed the established standard dose and regimen in 

terms of immunogenicity for use in a more severely immunocompromised, vaccinia‐naïve 

population with HIV infection.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Durability data come from the Phase 2 core study and a 2-year follow-up boost study, 

NCT00316524 and NCT00686582. The core study was a Phase 2, partially randomized, 

partially double-blind, placebo controlled study with immunogenicity and safety endpoints. This 

trial enrolled 745 healthy adults into the following 4 groups:

❑ Vaccinia-naive subjects: JYNNEOS® 2 doses 4 weeks apart

❑ Vaccinia-naive subjects: JYNNEOS® single dose

❑ Vaccinia-experienced subjects: JYNNEOS® single dose

❑ Vaccinia-naive subjects: Placebo

The boost study was a Phase 2 open-label trial that re-enrolled a subset of participants from the 

initially vaccinia-naive JYNNEOS® dose groups with immunogenicity and safety endpoints. A 

single JYNNEOS® boost vaccination was administered to 152 subjects 2 years after the initial 

regimen. A single boost vaccination with JYNNEOS® in subjects primed with either 1 or 2 doses 

of JYNNEOS® 2 years earlier elicits an immune response equal or higher than the initial peak 

following the standard 2-dose schedule. Antibody responses post-boost at the 2 years timepoint 

are already very high at the one-week readout, indicating a strong memory response.

In summary, JYNNEOS® has a favorable safety profile, with significantly fewer overall AEs as 

compared to ACAM2000® and no signal of inflammatory cardiac disorders. Immune responses

are comparable or higher than those with replicating smallpox vaccines. Boost data at the 2-

year timepoint indicate a strong memory response, irrespective of a 1- or 2-dose initial 

vaccination regimen. JYNNEOS® is easy to administer via subcutaneous injection, is suitable for 

prevention of smallpox and monkeypox in the general adult population, and does not require 

exclusion of populations contraindicated for replicating vaccine.

Discussion Points

Dr. Atmar recalled that MVA was originally developed in the 1970s to somewhat attenuate the 

response to the vaccinia vaccine and to be used in immunocompromised patient populations, 

which was around the time that smallpox was being eradicated. Looking at these data from a 

couple of decades ago, it was difficult to tell what kind of efficacy data there were against 

smallpox when administered alone. He asked whether Dr. Weidenthaler was aware of any 

efficacy data with an MVA-like construct against smallpox in the historical studies.

Dr. Weidenthaler replied that this brought them back to the historic roots of the company. This 

product was initially developed in the Bavarian State Vaccination Institute in the 1960s and 

1970s and was, indeed, registered in Germany and was administered in 120,000 children in 

Germany in the early 1970s. It was initially supposed to be a pre-vaccination for the replicating 

smallpox vaccines. Interestingly, he was born in 1973 and was one of the children in Bavaria 

who received it. He never received the replicating vaccine after that because they were 

discontinued roughly at the same time. When the 120,000 doses of MVA were administered in 

Germany, there was no longer active circulating smallpox in Germany. This is why there is a 

large body of experience in terms of safety, but safety was not captured at that time in the way 

that is now according to current standards. In terms of efficacy, it is probably not possible to 

have a meaningful readout when it was given in a geographic region where smallpox was not 

circulating at the time.

Regarding the primary safety study for JYNNEOS® vaccine, Ms. Bahta inquired as to how long 

the 6 cases of cardiac AESIs thought to be causally related to JYNNEOS® vaccination were 

followed.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Dr. Weidenthaler responded that it depended upon the trial. Most of the trials had a standard 6-

months follow-up period. There was an initial period of 4 weeks post-vaccination during which 

the subjects had frequent site visits and the targeted physical exams. In all of the trials, there 

has been a least a 6-month long-term follow-up that was conducted via phone conversation. 

One of the trials had a 1-year follow-up.

Dr. Kimberlin (AAP Red Book) asked whether Dr. Weidenthaler could further describe any 

possible additional studies or exploration for indication in pediatric patients, given that 

monkeypox can have pretty devastating effects in children.

Dr. Weidenthaler indicated that for the smallpox development that they initially had in mind, they 

have a pediatric waiver for that indication because in the absence of smallpox, there was an 

agreement that it would be unethical to perform this intervention and trial in children. The last 

cases of monkeypox were imported into the US in 2003. Monkeypox is no longer circulating in 

the US at this time. Therefore, it is not feasible from an ethical perspective to run pediatric trials 

in the US. Such trials probably could be run in African Countries. Some data are soon to be 

published about MVA as a vector platform. The MVA-BN construct is used as the boost 

component of Janssen’s heterologous Ebola vaccination prime boost regimen. They have 

generated quite a lot of pediatric data that is soon to be published. Bavarian Nordic is trying to 

combine this with data that they have previously generated in pediatric populations with other 

recombinant products in pediatric populations, and hope to be able to provide a more 

comprehensive overview of that in the near future. There are no plans at this time to run a 

specific pediatric trial for human smallpox or monkeypox with this vaccine.

Variola Virus PRNT Assay for the Assessment of JYNNEOS® Vaccinee Sera 

Christina Hutson, PhD

Lead, Virus-Host Molecular Interactions Team

Poxvirus and Rabies Branch

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Dr. Hutson gave a presentation on the Variola Virus PRNT assay for the assessment of 

JYNNEOS® vaccinee sera. All of the known remaining variola virus stocks are only in two 

repositories in the world, one located at the CDC in the US and one in Russia. All studies with 

live variola virus must be conducted in a Biosafety Level (BSL)-4 laboratory and are all highly 

regulated and must be approved by the WHO.

In collaboration with Bavarian Nordic, CDC sought and obtained WHO approval to examine 

serum from a JYNNEOS® non-inferiority clinical study. This was the Phase III clinical trial that 

Dr. Weidenthaler mentioned with 200 vaccinia-naïve subjects that assessed vaccination with 

JYNNEOS® versus ACAM2000®. Sera was taken at pre and peak time points post-vaccination, 

with the peak time points differing for the two vaccine regimens. FDA had a primary endpoint of 

vaccinia virus Western Reserve (VACV-WR) neutralization; however, they did request that a 

subset of samples be tested directly against variola viruses that had not been used in the 

eradication campaigns.
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CDC changed the parameters of its assay to make it more similar to Bavarian Nordic’s PRNT 

assay and to increase objectivity and quality control (QC). After these changes, CDC performed 

reproducibility and sensitivity evaluation of the variola PRNT. These results were written up and 

submitted to the FDA as a Redevelopment Report. In addition, an Analytical Plan (AP) was 

submitted that summarized the method, samples, statistical methodology, responsibilities, and 

timelines for testing clinical trial samples in the variola PRNT.

There are some slight differences in the PRNT protocol depending upon the virus used. VARV 

and serum can be incubated overnight. Twelve dilutions are done starting with 1:10 and going 

out to 1:20,480 and those are run in duplicates. After that overnight incubation, the monolayer 

with that virus/serum combination is inspected for 1 hour before adding overlay. This is allowed 

to grow for 96 hours in the case of variola. After 96 hours, the crystal violent stains are added to 

visualize plaque. Any virus that has not been neutralized can be seen as a plaque or clearing of 

the cells. One of the QCs implemented for the Bavarian Nordic PRNT included the use of a CTL 

analyzer, which allowed automated counting of the plaques. This also allowed for some 

additional QC measures such as if greater than 20% of the monolayer is removed, that well is 

automatically rejected. Alternatively, if there is some monolayer that is missing but it is less than 

20%, the CTL will actually normalize the plaque counts to that well to be utilized.

Once the Redevelopment Report and the AP were approved by the FDA, CDC received a total 

of 200 blinded samples organized into batches of 100 pre-vaccination samples (50 per vaccine)

and 100 post-vaccination samples (50 per vaccine). Each batch contained 4 samples of preand post-vaccination serum from 1 JYNNEOS® vaccinated individual and 1 ACAM2000®

vaccinee. If one sample failed QC testing, the entire batch would be repeated. Once testing was 

finished, the 50% neutralizing titers of JYNNEOS® vaccinees trended lower than ACAM2000®

vaccinees, but this was not statistically significant. Some additional comparisons were done, 

such as the average fold rise and the proportion of group to reach 4x or 8x rise in titers. None of 

those comparisons showed a statistically significant difference.

In summary, in the absence of a dermatologic “take” in these next generation vaccines, it is 

really important to determine neutralization in vitro as a surrogate measure of efficacy. VARV 

neutralization is particularly informative as a surrogate measure of smallpox vaccine efficacy

when the vaccine was not used during the eradication campaign. These data provided 

increased confidence that this vaccine would be protective against smallpox. JYNNEOS®

vaccinees trended lower than ACAM2000® vaccinees, with no statistically significant difference. 

CDC has received WHO approval to do additional in vitro work with live VARV to examine the

long-term titer/neutralization levels from JYNNEOS®. Specifically, CDC hopes to test some of 

the samples from the DRC study.

Discussion Points

Dr. Atmar observed that there appeared to be about a 4-fold difference in neutralizing antibody 

titer between ACAM2000® and JYNNEOS®, which is often thought to be important. Although, it 

is unknown what level of antibody is protective in people. He wondered what level they were 

expecting to detect based on the analytic plan in terms of what kind of power they had.

Dr. Hutson replied that this is certainly not meant to be a non-inferiority study. This was just a 

subset of samples from that study. They had enough numbers to do a statistical comparison, 

but it was not meant to determine if JYNNEOS® was inferior or non-inferior to ACAM2000®. 

They certainly could say that there is a trend in this group of individuals assessed, but it was not 

statistically significant and the numbers were not high enough to determine non-inferiority.
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Vaccinating Against Monkeypox in the DRC JYNNEOS®

Brett Petersen, MD, MPH

Orthopoxvirus WG Team Lead

United States Public Health Service

Epidemiology Team Lead, Poxvirus and Rabies Branch 

NCEZID National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Dr. Petersen provided an introduction to an ongoing study on Vaccinating Against Monkeypox in 

the DRC JYNNEOS®. By way of background monkeypox is caused by the monkeypox virus, 

which is an orthopox virus. Its clinical presentation is very similar to smallpox. It presents with a 

disseminated vesicular/pustular rash associated with systemic symptoms of fever, malaise, and 

lymphadenopathy. It is acquired primarily through zoonotic transmission following contact with 

infected animals, although there is human-to-human transmission via respiratory droplets and 

lesion exudates. The animal reservoir is believed to be small rodents (e.g., rope squirrel, 

Gambian rat, dormouse).

Monkeypox is being increasingly recognized as a re-emerging disease. There have been 

increases in monkeypox case reports from many countries that have not reported monkeypox in 

the past or have not reported them for many years. There have been exportation events as well 

to the US in 2003, the UK 2018, Israel in 2018, Singapore in 2019, and the UK in 2019 [Durski, 

KN et. al Emergence of Monkeypox – West and Central Africa 1970-2017 MMWR. 2018 Mar 16; 

67(10):306-310].

All recent exportation events originated in Nigeria. An index case was reported in Nigeria in 

September 2017, with 183 confirmed cases and 9 deaths reported in 18 states through 

December 2019. Sporadic cases continued to be reported, with 6 suspected cases reported in 

December 2019. The majority of confirmed cases (85%) are from 4 states: Lagos, Delta, Rivers, 

and Bayelsa. The experience in Nigeria has highlighted the nature of re-emerging infections 

with monkeypox, as well as pointing out how much is not known about how and why monkeypox 

appears to be re-emerging [Outbreak of human monkeypox in Nigeria in 2017-18: a clinical and 

epidemiological report. Yinka-Ogunleye A, Aruna O, et el. Lancet Infect Dis. 2019 

Aug;19(8):872-879. https://ncdc.gov.ng/themes/common/files/sitreps/].

Looking at monkeypox in the DRC, 5060 monkeypox cases were reported with 103 deaths 

(CFR 2%) from 18 provinces in 2019. The CDC has engaged with the DRC for many years to 

provide enhanced surveillance in one of the provinces where monkeypox is endemic, the 

Tshuapa Province. As part of this collaboration and program, approximately 500 samples from 

suspect monkeypox cases are submitted per year of which approximately 300 are confirmed to 

be cases. The annual incidence rate in this province is calculated to be 4.4/10,000. Of note, the 

annual incidence in healthcare workers is almost 4 times the overall incidence rate at 

17.4/10,000. That means that 1/100 confirmed cases have been among healthcare workers.

In terms of preventing monkeypox, it can be quite difficult to implement public health measures 

that would prevent the disease in these austere environments with limited resources. Even 

simple measures like avoiding contact with animals that could harbor the virus, isolating infected 

patients, using personal protective equipment (PPE) when caring for patients, and practicing 

good hand hygiene after contact with infected animals or humans can be difficult to accomplish 

in these areas. Smallpox vaccination administered 3–19 years previously appeared to provide 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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over 85% protection against monkeypox disease acquisition in studies of close contacts with

cases. These studies were performed during the smallpox eradication era. However, routine 

smallpox vaccination has not been implemented as a prevention measure for monkeypox 

largely due to the safety profile of the traditional smallpox vaccine.

With the advent of third generation vaccines, there has been interest evaluating these vaccines 

for the prevention of monkeypox as this does provide a unique opportunity to evaluate this 

vaccine in an area where there is actual natural orthopox virus infection. With this in mind, CDC 

began a collaboration with the DRC Ministry of Health and the Kinshasa School of Public Health

in 2015 to develop an Investigational New Drug (IND) Protocol to evaluate JYNNEOS® vaccine 

in a prospective cohort of adult healthcare workers at risk for monkeypox in the DRC. The 

objectives of the study were to: 1) evaluate the safety of JYNNEOS® vaccine; 2) evaluate the 

immunogenicity of JYNNEOS® vaccine; and 3) evaluate the effectiveness of JYNNEOS®

vaccine to prevent naturally occurring human monkeypox.

In terms of the study design, the vaccine was administered to study participants on Days 0 and 

28. All participants are monitored over a 2-year time period and study visits occur on Days 0, 14

(on a subset of participants), 28, 42, 180 and 1 year, 1.5 years, and 2 years. Blood draws are 

performed during each study visit for immunogenicity evaluation. On each vaccination day, and 

AE diary is given to the vaccine recipient for the safety analysis. Exposure diaries are completed 

throughout the study to document any contact with confirmed or suspect monkeypox patients, 

as well as any disease occurrence in the study participants.

The study began with the enrollment and vaccination of 1000 participants in Kinshasa and 4 

health zones in the Tshuapa Province in 2017. These individuals received the liquid frozen 

formulation of the vaccine. Over 97% received 2 doses. There have been excellent return rates

for follow-up study visits, with over 88% returning through the 2-year timepoint. This first cohort 

has completed the 2-year monitoring period. No monkeypox disease was identified among 

participants during that 2-year monitoring period. Although, 1 study participant who was 

vaccinated with JYNNEOS® in May and June 2017 developed monkeypox in November 2019

and was identified through routine surveillance.

Due to the success of the first cohort, there was interest in expanding the study to evaluate a 

lyophilized, or freeze dried formulation of the vaccine. In this cohort, 600 participants were 

enrolled and vaccinated in 2 health zones in the Tshuapa Province in 2019. Over 97% of 

participants received 2 doses, and return rate again were excellent for follow-up study visits at 

88% by Day 180. To date, no vaccine-associated SAEs have been reported and no monkeypox 

disease has been identified among participants.

From the first cohort of 1000 participants who received the liquid frozen formulation, some 

preliminary safety analyses have been completed. Local vaccine site reactions and general 

systemic symptoms were observed in study participants, although the frequency was quite 

lower than what was observed previously in clinical trials. When comparing previously 

vaccinated naïve individuals, generally less adverse reactions were observed in those who were 

previously vaccinated as expected with largely no significant differences.

In terms of SAEs, there have been 12 study participant deaths reported in the first cohort. 

However, none of these has been determine to be vaccine-associated as other etiologies were 

identified, including: acute hepatitis and severe anemia; skin infection of the leg (distant from the 

vaccine site injection); cerebral vascular accident secondary to hypertension; alcohol 

intoxication (2); cerebral vascular accident secondary to HIV infection and cryptococcal 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

53

meningitis; traumatic head injury; acute gastroenteritis associated with severe malaria; 

opportunistic infections/AIDS; hepatic cirrhosis; suspected complications of tuberculosis; hepatic 

cancer, and hepatitis B virus infection. For reference, the estimated annual average crude death 

rate in the DRC is 9.6 deaths/1000 population* compared to what was observed with this cohort 

of 6 deaths/1000 annually among study participants [*United Nations Department of Economic 

and Social Affairs. Additionally, 4 female study participants became pregnant within 6 months of 

receiving the study vaccine despite being advised to avoid becoming pregnant for one month 

(28 days) after each study vaccine administration. These pregnancies were followed up through 

delivery, with 3 participants delivering healthy babies and 1 participant experiencing a 

spontaneous abortion at an estimated 37 weeks gestation based on her last menstrual period. 

For background, the estimated annual infant death rate in the DRC is 65 infant deaths/1000 live 

births* (https://population.un.org/wpp/Download/ Standard/Mortality/).

CDC has begun performing immunogenicity testing on the serum samples collected. A total of 

6734 samples were available for testing from 999 participants in the first round of testing. An 

ELISA was adapted for use to specifically test responses to JYNNEOS® vaccine and preliminary 

IgG and IgM serology analysis have been completed. In terms of the seroconversion rates, 99% 

of participants seroconverted to IgG and 24% seroconverted to IgM. To go into more detail 

about the IgG immune response broken out by naïve and prior vaccination, the kinetics of the 

antibody response is as expected with those with prior vaccination developing seroconversion at 

earlier timepoints compared to those who are naïve. There was no significant difference on Day 

42 of the maximal immune response in terms of seroconversion rates with 99% of those naïve 

and 97% of those previously vaccinated seroconverting. Even out to Day 730, the 2-year 

timepoint, seroconversion is being maintained in 77% of all samples and being slightly higher in 

those with prior vaccination (81%) compared to those who are naïve (71%). Looking briefly at 

the IgM response, 24% of participants seroconverted among all of the samples. Seroconversion 

was higher among naïve (50%) versus prior vaccinated (11%) participants. That would be the 

expected pattern. Providing a gross comparison to seroconversion rates from prior studies from 

the Bavarian Nordic investigators’ brochure of clinical trial data available to date, the CDC 

seroconversion rates are largely comparable to those previously reported results.

As mentioned, this is an ongoing study and much work remains to be done. In terms of 

evaluating effectiveness, CDC has collected the surveillance data from areas of enhanced 

surveillance and plans to evaluate that to determine whether there is a way to evaluate 

effectiveness. They also will analyze the reported exposures to monkeypox. With regard to 

safety, the safety data analysis including comparisons with previously collected clinical study 

data will be finalized. For immunogenicity, there are plans to quantitate the neutralizing antibody 

response to vaccination and the CDC is currently performing the PRNT analyses on these 

samples, which they hope to present to ACIP during a future meeting. CDC will continue to 

monitor the second cohort of study participants who received the freeze-dried formulation of the 

vaccine, which will include complete safety, effectiveness, and immunogenicity analyses and a 

comparison of the liquid frozen and freeze-dried vaccine formulations. There also is interest in 

additional studies with this cohort to provide evidence of persistence of immunity after the 2-

year time point. With this cohort, there is a plan to conduct a vaccine booster study in which a 

single dose of JYNNEOS® will be administered to a cohort of previous study participants 3 years 

following primary vaccination with JYNNEOS®. For this study, serum will be collected at Days 0, 

7, and 14 for immunogenicity and evaluation of memory response.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Discussion Points

Dr. Hayes (ACNM) pointed out that if a woman delivers at 37 weeks after her last menstrual 

period, it is not considered a spontaneous abortion. It is considered a pre-term birth and would 

be documented as being born alive or deceased.

Dr. Frey asked whether Dr. Petersen could share any additional information on the participants 

who developed monkeypox as it related to any underlying conditions, comorbidities, or the 

antibody response to the vaccine and how severe the disease actually was.

Dr. Petersen indicated that with the individual who was vaccinated but later developed 

monkeypox, they are still trying to gather more clinical information to determine whether that 

was a severe case or whether it may have been ameliorated from the vaccination. What they do 

know is that the individual was 42 years of age at the time of vaccination, 45 years of age at the 

time of illness, male, reported being previously vaccinated, had a scar suggesting previous 

vaccination, did not report any significant past medical history, and were taking some 

medications at the time of vaccination (e.g., paracetamol and artemether-based combination 

therapy for malaria). The samples from this individual have been identified and this does appear 

to be someone who did not develop a robust immune response.

Dr. Hunter commented that he cared for one of the cases of monkeypox in 2003 for a few days 

in a community hospital before the patient was transferred to an academic medical center, and 

could attest that preventing monkeypox would have significant benefits to the utilization of 

medical and public health resources in that type of situation. He was thinking theoretically that in 

a clinical setting, having a vaccine that does not involve an infectious lesion could have 

significant advantages.

Dr. Petersen agreed that this type of vaccine could play a role in prevention of monkeypox, 

which was a large part of the rationale behind conducting this study to demonstrate feasibility 

and effectiveness in the setting of natural monkeypox infection.

Dr. Kimberlin (AAP Red Book) asked Dr. Petersen to comment on antiviral drugs that have 

activity, such as cidofovir or the relatively newly licensed smallpox drug.

Dr. Petersen indicated that a number of antivirals demonstrate effectiveness against 

orthopoxvirus infections. Tecovirimat is licensed for the treatment of smallpox disease. It would 

be effective based on mechanism of action and animal study data to provide benefit in treating 

other orthopoxvirus infections. Its use clinically has been limited in that there are not a lot 

orthopoxvirus infections to begin with, although it has been used in at least one infection in a 

laboratory-involved exposure. It has not been widely used to treat people with poxvirus 

infections and has not been evaluated directly to treat monkeypox. 

Dr. Kimberlin (AAP Red Book) asked whether there would be an opportunity to provide 

tecovirimat in Africa in patients who acquire monkeypox and are being followed as part of this 

study.

Dr. Petersen said that there certainly is interest in evaluating antivirals for treatment of 

monkeypox. The current limitation is resources, but there are talks to pursue effective clinical 

studies to evaluate the use of tecovirimat and other antivirals for treatment of monkeypox.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Dr. Bell requested more information about the epidemiology of monkeypox at the time of the 

clinical trials and verification of her presumption that given the expected incidence of 

monkeypox among healthcare workers in general in this area and the size of the trials, it would 

be challenging to say a lot about effectiveness.

Dr. Petersen said that even though this is an endemic disease that affects quite a few people, 

the frequency is still quite low even in these areas of high endemicity. In terms of study design 

and conducting an ideal RCT, it was not really possible to do that given the rarity of the event. 

Therefore, they designed the best study that they could under the circumstances and the data 

available. They have tried to power the study to detect a difference in these healthcare workers 

over the 2-year time period. That was the calculation that may be able to demonstrate some 

effectiveness, given the retrospective data available and reach a certain number of monkeypox 

infections over this 2-year time period. They are still in the process of evaluating that kind of 

effectiveness analysis and what they actually will be able to say. They do have the exposure 

data and do know that study participants did have contact with patients with suspect or 

confirmed monkeypox, so the hope is that the combined effectiveness analysis demonstration of 

exposures in combination with the immunogenicity will provide a convincing argument for 

effectiveness for this vaccine to prevent monkeypox.

Dr. Schaffner (NFID) recognized that out of the CDC stockpile, about 200 laboratorians receive 

ACAM2000® each year. He would think there would be many more recipients of this vaccine in 

the military each year and wondered if Dr. Petersen could comment on that to put this into 

perspective for the ACIP members to better understand how much of this vaccine is being used 

each year.

Dr. Petersen indicated that it is good to distinguish the civilian smallpox vaccine campaigns from 

the military vaccine campaigns. The numbers he quoted represented smallpox vaccines being 

used in civilians. Smallpox vaccines are being administered to Active Duty military personnel. 

Though he did not have the numbers readily available, it is in the thousands annually and he will 

provide those numbers.

ACIP Orthopoxviruses: Clinical Guidance and Next Steps

Agam Rao, MD

CAPT, US Public Health Service

Co-Lead, ACIP Rabies WG

NCEZID National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Dr. Rao pointed out that JYNNEOS® is a new vaccine for orthopoxviruses and for that reason 

the WG determined that a policy question, systematic review, GRADE, and EtR have to be 

presented to the ACIP before the committee can vote on a recommendation. The WG drafted 

this policy question, “Should JYNNEOS® be recommended for persons who are at risk for 

occupational exposure to orthopoxviruses?” This policy question is not intended to be a 

preferential recommendation for JYNNEOS® over another vaccine. It is just whether JYNNEOS®

should be recommended by ACIP at all.

For the PICO question, the “population” is persons who may be at risk for occupational 

exposure to orthopoxviruses. In the most recent update of the ACIP recommendations, persons 

who are at risk for occupational exposure include healthcare workers who administer vaccine, 

change bandages, are involved in clinical trials, research laboratorians, et cetera. The 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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“Intervention” is vaccination with JYNNEOS®. The “Comparison” is vaccination with 

ACAM2000®. The last component of the PICO is “Outcome.” The WG brainstormed about all the 

potential outcomes that could impact the committee’s decision to vote for or against 

recommending JYNNEOS®. Those outcomes that would help the committee understand the 

effectiveness of JYNNEOS® compared to ACAM2000® are prevention or reduction of 

orthopoxviral disease and immunogenicity against all orthopoxviruses. Those outcomes that 

would help explain safety are SAEs, myocarditis and pericarditis, and minor AEs. By prevention 

or reduction of disease of orthopoxvirus, the WG is accounting for the fact that some 

orthopoxviruses may be prevented by the vaccines but others may only be reduced in severity. 

Prevention, reduction, immunogenicity, SAEs, and myocarditis/pericarditis were deemed 

“critical” or “important” outcomes for deciding the policy question. Minor AEs were deemed “not 

important” for deciding the policy question. This table summarizes the completed PICO question 

drafted by the WG with the four “critical” or “important” outcomes listed in the outcome section:

Policy question: Should JYNNEOS® be recommended for persons who are 

at risk for occupational exposure to orthopoxviruses?

Population Persons who may be at risk for occupational exposure to orthopoxviruses

Intervention Vaccination with JYNNEOS®

Comparison Vaccination with ACAM2000®

Outcome

1) Prevention or reduction of disease by orthopoxviruses

2) Immunogenicity against all orthopoxviruses

3) Severe adverse events

4) Myo-/ peri-carditis 

Once the WG drafted the policy question, they began working on the systematic review of the 

published literature. With the help of the CDC librarian who has expertise in systematic review 

searches, they developed the search terms “JYNNEOS,” “Imvamune,” Imvanex,” and “Modified 

Vaccinia Ankara.” The search was limited to human data only, no animal data, and they 

searched these databases: Medline, Embase, Cochrane Library, CINAHL, NTIS, Scopus, 

Clinicaltrials.gov, and Global Index Medicus. The WG is in the process of doing title and 

abstract sorting for the 740 articles identified by this search. Once the WG completes the 

systematic review, they will conduct the GRADEing for all four “critical” or “important” outcomes. 

The WG will then complete the ACIP EtR Framework for each outcome. The WG anticipates 

being able to present all of this to the ACIP during the February 2021 meeting and possibly 

could have a vote on this policy question as soon as the June 2021 ACIP meeting.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Robert Atmar, MD

ACIP Member 

Chair, Dengue Vaccine Work Group

Dr. Atmar reported that between March 2020-October 2020, the Dengue Vaccines WG has 

engaged in a number of discussions. The WG initially reviewed the February 2020 ACIP 

Dengue Vaccines session and discussion of possible phased implementation of CYD-TDV

vaccine in Puerto Rico; heard data from Sanofi Pasteur on a CYD-TDV cost-effectiveness 

study; examined the acceptability of a CYD-TDV vaccination program for 9-16 year old children 

in Puerto Rico based on input from pediatricians, school officials, and key informant interviews; 

heard an overview of two economic analyses by a CDC ACIP health economist; reviewed 

preliminary results of a CDC Phase 1 evaluation of dengue IgG tests and their performance in 

identifying people previously infected with dengue; and reviewed initial drafts of the Evidence to 

Recommendation (EtR) results for CYD-TDV.

The WG engaged in considerable discussions about a phased approach to work out the 

logistics and feasibility of pre-vaccination screening in Puerto Rico. The discussions included 

observations that keeping an ACIP recommendation simple is desirable, although possibly 

challenging. There were suggestion that an MMWR background document could comment that

CYD-TDV vaccine poses novel challenges that would make a phased implementation 

potentially helpful. Ultimately, territorial health departments will be responsible for determining 

how to roll out the vaccine.

In terms of the WG’s discussion regarding acceptability, CYD-TDV appears acceptable to

Puerto Rico stakeholders. However, further education is needed for physicians and parents

regarding the benefits and risks. No information has been available to the WG during the past 6 

months on vaccine acceptability and feasibility in other US territories. While efforts are under 

way to obtain that information, it may not be available by February 2021.

In the Notre Dame cost-effectiveness study for which a pre-print is available, the base case 

scenario was that a diagnostic assay would have a specificity of 95% and sensitivity of 80%, 

there would be 50% dengue seroprevalence in the target population, 9 year olds would be 

vaccinated and followed over a 10-year period, with 80% of the 9 year olds screened. Based on 

that cost-effectiveness analysis, 3415 hospitalizations would be averted. There is a ratio of 18.6 

hospitalizations averted for each additional hospitalization that might occur due to vaccinating a

child who on initial screening was determined to be seropositive who was in fact seronegative 

and had not been previously infected with dengue. The Notre Dame study found incremental 

cost-effectiveness ratios (ICERs) for hospitalizations averted of $16,000 ($9,400 - $29,000) and 

quality-adjusted life-years (QALYs) of $122,000 ($74,000 - $182,000). The estimated range 

based the uncertainty of model parameters to fit the vaccine trial data that had been obtained 

previously [Espana et al. MedRxiv doi: https://doi.org/10.1101/2020.10.07.20208512].

Dengue Vaccines 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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One of the critical pieces of information that the WG is still awaiting are the pre-vaccination 

laboratory screening tests and the characteristics of those tests. The EtR judgments are 

dependent upon the performance of pre-vaccination screening tests for prior dengue infection to 

sensitively, and more importantly specifically, detect prior dengue infection. There is a second 

phase CDC evaluation of dengue IgG candidate assays showing good specificity and sensitivity 

in the primary analyses to examine early convalescent serum samples that is pending. The 

second phase testing will be assessing samples from later convalescent periods and from 

people who have been infected previously with Zika virus and a variety of other control samples. 

With the assumption that one or more of these commercially available dengue IgG assays will 

meet the international target product profile for acceptable specificity of 95% and sensitivity of 

85%, the expected judgment on benefits/harms in the WG’s initial discussion would be that it

“favors intervention.” The WG has not had discussions about what such a recommendation 

would be if an assay did not achieve the target profile.

Anticipated WG discussions over the next several months will include efforts to try to finalize the 

EtR incorporating the results of the dengue IgG lab test evaluation. These discussions are likely

to focus on health equity in terms of access to the diagnostic test and the vaccine; feasibility in 

Puerto Rico and other US territories, including the cost and availability of laboratory testing; 

whether a recommendation should be shared decision-making versus unqualified if a 

recommendation is made; and new data in an August 2020 Science paper suggesting that prior 

Zika infection enhances risk of severe dengue [Katzelnick et al, Science 369:1123-1128 (2020)].

In terms of the Dengue Vaccine WG’s 2021 schedule, the presentation topics for the February 

2021 ACIP meeting are anticipated to be CDC assessment of laboratory tests for prevaccination screening, and the EtR Framework with draft CYD-TDV recommendations. An ACIP 

vote on the CYD-TDV recommendations is anticipated for the June 2021 ACIP meeting.

In closing, Dr. Atmar posed the following questions for the ACIP members:

❑ Are there specific data ACIP would like presented?

❑ Are there other considerations the WG should address?

Discussion Points

Dr. Maldonado (AAP) asked other than hospitalization what other morbidity was taken into 

account in the Notre Dame ICER assessment and if mortality also was assessed.

Dr. Waterman indicated that the ICER assessment in the Notre Dame study looked at 

hospitalizations, severe illness, and QALYs. There were no deaths in the clinical trial, so 

mortality was not assessed in this study. Deaths with dengue are fairly rare at less than 0.1% 

with good clinical management.
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Introduction

Katherine Poehling, MD, MPH

Chair, Pneumococcal Vaccines Work Group

Dr. Poehling introduced the Pneumococcal Work Group (WG). The Pneumococcal WG’s terms 

of reference are to: 1) review current data including efficacy, effectiveness, immunogenicity,

epidemiology, and cost-effectiveness of pneumococcal conjugate and polysaccharide vaccines 

and assess the strength of the evidence; 2) review current recommendations considering up-todate evidence; and 3) revise or update recommendations for pneumococcal vaccine use as

needed.

Overview

Miwako Kobayashi, MD, MPH

Respiratory Diseases Branch

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Kobayashi briefly summarized the rationale for the last ACIP vote on pneumococcal 

vaccines in June 2019 and the reasons for reactivating the WG. In terms of the history of ACIP 

recommendations on pneumococcal conjugate vaccines (PCV), the 13-valent PCV vaccine 

(PCV13) was first recommended for use in adults with immunocompromising conditions, 

cerebrospinal fluid (CSF) leaks, or cochlear implants in 2012. In 2014, ACIP recommended 

routine use of PCV13 in series with the 23-valent pneumococcal polysaccharide vaccine 

(PPSV23) for all adults ≥65 years old. ACIP recognized that there would be a need to reevaluate this recommendation because it was anticipated that PCV13 use in children would 

continue to reduce the disease burden among adults through reduced carriage and 

transmission of vaccine serotypes from vaccinated children, or indirect effects. This table 

summarizes the EtR Framework presented during the June 2019 ACIP:

Pneumococcal Vaccines 
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The WG agreed that PCV’s greatest impact on adults has been through indirect effects from 

pediatric vaccination. Since 2014, consistent population-level impact from PCV13 use among 

older adults had not been observed and continued use of PCV13 in older adults was not 

considered to be cost-effective by usual standards. On the other hand, frequent changes in 

recommendations may negatively impact the perceived importance of future adult vaccine 

recommendations and present implementation challenges. Some WG members favored the 

scientific rationale for changing the recommendations, while others considered that the 

acceptability and feasibility issues were more important and preferred keeping the 2014 

recommendations. In 2019, ACIP voted to remove the 2014 recommendation for routine PCV13 

use among adults ≥65 years old and to recommend administration of PCV13 based on shared 

clinical decision-making for adults ≥65 years old who do not have any immunocompromising 

conditions, CSF leaks, or cochlear implants and who have not previously received PCV13. The 

recommendation for adults with these conditions was unchanged.

Currently, there are two new adult PCV products that are expected to be considered for 

licensure in 2021. One is the 15-valent vaccine (PCV15) by Merck. In addition to PCV13 

serotypes, this vaccine contains serotypes 22F and 33F. The other is the 20-valent vaccine 

(PCV20) by Pfizer. In addition to the PCV13 serotypes, this vaccine contains serotypes 8, 10A, 

11A, 12F, 15B, 22F, and 33F. All of these additional serotypes are currently included in the 23-

valent PPSV23 vaccine, which is currently recommended for all adults ≥65 years old.

Because two adult PCVs are expected to be licensed in 2021, the Pneumococcal WG was 

reactivated to review considerations for and evidence supporting the use of higher valent

pneumococcal conjugate vaccines in the general population of US adults and adults with certain

underlying conditions. In addition, the WG will present policy options for an ACIP vote following 

licensure.

Dr. Kobayashi briefly summarized the current epidemiology of invasive pneumococcal disease 

(IPD) in the US from the Active Bacterial Core (ABC) surveillance data and presented the WG 

proposed work plan. Since PCV13 replaced PCV7 in 2010, the incidence of PCV13-type IPD

declined markedly in children under 5 years of age who are targeted for vaccination. Reduction 

of PCV13-type IPD incidence also was seen in adults. The observed reduction is likely due to 

indirect effects from PCV13 use in children. In 2014, PCV13 was recommended for all adults 

≥65 years of age. However, no population level impacts were observed on PCV13-type IPD 

incidence in this age group. The trends of IPD associated with non-PCV13 types remain 

relatively stable in adults.

In 2017-2018, PCV13-type IPD accounted for approximately 23% of all IPD in children less than 

5 years of age, 30% in adults 19-64 years of age, and 27% in adults ≥65 years of age. PCV-13 

serotypes were more common than others. Serotypes 3, 19F, and 19A were the most common 

remaining PCV13 types in all age groups. Serotype 3 by itself was identified in 10% or more of 

all IPD in all age groups. The 2 additional serotypes contained in PCV15 accounted for 

approximately 13% to 16% of IPD. The additional serotypes contained in PCV20 but not in 

PCV15 accounted for 14% of IPD in adults ≥65 years of age to 21% of IPD in children less than 

5 years of age.

As mentioned earlier, PCV20 for adults is expected to be approved for licensure in mid-2021 if 

priority review is granted by the FDA. PCV15 for adults is expected to be approved in mid- to 

late-2021 depending upon the type of review that would be granted by the FDA. Licensure of 

PCV15 in children is anticipated in Q2 or Q3 of 2022 and licensure of PCV20 in children is 

projected for mid-2023.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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In the months leading to the ACIP vote, the Pneumococcal WG plans to review the following 

pieces of evidence:

❑ Immunogenicity and safety from Phase III studies for PCV15 and PCV20

❑ Epidemiology of pneumococcal disease and vaccine-preventable disease burden for:

➢ Invasive pneumococcal disease

➢ Non-invasive pneumococcal pneumonia

➢ Mortality

❑ Expected public health impact and cost-effectiveness of PCV15/PCV20, including the 

following: 

➢ Estimated direct effects in adults

➢ Estimated indirect effects from vaccine use in children

➢ Impact on health equity

❑ New evidence on the effectiveness of PPSV23

❑ GRADE and EtR to summarize the evidence

During the February 2021 ACIP meeting, the WG plans to present further details on the current 

epidemiology of pneumococcal disease, including both invasive and non-invasive disease; data 

from the Phase III clinical trials for the new vaccine products; and the policy question(s)

proposed by the WG. The WG’s current goal is to review all of the relevant evidence to have 

votes on the vaccine recommendations soon after licensure.

Discussion Points

Dr. Hunter commented that it is very unfortunate that the adult vaccines will come out before the 

childhood vaccines, given that it is going to make the ACIP’s decision about making 

recommendations extremely difficult because there will not be indirect/direct effects that would 

be very easy to figure out. 

Pablo Sanchez, MD

Chair, Cholera Vaccine Work Group

Dr. Sanchez introduced and described the Cholera Vaccine Work Group (WG). In 2017, ACIP 

recommended the cholera vaccine CVD 103-HgR (VaxchoraTM) for adult travelers 18–64 years

of age from the United States (US) to an area of active cholera transmission. This WG will now 

review more recent pediatric data to inform whether ACIP should recommend cholera vaccine 

for travelers 2–17 years of age.

The policy topic under consideration by the WG is, “Should ACIP cholera vaccine 

recommendations be expanded to include children and adolescents aged 2–17 years?” The WG 

activities to address this question will be to review available safety and immunogenicity data for 

CVD 103-HgR among children and adolescents; develop evidence-based recommendations 

Cholera Vaccines 
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using the GRADE (Grading of Recommendation Assessment, Development and Evaluation) 

approach; and eventually publish an update in the MMWR.

It is important to note that the company that makes the cholera vaccine, Emergent, has made 

the decision to temporarily discontinue product distribution as of December 17, 2020 due to 

significant reductions in demand. VaxchoraTM is the only licensed and approved cholera 

vaccine.

Discussion Points

Dr. Mark Schneider (Emergent) indicated that he was joined by his colleague, Dr. Stephanie 

Campbell, and thanked ACIP for the invitation to join the meeting and provide remarks. 

Emergent has made a very difficult decision to temporarily discontinue distribution of 

VaxchoraTM (Cholera Vaccine, Live, Oral) and Vivotif® (Typhoid Vaccine Live Oral Ty21a) due to 

market reduction in demand. Emergent continuously assesses travel data from a wide range of 

sources to include, but not limited to, government institutions, research firms, and industry 

experts that all point to a protracted recovery period for international travel due to the COVID-19 

pandemic. Pending further notification, the last shipment date for VaxchoraTM will be December 

17, 2020. Customers can continue to order the product through that date. All products being 

distributed through December 17th will have an expiration of January 2021 for Vivotif® and June 

2021 for VaxchoraTM. That said, Emergent remains fully committed to addressing the needs of 

public health and travel medicine and seeks to properly position themselves to return these 

products to market in anticipation of the return of global travel in the near future.

Dr. Cohn indicated that CDC/ACIP did not realize that Emergent was planning to speak and that 

this would not be the appropriate time to speak, given that they must follow the agenda as 

posted and not have outside companies speak unless they were previously approved. She 

requested that Emergent hold their comments at this time and that an effort would be made to 

find time on the agenda at a later time.

Mark Gibbons

President and Chief Executive Officer

RetireSafe Organization

Dr. Romero and members of the committee, good afternoon. My name is Mark Gibbons. I’m 

President and CEO of the RetireSafe Organization. RetireSafe is an organization whose 

mission is to educate and advocate on behalf of older Americans on issues including Social 

Security, Medicare, health, safe retirement, and financial well-being. We believe that older 

Americans must have a voice in public healthcare policies that affect them. Older Americans are 

an important population. Currently, there are nearly 70 million Americans over the age of 60. 

Due to immune system decline as part of aging, as well as the prevalence of chronic disease 

comorbidities, many of them are particularly vulnerable to infectious diseases such as influenza,

pneumococcal pneumonia, and of course COVID-19. Vaccines for these and other conditions 

can truly be a matter of life or death for so many. We must keep this population, their increased 

risk, and their access needs at the forefront of vaccine development and ACIP consideration.

One of our major concerns is a need for more expertise and representation for older Americans 

Public Comment 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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among ACIP members. As ACIP deliberates on important vaccine issues, we need to hear from 

experts who understand health factors and needs of older adults, as well as how their behaviors 

and lifestyles impact being able to fully benefit from these immunizations. The make-up of ACIP 

members should better reflect clinical expertise in these areas such as gerontology and the 

ability of vaccinations to work well for patients with chronic diseases and conditions often 

associated with advancing age. Even before the pandemic, older Americans face challenges in 

accessing care. The pandemic has obviously made that worse. There is a clear need to not only 

develop new vaccines, but also to consider the technology and innovation of new methods of 

making them available, accessible, and usable to those who need them, including the potential 

for oral options. We believe that we need to incorporate that reality into ACIP thinking. We urge

ACIP to be open to expansion of working groups and panel membership to include both clinical 

and cultural expertise. We need to keep looking at innovative platforms and solutions to 

providing immunizations to our vulnerable population. Please let our voices be heard. Thank 

you.

Joanna Colbourne

Deputy Executive Director

National Foundation for Infectious Diseases

Good afternoon. Hello, my name is Joanna Colbourne. I am the Deputy Executive Director of 

the National Foundation for Infectious Diseases, or NFID. The 2020-2021 influenza season is 

expected to be characterized by an unprecedented dual threat, co-circulation of influenza and 

the novel coronavirus SARS-CoV-2 that causes COVID-19. In addition, amidst the pandemic,

immunization rates have decreased for recommended vaccines across all age groups, with 

demand plummeting as much as 95% for some vaccines. We must reverse this trend now to 

avoid seeing outbreaks of flu and other vaccine-preventable diseases across the country. 

Influenza, or flu, and COVID-19 can be dangerous for anyone, but for more than 6 in 10 US 

adults living with a chronic health condition, including heart disease, lung disease, and diabetes 

flu and COVID-19 may be especially dangerous. Adults with chronic health conditions 

experience an inflammatory reaction caused by influenza infection that can worsen their 

underlying disease and lead to a number of serious outcomes including hospitalization, heart 

attack, or stroke, catastrophic disability, and death. To make matters worse, many of the 

underlying health conditions that make adults vulnerable to flu are also linked to increased 

vulnerability to COVID-19. Although there is currently no approved COVID-19 vaccine in the US, 

there are safe and effective vaccines they can help protect against flu and many other vaccinepreventable diseases. To address this urgent public health threat, NFID has launched the “Keep 

Up The Rates” flu awareness campaign in recent months. “Keep Up the Rates” is a national 

campaign to encourage all individuals to receive recommended vaccines that may have been 

delayed during the COVID-19 pandemic. To date, more than 100 leading organizations have

joined and are sharing information and resources in support of this critical public health initiative.

Earlier this month, NFID released a new “Call to Action: The Dangers of Influenza and COVID19 in Adults with Chronic Health Conditions,” which was the result of a multidisciplinary 

roundtable to explore the potential impact of influenza and COVID-19 on adults with chronic 

health conditions. The campaign includes more than 35 leading medical organizations that are 

sharing best practices for administering flu vaccines amidst COVID-19 mitigation efforts. NFID

and its partners are urging all healthcare professionals, particularly specialists treating adults 

with chronic health conditions, to implement strategies from the “Call to Action” and utilize tools 

or resources from the “Keep Up the Rates” campaign, all of which are available at www.nfid.org. 

It is the responsibility of all healthcare professionals to educate, motivate, and insist that

patients prioritize annual flu vaccination this season and stay up-to-date on all recommended 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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vaccines. Thank you for your time and attention today and special thanks to the members of 

ACIP for the work you continue to do.

Michael Arnold

Parent and Activist 

Yes, hello. My name is Michael Arnold and I’m here to talk about vaccine problems and 

solutions. Vaccines are not tested against placebo, saline, and manufacturers have no liability

for serious injury or death. Vaccine ingredients, as explained by Dr. Sherri Tenpenny, have

many toxins in them such as aluminum, formaldehyde, mercury, polysorbate 80, and aborted 

fetal tissue deoxyribonucleic acid (DNA). There is a chart from the journal of the American 

Academy of Pediatrics (AAP), December 2000, which shows how vaccines did not play a major 

role in the decline of disease. It was clean running water. The book, “How to End the Autism 

Epidemic” by J.B. Handley explains in Chapter 5 how aluminum plays a major role in the autism 

epidemic by causing encephalitis. In the book, “Vaccines: Are They Really Safe and Effective?”

by Neil Z. Miller, there is a graph. Doctors, pediatricians, were surveyed and they were asked 

about the Hepatitis B vaccine, and 87% said they did not believe that that vaccine was 

necessary for their patients. Okay, well there’s Justice for Evee. Evee died 36 hours after her 

vaccinations. The Medical Examiner (ME) said it was because of sudden infant death syndrome

(SIDS), but Evee’s mother is fighting for a tissue sample so that she can prove that it was 

actually VIDS, vaccine-induced death syndrome, not SIDS. Christopher died shortly after the 

GARDASIL® vaccine for human papillomavirus (HPV). You can learn about him from

learntherisks.org and #neverforgetChris. Adam got autism after his wellness visit like thousands 

of other babies, and you can learn about that from the documentary about him. Solutions. Take 

Hepatitis B off the schedule as soon as possible. Ask Congress to terminate the National 

Childhood Vaccine Injury Act (NCVIA)of 1986. Ask Congress to change vaccines from a biologic 

to a drug. Ask the CDC and WHO to get clean water and proper sanitation for the world’s 

poorest 1 billion people and work with the Behavior Analyst Certification Board (BACB), 

bacb.com.

Michaela Jackson

Prevention Policy Manager

Hepatitis B Foundation

My name is Michaela Jackson. I am the Prevention Policy Manager for the Hepatitis B 

Foundation. The current health emergency has shown that prevention truly is essential for the 

health of the public. As one of the primary causes of liver cancer and an underlying condition 

that can increase severe outcomes from COVID-19, preventing Hepatitis B infection should be 

an immunization priority. Today, we are advocating for a universal Hepatitis B vaccination 

recommendation to help protect the 75% of adults who are susceptible to Hepatitis B virus.

Adult HepB vaccination rates are low amongst healthcare workers despite recommendations. 

They comprise 6% of the US population and face significant exposure to blood-borne diseases 

daily. Yet only 61% of health care workers have completed a full vaccine series. The 

disproportionate emphasis on the flu vaccine and the lack of targeted immunization messaging 

for healthcare workers have been identified as major barriers to increasing this percentage. In 

addition, the average age of a nurse in America is 50 years old. The majority of the nurse

population are between 45 and 59 years old. This highlights issue that current guidelines fail to 

capture. Susceptible individuals were born before the universal infant HepB vaccine 

recommendation. These individuals are relying upon their providers to recommend the HepB 

vaccine, which becomes problematic if the providers are unaware of a person’s job or other risk 

factors. Other essential workers are at risk as well. In the past decade, there have been 18 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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documented outbreaks of HepB in non-hospital settings. Our foundation has heard stories from 

essential workers who have developed HepB after being stuck by a needle on the job. Studies 

show that 95% of needles are still discarded in municipal waste streams, despite national and 

state protocols for disposal. The average risk of contracting HepB from a needlestick exposure 

ranges from 6% to 30%, placing all unvaccinated workers who may come in contact with a 

needle, such as food service employees or sanitation workers, at significant risk for infection. 

Protection should not be contingent upon which job you have. Accessing the vaccine is another 

barrier to increasing immunization rates. Some state and federal programs recover the cost of 

HepB vaccines for adults if they’re in one of the high-risk categories named by ACIP. However,

some of those risk factors, such as diabetes or fatty liver, can go undetected for years. This 

means that a person who is at risk may not be able to access the vaccine due to costs simply 

because the risk factor has yet to be identified. Despite ACIP recommendations that anybody 

who wants to be vaccinated for HepB can get immunized, many Insurance programs, including 

Medicare, will not cover this group. Current HepB vaccination guidelines are simply not enough. 

The complexities of the current recommendations act as a barrier to achieving satisfactory adult 

HepB immunization rates, but ACIP has the power to change that. With a recommendation for 

universal adult HepB vaccination, we could be one step closer to eliminating viral hepatitis in the 

United States. Thank you for your time today.

Kimberly Hall

Florida Freedom Keepers

Good afternoon. My name is Kimberly Hall. When I was 25, I lost twin girls at 23 weeks 

gestation. The doctors told me it was unexplainable. My twins would be 5 years old this year. I 

am 5 years still recuperating from the memory of the profound pain, confusion, trauma, and

complete upheaval of my entire life. It was at 22 weeks with the nurse taking my basic vitals 

requested me to take a shot for pertussis. When I stated that I didn’t know what pertussis even 

was, the nurse shortly explained to me that it would protect me from obtaining this disease and 

alongside that, I would be passing on protection to my twins. I was not given any further 

information about this medical intervention. What information is there really that shows it 

provides any protection that she claimed? What is available states that a Proceedings of the 

National Academy of Sciences (PNAS) study, and I quote, “While all groups possessed robust 

antibody responses, key differences in T-cell memory suggest that aP vaccination induces a 

suboptimal immune response that is unable to prevent infection.” There is also available a 2017

review of 15 published articles that determined that while vaccination boosted maternal 

antibodies, evidence was lacking on whether or not this had any impact on reducing the 

incidence of pertussis, serious complications, or death in infants. It seems the Tdap vaccine 

does not prevent the spread of disease or even prevent you from catching the disease. If today I 

pull up the CDC website, I very clearly see that the CDC recommends pregnant women to get 

the whooping cough vaccine between 27 and 36 weeks of each pregnancy. Why was I offered

this at 22 weeks? That nurse represents this country’s entire lack of any informed consent with 

these injected biologics. The Food and Drug Administration (FDA) has classified Tdap as a 

Category C drug because of this complete insufficient evidence regarding any administration in 

pregnant women. The argument is used that it could be seen as unethical to test such a 

vaccine, but it is being pushed and coerced on woman every day as a complete off-label use. 

Furthermore, the FDA has never even approved a vaccine specifically for use in pregnancy to 

prevent disease in the infant. I was not given any information of the injected ingredients: 

formaldehyde, glutaraldehyde, aluminum hydroxide, polysorbate 80, phenoxyethanol,

ammonium sulfate. In what doctor’s insane mind does this ingredient list seem like an injectable 

concoction for a pregnant woman carrying an undeveloped fetus? Why is it the GARDASIL®

package insert reference to page 10, where it shows the use in populations of pregnancies 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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within clinical trials? The GARDASIL® vaccine contains 225 micrograms of aluminum hydroxide

and 7 of 55 women lost their babies (12.7%). GARDASIL® vaccine was made with more than a 

50% increase of aluminum, 500 micrograms and 17 of those 62 women lost their babies. That 

percentage spiked up 27.4%. It is shown through the studies and science that aluminum 

hydroxide alone plays a major role, causing fetal demise and spontaneous abortions with the 

Tdap containing more than 300 micrograms. The CDC and vaccine manufacturers are both 

completely exempt from liability, exempt from providing randomized control trials (RCTs), and 

exempt to provide any evidence to do what you claim it will do and only to show it could create 

antibodies. That doesn’t equal immunity. It is awfully disappointing that in 2020, we have such a 

widespread knowledge deficit within the scientific community. Thank you.

Albert Faro, MD

Vice President of Clinical Affairs

Cystic Fibrosis Foundation

Good afternoon. My name is Dr. Albert Faro and I’m the Vice President of Clinical Affairs at the 

Cystic Fibrosis Foundation (CF Foundation). On behalf of the foundation, thank you for this 

opportunity to provide comments to the Advisory Committee on Immunization Practices 

regarding developments in allocation of COVID-19 vaccines. The CF Foundation is a national 

organization actively engaged in the research and development of new therapies for cystic 

fibrosis (CF), a rare life-threatening genetic disease that affects over 30,000 people in the 

United States. The build-up of thick, sticky mucus in the lungs characteristic of the disease 

makes people with CF particularly prone to chronic airway infections, punctuated by pulmonary 

exacerbations, events associated with morbidity and mortality in people with CF. A significant 

proportion of pulmonary exacerbations are triggered by respiratory viral infections. With 

continued progression of the disease, individuals with CF and advanced lung disease may 

pursue lung transplantation. Due to the known risks posed by respiratory viral infections, the 

unique dangers of the SARS-CoV-2 virus and the multi-system manifestations of CF, some 

people with CF, such as those with advanced disease or who are post-transplant and therefore 

immunocompromised, should be considered at high-risk for poor outcomes from COVID-19 

infection. The strongest evidence to date on the dangers of COVID-19 for people with CF 

comes from a forthcoming global analysis of 181 COVID-19 cases among people with CF. From 

that analysis, it appears CF patients with advanced lung disease and those that are post-lung 

transplantation, are at risk of severe outcomes, including death. We therefore urge the advisory 

committee to consider information beyond the CDC’s list of comorbid conditions to inform 

prioritization determinations. That list may mischaracterize the true risk for some rare disease 

populations like CF. We further urge the advisory committee to give equal priority to anyone with 

a condition that puts them in a high risk for severe disease from COVID-19 instead of adopting 

the National Academy of Medicine’s (NAM) recommendation to first prioritize people with 

multiple comorbid conditions for access to a vaccine—a focus that relies on multiple conditions 

and neglects other indications of disease severity and vulnerability. We believe that scenario 

inappropriately disadvantages someone whose underlying disease condition is advanced or 

severe. This segment of the population should be prioritized for early access to a vaccine and 

includes patients with CF with advanced disease or who are post-transplant. Thank you again

for your attention and consideration of people with CF as you tackle these critical issues. 
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Del Bigtree

Founder

Informed Consent Action Network

I want to thank the committee for giving me this opportunity to speak. I want to say that, you 

know, given that almost everything we talk about these days involves discussion of COVID-19, I 

want to say I found it shocking that in the discussion about the flu shot this morning, there was 

no discussion about the risk of COVID-19 being increased by flu shots, given the fact that 

there’s so many studies that are showing this type of connection. Specifically, we have the 

Cleveland Clinic study that’s entitled “Safety of Influenza Vaccine During COVID-19.” It found a 

highly statistically significant increased rate of mortality, ICU admission, and hospitalization for 

COVID-19 among those that received a flu shot in 2019 as compared to those that did not. In 

fact, it reflected that those receiving the flu shot in 2019 had a 175% increased rate of mortality 

and a 195% increased rate of ICU admissions. Additionally. There was a gigantic study that just 

came out looking at 39 countries called “Positive Association Between COVID-19 Deaths and

Influenza Vaccine Rates in Elderly People Worldwide.” Given that there are those studies and 

studies out of Japan that have shown 400% increased risk in other upper respiratory infections 

amongst those that got flu shots compared to those that didn’t. All of this science around the 

world is pointing to there may be a real danger to giving flu shots during COVID-19, yet the CDC 

seems to plow forward with this idea of a twindemic and using it as a way to force the largest flu 

vaccine campaign in US history. We’re also watching the 59 deaths from flu shots and growing 

in South Korea where they are involved in this mission, yet none of this seems to matter to you 

at the Advisory Committee of Immunization Practices, which is really shocking. Given the lack 

and waning confidence that the American public now has in the CDC, it seems by many articles 

to be at the lowest point in history, how do you expect to be relevant or even be considered 

necessary in a process of protecting our population when you’re not even having the most 

obvious conversations you should be having when it comes to vaccinations. This is your world. 

This is what you’re supposed to be looking at. We are supposed to have confidence that when 

there are studies all around the world showing a risk of delivering a flu shot vaccine and the 

increased risk of death from COVID-19 that certainly it’s a conversation and you’ll be able to 

bring up studies to discount or, you know, somehow refute this issue. Instead, you avoid it 

altogether, which is continuing to drive the confidence in the work that you do down to the floor. 

I would like to see you be a little more responsible with these conversations, given that they are 

so important and may include and involve the risk of death for hundreds of thousands if not 

millions of people in this country and around the world. Thank you.

Erin Olszewski, RN

US Citizen

Yes. Hello. Good afternoon and thank you for having me today. My name is Erin Olszewski and 

I’m a Registered Nurse (RN). This year, I also became a COVID whistleblower who uncovered 

the fraud, negligence, greed, and unnecessary deaths being covered up in New York City’s 

(NYC’s) Elmhurst Hospital and the CDC at the height of that pandemic, with actual video and 

audio indisputable proof. So, we both know the numbers you’re basing your new COVID

vaccine recommendations off of are inflated and fraudulent. You cooked the books on vaccines 

just like you’ve been cooking the books on COVID. You’ve rigged the studies, you’ve covered 

up the data, you’ve buried the injuries and deaths, you’ve removed yourselves and the vaccine 

manufacturers from all liability, and you’ve lied to the American people long enough. I needed to 

alert the American public to something they may not know. There is a CDC scientist

whistleblower named Dr. William Thompson who the CDC is attempting to cover up. Dr. 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Thompson discovered that the measles, mumps and rubella (MMR) vaccine was causing a 

dramatic rise in autism in African American boys. However, his CDC bosses have ordered him 

to silence. I believe that this is the year of the whistleblower and accountability, especially as it 

relates to our minority populations. Most recently, yesterday in fact, whistleblower Tony 

Bobulinski came forward exposing even more fraudulent activity happening within our 

government. If there is any hope in recovering the trust of Americans, the executive government 

needs to step up, do what’s right, and immediately subpoena Dr. William Thompson and all his 

CDC co-authors to testify before Congress. Congressman Bill Posey here in Florida has 

thousands of damning CDC documents Dr. Thompson handed to him. If forced to testify, Dr. 

Thompson stated he’s not going to lie. The public deserves the truth before this panel continues 

their unethical practices of adding even more vaccines to the already overly crowded, toxic,

liability-free schedule. Each one of you on that panel know that the science has been corrupted. 

Yet, you continue to dish out fraudulent data because money, power, and greed is much more 

lucrative than protecting public health. The CDC and mainstream media continue to bury this 

information. They know that vaccines are causing detrimental harm and death to children and 

adults. Yet here we are today watching you discuss a fast-tracked, liability-free COVID vaccine

for a virus with a 99% survival rate. A quote from your very own silenced CDC scientist, Dr. 

William Thompson, in 2004 to Dr. Brian Hooker, “That’s the deal. That’s what I keep seeing 

again and again and again where the senior people at CDC just do completely unethical vile 

things and no one holds them accountable. Your time is running out, because the American 

people are waking up and accountability is coming for you mark my words. First, do no harm. I 

hope all of you do some soul-searching and remember why you’re here. Thank you. 

Susie Olson Corgan

Representing Self

Hello. My name is Susie Olson Corgan. Thank you so much for the opportunity to speak today. I 

have been attending the ACIP meetings, as well as Board of Health (BOH), Department of 

Justice (DOJ), and National Vaccine Advisory Committee (NVAC) meetings. The thread among 

these meetings has been vaccine hesitancy. The one thing I have heard many of you say is that 

vaccine hesitancy is due in large part to anti-vaccination campaign. As you know, most of these 

campaigns are carried out on social media. However, social media censorship is at an all-time 

high. Major platforms such as YouTube, Facebook, Instagram, Pinterest, Linked-In, Vimeo, and 

even search engines like Google are frequently removing contents and banning accounts 

without warning or explanation that even has the slightest appearance of questioning the current 

vaccination program. Despite the fact that this information is being censored, vaccine hesitancy 

is still on the rise. Some of the reasons that people are questioning vaccine are the following:

the withholding of the COVID-19 vaccine trial data, lack of transparency regarding adverse 

events (AEs) in the trials, using another vaccine as the placebo—a placebo to be an inert 

substance, concurrent studies phases, lack of liability if something goes wrong—and this 

applies not only to the COVID-19 vaccine candidates, but also to those currently on the 

recommended childhood vaccination schedule, partnerships with organizations such as the 

Gates Foundation to create marketing campaigns, and questioning whether there has been 

corporate capture of our regulatory agencies. I know that some of these issues are out of your 

scope, but you have enormous influence among the medical and scientific communities 

worldwide. They will consider any recommendations that you make. I urge you to consider 

increased transparency throughout this process. Vaccine hesitancy will continue to rise and if 

and when a COVID-19 vaccine candidate is approved for distribution, supply will not be your 

primary issue—demand will be. Thank you.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

69

Charles Lee, MD

President Elect

American College of Correctional Medicine

Thank you very much. I am Charles Lee. I am the President Elect of the American College of 

Correctional Physicians (ACCP). I’d like to thank the academy for allowing me to give this 

presentation on behalf of the inmates and correctional workers throughout the country. Just 

yesterday, there was a news release that 75% of inmates at the Marquette Michigan Prison 

were positive for coronavirus. In addition to that, 42% of the employees were positive. Also, 

about a month ago, there was an article about in Virginia, 70% of the inmates were positive. 

Inmates’ rate of infection of coronavirus is 5 times that of the general population and the death 

rate is 1.5 times that of the general population. Correctional workers and inmates go home.

They contract the illness, disease, coronavirus, within the institution and conceivably can spread 

it to their family, friends, neighbors, stores, and wherever they may be. Ninety percent of 

inmates are released at some point in time. They, too, are our friends, family, and neighbors. In 

a correctional facility, it is extremely challenging to follow the CDC guidelines of masking,

sanitizing, and distancing. Consequently, it is a big challenge to keep them safe. In October, the 

National Academy of Science, Engineering, and Medicine (NASEM) developed a framework of 

prioritization for coronavirus. It was Phase 1b in rural facilities where there are older patients 

with comorbidities in congregate settings, and Phase 2 for employees and inmates in 

correctional facilities. I will be submitting a resolution to the American Medical Association

(AMA) along these same lines that hopefully in November will be approved. We asked the ACIP 

to adopt the National Academy’s framework of prioritization for the vaccine of a safe, and 

effective, and FDA-approved vaccination. I thank you very much.

Kermit Kubitz

Individual

Thank you. I am 73 years old and was a polio pioneer in 1954. My wife and I have just gotten 

our flu shots in the last two weeks—in my case, the high-dose flu shot. I support Emergency 

Use Authorization (EUA) of COVID-19 vaccines showing preliminary efficacy and safety with the

3 following recommendations. First, there should be a substantial review of effectiveness for a 

group of 5,000 to 10,0000. Second, use new serology methods to study immune response. 

Third, give similar EUA approval for follow-on vaccines, including those with adjuvants for better 

protection. On the first point, the effectiveness of COVID-19 vaccine may be uncertain. 

Uncertainty results from the novel technologies used, the possibility of differential effectiveness

for different groups, and the number of degrees of freedom (i.e., behavior variability among trial 

program participants, including NPIs; that is, non-pharmaceutical interventions such as masks 

and social distancing). Therefore, I recommend follow-up studies of effectiveness, not just 

safety, in approximately 5,000 to 10,000 vaccinated patients, including stratified groups of older 

patients and those with other health conditions. Second, follow-up on effectiveness for 

vaccinated patients should include serology studies to permit evaluation of the types of immune 

responses resulting from vaccination. Just as we are using novel vaccines such as mRNA, we 

should use innovative serology techniques such as the Multiplexed Identification of T-cell 

Receptor Antigen (MIRA) available now. Third, the FDA and CDC must be prepared through 

EUA follow-on vaccines which show greater effectiveness or duration of immunity. This should 

include single dose vaccines or vaccines using newer adjuvants like AS03 or CPG1018 which 

can stimulate a stronger immune response. But in order to do this, that is included follow-on 

vaccines, the FDA and CDC also need to understand and evaluate the effects of multiple 

vaccination iterations (i.e., what if you get an mRNA vaccine and then a subunit or inactivated 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

70

virus vaccine?). We need to understand what happens if you have antibody response to a 

subsequent vaccine. Thank you for your work. Keep it up. Keep it up. 

Antony Hsu, MD, FACEP

Clinical Emergency Physician

American Colleges of Emergency Physicians

Good afternoon, ACIP. Thank you for what you do. I’m an actively practicing Clinical Emergency 

Physician with a concern for my family, children, community, city, state, nation, and humanity in 

that order. I’m not an epidemiologist or health care economist, but I do know a few and as a 

frontline emergency physician balancing community practice and academic pursuits with 

national advocacy, I base my advice on the more than 60,000 patient encounters and diverse 

work and life background I have had. The topics I’d like to address first are SARS-CoV-2 

vaccine safety concerns that I’ve heard and thought about while working on an Indian 

Reservation in Montana in September: 1) Regarding generating trust on sufficient testing and 

safety, open up the books about side effect profiles of each vaccine. Transparency is needed in 

times of rationing to promote trust in government; 2) Consider community nomination 

committees to reach out to social influencers, faith-based, elected government representatives,

and medical and scientific representatives for trust-building teams; 3) Consider anonymous 

polling by a panel of renowned experts about whether they would immunize themselves and 

their families, but their votes must remain anonymous to engender trust; and 4) Consider 

ranking the efficiency of each vaccine for each population profile. On the second larger topic of 

vaccine distribution, my thoughts are: 1) Ensure complete informed consent based on 

continuously updated benefit and risk profiles; 2) Consider buy-in for healthcare workers and 

gradually broadening the enrollment as safety and efficacy numbers are sustained and 

continuously reevaluated; 3) Consider calculating a relative risk reward or r

3

ratio for each 

person. This r

3

ratio addresses the risk of vaccination versus the risk of delayed vaccination. 

Gradually slide scale the availability based on the r3 ratio. This can defer depending on local,

regional, and national priorities. The r

3

ratio method might avoid the concern of favoritism with 

an A, B, C, D or a 1, 2, 3, 4 approach and replaces it with a straightforward sliding scale. Each 

manufacturer can then provide what their sliding scale criteria are, especially since the safety 

profile for each vaccine may differ; 4) As availability improves, consider peer navigators and 

influencers discussed previously to step up messaging; 5) The nation must buttress its system 

for the distribution of preventive healthcare. Specifically, emergency departments (EDs), which 

operate 24/7/365 already vaccinate for tetanus, diphtheria, and pertussis. They have not been 

included in outreach, but they are at the frontline for pandemic responses. There are pilot 

projects in the States of Michigan and Washington that vaccinate for influenza and hepatitis A. 

Hospitals have the facilities to store vaccines that require extremely low temperatures and have 

security 24/7; and 6) EDs are uniquely positioned to work with public agencies for the work of 

mass immunization to ensure all people can be reached, including those facing homelessness 

and the underinsured for whom Eds may be the most likely source of care. Thank you so much 

for taking the time to listen to my suggestions and thank you for what you do.

Kim Freitas

Mother

Hello, and thank you for the opportunity to speak. I would like to discuss some critical areas of 

concern regarding the COVID vaccine. It is unethical to vaccinate a person using a high-risk,

untried, liability-free vaccine when you have a safe and proven medicine available. Per the 

CDC, over 98% of the population recovers from COVID-19. We cannot risk injury to an 

otherwise healthy person using a vaccine we know very little about. One of the biggest areas of 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

71

concern is enhanced illness, when the vaccine triggers a reaction which causes a person to 

acquire the exact virus you are trying to protect them against. We have seen this happen in 

previous coronavirus animal trials, which are currently being skipped during COVID trials. These 

trials are also being conducted on healthy people, yet the vaccine is due to be administered to 

our most vulnerable populations first, who typically have the health issues with at least 1 if not 3

underlying conditions that makes them high-risk. How can we use an untested vaccine on them 

when we have no idea what the outcomes will be? Also, how can we disperse a product that is 

free from liability, especially a warp speed vaccine using mRNA technology that has never been 

used before? No contraindications have ever been studied regarding administering the COVID

vaccine with other vaccines. This means it should not be administered in the same day, week,

or even month with other vaccines. Who is going to monitor and control that? Which leads to my 

next concern, viral priming. This occurs from the heavily pushed flu vaccine. Studies have 

shown that the flu vaccine makes us 36% more likely to get an upper respiratory illness (URI),

which includes COVID-19. We should be warning against use of the COVID vaccine for those 

who have already received the flu vaccine. Let’s also be very clear that the recipient of the 

vaccine should be given the vaccine insert—not a short list of information. True informed 

consent involves knowing all of the risks, not just watered-down points. Lastly, we must have 

transparency from the Data and Safety and Monitoring Boards (DSMBs) who oversee these 

trials. J&J, AstraZeneca, and Oxford trials only provided fragmented information that we are not 

clear about adverse reactions during the ongoing trials. At one point, transverse myelitis was 

mentioned by the media, but then the wording was changed to a much vaguer language on the 

trial patient information sheets. In closing, we demand tested, tried, and proven vaccines that 

offer benefits greater than the already 98% recovery time with little to no interventions. These 

vaccines might be liability-free by the makers, but that does not make you, the advisory 

committee, morally free from the harm that can be caused by the decisions that you make.

Please remember, where there is risk there must be choice. Thank you.

Friday: October 29, 2021

Centers for Disease Control and Prevention (CDC)

Dr. Messonnier shared a few updates about the breadth of CDC’s work on the response to the 

COVID-19 pandemic. CDC has been actively responding to the COVID-19 pandemic for nearly 

300 days. This meeting marked Day 298 since NCIRD activated in January. To date, 7400 CDC 

staff have participated in the response, representing 3.5 million hours logged in responding to 

this event. Given that CDC staff is comprised of about 10,000 people total, this reflects that the 

vast majority of CDC staff have been engaged directly in the response and she expects the rest 

have been engaged in filling behind those who have been deployed. While they would hear 

about CDC’s epidemiology and vaccine-related activities during the emergency meeting on 

October 30th, CDC staff remain committed to responding more broadly, including activities to 

support data and analytics; laboratory diagnostics and testing; global migration, including 

travelers’ health; contact tracing; student travel support; health systems; and mitigation for 

schools, worksites, and food systems.

Agency Updates
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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In terms of routine vaccine coverage, CDC recently published results from the 2009 National 

Immunization Survey (NIS)-Teen and NIS-Child surveys. Both reports identified strong 

immunization coverage, but also areas where more could be done to reduce disparities. The 

results of the 2019 NIS-Child found that only 1.2% of children had received no vaccinations by 

24 months of age, but there continued to be disparities in coverage by race, ethnicity, poverty, 

and Metropolitan Statistical Area (MSA). NIS-Child was released in August and vaccination 

generally was showing improvement. However, the impact of the COVID-19 pandemic on 

childhood immunization has been extreme. Despite many efforts, child and adolescent 

vaccination coverage are lagging. The gap in measles vaccine is telling at approximately 1.5 

million doses of measles vaccine behind where it should be this year. That means that a large 

number of children are unprotected against routine childhood diseases. This is a call to action to 

everyone at this meeting that children must be caught up on their vaccinations. If they fall 

behind, they continue to fall behind. That puts the US at risk for vaccine-preventable disease 

epidemics, as well as for HPV and the cancers related to it. She expressed her hope that 

everyone would emphasize the importance of getting people caught up on these visits.

CDC is also working to improve influenza vaccine coverage this season and to address 

disparities in influenza vaccination and influenza outcomes. The estimates from last season 

show that vaccine coverage increased slightly among adults from the previous season. 

However, racial and ethnic disparities in influenza vaccination persist. In an average year, more 

than half of US adults remain unprotected against influenza. A recent analysis of influenza 

hospitalization rates by race and ethnicity during 10 influenza seasons showed that nonHispanic Black persons had the highest influenza hospitalization rates, followed by nonHispanic American Indian or Alaska Natives (AI/AN) and then Hispanic or Latino persons 

compared to non-Hispanic Whites. Among other activities to address these ongoing disparities, 

CDC, the American Medical Association (AMA), and the Ad Council launched a collaborative 

campaign called “No Time for Flu” to increase awareness about the importance of influenza 

vaccination, especially among African American and Hispanic audiences. This year, there has 

been a large upsurge in demand for influenza vaccine compared to other years. That is great 

news, but CDC needs help sustaining that increase throughout the last quarter of 2020. While 

they would like everyone vaccinated in October, they still need to keep passing the message 

along that if folks did not get their vaccine in October, it is still not too late to get vaccinated in 

November and December.

While Acute Flaccid Myelitis (AFM) is not vaccine-preventable, it is a topic of concern and it is 

uncertain how the pandemic and recommended social distancing will affect enterovirus (EV) 

circulation in the US. While the CDC was prepared for a surge in cases considering that 2020 

was anticipated to follow the pattern of national increases in AFM every 2 years, that is not 

being seen. The agency is still on high alert for AFM, but will need to continue to determine the 

effect social distancing has on that as well as on other respiratory viral diseases.

In a time when there is so much bad news, Dr. Messonnier said she wanted to end on a happy 

note. World Polio Day was celebrated on October 24, 2020 as an opportunity to highlight global 

efforts toward a polio-free world and honor the tireless contributions of those on the frontlines in 

the fight to eradicate polio from every corner of the globe. This year there is additional reason to 

celebrate in that on October 25, 2020, the Africa Region was officially certified as wild poliovirus 

(WPV)-free. With the African Region certification, 5 of the 6 WHO regions representing over 

90% of the world’s population are now free of WPV.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Centers for Medicare and Medicaid Services (CMS)

Ms. Hance reported that CMS issued the fourth COVID-19 Interim Final Rule on October 28, 

2020 with a comment period that addresses coverage of COVID-19 vaccines in Medicare, 

Medicaid, and private health plans. In addition, CMS issued 3 COVID-19 toolkits aimed at state 

Medicaid agencies, providers who will administer COVID vaccine, and health insurance plans. 

All of these materials are available on https://www.cms.gov/. Regarding influenza, CMS has 

coordinated with CDC on the release of their influenzas campaign materials. Influenza materials 

include videos, flyers, and drop-in articles all of which are available in both Spanish and English 

and are all available on https://www.medicare.gov/. In addition, consumers who subscribe for 

email updates from Medicare have received a specific email about the importance of influenza 

vaccine. Post-cards also have been sent to those who are dually eligible for Medicare and 

Medicaid. The CMS Office of Minority Health (OMH) has also included influenza vaccine 

information on their website. Specific to pediatric vaccines, CMS has repeatedly emphasized 

the importance of routine immunizations to states and other partners. In June and July, CDC 

Immunization Services Division (ISD) staff joined CMS calls with state Medicaid and children’s 

health insurance program staff and emphasized the need for catch-up vaccines. CMS has a 

Connecting Kids to Coverage National Campaign. Materials specific to vaccines are available 

on that website: https://www.insurekidsnow.gov/campaign-information/index.html

Food and Drug Administration (FDA)

Dr. Fink reported that earlier in October, the FDA published guidance on data to support 

Emergency Use Authorization (EUA). The Vaccines and Related Biological Products Advisory 

Committee Meeting (VRBPAC) convened an open meeting for a general discussion for 

considerations for the development, licensure, and/or EUA of COVID-19 preventive vaccines. 

He indicated that he would be discussing the VRBPAC meeting in more detail during the 

COVID-19 session of the emergency ACIP meeting on October 30, 2020.

Health Resources and Services Administration (HRSA)

In terms of Ebola vaccine coverage by the Countermeasures Injury Compensation Program 

(CICP), Dr. Rubin reported that the National Vaccine Injury Compensation Program (VICP) 

continues to process an increased number of claims. In Fiscal Year (FY) 2020, petitioners filed 

1191 claims through the program. $186.8 million was awarded to petitioners and $31 million 

was awarded to pay attorney fees and costs. In addition, at the end of the FY 2020, HRSA had 

a backlog of 966 vaccine injury claims awaiting review. As of October 1, 2020, the CICP 

determined that 39 claims were eligible for compensation totaling $6 million. The CICP also 

published a Notice of Proposed Rulemaking (NPRM) for the Smallpox Countermeasures Injury 

Compensation Table on October 15, 2020. The comment period ends on December 14, 2020.

Indian Health Service (IHS)

Dr. Weiser reported that IHS has established a COVID Vaccine Task Force that is developing a 

system-wide plan for vaccine allocation and distribution for IHS Tribal & Urban Indian Health 

Centers that choose to receive their vaccine from IHS. The COVID Vaccine Task Force has a 

focus on distribution, prioritization, administration, communication, data management, and 

safety. Vaccine adverse event monitoring through the Vaccine Adverse Event Reporting System

(VAERS) and active internal reporting systems based on current for COVID-19 treatments have 

been developed. The IHS appreciates the development of the new element in VAERS this year 

for the first time for reporting specifically to the IHS. The IHS Pharmacy and Therapeutics 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Committee will be providing outreach to IHS Tribal & Urban Indian Health Centers to ensure that 

they are familiar with reporting systems and understand the importance of close safety 

monitoring. While data published in the MMWR in August described at least a 3-fold higher 

incidence of COVID-19 for AI/AN compared to non-Hispanic Whites, data on underlying 

conditions, hospitalizations, and mortality are insufficient at this time to fully assess the severity 

of the COVID-19 pandemic in AI/AN communities. Despite this, IHS greatly appreciates the 

continued assistance provided by the CDC Tribal Support Unit. The IHS is monitoring ILI for the 

2020-2021 influenza season and also has created a COVID-like illness (CLI) surveillance report. 

Influenza vaccination activities demonstrate higher uptake of influenza vaccine earlier in the 

season compared to previous years. As of October 10, 2020, 11.6% have received at least one 

dose of seasonal influenza vaccine in patients 6 months of age and older compared to 8.5% at 

the same time last year. During COVID-19, routine and catch-up AI/AN childhood immunization 

coverage has decreased. IHS has engaged in various initiatives to promote routine and catchup immunizations during COVID-19. This has included hosting webinars and sharing CDC and 

HHS communication and education materials, provider resources, and toolkits. IHS appreciates 

CDC’s ongoing support in these efforts as well. 

National Institutes of Health (NIH)

Dr. Beigel provided a few NIH updates of interest to ACIP. There was a report in the New 

England Journal of Medicine (NEJM) about a month ago for the National Institute of Allergy and 

Infectious Diseases (NIAID) Phase I study of the Moderna COVID-19 vaccine, mRNA-1273. As 

a follow-on to a prior report, this report details the experience in older adults defined in this 

study as ≥56 years of age and shows that the vaccine is well-tolerated and generated a very 

robust immune response. That set the stage for including that population in the larger pivotal 

studies. NIAID continues to support the large pivotal Phase III studies through its COVID-19 

Prevention Network (CoVPN). Moderna has completed full enrollment of the mRNA-1273 Phase 

III study. A fourth vaccine study has been started as well for the Janssen (J&J) product. This 

provides 4 large, currently ongoing pivotal studies to try to provide an effective vaccine for 

COVID-19. NIAID awarded a contract to begin development of a vaccine for enterovirus-D68 

(EV-D68) that causes Acute Flaccid Myelitis (AFM).

Office of Infectious Disease Policy and HIV/AIDS (OIDP)

To help support the influenza vaccination efforts by CDC, OIPD developed an online toolkit that 

provides materials designed to encourage people to get their influenza vaccine by Halloween 

known as “Boo to the Flu.” These materials are available at https://www.vaccines.gov/flu-toolkit. 

OIPD continues to work on updating the National Vaccine Plan (NVP) with support from the 

Interagency Vaccine Work Group whose members include the federal agencies represented on 

ACIP plus others. The NVP is scheduled to undergo an abbreviated public comment period in 

November, with a plan to release the revised plan by the end of 2020 or in early 2021. The 

National Vaccine Advisory Committee (NVAC) met on October 16, 2020 and reviewed a draft 

report containing responses to questions on COVID-19 vaccination hosted by Admiral Brett 

Giroir, the Assistant Secretary for Health (ASH). The committee will meet again in December to 

continue work on this. The NVAC website will be update once this report is finalized.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Introduction

Grace Lee, MD, MPH

ACIP Chair, Herpes Zoster Work Group

Associate Chief Medical Officer for Practice Innovation

Lucile c rd ildren’s os it l

Professor of Pediatrics, Stanford University School of Medicine 

Dr. Lee introduced the zoster vaccine session, reminding everyone that ACIP made the 

following recommendations in October 2017:

Since October 2017, there have been a few notable updates. Effectively July 1, 2020, 

ZOSTAVAX® no longer will be sold in the US. The remaining product will expire by November 

18, 2020. In terms of RZV, 33 million doses of SHINGRIX have been distributed from launch 

through the second quarter of 2020. SHINGRIX inventory is currently available to meet the 

demand across all distribution channels. The European Medicines Agency (EMA) approved an 

expanded indication on August 25, 2020. SHINGRIX is now approved in the European Union

(EU) for prevention of herpes zoster (HZ) and postherpetic neuralgia (PHN) in adults 50 years of 

age or older and adults 18 years of age or older at increased risk of HZ1. An sBLA was

submitted to the FDA on September 24, 2020 to expand the indication of SHINGRIX to include 

the prevention of HZ in adults 18 years of age who are at increased risk of HZ due to 

immunodeficiency or immunosuppression caused by either disease or therapy following the 

EMA’s approval [

1https://www.ema.europa.eu/en/medicines/human/EPAR/shingrix#assessmenthistory-section].

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Zoster Vaccines
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Another important update to highlight in the context of the COVID-19 pandemic is that in adults 

65 years of age and older in the US, the WG has been reviewing weekly uptake data for RZV 

between January 6, 2019 ‒ July 20, 2019 that was steadily increasing over time. However, 

during the same time period between January 5, 2020 ‒ July 18, 2020, there was steep decline 

in the number of doses administered after the national emergency was declared on March 13, 

2020. This is concerning because there is a cohort of older adults who may not be protected 

against HZ and its complications. These numbers are now rising and the Herpes Zoster Work 

Group (HZWG) anticipates continuing to track how the pandemic is affecting healthcare 

utilization and vaccination rates in the US. She emphasized the hope that their immunization 

partners would continue to support vaccination efforts for all age groups during the pandemic. 

This is affecting children, adolescents, and adults throughout healthcare systems [CDC, 

Unpublished Data].

In June 2019, the ACIP HZWG presented a summary of RZV post-licensure safety monitoring 

activities to date in three systems, including the Vaccine Adverse Event Reporting System 

(VAERS), Vaccine Safety Datalink (VSD), and Medicare data. The HZWG’s interpretation of the 

findings also were presented. The HZWG has met 14 times since that meeting to review the 

data on RZV post-licensure safety and uptake monitoring, review the RZV efficacy and 

immunogenicity data in both immunocompetent and immunocompromised adults, and to 

develop the PICO for use of RZV in immunocompromised adults in order to develop the 

Evidence to Recommendations (EtR) Framework needed to guide a recommendation.

The presentations during this session focused on an update of post-licensure safety monitoring 

of RZV in VAERS, a VSD update on post-licensure safety monitoring of RZV, data on the risk of 

Guillain-Barré syndrome (GBS) following HZ infection, and a summary and planned risk-benefit 

analysis regarding use of RZV in immunocompetent adults.

Update on Post-Licensure Safety Monitoring of RZV (SHINGRIX)

John R. Su, MD, PhD, MPH

Tom Shimabukuro, MD, MPH, MBA

Immunization Safety Office

Centers for Disease Control and Prevention

[Note: Dr. Shimabukuro presented on behalf of Dr. Su, who was experiencing a power outage and connectivity issues due to severe 

storms overnight that left many areas of Georgia without power].

Dr. Shimabukuro provided an update on post-licensure safety monitoring of RZV in the VAERS. 

As a reminder, VAERS is a passive surveillance system that is co-managed by the CDC and 

FDA. Anyone wishing to file a report with VAERS can go to the website to complete an 

electronic form online. VAERS accepts all reports from all reporters and does not judge 

causality or clinical severity of the event. Instead, VAERS is an early-warning system that 

identifies potential vaccine safety concerns for study in more robust data systems. The 

strengths of the system are that it can rapidly detect safety signals and rare AEs. However, the 

primary limitations is that causality cannot be assessed from VAERS data alone. It is a signal 

detection or hypothesis-generation system that requires additional follow-up with more robust 

systems when signals are detected. 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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CDC performed a descriptive analysis of RZV reports from October 2017 through June 2018 

that was published in the MMWR in 2019. Most reports (97%) were non-serious, which is 

consistent with what is observed with other vaccines administered in this age group. The most 

common AEs were systemic like fever, chills, and headache and also injection site reactions. 

That analysis has been updated with data through October 2020. Although there are more 

reports, there are no appreciable changes proportion-wise in the safety profile. The breakdown 

of non-serious events remained at about 97%, which is consistent with the initial data. Over 

90% of RZV doses are given alone without other concomitant vaccines. This table provides a 

more specific breakdown of the AEs as coded by the Medical Dictionary for Regulatory Activities

(MedDRA), demonstrating that they look very similar to the initial data:

Signs and symptoms 

(MedDRA Preferred Terms)*

38,902 total reports

n (%)

 Pyrexia (fever) 9,294 (23.9)

 Chills 7,965 (20.5)

 Pain 7,820 (20.1)

 Headache 7,444 (19.1)

 Injection site pain 7,359 (18.9) 

 Fatigue 6,362 (16.4)

 Pain in extremity 6,165 (15.8)

 Injection site erythema 5,609 (14.4)

 Myalgia 4,424 (11.4)

 Nausea 4,223 (10.9)

*Not mutually exclusive; a report may contain more than one MedDRA Preferred Term

There was a signal in the VSD Rapid Cycle Analysis (RCA) fairly early on for GBS, as well as a 

finding of an association in the CMS data. During the period from October 2017–April 2019,

there were 46 reports of GBS. Of these, 31 met the Brighton Level 1–3 diagnostic certainty 

(N=24) or were physician-diagnosed (N=7). Among them, 29 (94%) developed symptoms within 

42 days of vaccination. During the analysis period from May 2019–October 2020, there were 44 

reports of GBS of which 27 met Brighton Level 1–3 diagnostic certainty (N=16) or were 

physician diagnosed (N=11). Among these, 25 (93%) developed symptoms within 42 days of 

vaccination—the risk window used for monitoring. Proportionality reporting ratios (PRR) and 

Empirical Bayesian (EB) data mining identified no disproportional reporting of AEs after 

SHINGRIX compared to other vaccines. There was one data mining finding, which was,

“Product administered to patient of inappropriate age.” This is a medication error, not an AE 

health event following immunization.

In summary, the RZV post-licensure safety monitoring findings in VAERS as of October 2020

are generally consistent with the safety profile observed in pre-licensure clinical trials. Most 

reported AEs were systemic or at the injection site. SAEs were rare at 2.6% of reports, which is 

similar to other vaccines administered to same age groups. The number and composition of 

reported GBS events are comparable to the last update. There have been no disproportional 

reporting findings of any AEs by PRR or EB data mining other than the medication error of 

product being administered in inappropriate age.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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VSD Update on Post-Licensure Safety Monitoring of RZV (SHINGRIX)

Jennifer Clark Nelson, PhD

Director of Biostatistics & Senior Investigator

Kaiser Permanente Washington Health Research Institute

Dr. Nelson indicated that this work was led by their KPW team in collaboration with CDC

colleagues at other VSD sites. As a reminder, the VSD is a public health and research 

collaboration that was established in 1990 between CDC and 8 participating integrated 

healthcare organizations in the US. It captures and curates medical care and demographic data

currently on over 12.1 million persons per year or about 3.7% of the US population. The VSD 

captures and links electronically available data elements and conducts manual review of 

medical charts since these data are not collected for research purposes. The key domains 

include immunizations, potential AEs primarily using ICD-9 or ICD-10 codes that occur in 

outpatient emergency department (ED) or inpatient settings.

The results Dr. Nelson shared during this session were obtained using VSD’s RCA targeted 

surveillance methodology that uses data like these from across the VSD. RCA was established 

in 2006 for near real-time vaccine safety monitoring. Like a traditional epidemiologic study, 

primary vaccine exposure and comparator populations, about 5 to 10 AE outcome targets of 

interest, and potential factors that may confound the relationship between exposure and 

outcome are pre-specified. Unlike a traditional epidemiologic study, RCA involves routine and

cumulative updating of study data (e.g., monthly) and repeated interim analyses over time to 

compare risks. Statistically significant findings are deemed to be preliminary “signals” that are 

fully investigated with numerous follow-up activities, including chart validation to confirm true 

incident cases.

In terms of the design details for the RZV surveillance activity, the aim was to sequentially 

monitor RZV safety among adults ≥50 years during the initial uptake surveillance period from

January 2018 – December 2019. The primary analysis involved comparing the RZV recipients 

with historical ZOSTAVAX® in the prior 2 o 5 years. The secondary analysis involved agecomparable concurrent comparators of those who had either a well visit or received another 

vaccine like pneumonia or Tdap during the RZV uptake period. A number of baseline covariates 

were measured (e.g., dose, concomitant vaccines, prior receipt of ZVL, health care utilization 

measures, and chronic medical conditions). In terms of the sequential testing plan, the interim 

analysis involved conducting the first analysis after 6 months of uptake in June 2018 and then

conducting 18 more monthly analyses subsequently.

Two sets of pre-specific health outcomes of interest (HOIs) were designated. For formal 

sequential analyses, the following 10 high priority outcomes were identified that occurred 

incidentally at 1 to 42 days post-vaccination:

❑ Acute myocardial infarction (MI), stroke 

❑ Convulsion, polymyalgia rheumatica, supraventricular tachycardia, Bell’s palsy 

❑ Anaphylaxis (days 0-1), giant cell arteritis, optic ischemic neuropathy, GBS
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Exploratory analyses were performed for other post-vaccination outcomes, including the 

following:

❑ 1-42 days: gout, pneumonia, non-specific adverse effects, stroke subtypes, pericarditis, 

myocarditis, and eye-related outcomes (e.g., keratitis)

❑ 1-7 days: systemic reactions, local reactions, urgent care or ED visit 

At the time of the final monthly analysis, almost 650,000 doses had been observed. There was 

steady uptake during the approximately 2-year surveillance period. Here are the primary 

sequential results for the 10 primary outcomes:

For most outcomes, no preliminary signal was observed and the estimated relative risk was <1. 

Two preliminary signals were detected, one of which was for Bell’s Palsy at the 5th analysis 

when there were 36 observed events as compared to 24 that were expected for an estimated 

relative risk of 1.5. This effect has attenuated over time with twice as much data and the relative 

risk is 0.90. A preliminary signal also was observed early on for GBS. This was at the second 

look during which 3 events were observed in the SHINGRIX group compared to <1 event 

expected based on historical data, with a relative risk at that time of >5. That effect also has 

attenuated considerably to the current estimated relative risk of 1.24. This is based on only 

about 6 presumptive AEs, so there is considerable uncertainty in this estimate.

Considerable further follow-up was done on the preliminary GBS signal found when using the 

ICD-10 coded definition, including a chart review to determine the true GBS status for these 6 

presumptive ZVL cases. Among those, 3 were ruled out as they had symptoms prior to 

vaccination and 3 were confirmed—2 as Brighton Level 2 and 1 as Brighton Level 3. Chart 

review also was conducted among 5 presumptive historical cases. Of these, 2 cases were ruled 

out, 1 case was unable to be validated as chart data were missing, and 2 confirmed as Brighton 

Level 2. Based on chart validated outcomes, the best estimates in VSD are that relative risk is 

1.55 (95% CI: 0.17, 18.60) assuming that 2 ZVL cases are confirmed or 1.03 (95% CI: 0.14, 

7.73) if all 3 cases are assumed to be confirmed.

9 March 9, 2021

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
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In summary, after receipt of about 650,000 doses of RZV were received in the VSD between 

January 2018 – December 2019, a preliminary signal was observed for Bell’s Palsy (RR=1.51), 

but this effect did not persist as more doses accrued (RR = 0.90). A preliminary signal also was 

observed for GBS (RR=5.25) based on ICD-9/10 codes, and this effect also waned over time 

(RR=1.24). Chart review was conducted to confirm true GBS case status. In the final chartconfirmed analysis, VSD does not have sufficient evidence to determine whether there is an 

increased risk of GBS. The relative risk that can be estimated based on these data is 1.55 (95% 

CI: 0.17, 18.60), but the confidence intervals are very wide and crossed 1. Overall, there is not 

sustained evidence of increased risk among RZV recipients for any of the pre-specified 

outcomes being followed. Considerable subgroup and secondary analyses have been 

performed that provide further reassurance of these primary results.

Discussion Points

Dr. Atmar requested a reminder about how the expected number is determined for the 

comparator, and if the GBS might be accounted for by some other infection that was circulating 

in the community during the period of surveillance. That is, is the control group a 

contemporaneous group that would take into account environmental and other issues in the 

communities at the time?

Dr. Nelson indicated that these are historical comparators who received ZVL in the 5 years prior 

to the uptake period for SHINGRIX, so the primary analyses are based on numbers of events 

observed in that population that are then adjusted for age, gender, site, and cardiovascular 

outcomes to equalize between groups. These results do not fully adjust for all of the 

confounders. Those analyses are currently in progress using end-of-study cumulative data. 

Additional analyses that use a group other than the historical group. This is a historical 

comparative group, so any other changes over time during the prior to SHINGRIX uptake 

compared to during SHINGRIX uptake cannot be untangled. Differences between the vaccine 

groups could be due to other things that changed during those two periods of time, which is why 

contemporaneous control groups are being used in the end-of-study analysis, such as people 

who received well visits during the SHINGRIX period and also had an influenza vaccine in the 

prior year or received other vaccinations during the SHINGRIX period. Several analyses have 

been performed to manage different biases that exist depending upon the type of observational 

study designs used. 

Risk of Guillain-Barré Syndrome Following Herpes Zoster

LCDR Tara Anderson, DVM, MPH, PhD

CDC Lead, Herpes Zoster Work Group

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Anderson presented a CDC-led analysis of the work on GBS following HZ. GBS is a rare 

immune-mediated disease of the peripheral nerves. In the US, the estimated annual incidence

across all ages 1 to 2 cases per 100,000 persons. Risk factors for GBS include increasing age, 

male gender, immunocompromised status, previous viral and bacterial infections, and recent 

vaccinations (e.g., some influenza and rabies vaccines). Regarding previous infections, the 

strongest evidence in the literature is for the viral infections cytomegalovirus (CMV), Epstein–

Barr Virus (EBV), hepatitis E, and Zika virus. The strongest evidence in the literature for 

bacterial infections is Campylobacter jejuni and Mycoplasma pneumoniae. As the HZWG 

discussed RZV post-licensure safety monitoring results, it was noted that in some instances 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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both disease and vaccination have been associated with GBS as with influenza virus infection 

and some influenza vaccinations. Therefore, the WG agreed that it would be important to further 

explore the risk of GBS following HZ.

A possible temporal association between HZ and GBS has been noted in a small number of 

case reports in the literature. One previous epidemiologic study by Kang, Sheu, and Lin in 2010 

reported an increased risk of GBS following recent HZ. In this population-based cohort study 

using Taiwan’s National Health Insurance Research Database (NHIRD), the investigators found 

that 0.03% of patients developed GBS within 2 months following HZ and that the adjusted 

hazard of GBS during follow-up period was 18.37 (95% CI, 10.22–33.01) times greater for 

patients with HZ than those without HZ. To the WG’s knowledge, there are no published 

epidemiologic studies in other settings or using other methods.

Therefore, the WG conducted a case series study that was designed to strengthen the 

epidemiologic understanding of the risk of GBS following HZ and to help clarify the benefits 

versus the potential risks of vaccination. The primary objective of the study was to evaluate the 

risk of GBS following HZ using a self-controlled case series (SCCS) analysis of healthcare 

claims data from 2 large national data sources. The secondary objective was to describe the 

characteristics of these GBS cases in terms of demographics and outcome severity (e.g., 

duration of GBS hospitalization, ICU admission).

To provide some brief background, the SCCS methodology was developed in 1995 for use in 

vaccine safety studies and has since been broadly applied in epidemiology. This approach is 

used to examine the temporal association between a transient exposure (e.g., HZ) and a 

subsequent event (e.g., GBS). The precise timing of the exposure and event is important. Only 

individuals with both the exposure and the event of interest are included in the analysis. Each 

case serves as its own control; therefore, confounding by time-invariant factors is eliminated. 

The SCCS method estimates the relative risk of rates in the risk window compared to rates in 

the control window.

Two data sources were used for this study. The first is the IBM MarketScan® Commercial

database that includes individual-level, de-identified healthcare claims for persons covered by 

employer-sponsored insurance. The MarketScan® Commercial data are a convenience sample 

drawn from IBM Watson Health’s clients, which include approximately 30 to 50 million persons 

enrolled annually since 2006. The second data source was the CMS Medicare database that 

include individual-level, de-identified healthcare claims information for Medicare beneficiaries. 

The CMS Medicare data include a 100% sample of all fee-for-service (FFS) clinical claims data 

from Medicare for approximately 50 to 60 million Medicare enrollees annually. Approximately 

one-third of Medicare beneficiaries are covered under Medicare Parts A, B, and D FFS.

The study populations for the analysis included: 1) MarketScan® Commercial Claims and 

Encounters (CCAE) data from 2010–2018 for persons 18–64 years of age with private health 

insurance with drug data supplied for those who enrolled in MarketScan® 180 days before 

through 365 days after the HZ index date; and 2) CMS Medicare data from 2014–2018 for 

persons ≥65 years of age with Medicare insurance with Parts A, B, and D enrolled in Medicare 

180 days before through 365 days after the HZ index date. Of note, no drug data were available 

prior to 2014. In addition, beneficiaries enrolled in Medicare Part C or Medicare Advantage 

managed care plans since drug claims data were not available for these populations.
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In terms of study exposure definitions, HZ cases were defined as persons with an ICD-9 or ICD10 outpatient claim with a primary or secondary diagnostic code for HZ. In order to capture 

incident HZ cases, persons were excluded for whom the first HZ code was a code for PHN. 

Persons with subsequent PHN codes were retained. Persons also were excluded with claim for 

administration of any zoster vaccine of either ZOSTAVAX or SHINGRIX within one day of the 

HZ claim, given that the HZ diagnostic code may more likely represent instances of miscoding. 

The HZ index date was defined as date of first HZ claim during the study period.

For GBS, cases were defined as persons with an ICD-9 or ICD-10 inpatient claim for GBS as 

the principle diagnostic code. To increase the specificity of the GBS diagnostic code, this was 

required to be paired with a procedural code for lumbar puncture, electromyography, or nerve 

conduction study for patients. These procedures are typically part of the diagnostic procedures 

for patients with GBS. Persons with GBS in the 180 day window prior to HZ were excluded. 

Persons also were excluded persons who had select previous infections and SHINGRIX during 

the 42-day period prior to GBS. These infections included the previously noted viral infections 

(e.g., CMV, EBV, influenza, hepatitis E, Zika) and bacterial infections (e.g., Campylobacter 

jejuni, Mycoplasma pneumoniae) that currently have the strongest association with GBS.

Several negative controls also were evaluated to validate the methods. Conditions were 

selected that were similar to GBS (i.e., acute, frequently result in hospitalization, low rate of 

reoccurrence) that were not expected to increase after HZ. These negative controls included 

appendicitis, nephrolithiasis, cholecystitis, and fractures of the upper limb. These were defined 

based on ICD-9 and ICD-10 codes. Persons were excluded with claims for these conditions in

the 180 day window prior to HZ.

As previously noted, SCCS design was selected in which only cases are included in the 

analysis and each case serves as its own control. In this analysis, the rate of GBS or negative 

controls were compared in the risk window as compared to the rate in the control window. The 

risk window for this study was the 1 to 42 day window after the HZ index data, which is 

comparable to the period typically used in vaccine safety studies. Two control windows were 

selected. The primary control window was the 100 to 365 days from the HZ index date. The 

secondary control window was the 43 to 99 days after the HZ index date. Conditional Poisson 

regression was used to compare rates in the risk window versus the 2 control windows.

In terms of the study results, a total of 489,516 persons with HZ were identified who were ages 

18 to 64 years from the 2010-2018 MarketScan® Commercial among whom 11 developed GBS 

during the 1 to 365 days following HZ. A total of 650,229 persons with HZ were identified who 

were 65 years of age and older from the 2014-2018 CMS Medicare data among whom 41 

developed GBS during the 1 to 365 days following HZ. For those 18 to 64 years of age, there 

was a slightly higher percentage of cases aged 50 to 64 years. For those 65 years and older, 

the highest percentage of cases was in the 70 to 79 year age range. Among those 18 to 64 

years of age, 82% of GBS cases were female. For those 65 years of age and older, 54% of 

GBS cases were female. Regarding the interval between HZ and GBS, a higher proportion of 

GBS cases among those 18 to 64 years of age occurred within the first 42 days after HZ 

compared to the primary control window. For those 65 years of age and older, a higher 

proportion of GBS cases was observed in the risk window and secondary window compared to 

the later primary control window. Regarding duration of GBS hospitalizations and ICU 

admissions, evidence was identified of more severe GBS among those 65 years of age and 

older with a median duration of hospitalization of 9 days and 51% admitted to the ICU.
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For the SCCS analysis, the rate ratio of GBS was increased during the 42 day risk window 

following HZ as compared to the primary control window for both age groups, with a rate ratio of 

6.3 (1.8–21.9) for those 18 to 64 years of age and a rate ratio of 4.1 (1.9–8.7) for those 65 years 

of age and older. For both age groups, the rate ratios during the 42 day risk window following 

HZ compared to the secondary control windows were not statistically significant based on the 

confidence intervals. For those 18 to 64 years of age, the rate ratios of the negative controls 

were not increased during the 42 day risk window as compared to either control window. These 

values ranged from 0.9 (0.7–1.3) to 1.2 (0.8–1.7) in the primary control window and 1 (0.9–1.1)

to 1.3 (0.8–2.0) in the secondary window. Given the confidence intervals, these values were not 

statistically significant. For those 65 years of age and older, the rate ratios of the negative 

controls during the 42 day risk window as compared to the control windows ranged from 1 (0.7–

1.5) to 1.4 (1.0–2.0) in the primary control window and 0.9 (0.6–1.4) to 1.5 (1.0–2.2) in the 

secondary control window. Although some confidence intervals indicated statistical significance, 

all negative control values were much lower than the rate ration of 4.1 observed for GBS in this 

age group during the 42 day risk window as compared to the primary control window.

There are several strengths and limitations for this study. Regarding strengths, large national 

datasets were used that include medical and pharmacy claims. The SCCS design inherently 

controls for potential confounders (e.g., gender, underlying medical conditions) and each case 

serves as its own control. The study inclusion criteria strengthened HZ and GBS case 

identification, while the exclusion criteria account for potential confounders (e.g., antecedent 

infections). Regarding limitations, a small numbers of GBS cases were identified in both data 

sources. MarketScan® is a convenience sample and is not nationally representative. There is a 

potential for miscoding or misclassification bias in claims data. Finally, it was not possible to 

validate GBS, HZ, or other diagnoses using medical record review.

In conclusion, this SCCS analysis identified an increased risk of GBS in the 42-day window 

following HZ compared to the primary control window of 100 to 365 days. This increased risk 

was identified across adult age groups and in two different large administrative data sources. 

The negative control results strengthened the findings. The negative control rate ratios clustered 

around the null effect of 1, with a range of 0.9–1.4 for the primary control window. These values 

were lower than rate ratios for GBS identified in both data sources. Finally, evidence was 

identified of more severe GBS in terms of longer duration of hospitalizations and a higher 

percentage admitted to the ICU among those ≥65 years.

Summary & Planned Risk-Benefit Analysis For Use of RZV in Immunocompetent Adults

LCDR Tara Anderson, DVM, MPH, PhD

CDC Lead, Herpes Zoster Work Group

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Anderson provided a summary of the session, ACIP HZWG discussions, and next steps that 

include a planned risk-benefit analysis for the use of RZV in immunocompetent adults. On 

behalf of the HZWG, she expressed gratitude to the Immunization Safety Office (ISO), the VAD, 

and the FDA for their contributions toward monitoring RZV safety. The WG also thanked the 

many CDC staff and other contributors who provided valuable information and insight.
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Two critical safety monitoring updates from VAERS and VSD were shared during this session. 

As discussed by Drs. Su and Shimabukuro regarding VAERS, SAEs have rarely been reported. 

RZV post-licensure safety monitoring findings in VAERS are generally consistent with the safety 

profile observed in pre-licensure clinical trials. As discussed by Dr. Nelson regarding the VSD 

RCA conducted based on data from January 2018 – December 2019, results from the final 

chart-confirmed analysis indicate that VSD has insufficient evidence to determine whether there 

is an increased risk of GBS.

As presented during the June 2019 ACIP meeting, FDA has conducted assessments of the risk 

of GBS following RZV in Medicare data in collaboration with CDC and CMS. The preliminary 

results of the cohort analysis presented during that meeting compared the post-vaccination GBS 

rate between persons ≥65 years of age who received RZV between October 2018 and 

December 2019 and historical controls who received ZVL between October 2012 and 

September 2017 indicated an elevated adjusted rate ratio of 2.34 (95% CI 1.01, 5.41). On the 

advice of the HZWG, FDA conducted additional analyses using SCCS methods. The FDA has 

additional results available from the claims-based SCCS analysis and the medical record review 

SCCS analysis. These results are currently under review t FDA, and will be shared during a 

future ACIP meeting.

As discussed during Dr. Anderson’s previous presentation, a possible temporal association 

between HZ and GBS has been noted in a small number of case reports and one previous 

epidemiologic study (Kang, Sheu, and Lin, 2010) reported an increased risk of GBS following 

recent HZ. In a CDC-led self-controlled case series analysis, an increased risk of GBS was 

identified 1–42 days following HZ compared to the primary control window of 100-365 days 

across adult age groups and in two different administrative data sources.

To summarize the HZWG discussions since the June 2019 ACIP meeting, the HZWG is 

currently reviewing evidence regarding use of RZV in immunocompromised adults. The HZWG

is concurrently reviewing and discussing findings regarding the possible risk of GBS following 

both disease and vaccination, and agrees that continued safety monitoring of RZV in VAERS 

and VSD is warranted. In addition, a dynamic risk-benefit assessment that incorporates new 

data on the risk of GBS associated with disease and vaccination will inform recommendations 

on the use of RZV in immunocompetent and immunocompromised adults. This planned riskbenefit analysis will evaluate the benefits of averted HZ cases and complications versus the risk 

of AEs. SMEs and the HZWG will collaborate on model parameters and scenarios and the 

outcomes per 1,000,000 vaccinated individuals to be estimated would include episodes of HZ, 

episodes of postherpetic neuralgia and other HZ complications (e.g., GBS), injection site 

reactions, systemic reactions, and rare adverse events (e.g., GBS).

Regarding next steps, the HZWG is committed to providing updates to the ACIP at the earliest 

opportunity. Future ACIP meeting presentations will address the FDA’s assessments of the risk 

of GBS following RZV in Medicare data, the results of the risk-benefit analysis results regarding 

use of RZV in immunocompetent adults, and RZV use in immunocompromised adults. Dr. 

Anderson posted the following questions for ACIP discussion and input:

❑ Does ACIP have any other suggested follow-up regarding RZV safety monitoring?

❑ Does ACIP have any feedback on planned risk-benefit analysis for use of RZV in 

immunocompetent adults, particularly any other outcomes of interest?
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Discussion Points

Dr. Romero observed that the presentation and extensiveness of these data serves to exemplify 

the degree and type of collections systems available to monitor vaccine safety in this country. 

This bodes well for the future with regard to monitoring newer vaccines that will be coming out.

Dr. Talbot emphasized the amazing amount of work that had been shown during this session. 

She requested clarification about whether they were saying that there is a signal following 

vaccination, but they are not yet clear if it is a random occurrence or a true event.

Dr. Anderson indicated that based on the results to date, the safety profile is reassuring. 

However, follow-up is continuing given the previous results from the FDA analysis showing an 

elevated adjusted risk in the Medicare data and given the study results she just presented 

regarding the risk of GBS that also has been noted for an association with GBS.

Regardless of GBS associated with HZ, Dr. Talbot noted that the numbers Dr. Anderson 

showed did not show risk after vaccination. They talk about GBS risk as being 1 in 1 million for 

influenza and she wondered whether Dr. Anderson could provide an idea of that number for the 

current shingles vaccine. She also asked what future studies are planned and what future 

evidence will be provided to ACIP, and said that she is slightly hesitant that this vaccine has a 

very powerful adjuvant.

Dr. Anderson said that she could not provide a number for the risk of GBS at this time. The 

results shared to data are related to the information she presented during this session based on 

the RZV versus the ZVL comparator groups, with an elevated adjusted ratio of 2.34. During a 

future meeting, the FDA intends to present the results of their SCCS analyses, which are under 

review at this time with FDA and they will share them as soon as possible.

Dr. Messonnier add that there are two studies that show a positive signal. However, the riskbenefit evaluation that would get to the additional risk of GBS compared to the risk of prevention 

of HZ has not been completed. The FDA is conducting a third study that is expected before 

February 2021.

Dr. Anderson confirmed that as Dr. Nelson shared earlier, the results of a VSD analysis initially 

indicated a signal for GBS. Over time, that signal has attenuated so now the results of that study 

do not have sufficient evidence to say that there is a signal in VSD. There has not been a signal 

in VAERS. In the results presented to date by the FDA from the original cohort analysis, there 

was an elevated risk in the RZV versus the ZVL comparator group. The results of the FDA 

SCCS analyses using Medicare data will be presented at another time, given that they are 

currently under review at the FDA. While awaiting the results of those analyses, the HZWG is 

discussing moving forward with the planned risk-benefit analysis in which new information 

related to the possible risk of GBS after vaccination and the risk of GBS after infection will be 

taken into consideration.

Dr. Messonnier said she thought Dr. Talbot was asking about the upper bound of potential 

increased risk. That is, GBS is 1 in 1 million for influenza. What is the absolute maximum risk 

and is there enough concern to act now as opposed to waiting for additional analyses?

Dr. Anderson said that at this point, there has not been sufficient evidence or information 

presented in order to be able to determine that.
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Dr. Lee emphasized what Dr. Romero said, which is that they absolutely rely on the surveillance 

systems to detect signals. This signal in VSD and the surveillance from VAERS were presented 

previously. Based on follow-up, those signals have attenuated in those databases over time. 

The HZWG is waiting for the FDA’s CMS analysis. That database has the greatest power to 

provide the information needed, in addition to making sure that these cases are validated. The 

way she would frame this is that in thinking about signals, a statistically signal was detected. 

After a statistical signal is identified, signal refinement and signal evaluation activities are 

undertaken. Those activities are underway in several systems. During this session, they heard 

that those signals are not identified in VAERS and have attenuated in VSD. The HZWG is 

looking forward to seeing the FDA’s CMS data because they have a large proportion of older 

adults who are receiving these vaccines, which she thinks will be very helpful to ensuring that 

ACIP is making decisions based on the best possible data. Also very important was the analysis 

of GBS following disease. Dr. Lee said she has not intuitively understood the high rate of GBS 

following HZ infection. She appreciated it following campylobacter or other types of infections, 

but had not had GBS on her radar. The reason she thinks this is important is because it is 

different from the way they are used to thinking about vaccine safety, which is against the 

background of the general population. It is very important to remember that the benefit-risk 

analysis is around people who get the disease and people who are vaccinated. Having the rates 

of GBS following HZ infection is incredibly helpful in terms of understanding the benefit-risk 

balance in the population, particularly for this vaccine. The HZWG absolutely thinks that vaccine 

safety needs to undergo continued monitoring. They presented the results during this session of 

the vaccine safety evaluation and evaluations on disease because they think it is so important 

from a transparency perspective to present all of these data to ACIP. They anticipate that more 

data will be forthcoming, but wanted to propose the benefit-risk analysis because of the 

statistical signal that is continuing to undergo evaluation as well as the new information 

regarding the risk of GBS following HZ infection.

Dr. Bell echoed the importance of these safety monitoring systems for all new vaccines. In that 

context, it is important to remember that the evaluation of this signal is ongoing. This type of 

issue must be assessed and worked out over time, so they must keep looking at it as more 

people are vaccinated in order to address signals as they arise. Perhaps the signal for GBS will 

change over time, which is what they are looking for. Another potential benefit of doing a riskbenefit analysis is the sensitivity analysis that could be part of the process that might help with 

some of the questions regarding the upper bound, where the risk-benefit balance would shift 

with respect to an association between vaccination and GBS, and so forth. There is benefit to 

using this risk-benefit analysis partially as another way of exploring the meaning and the 

potential impact of these signals as they arise.

Dr. Hunter said he was very reassured by the data being presented, and reminded everyone 

that he is the person who voted against the preferred recommendation. He said that while he 

needed more data, he was almost to the point of being able to tell his patients that they would 

be at lower risk by getting the vaccine because it would protect against getting an HZ outbreak.

Ms. McNally asked when the HZWG estimates an update on the risk-benefit analysis and the 

FDA assessment. 

Dr. Anderson indicated that they would be presenting these as soon as possible during an 

upcoming ACIP meeting, ideally in February 2021.
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Dr. Cohn reassured everyone that when the FDA analyses are available for review by the 

HZWG, any concerning data that would necessitate the need to meet earlier in order for the 

ACIP to review the data before February 2021, that absolutely could be done.

Tick-Borne Encephalitis Vaccine 

Introduction

Katherine Poehling, MD, MPH

Chair, Pneumococcal Vaccines Work Group

Dr. Poehling introduced the Tick-Borne Encephalitis (TBE) Vaccine Work Group (WG) and 

session. The TBE Vaccine WG formed in September 2020 following notification that Pfizer plans

to submit a Biologics License Application (BLA) to the Food and Drug Administration (FDA) for 

their TBE vaccine by the end of 2020. Several TBE vaccines are manufactured and licensed 

internationally, but none are produced or licensed in the United States (US) and there are no 

existing ACIP TBE vaccine recommendations. If Pfizer’s TBE vaccine receives priority review 

designation, FDA’s goal is to take action on an application within 6 months1. Licensure is 

possible by the third quarter of 2021 [https://www.fda.gov/patients/fast-track-breakthroughtherapy-accelerated-approval-priority-review/priority-review].

The purpose of the ACIP TBE Vaccine WG is to discuss use of TBE vaccine in US adults and 

children visiting or living in TBE-endemic areas and laboratory workers. The Terms of 

Reference for the TBE Vaccine WG are to: 1) review information on TBE, including its 

epidemiology, clinical presentation, diagnosis, treatment, and outcome; 2) review data on 

infection risk and burden for US civilian and military travelers and laboratory workers; 3) review 

data on vaccine safety, immunogenicity, and effectiveness; 4) provide evidence-based 

recommendation options for ACIP; 5) identify areas in need of further research for informing 

potential future vaccine recommendations; and 6) publish ACIP recommendations in the 

Morbidity and Mortality Weekly Report (MMWR).

Topic discussed during this session included the following:

❑ Background on TBE disease and vaccines

❑ Immunogenicity and safety of Pfizer’s TBE vaccine

❑ Next steps for the TBE Vaccine WG

Background on TBE Disease and Vaccines

Susan Hills, MBBS, MTH

Arboviral Diseases Branch

Division of Vector-Borne Diseases

Centers for Disease Control and Prevention

Fort Collins, Colorado

Dr. Hills presented background information on TBE disease and vaccines as an introduction for 

ACIP members. TBE virus is a flavivirus with three main subtypes: European, Siberian, and Far 

Eastern subtypes. TBE virus is primarily transmitted to humans through the bite of an infected 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Ixodes species tick, mainly Ixodes ricinus or Ixodes persulcatus. Infections are usually acquired 

in wooded or surrounding areas during recreational (e.g., camping, hiking, fishing, cycling or 

foraging for mushrooms/berries/flowers) or by persons involved in outdoor occupations such as 

in the forestry service or in military training. TBE virus transmission also can occur occasionally 

through other means such as ingestion of unpasteurized dairy products from infected cattle, 

sheep, or goats; slaughtering of viremic animals; laboratory exposure; and rarely through blood 

transfusion, transplantation, or breastfeeding.

TBE virus is focally endemic in a geographical region spreading from Western and Northern 

Europe through to Eastern and Northern Asia, reflecting the distribution of the vector of ticks. In 

endemic areas, there are approximately 5,000 to 13,000 cases reported annually and the 

number of reported cases varies from year-to-year. Most cases occur from April through 

November, with a peak number of cases reported during early and late summer when ticks are 

most active. Most cases result from exposures occurring in areas under 2,500 feet. However, 

the geographic range of TBE virus appears to have expanded to new areas during the last 30 

years, including altitudes up to and including 5,000 [Dobler et al, Wien Med Wochenschr 2012].

In terms of the clinical features of TBE, the incubation period is typically between 7 to 14 days

but can range from 4 to 28 days. About 25% of persons with TBE virus infection develop clinical 

symptoms. The clinical presentations of disease can range from a non-specific febrile illness 

through to neurologic illness presentations (e.g., meningitis, encephalitis, or 

meningoencephalomyelitis). A monophasic or biphasic illness can occur. A monophasic illness

is more typical for patients infected with the Far Eastern and Siberian subtypes of the virus. The 

biphasic illness is more typical with the European subtype and has a clinical course that 

consists of a first phase of non-specific febrile illness, followed by remission of symptoms, and 

then a second more severe phase with neurologic illness. There is no specific antiviral treatment 

for TBE and clinical management consists of supportive care.

The frequency of neurologic sequelae depends upon the viral subtype. Sequelae occur in up to 

30% of patients with the European subtype and up to 80% of patients with the Far Eastern 

subtype. For the Siberian subtype, sequelae rates fall in the middle of these other rates. Case 

fatality rates similarly depend upon the viral subtype. The case fatality rate is about 1% to 2% 

with the European subtype, about 20% with the Far Eastern subtype, and somewhere in the 

middle of those rates with the Siberian subtype. The incidence and severity of disease are

highest in older persons.

Overall, TBE cases in US persons are rare. Cases are reported occasionally among US civilian 

and military travelers. There are 2 recent cases series publications, including 5 cases reported 

among civilian travelers that were diagnosed at CDC in the 10 years from 2000-20091 and 8 

cases reported among military service members or their family members stationed in Europe 

during the period 2006-2018, including 7 cases in 2017 and 20182[

1CDC. MMWR Morb Mortal 

Wkly Rep 2010; 2Mancuso J et al. MSMR 2019].

TBE vaccine is of substantial interest to the Department of Defense (DoD) in relation to these 

cases among military persons stationed in parts of Europe. Dr. Hills indicated that she would not 

be discussing these cases in any more detail as the WG would be presenting a more thorough 

review and a discussion of traveler, military, and laboratory cases for ACIP members during the 

February 2021 meeting.
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89

Four TBE vaccines are currently available internationally, including the 2 in Europe and 2 in 

Russia shown in the table, in addition to 1 vaccine that is available in China for which limited 

information is available in the public domain:

Trade Name Manufacturer (Location) Age Group

FSME-IMMUN, 

TicoVac

Pfizer (Austria) ≥1 year

Encepur Bavarian Nordic (Denmark) ≥1 year

EnceVir Microgen (Russia) ≥3 years

TBE-Moscow Chumakov Institute (Russia) ≥3 years

The Pfizer TBE vaccine is marketed in Europe as FSME-IMMUN® or TicoVac, which the ACIP 

TBE WG is considering at this time. Bavarian Nordic is considering licensure of their TBE 

vaccine, Encepur, in the US. However, there is not a fixed timeline for submission of a BLA at 

this point. The European vaccines are licensed in children from 1 year of age and the Russian 

vaccines from 3 years of age. Pfizer’s TBE vaccine is an inactivated vaccine that is available in 

pediatric and adult formulations. The original formulation of this vaccine was first used in Europe 

in the late 1970s. The current vaccine formulation has been used since 2001 or approximately 

20 years. This vaccine is currently licensed in more than 30 countries in Europe.

In summary, TBE is a focally endemic disease with the geographic risk area extending from 

Western and Northern Europe through to Northern and Eastern Asia. The virus is transmitted to 

persons primarily through tick bites when visiting or working in wooded areas in endemic 

regions, although other modes of transmission can occur. TBE virus can cause clinical disease 

that can be severe and there can be high case fatality and sequelae rates with some of the TBE 

virus subtypes. Cases among travelers are rare. At this stage, one TBE vaccine among several 

available internationally will be submitted for licensure in the US, which is the Pfizer vaccine. 

The vaccine is an inactivated vaccine that has both adult and pediatric formulations, which has 

been used in its current formulation for roughly 20 years in Europe. A TBE vaccine has never 

previously been licensed in the US. As a result, there are no existing TBE vaccine ACIP 

recommendations.

I uno enicit nd S et o izer’s E ccine

Heinz-Josef Schmitt, MD, PhD

Global Viral Vaccines Medical and Scientific Affairs Lead, Pfizer

Dr. Schmitt presented data on the immunogenicity and safety of Pfizer’s TBE vaccine. FSMEIMMUN® is an inactivated whole-virus vaccine that was developed and then first licensed in 

Austria in 1976. This is a vaccine that does not seek a new license to begin with and has a long 

history. Lifecycle management addressing local needs and new situations is not as clear-cut 

from the literature with a new license application, but it is somewhat complicated in some 

respects. The vaccine is basically a suspension of purified TBEV-EU subtype strain that was 

isolated in Austria in the small town of Neudörfl. It is propagated in chicken embryo fibroblast 

cells derived from pathogen-free eggs. It is highly purified by the use of continuous-flow zonal 

ultracentrifugation, free of thiomersal, and uses human serum albumin (HSA) as a stabilizer. 

Approved tradenames outside of the US are:
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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❑ FSME-IMMUN® / Tico Vac with adult and pediatric formulations with 2.4μg or 0.5mL of TBEV-EU for use as of 

16years of age

❑ FSME-IMMUN® Junior / Tico Vac Junior with 0.25mL with 1.2μg of TBEV-EU for use in children and adolescents 

1–15 years of age

❑ US tradename to be determined

In terms of historical development, the vaccine was first approved in Austria as a vaccination for 

high-risk groups. In 1981, TBE mass vaccination was introduced in Austria. In 1999, thiomersal 

and its stabilizer was removed in fulfilment of European Pharmacopoeia (Ph. Eur.)

requirements. In 2000, HSA was removed and use began of a production virus seed free of 

potential contaminating mouse brain protein, achieved by subjecting the master virus seed to 2 

sequential passages in primary chick embryo cells. These changes to the manufacturing 

process and final formulation required a new marketing authorization to be obtained. The newly 

approved vaccine was called FSME-IMMUN®. HSA removal was associated with a substantial 

increase in the rate of high fever in infants and young children. In 2001, HSA was again added 

to the TBE vaccine, which was again named FSME-IMMUN® and licensed based on a new 

clinical development program. The incidence of adverse reactions (AEs) decreased to expected 

levels. FSME-IMMUN® Junior was launched in 2003. This graphic depicts the large body of 

evidence and extensive experience that has accumulated for over 40 years with FSME, which 

Dr. Schmitt further described for the boxes shown in pink:

The FSME-IMMUN® TBE vaccination schedule is highly complicated, which relates to the fact 

that there has never been an efficacy study. The only marker for protection is neutralizing titers 

or serology based on ELISA. Whenever the titer grouped to below a certain threshold, people 

were advised to give a booster dose. There are 2 doses for adults and children given 1 to 3 

months apart. There also is a rapid schedule in which the vaccine doses are given 2 weeks 

apart, which is of particular of interest for travelers. The third dose is given 5 to 12 months later. 

Usually, the third dose would be called a “booster” dose. While there is good reason to think that 

this is a booster dose, the 3 doses have been called the “primary series” throughout the history 

and on the label. Following serology, the first booster (e.g., Dose 4) was given 3 years later. 

5

 er e rs S E ccu ul ted L r e od o 

E idence nd E tensi e E erience

Heinz et al. (2013 ) 2013;19(1):69 76; Heinz et al. (2015 ) 2015 ;20(13):9 16. Loew Baselli et al. (2011 ) 29: 7307 7319; Pfizer, data in file.

 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 

 osin 

S et nd I uno enicit 

Evaluation of vaccination in 

Siberian and Far Eastern subtypes 

Safety and immunogenicity 

Post marketing Surveillance 

Immune system stimulation 

Protection in healthy elderly 

Post marketing surveillance 

Immune response in adults (L w Baselli) Vaccination safety data (P llabauer)

Field effectiveness 

Characterization 

of Far Eastern subtype 

 

Antibody response 

Seropositivity by NT (P llabauer)

Serological 

response 

in elderly 

 

Seropersistence in adults (L w Baselli)

Vaccination safety data (P llabauer)

Broad Cross neutralization 

Immune response in children, adolescents, and elderly Molecular Basis of the 

Divergent Immunogenicity 

L unc o 

 I In ect in ustri 

L unc o current or ul tion 

 I 

Dosing in adults 

Booster effectiveness 

 

Rapid immunization 

data (L w Baselli) Dosing in children (P llabauer)

Rapid immunization 

data 

Studies Reviewed in Current Presentation
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

91

Later boosters (doses >5) are given every 5 years. The titers dropped in those >60 years of 

age, so the booster is supposed to be given every 3 years after 60 years of age.

There is no known serological correlate of protection for TBE, even after 40 years. There are 

more than a dozen ELISAs and they use different test strains. Usually in all Pfizer studies, this 

was the seed strain. It is very important to keep in mind that use of different strains may produce 

different results. One other strain is used in the ELISA that is the seed strain of the competitor 

vaccine, which is a mutated K23 antigen. For the purpose of the Pfizer vaccine and Immunozym 

FSME-IgG ELISA, about 126 VIE U/ml are considered positive, 63−126 VIE U/ml are

considered borderline, and <63 VIE U/ml are considered negative. For the neutralization assay 

(NT), Pfizer used the Adner method described in 2001 for which a neutralization value of ≥ 1:10 

is considered positive [Adner N et al (2001) Pharmacokinetics of human tick-borne encephalitis 

virus antibody levels after injection with human tick-borne encephalitis immunoglobulin, 

solvent/detergent treated, FSME-BULIN S/D in healthy volunteers. [Scand J Infect Dis

33(11):843-7].

The studies Dr. Schmitt described used the vaccination schedule described earlier of the 

primary series of 3 doses, with the first booster dose 3 years after the third dose and the second 

booster at 5 years, except in those who are over 60 years of age for whom it is 3 years. For the 

adult schedule, there is a blood draw at baseline, 21-35 days after Dose 2, and 21-28 days after 

Dose 3. In the dose finding study, 0.6μg, 1.2μg, and 2.4μg of the Neudörfl strain were used. 

Very nice seroresponse rates were achieved with 1.2μg and 2.4μg. These were further 

assessed with regard to titers and reactogenicity. Titers differed for the 0.6μg antigen dose with 

lower titers and higher titers for the 1.2μg antigen dose. While the seropositivity rates between 

1.2μg and 2.4μg are quite similar, the titers are much higher with the higher antigen dose. At the 

time, an efficacy study was never done and never planned, so the goal is to go for the higher 

titers if reactogenicity allows. There was not much of a difference in terms of the reactogenicity

studies. Systemic reactions were mainly mild and their frequency decreased with later doses. 

The occurrence of local reactions was not dose-dependent and their frequency was lowest after 

Dose 2. Fever >38°C was observed at a very low rate. Only 1 case of fever was reported in the 

2.4μg dose group. No unexpected AEs or vaccine-related SAEs were observed during the 

study. This is why the 2.4μg dose was chosen in the end for the adult preparation.

In terms of the primary series (Doses 1, 2, 3) it was important to know when to give Dose 3. A 

study was conducted in which blood was drawn after Dose 3, after 2 years, after 3 years, and 

then the first booster dose is given. Blood is drawn before and after Dose 4. One month after 

primary immunization, seropositivity rates were close to 100% using ELISA and 100% using NT. 

By 2 and 3 years after primary immunization, seropositivity rates had decreased from 99.1% to 

87%. After the first booster, seropositivity rates increased to 100% regardless of the test 

method. Between 1 month and 2 years after primary immunization, GMCs/GMTs decreased 

about 4-fold. After the booster vaccination, GMCs/GMTs increased above 1-month levels. The 

geometric mean of the fold increase between pre-booster and the post-booster antibody levels 

were 11.2 using ELISA and 7.5 using NT. No SAEs were reported during this study.

Turning to the study of the rapid schedule that is of particular interest to Americans wishing to 

visit Europe or Asia, there is a pre-vaccination baseline blood draw and a second dose at Day 

10-13. There are then repeated blood draws post-Dose 2 at Days 3, 7, 14, 21, and 42. Similar 

developments were seen in terms of GMCs and GMTs, with peaks reached 21 days after Dose 

2. Seropositivity was 21% at 3 days, 28% at 7 days, 92% at 14 days, 96% at 21 days, and 98% 

at 42 days by ELISA. Seropositivity was 89% at 3 days, 96% at 7 days, 98% at 14 days, 100% 

at 21 days, and 100% at 42 days by NT. In terms of reactogenicity, most systemic and all local 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

92

reactions were mild. The most frequently reported systemic reactions were myalgia, headache, 

and fatigue. Injections-site pain and tenderness were by far the most frequent local reactions. 

No SAE experiences were reported.

The schedule and dose finding were the same for the pediatric studies. This is somewhat 

complicated based on the publication. The basic principle is that there are 2 dose-finding 

studies (N = 1278) and 1 open label safety study (N = 2417) with the pediatric formulation in 

children and adolescents 1–15 years of age. The conclusions were that the FSME-IMMUN®

pediatric vaccine formulation is safe and highly immunogenic for children <12 years of age and

also for adolescents <16 years of age. Both the 0.6μg and 1.2μg doses were highly

immunogenic in both age groups. The 0.3μg dose induced slightly lower seroconversion rates, 

with the lower level of the 95% CI after dose 2 in the older age group below 85%, the predefined lower limit for the optimal vaccine dose. Based on the results of these dose-finding 

studies, 1.2μg was considered the preferred dose for children 1–15 years of age. In both age 

groups, a clear dose-dependent immunogenic response was seen for GMCs after Doses 2 and 

3.

FSME-IMMUN® was found to be safe in children 1–15 years of age at all 3 doses. Fever and 

other adverse reactions were not dose-dependent. Fever was more frequent in the younger age 

group, with most cases of fever mild in severity. Total systemic reactions, excluding fever, 

occurred at a relatively low frequency of <13% after Dose 1 and were comparable between the 

three dose groups. Local and systemic adverse reactions occurred at a much lower frequency 

after Doses 2 and 3. No serious adverse reactions were reported in either age group. In the 

open label safety study, fever rates after Dose 1 were low (9.7%) and decreased after doses 2 

and 3 (2.4% and 2.4%, respectively). Fever was more frequent in the youngest age class, with 

most cases of fever being mild in severity. The most common systemic reaction, excluding 

fever, was headache.

From the open label study in more than 2000 children, the most common local reactions were 

injection-site pain and tenderness. The important message then and now is that no vaccinerelated SAEs were observed during the studies. In terms of seropersistence in children and 

adolescents after the 3-dose primary immunization series, seropositivity rates were quite high 

and decreased over time from 99% to 86%. Titers by NT were 375 at 1 month and decreased to 

47 at 58 months.

Based on almost 20 years of experience and over 47 million doses distributed of the new 

formulation since 2000, it is concluded that TICO-VAC is well-tolerated and there are no safety 

concerns at this point. The following table summarizes safety data from the most important 

studies for children and adults:
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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There are 2 publications regarding long-term serology, 1 in adults and 1 in children. Blood was 

drawn in the Spring of every year. If the titer dropped below a pre-defined threshold, the 

respective trial subject received a booster dose to make sure that he/she was protected for the 

upcoming season. The seropersistence-rate through 10 years after the first booster (Dose 4) 

across all age groups measured by ELISA were consistent with the results as measured by NT.

A TBE antibody response by ELISA before and after the catch-up vaccination in a study by 

Schosser in 2014 showed that subjects who missed the second, third, or fourth dose who 

receive one more booster dose achieves the same amount of titers regardless of whether they 

had 3 or 4 doses previously. This is important for Americans traveling to Europe. This table 

illustrates that while booster doses in this study had not been given for up to more than 20 

years, there were very high response rates in all age groups:

30

S et 

 ccin tion S et t ro i ot l linic l Studies

Source: P llabauer et al . 28, 2010; L w Baselli et al. , 24, 2006.

 I l

S to n 

Loc l in 392/2977 1 3.2%

 enderness 890/2977 2 9.9%

 e d c e 171/2977 5.7%

 e er 2 3/2947 0.8%

 uscle in 144/2977 4.8%

 use 5 9/2977 2.0%

 oint in 3 8/2977 1.3%

 ti ue 186/2977 6.2%

 l ise 133/2977 4.5%

L deno t 1 7/2977 0.6%

 I 2 l unior

S to n 

Loc l in 272/2417 11.3%

 enderness 438/2417 18.1%

 e d c e 261/2417 1 0.8%

 e er 230/2374 9.7%

 uscle in 8 5/2417 3.5%

 use 7 6/2417 3.1%

Loss o etite 7 1/2417 2.9%

 n es in slee in e iour 6 6/2417 2.7%

 estlessness

(only age 1 5 years) 5 3/584 9.1%

 ti ue

(only age 6 15 years) 102/1833 5.6%

 l ise

(only age 6 15 years) 7 6/1833 4.2%

36

 tc u Stud ELIS es onses

(Schosser, 2014 In adults 16 years (N=1115) and children 6 15 years (N=135))

Pfizer data on fileSchosseret al. (2014) 32:2375 81.

 e rou i e Inter l ro L st ccine to tc u ose n 

 e rs

 e rs 2 d s 2 

 e rs 2 2 d s 

1 0 12 years (3652 4747 days) 257/259 9 9.2

1 3 15 years (4748 5843 days) 8 1/8 3 9 7.6

1 6 18 years (5844 6939 days) 5 1/5 1 100.0

1 9 20 years (6940 7670) 1 0/1 0 100.0

 21 years ( 7671 days) 6/6 100.0

 e rs

 e rs 2 d s 2 2 2 2

 e rs 2 2 d s 

1 0 12 years (3652 4747 days) 4 3/4 4 9 7.7

1 3 15 years (4748 5843 days) 1 5/1 5 100.0

1 6 18 years (5844 6939 days) 1 0/11 9 0.9

1 9 20 years (6940 7670) 4/4 100.0

 21 years ( 7671 days) 2/2 100.0

 dult Su ects it ut ti e Sero rotection 2 l ter Stud ccin tion E c Irre ul r Inter l te or Sensiti it n l sis Irre ul r Inter l equire ent 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

94

In terms of the breadth of subtype coverage, a hybrid neutralization test is used to standardize

the growth rates of the different viruses. In the end, what is in the label is that all 3 subtypes are 

covered by FSME-IMMUN®. There now are additional data to show that this is still true today.

In terms of vaccine effectiveness, vaccine uptake was very high in Austria from 1979-2019 at up 

to 88%, which resulted in a decrease in the number of TBE cases. There was no such effect in 

neighboring countries. From that followed vaccine effectiveness calculations. Irrespective of 

whether a regular schedule is given, effectiveness is about 90%. Based on data from a TBE 

outbreak due to dairy products in Germany in 2017, vaccine effectiveness was demonstrated to 

be 80% to 100% among those who ingested TBE virus. 

To highlight some additional topics, two studies show that there is no association with multiple 

sclerosis (MS). In one study, 28 subjects with MS were vaccinated and there was no sign of 

clinical recurrence of the disease. While vaccine is not licensed to be given in pregnancy, there 

are 138 cases of pregnancy in the databases from the full 40 years. At this time, there is no 

signal that would raise any concerns. There are no data on simultaneous administration with 

other vaccines.

In summary, this is a 40-year old product and there is no efficacy study. The complexity of the 

study results from the fact that serology is followed, and the vaccine is well-tolerated. 

Next Steps for the TBE Vaccine WG

Susan Hills, MBBS, MTH

Arboviral Diseases Branch

Division of Vector-Borne Diseases

Centers for Disease Control and Prevention

Fort Collins, Colorado

Dr. Hills presented the current planned timeline for the TBE Vaccine WG’s activities and 

presentations to ACIP. As mentioned earlier, they are working on the basis of possible licensure 

of the vaccine in the third quarter of 2021. This session was utilized to present background 

information on TBE and vaccine immunogenicity and safety data. During the February 2021 

ACIP meeting, the WG intends to present data on traveler and laboratory worker risk data and 

additional data and considerations relevant to vaccine recommendations. In June 2021, the plan 

is to present GRADE and EtR data to ACIP. An ACIP vote on vaccine recommendations and 

finalization of the MMWR are anticipated in October 2021.

Discussion Points

Dr. Bell inquired as to whether there are any data about breakthrough infections, understanding 

that there is not a correlate of protection and that this is a rare disease.

Dr. Schmitt indicated that there is information on breakthrough disease. Basically, there are two 

types. The first is those subjects who are non-responders who have IgM and IgG later on that 

looks like a primary infection. The second are breakthrough cases where there is little IgG to 

begin with and high IgG right from the beginning, which is the real breakthrough case. Overall, 

breakthrough cases are quite rare. There is a recent published series from Germany, which is 

an endemic country. Among a population of 85 million, there were 6000 TBE cases and 

approximately 200 vaccinated subjects with all types of doses, irregular schedules, and so forth.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Dr. Hunter asked whether there is any change this pathogen could be in other Ixodes tick 

vectors and therefore become established in any of the ticks in North America.

Dr. Schmitt said that he did not know, but guessed the spectrum is broader than Ixodes. There 

are other tick species in Russia and Japan, but he will follow up to find out.

Dr. Hills added that there is another tick-borne flavivirus in the US, Powassan virus, which she 

will follow up on.

Dr. Sanchez requested additional information about the sequelae of this infection in terms of 

morbidity and mortality and whether there is any cross-reactivity or cross-protection for 

Powassan virus.

Regarding sequelae, Dr. Schmitt reported that the death rate is 0.6% in a population-based 

study in Latvia over an 18-year observation period. In other countries in Russia it is much higher 

at up to 30%. Dr. Hills has presented those data previously. Overall, it is very difficult to 

compare mortality rates based on different hospitalization systems, who pays for what, and all of 

that. There are several studies on sequelae in adults such as paresis, mental changes, 

psychiatric changes, et cetera of up to 40% to 50%. In children, it is believed to be a mild 

disease. Children who have symptomatic TBE usually present with meningitis and less with 

encephalitis. However, there are now data to show that these children may have mental 

sequelae as well that may affect academic performance, concentration, and so forth. He is 

happy to follow up on this further. For Powassan virus, there are no serology data to look for 

cross-protection or any cross-reaction.

Dr. Erin Staples, the SME, indicated that the genetic relatedness for Powassan virus is such 

with TBE that they do not think there will be cross-protection provided by the TBE vaccine. 

Limited studies have been done on Powassan virus, and they were mostly in animal models that 

also suggest that the vaccine may not provide protection.

Dr. Romero asked whether there is any evidence of transplacental transmission from mothers to 

babies if the mother is infected during pregnancy and Dr. Sanchez asked about transmission 

through breastmilk.

Dr. Schmitt indicated that there are 6 such reports in the literature of transmission from mother 

to baby and to date, there is no indication for transmission. With very limited data, he would 

tentatively say that there is likely not transmission from mother to baby. There are some older 

reports with missing data, but from all that is known, this is unlikely. While it could be in breast 

milk, he did not know of publications to support this. He would assume that in the viremic phase, 

if the mother has a TBE virus, a high fever, and is breastfeeding at that time, it may be in the 

milk. He will follow up on that as well.

Dr. Staples added that this will be covered in the February ACIP meeting in presentations about 

all of the risk groups and known modes of transmission to clearly document potential risk.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Introduction

Sharon Frey, MD, FACP, FIDSA

Saint Louis University School of Medicine

Chair, ACIP Human Rabies Prevention WG

Dr. Frey introduced the Rabies WG session. As a reminder, the Rabies WG was introduced in 

October 2018. During October 2019 and February 2020, the WG: 

❑ Presented a review of vaccine safety and WG considerations for changes to the preexposure prophylaxis (PrEP) series

❑ Presented a systematic review of published literature about primary immunogenicity and 

duration of immunogenicity of intramuscular (IM) [0, 7 days] PrEP series involving human 

diploid cell vaccine (HDCV) and purified chick embryo cell vaccine (PCECV) vaccines

❑ Gathered feedback from ACIP about the data needed in order to consider shortening the 

PrEP series from IM [0, 7, 21/28 days] to IM [0, 7 days]

The WG’s focus continues to be that rabies is nearly always fatal and that no proposed changes 

should be considered that could be inferior to current IM [0, 7, 21/28 days] series. The WG 

considered improvements to the current PrEP recommendations that are supported by robust 

data, enable an anamnestic response for the duration of a recipient’s life, and are based on 

what is known about compliance, acceptability, and reasons for current guidance.

The WG’s activities related to PrEP since the last ACIP meeting have included the following:

❑ Comprehensive re-review of PrEP in the context of ACIP’s feedback:

➢ Reviewed the purpose of PrEP and expectations for data if changes proposed are 

accepted

➢ Deliberated over policy questions that can be confidently proposed that are an 

improvement from current recommendations and grounded in data

➢ Leveraged WG members’ rabies subject matter expertise in immunology, historical 

basis of current recommendations, travel medicine, clinical practice, public health,

veterinary medicine, and considerations made by WHO in the 2018 update of PrEP 

recommendations

➢ Completed GRADE and EtR framework for 2 policy questions

❑ Completed discussions about newly licensed rabies immune globulin (RIG) products and 

data to support any changes to anatomic site(s) of RIG administration

Rabies Vaccine
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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The WG faced a number of challenges during its deliberations. For instance, some of the 

previous recommendations were based on expert opinion and some of the current 

recommendations are legacy from an extremely conservative approach to less optimal rabies 

vaccines. Limited data exist to modify recommendations that are known to be excessive. The 

diverse recipients of PrEP including research laboratorians, bat biologists, veterinarians, animal 

control experts, spelunkers, and travelers to canine-rabies endemic countries make it difficult to 

create “one-size fits all” recommendations given differing types and levels of risk. In addition, 

compliance to current ACIP recommendations has been of concern in that veterinarians are 

known to be non-compliant with titer checks and PrEP is not covered by the employer or 

insurance for many professions.

The WG’s agenda for this session were to present the results of the WG’s deliberations, obtain 

feedback and discussion from the ACIP, answer tough questions, and determine whether the 

proposed policy questions could be voted on during the February 2021 ACIP meeting. To 

achieve these goals, the agenda for this session included the following presentations:

❑ Background and Summary of WG Considerations

❑ Minimum Antibody Titer and Implications on ACIP Recommendations

❑ More Fundamentals of Rabies Immunology

❑ Review of Policy Questions and Systematic Review about the PrEP Schedule and 

Presentation of GRADE

❑ Evidence to Recommendations Framework 

❑ Summary and Next Steps

Rabies PrEP in the US and WG Considerations

Agam Rao, MD, FIDSA

CAPT, United States Public Health Service

Poxvirus and Rabies Branch

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Dr. Rao explained that human rabies is an acute, progressive encephalomyelitis that is nearly 

always fatal. It is transmitted from infected mammals. Worldwide, dogs are the most common 

cause. There are approximately 59,000 human cases of rabies worldwide each year. In the US, 

bats are the most common cause. Canine rabies virus variant (RVV) has been eliminated since 

2007 in the US, with only 0-4 human cases each year. One of the reasons there are few cases 

in the US is that over time, rabid domestic animals (e.g., livestock, cows, and dogs) has 

decreased because of various implemented measures. During the same time and for multiple 

reasons, rabies among wild animals has increased.

However, there is still a lot of potential for human rabies in the US. Approximately 5000 animals 

test positive for rabies each year. Mammal reservoirs vary by geography. Terrestrial or wildlife 

rabies is the RVV for which wildlife are the reservoir. Non-terrestrial rabies is the RVV for which 

bats are the only reservoir. Terrestrial rabies are restricted to specific US regions, while nonterrestrial rabies can be found in all US states except Hawaii as depicted in this map:
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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There are multiple prevention strategies for human rabies and that is why there are so few 

cases like behaviors such as avoiding trying to pet wild animals, animal vaccinations of pets and 

of wildlife through oral baits, education and training (e.g., awareness of the need to seek 

medical care for exposure; training for proper use of personal protective equipment (PPE) if 

handling bats or working in a laboratory), PEP, and PrEP.

For the general US population, if a rabies exposure is going to occur, it occurs during 

occupational or recreational activities inside the US. It is a “recognized” exposure which is a 

very important concept meaning that it is a bite or scratch from a racoon, mongoose, or fox that 

has rabies for instance. It is an exposure that any person with intact mental status would realize 

that they had and would seek medical attention and PEP. It is not an exposure that would go 

unnoticed. PrEP is not advantageous for the general US population and has never been 

recommended by ACIP for the general population. As a side note, it is expensive and is typically 

not covered by insurance.

It is important to keep in mind that rabies PrEP is not a substitute for PEP. Anyone who gets 

PrEP should still get PEP if he or she has an exposure. The current vaccine series for healthy 

persons who have an exposure is: A) for someone who received PrEP, 5 total vaccines and no 

RIG; or B) for someone who did not receive PrEP, 4 vaccine doses and RIG are given as PEP 

after an exposure occurs. PrEP is not a substitute for PEP. Someone who gets PrEP actually 

ends up getting more total vaccines if the number of vaccines given as part of PrEP are 

counted. The benefits of PrEP are that it eliminates the need for RIG, which is expensive and 

may not be easily available during some international travel. It shortens the PEP series for 

persons who may have multiple rabies exposures in their lifetime. In addition, it provides some 

protective coverage if a delay in PEP administration could occur or if the exposure type is the 

sort that only laboratorians have such as a high concentration of rabies virus.
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Rabies risks that warrant PrEP are higher than those of the general population. Persons should 

receive PrEP if they have any of the following:

❑ An unrecognized exposure, meaning an exposure that a person with intact mental status 

may not notice and so PEP is not sought

❑ A potential for exposure to high potency virus or unusual exposures (e.g., high concentration 

or research grade rabies virus, aerosolized rabies virus, or non-rabies lyssaviruses) all of 

which are only potential exposures for laboratorians

❑ Opportunities for frequent contact with potentially rabid mammals because of one’s job or 

recreational activities (e.g., bat biologist, veterinarian, or spelunker)

❑ Travel to a canine rabies endemic country where one may not have easy access to PEP, 

such as a rural region within that country

The WG organized this information into the 3 risk groups, including: 1) laboratorians who have 

high potency or unusual exposures, unrecognized exposures, and/or frequent contact with 

potentially rabid mammals; 2) persons who frequently handle bats or enter environments with 

high concentrations of bats (e.g., bat biologists and some pest control workers) who may have 

unrecognized exposures and/or frequent contact with potentially rabid animals; and 3) persons 

who work with animals (e.g., wildlife workers and veterinarians) or who may come in contact 

with dogs in a canine-rabies endemic country (e.g., travelers) who have frequent opportunities 

for recognized exposures. The highest risk is for the laboratorians.

These photographs illustrate recognized and unrecognized exposures:

On the top of this above set of photos are exposures from terrestrial mammals with a tooth size 

of 15-50mm and bite strength of as much as 320 pounds of pressure, which would make it 

difficult not to know if one was bitten by one of these animals. On the bottom is exposure from 

bats. The tooth size is 2-10mm and the bite strength is only about 2 pounds of pressure. For the 

vast majority of people, that is still going to be a recognized exposure. However, someone who 

 

 
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is swarmed by a cave full of bats may not know whether they had an exposure. This is the 

population of people who are referred to as those who frequently handle or enter environments 

with a high density of bats, and who are placed in their own category to separate them from the 

general population.

This is a table from the current ACIP rabies recommendations. Pre-exposure recommendations 

including schedules and frequency of titer checks are listed in the last column, but those are 

different depending upon risk level in the first column. For example, at the bottom of the first 

column is the risk category for the general population which has very little risk for rabies. No 

PrEP is needed for the general population. Moving up the table, risk increases. The risk 

categories (Infrequent, Frequent, and Continuous) in the first column correspond nearly 

completely to the 3 risk groups described earlier. Those in the highest risk group are 

laboratorians who can have recognized and unrecognized exposures and may be exposed to 

aerosol generating procedures and high concentrations of virus, those in the second risk group 

have recognized and sometimes unrecognized risks, and those in the third risk group have only 

recognized risks:

What is different is the Typical Populations column here. This section has been very confusing 

to clinicians and public health authorities. One type of laboratorian is in the second risk category 

instead of up in the highest risk category with the other laboratorians. Travelers remain in the 

third risk group, but some occupations are listed in both the second and third risk categories. 

For example, veterinarians and animal care workers are listed in both risk groups but the 

distinction pertains to whether they work in terrestrial or non-terrestrial regions.

The WG thought a lot about whether working in terrestrial or non-terrestrial region should have 

any impact on PrEP recommendations and concluded is that it is important for PEP 

recommendations but not for PrEP. That is, one’s occupation is the most important factor for 

the purposes of PrEP. Someone who works in a terrestrial rabies region as a wildlife worker 

may have more opportunities for exposure to a rabid animal than wildlife workers in a region

without terrestrial rabies. The WG concluded that the number of potential risks does not matter 

for PrEP.
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There are more opportunities for exposure in terrestrial versus non-terrestrial regions, but the 

exposure type remains a recognized exposure. Going back to the WG’s categories, the WG 

believes that there is no reason for whether the work occurs in a terrestrial region versus a nonterrestrial region to figure into the risk categories for PrEP. This revised table shows the 

changes the WG made to the current table after all of this deliberation:

For the purposes of removing any confusion about the previously titled “Continuous, Frequent, 

and Infrequent” risk groups, the WG used #1, #2, and #3 based on the type of risk they have. 

The differences in the typical populations and the fact that terrestrial and non-terrestrial regions 

does not figure into the decisions is clear from these 2 columns. What are left to fill out are the 

last 2 columns of the table. The WG’s goal for primary immunogenicity was to identify the same 

series for all 3 risk groups, given that this will result in the least amount of confusion. The goal 

for long-term immunogenicity is more complicated. Since those in the #1 and #2 risk groups 

have risk for unrecognized exposures, the goal for long-term immunogenicity is different from 

those in the #3 risk group. Those with unrecognized exposures should have titers persistently 

found to be over the minimum acceptable antibody cut-off in the event that they have an 

unrecognized exposure and do not seek PEP. The goal for those in the #3 risk group for longterm immunogenicity is different. It is to ensure that if an exposure occurs 20 years after PrEP 

was completed, the person will still have an anamnestic response to an exposure. If they cannot 

be guaranteed to be “previously immunized” 20 years after completion of PrEP, they cannot be 

given the shortened PEP series that is typically given to someone who received PrEP. The last 

3 presentations during this session provide information that fills in the WG’s preferences for 

these two columns “Primary Immunogenicity” and “Long-Term Immunogenicity.”

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
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The next two presentations provide more background information to fill in the last two columns.

The first is a presentation about minimum acceptable rabies antibody titer and implications on 

ACIP recommendations. The purpose of this talk is to share problems with the current ACIP cutoff titer, propose a solution, and outline the potential implications of the proposed change. The 

other presentation regards pertinent fundamentals of rabies immunology. The purpose is to 

show how efficacious the current vaccines used for rabies are. ACIP recommends only IM use 

of rabies vaccines for several reasons and is not proposing a change to that. However, 

intradermal (ID) is used more worldwide because of the cost-savings associated with ID 

administration. Because there is so much international data for ID, a second purpose of this 

presentation is to show why the WG feels that ID data can be used to inform decisions about IM 

administration.

During the February ACIP meeting, the committee pointed out various factors that will weigh 

into their decision to vote for or against any changes to the current ACIP recommendations, 

which include the following:

❑ 2008 ACIP recommendations have been effective

❑ Rabies is nearly 100% fatal

❑ Proposed changes must:

➢ Be supported by robust data

➢ Address the evolving rabies landscape

➢ Reflect new data and increased confidence in modern cell culture vaccines (CCVs)

➢ Not have suboptimal immunogenicity to current PrEP 

❑ WHO and ACIP recommendations do not have to align

➢ Dose and cost-sparing options are top priority for WHO, but not necessarily for the 

US population

Minimum Acceptable Rabies Antibody Level

Susan Moore, PhD, MS HCLD (ABB)/adjunct professor

Diagnostic medicine/pathobiology/College of Veterinary Medicine

Kansas State University, Manhattan, Kansas

Dr. Moore expressed gratitude for the invitation to speak to ACIP about minimum acceptable 

rabies antibody level. As part of the presentation, she explained the rationale and history of the 

minimal antibody level and technical issues related to the testing and reporting of this level to 

explain the proposal for changing the minimal rabies antibody level to 0.5 IU/mL.

To start, as Dr. Rao presented, PrEP is not indicated for the general US population. It is 

indicated for persons who are at risk for unrecognized exposures to rabies virus, work with high 

potency rabies virus and may have unusual exposures to rabies (e.g., aerosolized), frequently 

are in contact with potentially rabid mammals (e.g., wildlife biologists), or travel to canine rabies 

endemic regions where they may be at risk of delayed PEP if a rabies exposure occurs. The 

minimum acceptable antibody level is the target level for primary immunogenicity 2 to 4 weeks 

after completion of a primary pre-exposure vaccination schedule and the target level at the 

intervals for which antibody level checks are recommended.
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Referring to the table Dr. Rao presented with the proposed revisions, the primary vaccination 

series will be in the column labeled “Primary Immunogenicity PrEP” and the frequency of 

antibody level checks will be indicated for each risk group in the last column titled “Long-Term 

Immunogenicity.” The minimum acceptable antibody level is the level that a healthy person 

would be expected to mount after completion of any ACIP-recommended primary series. The 

minimum acceptable antibody level is also the level used as the goal when levels are checked 

at various time points. For the future presentations during this session, when the WG’s 

proposed recommendations are presented, ACIP members may wonder what impact those 

recommendations may have if the minimum acceptable antibody level is set at one value versus 

another.

As an introduction, Dr. Moore first established why/how the minimal level is important. This level 

is used as an indication of a successful primary pre-exposure vaccination series and is used to 

monitor for evidence of immunity. The current antibody level as stated in the ACIP 

recommendations are confusing and difficult to interpret. To emphasize this point, she showed 

what is posted on the Kansas State University (KSU) Rabies Laboratory website to aid clients in 

interpretation of rabies serology results, which she wrote years ago in response to the many 

questions the KSU Rabies Laboratory received on the reported results in relation to what the 

ACIP says. KSU is one of 3 places that perform rabies serology testing on human samples for 

the public and much time and effort is spent in explaining how the reported results relate to the 

ACIP minimal acceptance level for antibody. In her years of directing the KSU Laboratory, this 

has been a major issue for reporting results. For a fatal disease such as rabies, the 

recommendations need to be crystal clear.

To understand the cut-off levels, Dr. Moore first talked about what is known about the immune 

response to rabies infection and the role of vaccination in protection, particularly the significance 

of neutralizing antibodies. Rabies is well-known to be 100% fatal, primarily due to the poor 

immunological response to infection. It also is known that rabies is nearly 100% preventable 

through pre- and post-exposure vaccination. High circulating antibody targeting the glycoprotein 

of the virus has been proven to be the most important component for immunity to rabies. For 

obvious reasons, no efficacy studies have been performed in human subjects for determination 

of the antibody level required for rabies protection. Instead, animal rabies vaccine challenge 

studies are utilized for surrogate data. In animal vaccine studies, some animals with low levels 

of antibody succumb to challenge. Conversely, some with no detectable antibody pre-challenge 

survive. No definitive titer is known to be universally protective. 

One of the first studies looked at the level of antibody associated with survival in animals was 

published in 1984 by Bunn and Ridpath. They used statistical methods to calculate probability of

survival from pre-challenge titers, concluding that at a level of 0.2 IU/mL, the probability of 

survival was 95% and at 0.5 IU/mL, it was 99%. Note that the test results are given in 2 ways, 

titer and IU/mL, which Dr. Moore addressed later. Other subsequent publications of summary 

studies in dogs, cats, ferrets, and wildlife gave similar results regarding practical significance of 

rabies antibodies. These papers also commented strongly on the variability of the test method 

and need for standardization in testing. In animals, the level of 0.5 IU/mL is robustly associated 

with survival and is the level used to verify adequate rabies immunity in pets traveling to rabiesfree areas of the world. In addition, though there is no absolute antibody level indicator, the level 

0.5 IU/mL is the consensual criterion for immunogenicity in rabies vaccine evaluation.
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The minimum level of rabies virus neutralizing antibody (RVNA) determined for humans was 

based on results of early vaccine clinical trials, where the rabies serology data came from either 

the mouse neutralization test (MNT) or the rapid fluorescent focus inhibition test (RFFIT). RFFIT 

results are reported in terms of the 50% endpoint titer and/or in IU/mL. Both the WHO and ACIP 

used the same rationale in setting this cut-off level, which was by evaluating the data to 

determine the minimal titer or IU/mL robustly associated with detection of specific RVNA. The 

WHO and ACIP cut-off levels are different AND are expressed in different ways. The WHO cutoff, which is 0.5 IU/mL, is approximately 5 times higher than the ACIP cut-off. ACIP states the 

cut-off level as a description. This a quote from the current recommendations, “Complete 

neutralization at a 1:5 serum dilution by the rapid fluorescent focus inhibition test (RFFIT).” This 

loosely converts to anywhere from 0.1 to 0.3 in IU/mL. No cases of rabies have occurred in the 

US using this cut-off, this fact is misleading because many factors contribute to survival. The 

ACIP recommendations also state that rabies serology results should be reported in IU/mL, but 

does not provide the relationship of the recommended level to reported values. The ACIP cut-off 

is neither a titer value or an IU/mL value.

This chart displays the history of published recommendations from WHO and ACIP regarding 

the level of RVNA representing an adequate antibody response and the laboratory methods 

recommended to measure the antibodies:

  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
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The WHO has consistently recommended 0.5 IU/mL. ACIP has recommend using the RFFIT 

method consistently, but has expressed the cutoff level variously and at times in unclear terms. 

In 1984 and 1991, two different levels were recommended for differing situations. In 1999, the 

level was expressed in a description of the reaction microscopically read on the RFFIT slide, 

“complete neutralization at a 1:5 serum dilution.” Unless one has performed the assay, there 

would be no reason to know that the calculation of a result of complete neutralization at a 1:5 

serum dilution is a titer of 1:11. The ACIP cut-off is confusing and hard to interpret for 

determination of a need to boost.

As mentioned, the test used for rabies serology is the RFFIT and can be reported in titers, 

IU/mL, or both. Dr. Moore briefly explained what actually is a complex series of steps for testing 

and reporting rabies serology results. A titer is the serum sample dilution that neutralizes a 

standard dose of live rabies virus. Titer values are variable due to the inherent variability in cell 

based serum neutralization methods. Anyone who has worked in a serology or virology 

laboratory knows that not all factors that affect a biological interaction, such as antibody 

neutralizing a virus or virus infecting a cell, can be exactly controlled over the course of the 

interaction. Ranges are given in laboratory methods for pH, temperature, incubation times, virus 

dose, cell count, et cetera to attempt to control the conditions, but there are many factors 

beyond these that can influence variability. This variability occurs within the same laboratory 

between each time the test is run and between laboratories. Titer values will vary between 

testing events, which is a given. However, the reference serum will vary in the testing event 

similarly as any other sample tested at the same time. This fact is used to standardize the titer 

value into International Units. 

In terms of how this is accomplished, Dr. Moore explained the steps to calculate first the titer 

and then to convert the titer to IU/mL. The RFFIT readout using a microscope is a count of the

virus positive fields on a slide out of 20 total fields. This count is entered into the Reed and 

Muench formula which gives the 50% endpoint titer value. The formula for the conversion of titer 

to IU/mL is simpler by taking the sample titer, dividing it by the reference serum titer, and then 

multiplying by the potency of the reference serum in IU/mL. Per the WHO “Laboratory 

Techniques in Rabies” manual, in the RFFIT, the reference serum is tested at a potency of 2 

IU/mL. For example, a sample serum titer of 50 divided by reference serum titer of 200,

multiplied by the potency of the reference serum 2.0 IU/mL, gives a value of 0.5 IU/mL. There is 

no direct correlation between titer and IU/mL because of the RFFIT variability previously 

mentioned. However, in most laboratories using internationally recognized RFFIT protocols, the 

ACIP cut-off (a titer of 1:11) is in the range of 0.1 – 0.3 IU/mL. In summary, rabies serology 

testing and reporting is all very complicated. The main point is that the ACIP cut-off level is hard 

to correlate directly to the associated titer value, and that there is a range of IU/mL values that 

can be associated with it.

In terms of how this works in real life, the following table helps to explain the complexity of the 

testing:
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RVNA result

Rabies Vaccine 

Boost 

Recommendation

Titer IU/mL

ACIP 

1:11

WHO 

0.5IU/mL

Lab A 

Low 

Challenge 

Virus Dose

10 TCID50

Mary 1:24 0.2 NO YES

John 1:90 0.6 NO NO

Reference 

Serum 1:300 2.0

Negative 

Serum 1:2 0.0

Lab B

Medium 

Challenge 

Virus Dose

50 TCID50

Mary 1:10 0.2 YES YES

John 1:37 0.6 NO NO

Reference 

Serum 1:125 2.0

Negative 

Serum 1:2 0.0

Lab C

High 

Challenge 

Virus Dose

100 TCID50

Mary 1:4 0.2 YES YES

John 1:10 0.6 YES NO

Reference 

Serum 1:35 2.0

Negative 

Serum 1:2 0.1

One of the variability factors in the RFFIT is the virus dose. Per the WHO “Laboratory 

Techniques in Rabies” manual, the virus acceptance range is 30 to 100 TCID50 with a target of 

50 TCID50. There are 3 laboratories: A, B, and C. Laboratory A uses a virus dose below the 

range, Laboratory B uses a virus dose near the target, and Laboratory C uses a high virus dose.

Each of the laboratories test the same samples, from Mary and John, as well as the same 

control sera—the reference serum which serves at the positive control and the calibrator for 

conversion of titer to IU/mL and the Negative control. The titer values vary between the 3

laboratories. The titer values (all, samples and control sera) decrease as the virus dose 

increases, yet the calculated IU/mL values remain the same. This shows that IU/mL values are 

less variable than the titer values. Conversion to IU/mL controls for the variability in the test.

Looking at these results from these 3 laboratories, it is possible to see how the titer results from 

Laboratories B and C recommend booster vaccination for Mary per the ACIP cut-off. However, 

all 3 laboratories’ IU/mL results using the WHO level indicate a booster vaccination is needed 

for her. The same is true for John in that Laboratory C’s titer result indicates a booster 

vaccination is needed per ACIP, but all other results say no booster needed. It can then be 

concluded that normal variability in laboratory testing of the RFFIT can lead to incorrect 

interpretations of antibody levels if the titer is not standardized into IUs.

For serum neutralization assays, anything that inhibits virus infection or growth will cause nonspecific neutralization reactions. These can be related to cell health, interfering factors in the 

serum or virus strength, et cetera. The ACIP cut-off is very near the lower limit of quantitation of 

the assay. This table shows the percentage of samples from unvaccinated subjects who 

produced a positive RVNA result in the RFFIT:
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False Positive Titer Results

IU/mL Study 1 Study 2 Study 3 Average

>/=0.1 2.4% 4.3% 1.3% 2.7%

>/=0.2 1.2% 2.9% 0.8% 1.6%

>/=0.3 1.2% 2.9% 0.4% 1.5%

>/=0.4 0.0% 0.0% 0.4% 0.1%

The percentage of non-specific neutralization results (false positives) increases the lower the 

cut-off level is set, introducing some uncertainty in accuracy at this level. For a disease that is 

100% fatal, the cut-off level should ensure minimal false positives.

The summary results displayed in the following table are from a number of rabies antibody 

monitoring events at veterinary conferences and veterinary schools. In purple shading are the 

percent of people with results above a 0.5 IU/mL cut-off and the percent of people with results 

above the ACIP cut-off. Using these percentages, the percent of people who need boosters 

based on the 2 different cut-offs were calculated and are in the Yellow shaded columns. The 

Pink column shows how the effect of changing the cut-off to 0.5 IU/mL, given in fold increase, 

has on the number of people recommended to receive a booster vaccination. Overall there is a 

2.5 fold increase in people recommended to receive a booster if the acceptable level changes to 

0.5 IU/mL:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
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In summary, an antibody level of 0.5 IU/mL is a better alternative to the current ACIP cut-off for 

defining the minimal antibody response to vaccination for several reasons. Repeatedly in 

published animal studies, 0.5 IU/mL is robustly associated with survival from challenge, and

data show that the 0.5 IU/mL is the RVNA level that assures minimal false positives in the 

RFFIT. In addition, using a standardized unit of measure, IU/mL provides results that are more 

accurate and precise than titer values. IU/mL is globally used to report rabies serology and is 

also the primary unit of measurement reported in the US. There are clear advantages for the 

proposal to change the cut-off from “complete neutralization at a 1:5 serum dilution” to 0.5 

IU/mL, including reducing confusion in interpretation for those at risk of this high stakes 

infection, increasing the precision and accuracy of the results, decreasing the risk of reporting 

false positive results, and using a unit that controls for the inherent variability of the RFFIT. The 

disadvantage is that there is real potential that more people would be recommended to receive 

a booster vaccination.

Discussion Points

Dr. Romero observed that this outstanding presentation provided ACIP with a good basis for 

making a decision regarding the proposed change.

Dr. Hunter inquired as to whether there were any numbers to show what percentage of people 

would need boosters that could be provided to the clinicians this would affect to increase their 

acceptance of the change. He suggested conducting a survey with veterinary, medical schools, 

and occupational health departments that could help with the “Acceptability” component of the 

EtR Framework.

Dr. Moore indicated that because the ACIP says that rabies serology results should be reported 

in IU/mL, that was a quandary for laboratories reporting this because they were struggling with 

how to report per mL when the cutoff is not given in that unit. The rabies laboratory at KSU does 

global work and wound up putting both cutoffs on the reporting, which the website explains. In 

talking to veterinary schools and at conferences, they were very conservative in saying that the 

WHO says 0.5 IU/mL and ACIP says 0.1-0.3 IU/mL. However, the 0.5 IU/mL is a more 

conservative cutoff. It seems like a lot of schools and occupational groups use 0.5 IU/mL. The 

actual increase in the number of people who would be getting a booster if the ACIP said 0.5 

IU/mL is not likely to be a large number. However, it is difficult to calculated.

Pertinent Fundamentals of Rabies Immunology

Deborah J. Briggs, PhD

Adjunct Full Professor

Kansas State University

Dr. Briggs expressed gratitude for the opportunity to speak about cell culture rabies vaccines 

and the fundamentals of rabies immunology. She provided a brief history about the production 

of rabies vaccines, explained why there are two routes of administration, and presented clinical 

data to show that the ID and IM routes of administration for cell culture rabies vaccines for both 

pre-exposure vaccination and PEP are equitable.

The first human rabies vaccines was developed from infected nerve tissue by Louis Pasteur and 

his colleagues in the late 1800s. Various versions of nerve tissue vaccines (NTVs) were used 

globally through the 1900s and even into the 2000s. These vaccines required multiple doses to 

be administered into the abdominal region of the patient over a lengthy period of time, and they 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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caused serious adverse reactions. One of the first improved rabies vaccines was the duck 

embryo vaccine developed in the 1960s, but it required 14 doses and produced low titers.

In 1976, the first field trial of HDCV was endorsed by the WHO. It was conducted in Iran due to 

the number of rabies cases in the country and the fact that there was a reliable WHO reference 

laboratory in Tehran. In that first clinical trial, 45 patients severely bitten by rapid wolves 

received HDCV and 44 of those patients also received antirabies serum and 1 patient who had 

been exposed to aerosol rabies only was not given the antirabies serum. Each patient was 

given 6 subcutaneous doses and all of those patients survived. This was actual proof that 

HDCV, the first generation cell culture rabies vaccine, was efficacious.

In 1980, two important events occurred. HDCV was licensed for IM use in the US and the WHO 

experts met in Essen, Germany and recommended a 6-dose IM PEP and a 3-dose IM regimen 

for PrEP. During this meeting, the WHO urged research into finding alternate routes of vaccine 

administration, including the ID route. That was because the cost of PEP was so high using 

HDCV that they wanted a lower cost vaccine or route of administration so that they could 

encourage low-income countries to replace NTVs with cell culture vaccines. In 1982, the US 

approved the ID administration of HDCV pre-packaged as a 0.1 mL dose. However, it was taken 

off of the market in 2001 due to the high cost of packaging that particular dose. From the late 

1980s through the 2010s, clinical trials were conducted investigating the immunogenicity and 

efficacy of the ID route of the administration of HDCV and newly developed cell culture rabies 

vaccines, including Purified Chick Embryo Cell Vaccine (PCECV) and Purified Vero Rabies 

Vaccine (PVRV). Data from those trials proved that these vaccines were as effective as HDCV 

when administered either IM or ID in both PrEP and PEP regimens.

Taking a closer look at the published data the WG examined comparing ID to IM in various 

clinical trials, the WG reviewed these data to determine whether data from ID administration 

studies could be used to inform recommendations for IM administration of cell culture rabies 

vaccines. The WG also reviewed efficacy data for cell culture rabies vaccines. There were 3 

basic factors the WG needed to verify in evaluating the equivalence of the IM and ID routes of 

administration: 1) equal efficacy, meaning that both routes will protect patients exposed to 

proven rabid animals; 2) equal primary immunogenicity, meaning that both routes will produce 

adequate levels of neutralizing antibodies in vaccinated individuals (in this case 0.5 IU/mL); and 

3) equal long-term immunogenicity (i.e., anamnestic response) in previously vaccinated 

individuals when they receive a booster vaccination series.

The very first study investigating the efficacy of PEP administered ID was conducted in Thailand 

by Dr. Phanuphak and his colleagues at the Thai Red Cross Society. Their goal was to find a 

safe, effective, and inexpensive strategy to replace the crude NTVs that were being produced 

and used in Thailand and to reduce the high cost of rabies deaths occurring in their country. The 

patients enrolled in this trial had experienced minor exposures to rabid animals. The CCV used 

was PVRV because its cost was lower than HDCV and the exposed patients were given one of 

4 regimens. Group 1 received the full IM vial (Day 0,3,7,14,28); Group 2 received 0.1 mL of 

vaccine administered ID at 4 sites (Day 0,3,7)l Group 3 received 0.1 mL of vaccine administered 

ID at 2 site (Day 0,3,7); and Group 4 received 0.1 mL of vaccine administered at 1 site (Day 

0,3,7). All of the ID vaccination regimens were given on Day 0, 3, 7 and on Day 28 the same ID 

groups received 1 more dose of 0.1 mL in the upper deltoid region. In this study, all patients 

survived. Regardless of whether patients received post-exposure PVRV via the ID or IM route, 

all patients developed neutralizing antibodies above 0.5 IU/mL by Day 14. Their antibody levels 

remained above 0.5 IU/mL through Day 35, which was the last day a blood sample was taken 

[Phanuphak et al. 1987. Asian Pacific J Allergy & Immunol. 5:33-37].
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The Thai Red Cross Society wanted to conduct a confirmation efficacy study to confirm that the 

earlier study investigating the efficacy of the ID route for PEP, which was done in collaboration 

with CDC in Atlanta. This study enrolled 100 patients who were severely bitten by confirmed 

rabid animals. All of the patients were followed for 1 year after vaccination. All of the patients 

received two ID doses of PVRV vaccine administered on each of Days 0, 3, 7 and 1 dose was 

administered on Day 30 and Day 90. This became known as the “Thai Red Cross ID PostExposure Regimen.” All of these patients survived. Table 1 shows the type of bites the patients 

received and the expected mortality rate, reflecting that there most certainly would have been 

deaths due to rabies infection without the administration of ID PEP in these patients:

Also as part of this clinical trial, blood was drawn in 10 patients during the study and titers were 

checked on Days 14, 90, and 360. Table 2 shows that all titers remained above 0.5 IU/mL

during the study:

Chutivongse S, Wilde H, Supich C, Baer G, Fishbein D. 1990. Lancet 335:896-8
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Over time, additional clinical data proved that the Day 90 dose was not required. That dose was 

dropped from the Thai Red Cross regimen. Further clinical studies and data have reduced the 

ID PEP regimen to the currently accepted WHO recommendation of a 1-week 2-site schedule 

given on Days 0, 3, and 7.

The immune response after pre-exposure vaccination by either IM and ID also has been 

investigated in several clinical trials. A study by Rescuenco is representative of the clinical data 

that the WG reviewed among many published studies looking at ID and IM PrEP vaccination. 

This study was conducted in the US to confirm that the ID route of administration for preexposure was as immunogenic as the IM route. It was done to find reliable strategies for 

administering PrEP to those persons at greatest risk due to their occupation in the event of a 

human rabies vaccine shortage in the US. Shortage of human rabies vaccines had occurred 

previously. This study enrolled 128 subjects and the vaccine that was administered was 

PCECV. Subjects were randomized to 1 of 4 groups. Groups 1 and 2 had not received vaccine 

previously. Group 1 received 3 doses on Days 0,7,21 and Group 2 received 3 IM doses on 

Days 0,7,21. Groups 3 and 4 were previously vaccinated and in this study received 1 dose of 

booster vaccine administered by either the ID or IM route in order to confirm a rapid anamnestic 

response. Previously unvaccinated subjects in both the ID and IM groups responded with 

equally high titers after vaccination. All subjects had titers above 0.5 IU/mL by Day 21 as had 

been reported in almost all published clinical study reports. The IM route of administration gives 

slightly higher titers than the ID group; however, the slightly lower titers that are produced in the 

ID group are not clinically significant. all subjects in both the IM and ID PrEP groups had titers 

above 0.5 IU/mL by Day 21 and all titers remained above that level through the end of clinical 

trial [Recuenco, S. et al. 2017. Vaccine 35:4315-20].

One of the most important reasons for administering PrEP vaccination to patients at risk of 

exposure to rabies is to eliminate the need for a rabies immune globulin in the event of future 

exposure, and to elicit a rapid anamnestic response in the patient after they receive booster 

vaccination. In a study conducted by Wongsaroj et al the Thai Red Cross Institute using PVRV, 

both Groups A and B received a 2-dose pre-exposure regimen administered on Days 0, 21. 

Group A received the series using the ID route of administration and Group B received the 

series by the IM route. The geometric mean titers (GMTs) in both Groups A and B were well 

above 0.5 IU/mL by Day 35. One year after the primary vaccination was administered and prior 

to the booster series, the GMT of the ID group was 0.35 IU/mL and the GMT of the IM group 

was 0.76 IU/mL. On Day 365, both groups received a 2-dose booster series of vaccine 

administered as 0.1 mL ID in one upper deltoid on each of Days 0, 3. All subjects had an 

anamnestic response to the booster series by 14 days later and the GMT rose to well above the 

0.5 IU/mL level, again confirming that PrEP administered either ID or IM is immunogenic and 

anamnestic response will occur when these patients receive a booster series of vaccine. Of 

note, there was no significant difference between the GMT on day 379 in the IM and ID groups 

after each group received the 2-dose 0.1 mL ID booster series on Day 0, 3 [Wongsaroj P et al. 

2013. Rabies neutralizing antibody after 2 intradermal doses on days 0 and 21 for pre-exposure 

prophylaxis. Vaccine. 31:1748-51]. An anamnestic response in pre-vaccinated subjects also has 

been confirmed in numerous other studies.

In terms of why additional CCVs are needed when the first one was so efficacious, throughout 

the decades since the development of CCVs numerous clinical trials have compared the CCVs 

that have been manufactured according to the WHO prequalification standards. HDCV is 

expensive to produce and it is very expensive for patients to purchase. There are now other 

equally efficacious and less expensive cell culture rabies vaccines that have come onto the 

market, including PCECV and PVRV. These less expensive vaccines have enabled millions of 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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lives to be saved and have eliminated the production and use of nerve tissue vaccine. 

Numerous clinical trials have been conducted and data published to confirm that these vaccine, 

when produced according to WHO prequalification standards, are efficacious, immunogenic, 

and will elicit a rapid anamnestic response to booster.

Data from a clinical trials conducted by Dr. Madhusudana et al1 showed that GMTs in patients 

after receiving the Thai Red Cross ID post-exposure regimen with either PCECV or PVRV were 

equivalent. Blood was withdrawn on Day 0 prior to vaccination and on Days 14, 30, 90, and 180. 

Again, all titers were above 0.5 IU/mL. Another study compared PCECV to PVRV. This study 

was conducted at two hospitals in Thailand by Dr. Wasi and her colleagues2. This study enrolled 

211 patients with Category II and III wounds who were placed into 3 groups. Groups 1 and 2 

received the Thai Red Cross ID PEP Regimen. Group 1 received PCECV and Group 2 received 

PVRV. Group 3 received the Essen 5-dose IM PEP regimen using PCECV. The GMTs for 

Groups 1 and 2 are almost exact. Group 3 had slightly higher GMTs as had been reported in 

numerous other studies with the IM route of administration. Again, this is not clinically significant 

[

1Madhusudana et al. 2006. Human Vaccines. 2:200-04; 2Briggs et al. 2000. Bull WHO.8(5):693-

98].

After reviewing the data shown during this presentation and numerous other peer-reviewed 

published papers, the WG concluded that ID and IM PEP are equally efficacious in patients 

exposed to confirmed rabid animals. ID and IM PrEP are both highly immunogenic routes of 

vaccination, with IM producing slightly higher titers in most clinical trials. There is no known 

clinical relevance attributed to the increased immunogenicity reported with the IM route. CCVs 

that meet WHO pre-qualification standards will produce equitable immunogenicity responses in 

both PreP and PEP regimens and when administered IM and ID. Patients who receive PrEP 

administered IM or ID will both have a robust anamnestic response to booster vaccination when 

administered either by the IM or ID route. The WG’s interpretation from these data is that when 

using high-quality CCVs, ID and IM routes of administration are equivalent among three 

clinically relevant immunologic factors: efficacy, immunogenicity, and anamnestic response.

Discussion Points

Dr. Frey emphasized how hard Drs. Moore and Briggs have worked on the WG and that they 

have been bombarded by endless questions by committee members.

Dr. Sanchez asked what data are available comparing the IM to ID in children specifically, as it 

seemed all of the articles shown were in individuals 18 years of age and older.

Dr. Briggs indicated that 35% to 60% of the patients in Asia and Africa were children. In Asia, 

much of the vaccine given post-exposure is given ID and is well-tolerated in children. There is 

no problem with IM in children either. There is a study of vaccination in malnourished children in 

India, who also responded very well to the vaccine. The ID route of administration has been 

used in India, Thailand, and the Philippines. A large percentage of those patients are children 

and there have been no problems.
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Pre-Exposure Prophylaxis Schedule: Grading of Recommendation 

Assessment, Development and Evaluation (GRADE)

Agam Rao, MD, FIDSA

CAPT, United States Public Health Service

Poxvirus and Rabies Branch

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Dr. Rao presented the GRADE for the two policy questions the WG developed for rabies PrEP, 

with the following assumptions:

❑ Rabies is 100% fatal

❑ Rabies vaccines are highly efficacious 

❑ Multiple layers of preventing human rabies (e.g., PrEP, animal vaccinations for rabies, PPE 

while working with rabies virus, PEP)

❑ Goal of PrEP differs for recognized versus unrecognized exposures:

➢ Recognized exposures: Anamnestic response from PrEP + shortened PEP series

➢ Unrecognized exposures: Sustained high titers such that “protection” provided by 

PrEP alone even if PEP is not administered

❑ ID data can be used to inform IM recommendations 

❑ An increase in the titer cut-off to 0.5 IU/mL has advantages and one potential disadvantage:

the booster could be indicated for a titer value that would have been considered acceptable 

in the past

As shown in Dr. Rao’s first presentation regarding the proposed revisions, the WG reorganized 

the risk groups and labels the Risk Category of the table using risk groups #1, #2, #3, and #4 

from highest risk to lowest. The GRADE presentation focused on the last 2 columns of the table, 

Primary Immunogenicity PrEP and Long-Term Immunogenicity. Primary immunogenicity is the 

immunogenicity that should be reflected in peak titers which occur about 2-4 weeks after 

completion of the primary PrEP series. In thinking about primary immunogenicity, the WG 

considered the goals of primary immunogenicity for each of the 3 risk groups for whom PrEP is 

indicated. The WG concluded that there is no difference in the goal for ensuring that titers are 

acceptable 2-4 weeks after completion of the primary series.

The WG thus drafted Policy Question #1 that applies to all 3 risk categories, “Should a 2-dose 

pre-exposure prophylaxis (PrEP) series involving HDCV or PCECV IM [0, 7 days] replace the 3-

dose series IM [0, 7, 21/28 days] for all those for whom rabies vaccine PrEP is recommended?” 

In terms of the PICO question, the population is persons for whom rabies vaccine PrEP is 

recommended, the intervention is [0, 7 days] rabies vaccine PrEP schedule, the comparison is a 

[0, 7, 21/28 days] rabies vaccine PrEP schedule, and the critical outcome is efficacy defined as 

primary immunogenicity with peak immunogenicity after completion of the primary vaccine 

series at 2-4 weeks after completion of the primary series. In terms of safety outcomes, AEs 

were not included as a critical outcome because these vaccines have a track record for safety 

over many decades. Summary data about the safety were presented during the February ACIP 

meeting from RCTs since the 2008 ACIP publication and VAERS data showed no change from 

previous reporting.
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Regarding the second blank column in the table, Long-Term Immunogenicity, the WG thought 

about whether the goals for long-term immunogenicity should be different for any of the 3 risk 

groups. Just to recap, those in the #1 risk group can have unrecognized, high-risk, and 

recognized exposures. That is why they are at highest risk. Those in the #2 risk group can have 

unrecognized and recognized exposures. Those in the #3 risk group can have only recognized 

exposures. What differentiates these groups in terms of recommendations is that those in the #1 

and #2 risk groups have potential for unrecognized exposures. As mentioned earlier in the day, 

what this means is that those persons could have exposures for which they do not seek PEP.

Thus, the goals for those in the #1 and #2 risk groups and those in the #3 risk group are 

categorized separately as follows:

❑ (Groups #1 and #2) Goal for Unrecognized exposures: Ensure titers are persistently high in 

case of PEP not being sought.

❑ (Group #3) Goal for recognized exposures: Ensure ability to mount an anamnestic 

response; titers need not be persistently high for anamnestic response.

The ideal way of dealing with long-term immunogenicity would be titer checks. That is already 

recommended by ACIP for those in the #1 and #2 risk groups listed here. However, for the third 

risk group, it would be a new recommendation for many. The WG discussed this and recognized

that persons in this risk group are not accustomed to having even a single titer drawn, so they 

wanted to consider a booster for this group as an alternative to ensure the goal of long-term 

anamnestic response. Data indicate that titer at the 1-year time point is indicative of long-term 

titers and that the ability to mount an anamnestic response is maintained. In the absence of data 

confirming that the [0, 7 days] series provides immunogenicity many years later, titers at the 1-

year time point could be indicative of a person’s long-term immunogenicity. Newer data as 

recent as a year or two ago found that people can mount an anamnestic response after the [0, 

3, 7 days] primary series for as long as 3 years later. Taken together, the WG felt that the titer 

value at any point during 1-3 years after completion of the primary series could be checked 

once to ensure long-term immunogenicity and a booster could be recommended if titers are

<0.5 IU/mL at the titer check. No further titer checks would be indicated because the persons in 

the #3 risk group have only recognized exposures, making them very different from the people 

in the #1 and #2 risk groups.

The WG thus drafted Policy Question #2 to address the booster question, “Should an IM 

booster dose of rabies vaccine (PCECV or HDCV) be recommended as an alternative to a titer 

check no sooner than Day 21 and no later than 3 years after the two-dose PrEP series IM [0, 7 

days] for those in the #3 risk category who receive PrEP?” In terms of PICO, the population is 

persons in the #3 risk category, the intervention is a Day 21 to Year 3 rabies vaccine booster 

after the [0, 7 days] rabies vaccine PrEP schedule, and the comparison is no rabies vaccine 

booster after [0, 7 days] rabies vaccine PrEP schedule. The critical outcome is efficacy defined 

as long-term immunogenicity (i.e., ability to mount an anamnestic response in response to a 

challenge like a rabies virus exposure or a booster dose of vaccine). Again and for the same 

reason as stated for the first policy question, a safety outcome was not included.

To retrieve the evidence for both Policy Question #1 and Policy Question #2, the WG performed 

a literature search of multiple biomedical and interdisciplinary bibliographic databases including 

Medline, Embase, Cochrane library, and the WHO Index Medicus. A broad and rigorous 

strategy was used to incorporate terms related to the concept of pre-exposure vaccination 

against rabies virus using HDCV or PCECV vaccines. The search was limited to 1965-2018,

which is a time period well before these CCVs were available. There were no language 

restrictions. The results were compiled in an Endnote Library and duplicate records were 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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removed. The search was updated through December 31, 2019 to ensure that records not 

captured in the original search were included. Records were included if they presented data on 

human rabies vaccines and:

❑ Involved immunocompetent adults 18 years of age or older (data from animal or in vitro 

studies or data from humans <18 years of age were excluded)

❑ Included data for intervention of interest (HDCV or PCECV rabies vaccine, pre-exposure, 

intradermal [1-site or 2 site] or intramuscular [1-site], any PFU) 

❑ Included data relevant to the outcome measures being assessed

❑ Planned categorization of primary data into comparative or single-arm studies; randomized 

control trials, prospective or retrospective cohort, case-control, cross-sectional studies 

(records that did not provide primary data [e.g., literature reviews or summaries, editorials, 

commentaries, opinions, clinical trial registries or protocols] and case reports or case studies 

were excluded)

The search identified a total of 258 papers, 142 of which were submitted for critical review. Of 

those submitted for critical review, 130 were excluded. All 12 of the remaining papers that met 

the WG’s criteria were used for the first policy question and 2 of the 12 were used for the 

second policy question.

As a reminder, the GRADE approach for assessing the type or quality of evidence involves 

consideration of several criteria. Assessing the type or certainty level of the body of evidence for 

each outcome begins with the study design. RCTs are initially classified as evidence type 1 

(high certainty) and observational studies as evidence type 3 (low certainty). Following the 

identification of the initial evidence type, the body of evidence for each outcome is assessed 

and downgraded if there is uncertainty about any of the five following criteria: Risk of Bias;

Inconsistency, which considers statistical heterogeneity and I2 or the variation across studies 

due to heterogeneity greater than chance; Indirectness or the generalizability of the body of 

evidence to the original PICO components; Imprecision, which considers the fragility of the 

relative and absolute effect measures as they relate to the 95% confidence intervals and optimal 

information size; and publication bias; and Other Considerations, including rating upward of the 

body of evidence from observational studies due to dose-response gradient, large or very large 

magnitude of effect, or opposing residual confounding.

After assessing on the described criteria, the body of evidence will be assigned an overall 

evidence type or certainty level. To provide context for interpretation of this, Type 1 or high 

certainty evidence means that the WG is very confident that the true effect lies close to that of 

the estimate of effect. Type 2 or moderate certainty evidence means the WG is moderately 

confident in the effect estimate. Type 3 or low certainty evidence means the WG’s confidence in 

the effect estimate is limited. Type 4 or very low certainty evidence means the WG has very little 

confidence in the effect estimate. As a reminder, the WG is not measuring how well the 

individual studies were conducted, but rather how much confidence they have in the estimates 

of effect from the body of evidence across each outcome.
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For the purposes of the evidence assessment, RCT refers to a trial which randomizes 

participants to an active intervention or a placebo or unvaccinated comparator arm. 

Observational studies refer to one-arm studies, studies for whom participants were not 

randomized, or studies that did not provide disaggregated data to allow for the comparison 

between the randomized arms. Evidence also was considered observational if only data from 

the vaccinated study arms were included in analysis for a given outcome.

Regarding the outcome for PrEP Policy Question #1, the search identified 2 RCTs that 

compared a 2-dose to a 3-dose primary series (Endy, 2019 & Soentjens, 2019). Across both 

studies, 100% of participants met the outcome of interest. There was unclear reporting of 

randomization and allocation concealment in both trials that led to some concerns with risk of 

bias. This forest plot shows the analysis of the 2 studies reporting on the outcome of

immunogenicity comparing the 2-dose to the 3-dose series. The first analysis displays the 

results from IM administration and the second displays the results from ID administration. The 

results taken together are listed below these. No heterogeneity due to route of administration is 

suspected as shown here and the pooled risk ratio is 1.00 with a confidence interval from 0.99 

to 1.01, so very tight as shown by the diamond to the right:
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The search identified 10 additional studies that compared a 2-dose to a 3-dose primary series.

These studies were treated as observational studies, although they were originally designed as 

randomized trials. In this meta-analysis, the randomization was broken to extract pertinent data

and that is why they were considered observation. The quality of the studies was evaluated with 

the Newcastle-Ottawa Scale (NOS) and minimal concerns were identified in 3 studies and no 

concerns were identified in the rest:

There were concerns for risk of bias in the 3 studies. The cohort representativeness of the 

target population was not ideal. The Sabchareon population was predominantly children. Study 

participants were not demonstrated to be free from the outcome of interest at start of the study

in that there were no Day 0 titers for the Cramer and Sabchareon studies. There was 

inadequate follow-up time to assess the outcome in the Cramer paper, with a follow-up of 1 

week after completion of the series rather than 2 to 4 weeks when peak titers would be 

expected. It is unclear whether anyone was lost to follow-up in the Kitala study based on the 

manuscript itself, so the assumption had to be made that everyone finished the Day 28 time 

point. Across these studies, 95.9% of participants met the outcome of interest after a 2-dose 

series and 97.9% of participants met the outcome of interest after a 3-dose series.

The following forest plot shows the analysis of the 10 studies that were treated as observational 

reporting on the outcome of immunogenicity comparing the 2-dose to the 3-dose series. Similar 

to the previous forest plot, the first analysis displays the results from IM administration and the 

second displays the results from ID administration. No heterogeneity due to route of 

administration is suspected. The I square is 0% here. The pooled risk ratio is 1.00 with a very 

tight confidence interval from 0.99 to 1.00:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
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This is the evidence profile of the GRADE assessment for the outcome of immunogenicity as 

measured by a titer at or above 0.5 IU/mL:

The WG assessed the body of evidence from RCTs and non-randomized studies separately. 

Because of concerns with unclear reporting of randomization and allocation concealment, the 

RCTs were rated down for risk of bias. The WG had no other concerns of the certainty of the 

evidence; therefore, they had moderate or level 2 certainty about immunogenicity for the RCTs. 

In the 2-dose arm and the 3-dose arm, 264 persons achieved 100% seroconversion. RR is 1, CI 

is 0.99-1.01, and the absolute effect is no fewer/1000 seroconvert in the 2-dose arm compared 

 

 

 

 

 

 

 

 

 

 

 

 

  

 

  

 

 

 

 

  

 

 

 

 

 
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to the 3-dose arm. That ranges from 10 fewer persons to 10 more. The second line of this table 

shows the WG’s certainty in the evidence of immunogenicity of the non-randomized studies.

The WG had no concerns about the evidence and therefore it remained at low certainty that the 

observational study started at or Level 3.

For Policy Question #2, the WG abstracted data from the Endy and Soentjens studies. To 

obtain these data, the WG broke up the randomization and treated them as observational 

studies. Per Policy Question #2, the comparison group comprises people who did not receive a 

booster after a 2-dose primary series. In these two studies, no direct comparison group was 

available. GRADE was performed in the absence of a comparison group. The quality of the 

studies was evaluated with the NOS. Minimal concerns were identified. Concerns for risk of bias 

include inadequate follow-up time to assess outcome as titers were drawn 7 days after the 

booster. This is the evidence profile of the GRADE assessment for the outcome of duration of 

immunogenicity as measured by a titer at or above 0.5 IU/mL after booster:

The best available evidence was informed by the single arms of 2 trials, which demonstrated 

complete achievement of immunogenicity following a 2-dose primary series, as well as after a 

booster provided. Therefore, it was treated as non-randomized (observational studies) and 

started at low certainty or level 3 evidence. The WG had no additional concerns with the body of 

evidence, so the certainty remained low at Level 3. The WG has low certainty that there is a 

meaningful difference between the level of immunogenicity achieved between 3 weeks and 3 

years among persons who received a booster compared to those receiving a 2-dose primary 

series.

 

 

 

 

 

  

 
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Discussion Points

Dr. Bell congratulated everyone on these clear and comprehensive presentations about a very 

complicated and difficult subject with a 100% fatality rate and limited information. She requested 

further information about the thinking behind Policy Question #2 in terms of why it would be 

easier to get someone to come in for a booster dose rather than having their blood drawn, or if 

there was something else about the difference between these two options.

Dr. Rao indicated that there were differences in the opinion on the WG and they vacillated 

between saying titer only or booster only, and then ultimately settled on giving both options. It is 

not clear how many people who have the 2-dose series would have a titer less than 0.5 IU/mL

and would subsequently require a booster. It is thought that more people would need a booster 

at the 1-year point than with the 3-dose series, but they cannot say for sure given the lack of 

data. Even if it was 50% to 60% of people, the discussion on the WG calls was that some 

people might find it annoying to have to get a titer and then make another appointment to get a 

booster. They thought that since the current schedule is for a 3-dose series, some people would 

consider it a preferable option to go straight to the third dose. The reason for the broad time 

period for the third dose is partly based on the fact that the third dose of the current 3-dose 

series is at Day 21 or Day 28, which is known to be effective in ensuring long-term 

immunogenicity. There are data out to 3 years showing that people can continue to have an 

anamnestic response at 3 years, which is why the WG felt comfortable saying that a booster 

would be acceptable at any point in that time period. The WG’s suspicion is that there probably 

is long-term immunogenicity beyond 3 years from the 2-dose series. The WHO actually adopted 

the 2-dose series without any additional requirements for a titer or booster. The WG is taking 

the most conservative route given the limited data up to 3 years to ensure that people receive 

either a booster or titer and that people’s convenience and preference is honored as much as 

possible. A titer is paid for out of pocket and costs about $50.00; whereas, going straight to 

booster can be as high as $1,800.00.

Dr. Poehling asked about the availability of obtaining a titer, given that she thought she heard 

that KSU was one of only 3 places that perform titers.

Dr. Rao said that KSU, Health Associates, and CDC perform titers. The current 3-dose schedule 

is for healthy people and they must get a titer repeatedly until that has been achieved. It already 

is a requirement for people in the continuous and frequent risk groups to have titers drawn 

serially at certain intervals. For those in the #1 risk group, it is every 6 months. For people in the 

#2 risk group, it is every 2 years. A huge section of the people who had previously been in the 

#2 risk group were moved to the #3 risk group, so a good portion of those people already were 

supposed to be getting titers every 2 years from the people who are now being asked to get a 

single titer once. The WG does not anticipate that there will be a major increase in the number 

of titers, given that so many people already are getting titers because they are 

immunocompromised or because they are in the high risk groups.

Dr. Talbot requested clarity about the cost per dose to receive the series, how much the vaccine 

costs, and if there are any data available on how compliant people are about getting their 

booster shot and having their antibody titers drawn.
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Dr. Rao indicated that they have been told that the clinic visit and shot together costs about 

$1,800.00 or so. Ryan Wallace from CDC added that the Medicare reimbursement cost for 1 

dose of rabies vaccine is $303.00. Dr. Rao noted that she included some manuscripts that 

discuss booster shot and titer compliance in the background reading. The WG feels that 

compliance with titers for those in the #1 risk group is high because they are laboratorians and 

their jobs require it, so it is an occupational issue that is enforced to continue working in the 

laboratory. People in the #2 risk group are not as compliant with the ACIP recommendations as 

they currently stand. Veterinarians in terrestrial regions used to be listed in this group, but they 

were moved to the #3 risk group. They are good about getting their titer checked immediately 

because they received the vaccine during veterinary school, partly because it is a requirement 

for school completion. Subsequently when they are in practice, people are not very compliant 

with titer checks beyond veterinary school according to the manuscripts and veterinarians on 

the WG. Animal wildlife workers and others in that group who are supposed to get titers, 

compliance is even worse and does not seem to be enforced. It does not seem to be forced by 

their occupations and is left up to the person. Because insurance does not cover PrEP, it is an 

out-of-pocket cost. Anything that can be done to maintain the protection intended, increase 

acceptability, and increase the ability to pay for it will be helpful.

Evidence to Recommendations Framework (EtR)

Agam Rao, MD, FIDSA

CAPT, United States Public Health Service

Poxvirus and Rabies Branch

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Dr. Rao reminded everyone that the Rabies Vaccine WG developed 2 policy questions for PrEP 

topics the first of which is, “Should a 2-dose pre-exposure prophylaxis (PrEP) series involving 

HDCV or PCECV IM [0, 7 days] replace the 3 dose series IM [0, 7, 21/28 days] for all those for 

whom rabies vaccine PrEP is recommended?” The population is persons for whom rabies 

vaccine PrEP is recommended, the intervention is [0, 7 days] rabies vaccine PrEP schedule, 

and the comparison is [0, 7, 21/28 days] rabies vaccine PrEP schedule. The only outcome was 

immunogenicity and safety was not included as an outcome given the review of safety data that 

she presented earlier. Again, the considerations for this recommendation are:

❑ Rabies is nearly always fatal

❑ PrEP is an important component of preventing human rabies in the US, but it is not the only 

component

❑ PrEP is indicated for persons with a rabies risk greater than that of the general population

❑ PrEP is critically important for persons with unusual exposures, unrecognized exposures, 

and frequent exposure to potentially rabid animals

❑ Travel abroad to canine-rabies endemic regions without quick access to PEP

No cases of rabies have occurred among persons who received modern CCV PrEP in the US. 

ACIP has recommended PrEP for decades. Many persons for whom ACIP recommends PrEP 

do not receive it. Rabies PrEP is very expensive and insurance typically does not cover the cost

and occupations often do not cover the cost. Some occupations do not enforce compliance with 

ACIP recommendations even though risk is typically because of occupation.
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The WG felt that the problem is of public health importance. PrEP is indicated for many persons 

in the US. All US animal care professionals (e.g., veterinarians, technicians, animal control 

officers), veterinary students, short-term and volunteer workers with hands-on animal care, 

persons who frequently handle bats or enter high-density bat environments, various laboratory 

personnel, and travelers to canine-rabies endemic regions who may not have quick and easy 

access to PEP if needed). Fewer people receive PrEP than ACIP recommends because the 

series involves 3 vaccine doses and out-of-pocket costs.

The WG determined that the desirable anticipated effects are minimal, given that they are pretty 

much equivalent to the 3-dose series. Out of 264 persons receiving 2-dose primary series, 

100% achieved titer ≥0.5 IU/mL 2-4 weeks after the second dose. Of the 264 persons receiving 

the 3-dose primary series, 100% achieved a titer level ≥0.5 IU/mL. Seroconversion is the target 

outcome of PrEP and is achieved with the proposed 2-dose series just as it is with the [0, 7, 

21/28 days] series.

The WG felt that the undesirable anticipated effects are minimal. No expected safety concerns

have been associated with US rabies CCVs. Safety data recently compiled from VAERS reports 

for HDCV and PCECV vaccines, those mentioned in the package insert, and those reported in 

25 trials published since the 2008 ACIP recommendations are unchanged from previous 

reports. These rabies vaccines have been used for decades and are considered to have a

favorable safety profile [Moro PL et al. Travel Med Infect Dis. 2019 May - Jun;29:80-81; Moro 

PL, et al PLoS Negl Trop Dis. 2016 Jul 13;10(7):e0004846; VAERS: Vaccine Adverse Event 

Reporting System; Dobardzic A et al. Vaccine. 2007;25:4244–51].

With regard to whether the desirable effects outweigh the undesirable effects, both 2-dose and 

3-dose primary series achieve complete immunogenicity at 2-4 weeks following completion of 

the series. Therefore, the WG feels that it favors both. The WG found the overall certainty of the 

evidence to be moderate, Level 2, due to the concerns for risk of bias.

The WG determined that the target population probably feels that the desirable effects are large 

relative to the undesirable effects. While no research evidence was identified, the target 

population would likely appreciate a shorter series that requires fewer vaccines, is less 

expensive, and provides the same primary immunogenicity as the current 3-dose series. 

Educational materials may be needed to ensure the target audience understands that the 

immunogenicity is unchanged from that of the current series for up to 3 years. Knowledge, 

attitudes, and practices (KAP) surveys may be considered to assess perceptions of the target 

population. The WG felt that there is no important uncertainty about or variability in how much 

people value the main outcomes. While again no research was identified, the target population 

values “protection” from rabies and there is likely no important variability in how people value it. 

The WG felt that the intervention is acceptable to key stakeholders. A shorter series would be 

appreciated by clinical providers, public health officials, and patients who all prefer a simpler 

vaccine schedule that is less expensive than the current schedule. It will be easier to schedule 

appointments for 2 vaccines than for 3 vaccines.

The WG found the intervention to be a reasonable and efficient allocation of resources. The 

estimated cost of a 3-dose PrEP series is approximately $1,800 per clinic visit and vaccine dose 

and these costs are often out-of-pocket. Fewer costs would be incurred by patients with a 

shorter series, thereby making intervention a reasonable and efficient allocation of resources to 

all populations for which it is indicated. Rabies vaccine shortages have occurred in the US. A 

shorter vaccine schedule may prevent an impact of such shortages on PrEP demands.
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The WG felt that there probably would be a reduced impact on health equity. While no research 

evidence was identified, the costs for rabies PrEP is often out-of-pocket so a shorter series 

could potentially make the PrEP series more accessible to persons who would not otherwise be 

able to afford it. There are a lot of people for whom ACIP recommends receipt of PrEP who 

have a higher risk than the general population.

The WG thought that the intervention would be feasible to implement. While no research 

evidence was identified, no barriers are expected with implementing a shorter series. With a 3-

dose series, it is often difficult to ensure that the third dose is administered before someone 

travels to a canine-endemic region or starts work that requires pre-vaccination. Having to wait 

until receipt of the third dose at 21 or 28 days is often seen as an inconvenience and people do 

not see themselves as being previously immunized before receiving the third dose. With the 

shorter regimen [0, 7 days], they would be considered previously immunized much sooner. As 

many people in the WG commented, travelers often do not schedule a travel clinic visit soon 

enough before their travel and this would facilitate that. Implementing a shorter series will be 

easier and management challenges are expected to be equivalent to those currently faced 

when deviations occur to the PrEP schedule.

The WG determined that the desirable consequences probably outweigh the undesirable 

consequences in most settings and that there is sufficient information to move forward with a 

recommendation. Therefore, the WG proposed the following draft recommendation to ACIP:

As a reminder, the second policy question was, “Should an IM booster dose of rabies vaccine 

(*PCECV or †HDCV) be recommended as an alternative to a titer check no sooner than day 21 

and no later than 3 years after the two dose pre-exposure (PrEP) series IM [0, 7 days] for those 

in the #3 risk category who receive PrEP?” The population is persons in the #3 risk category for 

whom rabies vaccine PrEP is recommended, the intervention is Day 21/Year 3 rabies vaccine 

booster after [0, 7 days] rabies vaccine PrEP schedule, and the comparison is no rabies vaccine 

booster after [0, 7 days] rabies vaccine PrEP schedule. It is important to note that this question 

is applicable only to people who would have sustained risk for rabies beyond the 3-year time 

point. For instance, this question would not apply a traveler planning a single trip to India who 

needs a one-and-done series.

The problem is that some persons have sustained risk for rabies (i.e., risk >3 years after 

completion of the primary series). For those in the #1 and #2 risk groups for rabies, serial titer 

checks are currently recommended by ACIP because of the risk to those groups for 

“unrecognized” exposures. In the absence of data to confirm long-term immunogenicity >3 

years after primary series, a titer check or booster for those in the #3 risk group can confirm 

long-term immunogenicity. A single titer check is indicated 1-3 years after the primary series 

because this value is indicative of long-term immunogenicity. A recommendation for titer checks

would be a new ACIP recommendation for those in the #3 risk group. Some persons in the #3 

risk group may prefer boosters to titer checks. While a titer is much less costly than a booster, a

titer may indicate the need for a booster. Some persons may prefer going straight away to 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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booster to avoid the inconvenience of multiple clinic visits. Some persons may have the cost of 

a booster absorbed by occupation. Facilitating the booster dose as soon as when the third dose 

of the current ACIP [0, 7, 21/28 days] series is administered will amount to no change for those

accustomed to that schedule.

Some may not know whether they will have risk for long-term immunogenicity and may prefer 

waiting for 3 years to receive the additional dose. Some may not be able to receive the third 

dose for an extended time period because of travel and will appreciate having a large time 

period to receive the booster. The WHO approved [0, 7 days] series without booster in their 

most recent recommendations in 2018. This idea of ensuring long-term immunogenicity beyond 

3 years is something the ACIP WG pursued because of recognizing that rabies is 100% fatal, 

they wanted to be as conservative as possible, and they wanted to work within the confines of 

the very limited data available for rabies. Data about immunogenicity will likely be available in 

the coming years. Given that the WHO has been using this 2-dose series without the option of a 

booster dose, the hope is that there will be data available from this. If the policy question is 

recommended by ACIP, the recommendation facilitates collection of data in the US before the 

next update of ACIP recommendations at 10 years or sooner on those in the #1 risk group 

among laboratorians at CDC and those in the #3 risk group through collaborations with 

veterinary schools where PrEP is required. If the data show that the IM [0, 7 days] series 

provides long-term immunogenicity alone and that there is no need for a titer or booster to 

ensure long-term immunogenicity, future ACIP updates may easily drop the booster dose 

requirement. This is an easy change to make and the proposed recommendation would be a 

step toward a simplified series like WHO’s of [0, 7 days] for primary and long-term.

The WG determined the problem to be of public health importance. Many persons in the #3 risk 

category may require long-term immunogenicity (e.g., career veterinarian). While a 2-dose [0, 7 

days] series may provide long-term immunogenicity, in the absence of data to confirm this, a 

titer check to determine if a booster is needed or a booster straight away provides the added 

insurance for this nearly 100% fatal illness. Allowing for the option of a booster straight away is 

important because for some persons in the target population, it is preferable to save time to 

bypass the titer and go directly to booster. For these persons, the cost is typically absorbed by

their occupation.

The WG felt that the desirable anticipated effects would be moderate. An anamnestic response 

to vaccine challenge, as measured by increase in antibody titer level ≥ 0.5 IU/mL, occurred for 

100% of persons who receive rabies vaccine booster at the 1-year time point and 3-year time 

point. These time points are markers of long-term immunogenicity. The WG suspects that 

persons who receive a 2-dose [0, 7 days] series will be able to mount an anamnestic response 

many years later regardless of booster. However, for a high stakes infection, the desirable 

effects are moderate in the absence of human data to confirm long-term immunogenicity after 3 

years.

The WG excepts that the undesirable anticipated effects would be minimal. There are no 

expected safety concerns associated with a booster dose. Safety data recently compiled from 

VAERS reports for HDCV and PCECV vaccines, those mentioned in the package insert, and 

those reported in 25 trials published since the 2008 ACIP recommendations are unchanged 

from previous reports. These rabies vaccines have been used for decades and considered to 

have favorable safety profile. The WG found that the desirable effects outweigh the undesirable 

effects and favors the intervention. There is a 100% response rate among those receiving a 

booster and there likely will be few additional AEs from receipt of a booster. The WG 

determined the overall certainty of evidence to be low, Level 3.
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The WG thinks that the target population feels that the desirable effects are large relative to the 

undesirable effects. It is probably that the target population likely wants to ensure long-term 

immunogenicity. Given limited data that 2-dose series alone will provide long-term 

immunogenicity, the benefits are expected to outweigh any inconvenience. Persons may 

experience less anxiety about acquiring this high-mortality infection by having the option of a 

booster or titer confirming titers ≥0.5 IU/mL. Some persons may experience discomfort or 

inconvenience from having to get booster.

The WG did not think there would be important uncertainty or variability in terms of the target 

population’s sentiments. While no research evidence was identified, the target population is

likely to desire a PrEP series that provides long-term immunogenicity and that there is not likely 

to be important uncertainty or variability because the target population is at increased risk for 

exposure to a life-threatening illness. The intervention is likely to be acceptable to the target 

population because stakeholders are invested in ensuring that the target population has longterm immunogenicity for rabies. Stakeholders are accustomed to accommodating for a third 

dose of rabies vaccine and will find it acceptable to have titer option or booster dose provided 

after the proposed [0, 7 days] primary series.

In terms of whether the intervention is a reasonable and efficient allocation of resources, the 

cost of a clinic visit and rabies booster can be very high at about $1,800 while cost of a titer 

along is about $50 and figuring in additional costs is about $100. That will still be much less than 

the booster dose. However, given the added insurance a booster would give for long-term 

immunogenicity, it would be a reasonable and efficient allocation of resources. Since not all 

persons who received the primary 2-dose series will require a booster, titer checks confirming 

titers ≥0.5 IU mL would be less costly and could be used to avoid a booster. Therefore, the WG 

feels that the intervention is a reasonable and efficient allocation of resources.

Regarding the impact on health equity, no research evidence was identified. However, the costs 

for rabies PrEP is often out-of-pocket. There is a potential for inequity because of the high costs 

of vaccine. Because titer is offered as an alternative to booster, the inequity could be resolved 

by choosing the titer option that is many times less expensive than booster. The WG did not 

know whether there would be an impact on health equity. However, they did feel that the 

intervention would be feasible to implement. Administrators of the booster are accustomed to 

accommodating multiple doses of PrEP beyond a [0, 7 days] series. They will have no difficulty 

with the feasibility of a booster dose after a 2-dose series. Recommending a booster may 

improve the feasibility of maintaining occupational compliance with rabies PrEP, including 

among those who are non-compliant with the current ACIP recommendation for titer checks. 

The WG determined that the desirable consequences outweigh the undesirable consequences 

in most settings and that there sufficient information to move forward with a recommendation. 

Therefore, the WG proposed the following draft recommendation to ACIP:
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Discussion Points

Dr. Bell suggested that it might be useful for the WG to do some more investigating about 

precisely what the cost of a dose of rabies vaccines is in various settings. In terms of the 

proposed wording for Policy Question #2, she emphasized the importance of making clear that 

there are 2 options. One is to get a booster dose and the other is to get a titer. It was not entirely 

clear to her based on the wording proposed that either is acceptable.

Dr. Rao said that apparently frequency of titer checks does not require a vote, GRADE, or and 

EtR. That is one of the reasons the WG struggled with this. It is true that only the booster 

component needs to be voted on and the titer part would be clinical guidance.

Ms. McNally agreed that from a consumer perspective, it would be helpful to be clearer 

regarding the options.

Dr. Sanchez asked about ID administration. Dr. Rao indicated that ID has not been 

recommended in the US for a very long time. As Dr. Briggs presented in her talk, ID was 

licensed briefly in the US but companies pulled out of providing it for ID purposes. If not licensed 

by FDA, so this introduces infection control issues in terms of using a single use vial for multiple 

people. It makes sense from a cost-saving perspective internationally, which is why the WHO 

endorses it. No ACIP recommendations are being provided for ID use due to how rarely it will be 

used in the US population, the risks from an infection control standpoint, and the fact that it is 

not FDA-licensed or packaged currently for the US. The purpose of Dr. Briggs’s study was more 

to explain why ID studies were included in the GRADE assessment.

Titer Frequency, Clinical Guidance, and Next Steps

Agam Rao, MD, FIDSA

CAPT, United States Public Health Service

Poxvirus and Rabies Branch

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Dr. Rao presented the revised recommendation table shown earlier with the WG’s PrEP 

preferences added, including guidance for titers, to the last 2 columns as shown here:
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WG’s preference for primary immunogenicity is now completed with the IM [0, 7 days] schedule, 

which addresses Policy Question #1. The long-term immunogenicity column for the booster 

dose for those in the #3 risk category is now filled in, which addresses Policy Question #2. The 

item that still has to be filled in is the frequency of titer checks in the long-term immunogenicity 

column. Dr. Rao reminded everyone that in her earlier presentation, she explained that the ideal 

way of ensuring long-term immunogenicity is through serial titers. That is something already 

recommended for those in the #1 and #2 risk groups because they can have unrecognized 

exposures. ACIP currently recommends the frequency of those titers to be every 6 months for 

those in the #1 risk group and every 2 years for those in the #2 risk group. The WG’s preference 

is for that to remain unchanged to ensure long-term immunogenicity for those in the #1 and #2 

risk groups.

The last piece of the table to consider is the titer option for those in the #3 risk group. As 

mentioned earlier, a titer check for persons in this risk group is not something that some of the 

people in this group are accustomed to. The WG was concerned that instituting a titer check as 

the only option for ensuring long-term immunogenicity beyond 3 years may not be followed by 

this group, which is why the booster option was proposed. For those for whom a titer would be 

preferrable as opposed to going straight away to a booster, the WG considered the available 

data. The data from the Strady et al article in 1998 showed that titers at the 1-year time point 

are a marker for long-term immunogenicity. New data from the paper that was included in the 

GRADE shows an anamnestic response occurs for 100% of people in the RCTs for up to 3 

years after the primary series. Since there are no data beyond the 3 year time point, out of an 

abundance of caution, the WG proposed a booster or titer check at the 2 year time point. No 

further titers would be needed for those in the #3 risk group because the reason for PrEP for 

those in this group is the ability to mount an anamnestic response.
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To summarize the clinical guidance that was presented during all of the day’s presentations, the 

table was updated for the risk groups. The WG reorganized the risk groups for PrEP and titles of 

three risk groups based on changing rabies landscape, included biogeography information for 

each risk group to make it easier to navigate and to clear up questions that have been 

problematic for clinicians and public health, and provided more examples of occupations for 

each risk group so that there is as little confusion as possible. To ensure long-term 

immunogenicity, a titer was introduced as an option for persons in the #3 risk group at 2 years. 

This clinical guidance, so it is not something for which GRADE, EtR, or a vote would be needed. 

The WG also is proposing changing the ACIP cutoff for minimal acceptable antibody titer to 0.5 

IU/mL. Moving on to the proposed changes the WG is suggesting that would require a vote is 

the suggestion for primary immunogenicity that the 3-dose series be shortened to a 2-dose 

series and that in addition to the titer option, an option be given for booster once to the people in 

the #3 risk category no sooner than Day 21 and no later than 3 years.

Dr. Rao explained that the advantages of the proposed change to 2 versus 3 doses is that the 

#1 risk group would receive 1 less dose of pre-exposure vaccine, they would be assured that 

they would have completed vaccination much sooner than if they had to get a third dose at 21 or 

28 days, and there would be no change to the fact that they would be getting titers every 6 

months. These are benefits for laboratorians. The #2 risk group would receive fewer vaccine 

doses in the primary series and titers every 2 years, which is the same as currently 

recommended. If anything, this would decrease the number of people who have to get this 

because the #2 risk group would be limited to people who have unrecognized exposures such 

as those handling bats or entering high-density bat environments. This represents a very small 

number of people. The #3 risk group is the IM [0,7 days] 2-dose series. Those who do not have 

sustained risk for rabies would not have to get a titer or booster beyond that initial 2-dose series. 

Those who do have risk for longer-term exposure because of their careers or recreational 

activities would have the option of getting a booster as soon as they would have with the 3-dose 

series or the option of a titer for people who would prefer the lower costs.

The WG considerations throughout their discussions about the approach to PrEP were very 

mindful of the concerns raised by the ACIP during the February 2020 meeting about making any 

change to the ACIP recommendations for rabies. Notably, the ACIP recommendations have 

changed quite a lot over time as more data have been provided and CCVs have become widely 

used. The 2008 ACIP recommendations have been effective and rabies is 100% fatal, so the 

WG understood that ACIP’s request was to ensure that any proposed changes are supported by 

robust data, address the evolving rabies landscape, reflect new data and increase confidence in 

modern CCVs, and do not result in suboptimal immunogenicity compared to the current PrEP. It 

also is important to note that the WHO and ACIP recommendations do not have to align. Dose 

and cost-sparing options are the top priority for the WHO. The WG did not feel that the 

increased cost associated with the titer or the booster in the #3 risk group would not be much, 

given that many of those people were in the #2 risk group and were supposed to be getting 

titers anyway.

Depending upon what ACIP thinks about the WG’s proposed revisions to the recommendations, 

there potentially could be a vote on the two PrEP policy questions during the February 2021

ACIP meeting. In addition, the WG anticipates beginning to present on PEP to ACIP in February 

2021 as well.
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Discussion Points

Dr. Lee emphasized the importance of being thoughtful about how the dynamic of the 

benefit/risk balance can change. She thinks it is great step forward that they are trying to 

streamline and continue to improve maximum effectiveness while minimizing any harms and/or 

challenges.

Dr. Poehling requested clarity regarding the #3 risk group in terms of whether their only choice 

is a booster if they do not get the titer at 2 years, or if it should read a titer once between 2 and 3 

years.

Dr. Rao recalled that the reason they made it a specific timepoint was because the table was 

beginning to be confusing and the ranges were somewhat out of control. The only reason they 

chose 2 years was because it was the same as for the #2 risk group. They certainly could 

change that.

Dr. Frey added that it is known that if a person has an elevated titer at 1 or 2 years, it typically 

will last out to 3 years or longer.

Dr. Kimberlin (AAP Redbook) asked whether any sensitivity analyses have been performed to 

determine whether the 100% seroconversion that was seen in the two studies with 263 or 410 

subjects holds up in larger trials. For instance, they would not necessarily put a lot of stock in an 

N=3 and 100%. He wondered about people’s comfort level making this kind of a change based 

on a few hundred people.

Dr. Rao responded that sensitivity analyses were not performed, but the confidence interval was 

extremely tight for the 2 studies that were demonstrated.

Dr. Cohn indicated that costs will be re-checked and presented during the next ACIP meeting if 

the companies allow it.

Dr. Talbot emphasized how fragile the healthcare system is and that she was struggling with 

this recommendation versus just giving the third shot in case they do not get it again in the 

future. She wondered whether there is any way to get serology data beyond 3 years. 

Dr. Rao said they are hoping that because the WHO has instituted this recommendation for the 

2-dose series that there will be data for that soon. The thought was that going forward, CDC 

would be able to collect data if this recommendation is accepted by ACIP and then they would 

know whether this titer or booster is even needed for the #3 risk group. The idea of long-term 

immunogenicity was not of concern to the WHO. It is really the ACIP WG who, out of an 

abundance of caution and wanting to ensure that there are definitely data, did not feel 

comfortable making the recommendation without the data.

Dr. Talbot questioned why they were in a hurry to make the change rather than waiting for the 

WHO data, particularly given that this is a 100% fatal disease.

Dr. Rao said that with the option for the #3 risk group, they are allow them to get the booster 

dose as soon as Day 21, which is the same as the current 3-dose series. What that amounts to 

is that if people want to get the 3-dose series, they can. However, it is not always convenient for 

people to get the third dose and it is not always needed because they are not going to have a 

risk beyond 3 years. The cost is such that people are not being compliant with recommendation 
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to get PrEP because it is so expensive and is out-of-pocket for them. The WG’s thought was 

that they are allowing people to continue to get the vaccine the way they current are, but they 

are also being given other options with the hope of improving the number of people who get the 

vaccine and accommodate for different preferences.

Dr. Frey added that there are scheduled titer checks that people are supposed to be getting 

done.

Bryan Baxter (Bavarian Nordic) indicated that based on some general market research 

conducted in major cities in the US, the average cost for PrEP per dose was about $450.00. 

These data can be shared with the ACIP. That was the cost for vaccine only in non-ED settings 

and not including the visit and consumables.

Dr. Romero said that rather than taking a deep dive into the cost and factoring everything in 

during the meeting, they can work with Dr. Rao to obtain this information offline.

Dr. Bell suggested checking in with the WHO rather than waiting for data, given that presumably 

they would know whether there have been any breakthrough infections in the intervening time. 

The advantage/disadvantage of the WHO environment is that people are getting exposed to 

rabies every day, most of whom presumably have not gotten PrEP. With the anticipation of 

coming to a vote at some point, the attempt to simplify the table may set them up for numerous 

questions when people miss the 2-year time point for the titer check.

Dr. Lee asked why there are out-of-pocket costs if this is a recommendation and someone has 

insurance.

Dr. Cohn indicated that they would present information on the cost summaries, reimbursement, 

et cetera during the next meeting.

Friday: October 30, 2020

José Romero, MD, FAAP

ACIP Chair

Amanda Cohn, MD

Executive Secretary, ACIP / CDC

Dr. Romero called to order the October 30, 2020 emergency meeting of the Advisory Committee 

on Immunization Practices (ACIP) focused solely on the topic of coronavirus disease 2019 

(COVID-19) vaccines. He emphasized that faced with a crisis of historic proportion, basic 

scientists, clinical scientists, clinical investigators, and volunteers have worked with 

unprecedented speed to develop, test, evaluate, and manufacture a plethora of potential 

vaccines against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The 

mandate given to the ACIP has been to develop equitable, just, and fair policy guidelines for the 

use of those vaccines that are proven to be safe and effective in preventing and mitigating 

SARS-CoV-2 disease. The volume of data that have been compiled, analyzed, synthesized, and 

Call To Order, Welcome, Overview, Announcements, & Introductions 
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presented to the ACIP voting members, liaisons, ex officio representatives and the public has 

possibly been more than ever presented for any other vaccine that has come before the ACIP. It 

can be said without hyperbole or exaggeration that no other national COVID-19 vaccine 

advisory group has dedicated as much time to addressing questions posed to the ACIP 

regarding the use of those COVID-19 vaccines.

Over the 7 months since its creation, the ACIP’s COVID-19 Vaccine Work Group (WG) has met 

more times than any other non-standing ACIP WG. Dr. Romero publicly acknowledged the 

extraordinary work in terms of time, effort, and quality that the members of the COVID-19 

Vaccine WG have dedicated to this effort. In addition to the official WG members, all ACIP 

members have given of their time to prepare for, attend, and meaningfully participate in the 

equivalent of 2 years’ worth of open public meetings in a 10-month timeframe. Dr. Romeo also 

acknowledged the extraordinary leadership of Dr. Nancy Messonnier, Director of the National 

Center for Immunization and Respiratory Diseases (NCIRD); Dr. Amanda Cohn, ACIP 

Executive Secretary; and Jessica McNeil, Assistant Executive Secretary for ACIP. In addition, 

he acknowledged the important support work provided by Ms. Stephanie Thomas and Ms. 

Natalie Greene who have provided much of the materials to be reviewed prior to the meetings. 

In closing, he thanked all who have dedicated, are dedicating, and will continue to dedicate their 

time to ACIP’s efforts to provide guidance for the use of safe and effective COVID-19 vaccines, 

emphasizing that he believed history would not forget their dedication to this task.

During the first day of the regular ACIP meeting on October 28, 2020, Dr. Cohn welcomed 

everyone and indicated that copies of the slides being presented during this meeting were

available on the ACIP website and had been made available through a ShareFile link for ACIP 

Voting, Liaison, and Ex-Officio members; videos of the live webcast would be posted on the 

ACIP website approximately 1 week after the meeting; and that meeting minutes also would be 

posted on the ACIP website, generally within 90-120 days of the meeting. She reviewed 

meeting logistics and reminded everyone that ACIP members agree to forgo participation in 

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

interests that potentially enhance a member’s expertise while serving on the committee, CDC 

has issued limited conflict of interest (COI) waivers. Members who conduct vaccine clinical trials 

or serve on data safety monitoring boards (DSMBs) may present to the committee on matters 

related to those vaccines, but are prohibited from participating in committee votes on issues 

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

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

company. 

Dr. Romero conducted a roll call of ACIP members. During the roll call of the regular ACIP 

meeting on October 28, 2020, ACIP members stated any COIs. These remained unchanged 

during the October 30, 2020 emergency ACIP meeting:

❑ Dr. Robert Atmar is serving as the Co-Director of the Clinical Operations Unit (COU) of the 

National Institutes of Health (NIH)-funded Infectious Diseases Clinical Research Consortium

(IDCRC) that is working within the COVID-19 Prevention Network (CoVPN) to evaluate 

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) vaccine candidates in 

Phase 3 clinical trials, including those produced by Moderna, AstraZeneca, Janssen,

Novavax, and Sanofi. 

❑ Dr. Sharon Frey is employed by Saint Louis University (SLU), which has a Vaccine 

Treatment Evaluation Unit (VTU) that is part of the IDCRC. She is currently serving as the 

Site PI for the Moderna and Janssen Phase 3 COVID-19 vaccine clinical trials.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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❑ Dr. Paul Hunter owns a small amount of stock in Pfizer and has received a small grant from 

Pfizer to conduct a quality improvement (QI) project on pneumococcal vaccines.

Given that no specific vaccine products were being recommended during this meeting, all voting 

ACIP members were permitted to participate in the discussion.

A list of Members, Ex Officio Members, and Liaison Representatives is included in the 

appendixes at the end of the full minutes for the October 30, 2020 ACIP emergency meeting.

Introduction

Beth Bell, MD, MPH 

ACIP, COVID-19 Vaccine WG Chair

Clinical Professor, Department of Global Health

School of Public Health, University of Washington 

Dr. Bell thanked Dr. Romero for his leadership, incredible assistance and support, and vision in 

the context of the ACIP’s work in addressing the COVID-19 pandemic and working on COVID19 vaccine policy. She then introduced the session for the October 30, 2020 emergency ACIP 

meeting, which focused on ACIP’s continued response to the ongoing pandemic and 

accelerated vaccine development. She reminded everyone that during the September 22, 2020 

meeting, ACIP reviewed the following topics:

❑ Overview of COVID-19 Vaccine Safety

❑ Enhanced Vaccine Safety Surveillance

❑ Vaccine Implementation

❑ Disparities Among COVID-19 Epidemiology

❑ Overview of Vaccine Equity and Prioritization Frameworks

❑ Phase 1 Allocation for COVID-19 Vaccine: WG Considerations

The COVID-19 Vaccine WG continues to meet on a weekly business. The topics this group has 

covered during October include the following:

❑ Review of Available Information on Reinfection of COVID-19

❑ Post-Infection Immunity

❑ Discussions to Finalize the Outcomes for GRADE (Grading of Recommendation 

Assessment, Development and Evaluation)

❑ Modeling Data for Initial Allocation of Vaccine

❑ Current Epidemiology of COVID-19 in Pregnant Women

❑ Review of Ethical Principles to Inform Initial Allocation of Vaccine

❑ Clinical Development Program for Two COVID-19 Vaccines, Including Data From Phase I/II 

Clinical Trials and Plans for Phase III Clinical Trials

❑ Further Discussions Regarding COVID-19 Vaccine Allocation

Coronavirus Disease 2019 (COVID-19) Vaccines
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Dr. Bell indicated that during this session, presentations would be provided in the following topic 

areas:

Vaccine Development & Regulatory

❑ Update from VRBPAC meeting

❑ NVX-CoV2373 Vaccine Candidate

❑ Janssen’s SARS-CoV-2 Vaccine Program

Implementation

❑ Update on Vaccine Implementation Planning

❑ Vaccinate with Confidence

Safety

❑ FDA Safety Surveillance Systems

❑ Post-Authorization Safety Monitoring Plans

Allocation and Epidemiology

❑ Modeling Strategies for the Initial Allocation of COVID-19 Vaccines

❑ Updates to Immunity and Epidemiology to Inform COVID-19 Vaccine Policy

❑ Ethical Principles for Early Vaccine Allocation

WG Interpretation

❑ WG Interpretation of Data

❑ Policy Questions, Evidence to Recommendation (EtR) Framework, and Outcomes

Dr. Bell reported that over 200 COVID-19 vaccines are currently under development. Within the 

US, 4 vaccines are in active Phase III clinical trials and 5 are in active Phase I/II clinical trials. In 

terms of the Phase III clinical trials in the US, AstraZeneca announced the removal of an FDA 

hold on its AZD1222 vaccine on 10/23/2020 and are resuming Phase III trials. Janssen

announced the lifting of its safety pause for its Ad26.COV2.S vaccine on 10/23/2020 and is

resuming Phase III trials. The Pfizer/BioNTech BNT162b2 vaccine trial reported having enrolled 

42,133 participants as of 10/26/2020. Of these, 35,771 participants have received their second 

vaccination. In addition, Pfizer/BioNTech reported that approximately 30% of US participants 

enrolled have “diverse backgrounds.” Enrollment is complete for Moderna’s messenger 

ribonucleic acid (mRNA)-1273 vaccine. As of 10/22/2020, approximately 30,000 participants 

have been enrolled and 25,654 of those participants have received their second vaccination.

In terms of the distribution of demographic characteristics of the participants in Moderna’s 

Phase III clinical trials in the US taken from their website, 63% of participants are White, 20% 

are Hispanic/Latinx, 10% are Black/African American, 4% are Asian, and 3% are Other 

Racial/Ethnic Groups. Approximately 8000 participants are ≥65 years of age. Of the 

participants, 22% are healthcare personnel (HCP) and 27% report living with comorbidities (e.g., 

diabetes, cardiac disease, lung disease, and obesity). Dr. Bell shared a table of the COVID-19 

vaccines in human clinical trials in and outside of the US, pointing out that there are additional 

inactivated vaccines in Phase I/II/III, 10 protein subunit vaccines candidates in Phase I/II, 7 nonreplicating viral vector vaccine candidates in Phase I/II, and 7 RNA vaccine candidates in Phase 

I/II.
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Food and Drug Administration (FDA) Update

Doran Fink, MD, PhD

Deputy Director-Clinical, Division of Vaccines and Related Products Applications

Center for Biologics Evaluation and Research, Food and Drug Administration

Dr. Fink provided an overview of the Vaccines and Related Biological Products Advisory 

Committee (VRBPAC) meeting on October 22, 2020 during this session. He first reminded 

everyone that the VRBPAC reviews and evaluates data concerning the safety, effectiveness, 

and appropriate use of vaccines and related biological products. VRBPAC is a committee of 

experts external to FDA that provides input upon request by FDA on certain regulatory actions 

(e.g., licensure of new vaccines) and on more general topics critical to advancing regulatory 

science. VRBPAC recommendations are non-binding, but are usually followed by FDA.

The VRBPAC met on October 22, 2020 for a general discussion of the development, 

authorization, and/or licensure of vaccines to prevent COVID-19. This was an open meeting 

with a live webcast that was accessible to the public. There was no discussion of specific 

COVID-19 vaccine candidates or any votes on recommendations. The agenda included the 

following topics:

❑ FDA Introduction and Presentation of Discussion Points

❑ Epidemiology, Virology, and Clinical Features of COVID-19 (CDC)

❑ NIH Activities in the Development of Vaccines Against COVID-19

❑ Biomedical Advanced Research and Development Authority (BARDA) Activities in the 

Development of Vaccines Against COVID-19

❑ CDC Plans for Safety/Effectiveness Monitoring & Evaluation During Emergency Use 

Authorization (EUA) Use and Post-Licensure FDA Surveillance Systems and Plans for PostMarketing/Post-Authorization Evaluation

❑ Operational Aspects of COVID-19 Vaccine Distribution and Tracking (CDC)

❑ COVID-19 Vaccine Confidence (Reagan-Udall Foundation)

❑ Licensure and Emergency Use Authorization of Vaccines to Prevent COVID-19: 

Manufacturing and Clinical Considerations (FDA)

❑ Open Public Hearing

❑ Committee Discussion and Recommendations

During that VRBPAC meeting, the FDA explained the considerations for manufacturing and 

clinical information needed to support licensure for EUA of COVID-19 vaccines, as described in 

two recent FDA guidance documents. The purpose of the guidance documents is to provide 

reassurance that FDA will rely on sound science, established regulatory standards, and a 

transparent process for evaluating COVID-19 vaccine candidates.

Dr. Fink first explained the clinical considerations for an EUA in detail, which are summarized as 

follows:

❑ EUA for a COVID-19 vaccine may be requested to allow for the vaccine’s rapid and 

widespread deployment for administration to millions of individuals, including healthy people, 

following a planned interim analysis in an ongoing Phase 3 trial

❑ A favorable benefit/risk determination to support issuance of an EUA in this scenario would 

require the following, in addition to adequate manufacturing information: 
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➢ Efficacy data showing protection against SARS-CoV-2 infection or disease with a 

point estimate of least 50% versus a placebo comparator and an appropriately alphaadjusted confidence interval lower bound >30%

➢ At least half of Phase 3 study subjects followed for both safety and efficacy for at 

least 2 months following completion of the full vaccination regimen

➢ Safety data from throughout clinical development (including well over 3,000 Phase 3 

vaccine recipients) to evaluate reactogenicity, serious adverse events (SAEs), and 

AEs of special interest (AESI)

➢ Sufficient cases of severe COVID-19 to assess for signals of enhanced disease

❑ Reasons for a median follow-up of at least 2 months after completion of the full vaccination 

regimen to support issuance of an EUA for a COVID-19 vaccine:

➢ Allows time for potential immune-mediated adverse reactions to be evaluated 

(uncommon but clinically significant immune-mediated adverse reactions to 

preventive vaccines generally have onset within 6 weeks following vaccination)

➢ Ensures that vaccine efficacy is assessed during the time period when 

adaptive/memory immune responses (rather than innate responses) are mediating 

protection

➢ Allows for early assessment of waning protection and signals of enhanced disease

❑ Following a successful efficacy analysis that supports issuance of an EUA, further 

evaluation of a COVID-19 vaccine would be needed:

➢ For ongoing benefit/risk assessments for continuation of the EUA

➢ To accrue additional data to support licensure and/or to inform labeling

❑ Continued evaluation of a COVID-19 vaccine made available under EUA would include:

➢ Longer-term follow-up for safety, including in larger numbers of vaccine recipients 

and in populations with lower representation in clinical trials

➢ More precise estimation of vaccine effectiveness

➢ More robust assessment of effectiveness against specific aspects of SARS-CoV-2 

infection or disease

➢ Characterization of duration of protection

➢ Investigation of immune biomarkers that might predict protection

➢ Ongoing monitoring for signals of enhanced disease

❑ Issuance of an EUA for a COVID-19 vaccine would be contingent upon the ability to conduct 

further vaccine evaluation through a combination of:

➢ Active follow-up of vaccine recipients under the EUA

➢ Passive monitoring for clinically significant adverse reactions using established 

reporting mechanisms (e.g., VAERS)

➢ Observational studies, including those that leverage healthcare claims databases

➢ Continuation of blinded, placebo-controlled follow-up in ongoing clinical trials for as 

long as is feasible and strategies to handle loss of follow-up
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❑ FDA does not consider issuance of an EUA for a COVID-19 vaccine to necessitate 

immediate unblinding of ongoing clinical trials or offering vaccine to all placebo recipients

➢ Trial participants may choose to withdraw from follow-up for any reason, including to 

receive vaccine made available under EUA

A number of specific topics were posed during the meeting for VRBPAC discussion, including 

the following:

❑ Please discuss FDA’s approach to safety and effectiveness data as outlined in the 

respective guidance documents.

❑ Please discuss strategies for continuation of blinded Phase 3 clinical trials if an EUA has 

been issued for an investigational COVID-19 vaccine

❑ Please discuss studies following licensure and/or issuance of an EUA for COVID-19 

vaccines to further evaluate safety, effectiveness, and immune markers of protection and 

evaluate the safety and effectiveness in specific populations.

To summarize the discussion from the meeting, VRBPAC expressed concerns about public 

vaccine confidence, consistent with those described in the Reagan-Udall Foundation 

presentation. Hesitancy around acceptance and use of COVID-19 vaccines will continue to be 

driven by speed of vaccine development and the perception of uncertainty and limitations of 

data. Issues with COVID-19 vaccine deployment could adversely impact public confidence in

vaccines in general. Regulatory actions to make COVID-19 vaccines widely available therefore 

need to be transparent, effectively communicated, and above all supported by adequate data.

There was broad agreement that data to support issuance of an EUA for a COVID-19 vaccine 

should not be less than the standards outlined by the October 2020 FDA guidance. Some 

VRBPAC members expressed concerns that a median follow-up of 2 months after completion of 

the vaccination regimen would not be sufficient to support an EUA for rapid and widespread 

deployment, in particular for vaccines manufactured for novel platforms. A successful interim 

efficacy analysis, with more limited COVID-19 cases and wider confidence intervals compared 

to a final analysis, would not be sufficient to support an EUA for rapid and widespread 

deployment. Other VRBPAC members considered 2 months medium follow-up to be sufficient 

to support issuance of an EUA. They felt that rare AEs and waning immunity could be monitored 

by surveillance during vaccine use under an EUA.

Some VRBPAC members were concerned about COVID-19 of any severity as the primary 

efficacy endpoint in current Phase 3 trials, given that there may be limited information on severe 

disease. FDA and some VRBPAC members discussed that primary endpoints were selected 

based on feasibility and prior experience with preventive vaccines. Vaccines are typically 

approved based on data showing prevention of laboratory-confirmed disease, regardless of 

severity. Experience supports that vaccine effectiveness increases with more specific (e.g., 

more severe) case definitions. While analyses to support EUA will include some information on 

severe disease, insisting on an adequately powered analyses of severe disease (which has a 

lower incidence than less severe disease) could delay the availability of an impactful vaccine.
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VRBPAC members expressed concern about clinical trial recruitment of, and accrual of data, in 

the populations most affected by COVID-19 (e.g., racial and ethnic minorities, elderly 

individuals, and individuals with medical comorbidities). FDA reported that published guidance 

and advice to COVID-19 vaccine manufacturers has advocated for inclusion of these 

populations in trials. While there is no regulatory mechanism for mandating trial recruitment, 

vaccine manufacturers have been publicizing enrollment demographics for their trials. This is 

important given that demographic and medical history data from trial participants will be 

considered in regulatory decisions and will be reflected in vaccine labeling to inform HCP and 

vaccine recipients. Vaccine manufacturers have been publicizing enrollment demographics for 

their trials.

There also was discussion regarding considerations for pediatric development and data to 

support use in pediatric populations, particularly with respect to careful evaluation of immunemediated reactions or enhanced disease and immunobridging approaches. There is a need for 

safety assessments that include careful evaluation for immune-mediated reactions or enhanced 

disease (e.g., MIS-C/MIS-A) to support benefit/risk considerations for pediatric enrollment in 

clinical trials and for vaccine authorization or approval in pediatric age groups. Immunobridging 

approaches to infer vaccine effectiveness in pediatric populations will benefit from an evolving 

understanding of natural and vaccine-elicited immunity.

There was broad agreement among VRBPAC members that blinded, placebo-controlled followup in ongoing trials should continue for as long as is feasible, including after an EUA. Concern 

was expressed that if a COVID-19 vaccine were widely deployed under EUA based on limited 

data, it could harm further accrual of critical data from placebo-controlled follow-up. There was 

agreement with the need for robust strategies for vaccine evaluation following licensure or

EUA to complement, and replace once it becomes infeasible, placebo-controlled follow-up.

VRBPAC raised questions about expanded access as an alternative to EUA. FDA explained 

that expanded access is another regulatory mechanism for making investigational products to 

address serious diseases available outside of clinical trials. An expanded access treatment 

protocol could be considered to allow for deployment of a COVID-19 vaccine. It is important to 

note that the benefit/risks considerations are similar to EUA, other considerations such as 

planning and implementation differ from EUA, and an expanded access treatment protocol 

would be conducted under Investigational New Drug (IND) regulations that require informed 

consent, Institutional Review Board (IRB) oversight, and investigator responsibilities for vaccine 

providers.

In terms of next steps, FDA will consider the October 22nd VRBPAC feedback provided in 

continuing to balance the public health goal of safe and effective vaccines to address the 

COVID-19 pandemic and the obligation to ensure that authorization or approval of any COVID19 vaccine complies with regulatory requirements for sufficient safety, effectiveness, and 

manufacturing information to support favorable benefit/risk for vaccine recipients. The VRBPAC

will be reconvened prior to any FDA action to approve or issue an EUA for a COVID-19 vaccine 

to evaluate and discuss data submitted in support of the licensure application/EUA request and 

vote on recommendations as to whether the data support vaccine licensure/proposed use of the 

vaccine under EUA.
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Discussion Points

Dr. Romero asked what the considerations are for unblinding individuals who withdraw from a 

study with regard to whether they receive placebo or vaccine.

Dr. Fink indicated that FDA cannot mandate that any vaccine manufacturer conducting a clinical 

trial unblind or not unblind the trial, or that unblind or not unblind any individual participant. This 

is a matter of ethical and scientific consideration and FDA would like the vaccine manufacturers 

who are conducting a trials to think very carefully about balancing the ethical and scientific 

implications of their decision to unblind.

Dr. Ault asked whether there is a video archive of the VRBPAC meeting that is available to the 

public, and for the expanded access whether there ever has been one of this order of 

magnitude with millions of doses of vaccine.

Dr. Fink indicated that there is a YouTube video recording of the VRBPAC available at the 

following link: https://www.youtube.com/watch?v=1XTiL9rUpkg&feature=youtu.be. There are 

recent examples of expanded access treatment protocols that have been used to provide 

vaccine to thousands of individuals or tens of thousands of individuals. One example was to 

address the meningococcal B disease outbreak on several college campuses prior to FDA 

licensure of the meningococcal group B vaccines. More recently, there has been an expanded 

access protocol for the non-US licensed yellow fever (YF) vaccine Stamaril® due to a shortage 

of the US-licensed YF vaccine YF-VAX® in travel clinics across the US. Having said that, these 

examples pertain to thousands and tens of thousands of vaccine recipients versus millions of 

vaccine recipients. The IND requirements for an expanded access treatment protocol certainly 

would add some complexities and feasibility concerns to using that regulatory mechanism.

Dr. Frey pointed out that safety may be a major driving factor for vaccine hesitancy. There have 

been two very nice examples of pause or halting rules to the studies that have occurred already. 

While this may be novel to the general community, it is actually a positive thing when people 

pause a study or hold a study from further enrollment until there are discussions and people are 

comfortable with the decision-making. She asked whether all of the studies being initiated are 

being scrutinized with the same rigorous standards of safety.

Dr. Fink responded that all of the Phase 3 studies underway have very close oversight from a 

DSMB that regularly reviews safety data and meets on an ad hoc basis to review, discuss, and 

consider whether any change in trial conduct is warranted following a safety signal, such as a 

SAE for which causal relationship to the study vaccine cannot be excluded. Furthermore, some 

studies in addition to the DSMB oversight have pre-specified study pausing rules that are 

triggered based on certain safety events.

Ms. McNally requested additional background on expanded access and how it differs from the 

traditional FDA approval process and the EUA, how a person who wanted to obtain a COVID-19 

vaccine would go about receiving it under expanded access, and whether the Reagan-Udall 

Foundation had any discussions with consumers regarding expanded access during its listening 

session.

Dr. Fink clarified that expanded access is not an approval process. The only approval process is 

licensure. There are several regulatory mechanisms for making an investigational product, 

including investigational vaccines, outside of clinical trials. An EUA is one of those mechanisms 

and it is dependent upon declaration of a public health emergency, such as COVID-19. 
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Expanded access does not require a declaration of a public health emergency, but it does have 

additional requirements for use of the investigational product as compared with an EUA. 

Expanded access is conducted under the IND regulations and can be of a range of sizes 

spanning from just 1 patient to hundreds or thousands of patients depending upon the need and 

data available to support its use. An idea was raised by the VRBPAC about use of COVID-19 

vaccine under expanded access, and the FDA is in the process of considering whether this 

would be an appropriate mechanism for deployment of a COVID vaccine. If that is considered, 

the vaccine manufacturer that has an active IND on file with the FDA would submit a protocol for 

use of the vaccine under expanded access regulations and potentially would work with other 

governing agencies, as was the case with the YF vaccine expanded access experience, to 

organize and implement the expanded access protocol. In terms of the Reagan-Udall 

Foundation, this was a question that was raised during the end of a VRBPAC meeting and he 

did not think that expanded access was addressed by the foundation’s efforts.

Dr. Lee expressed gratitude for all of the work FDA and VRBPAC have done to get them to this 

place. She asked how often FDA anticipates the continuing evaluations of COVID-19 vaccines 

data under an EUA to occur, and whether there have been discussions around potential 

thresholds that would change decisions as data continue to accumulate. In terms of Dr. Fink’s 

mention that an EUA would be contingent on follow-up on safety and effectiveness and 

specifically observational studies that leverage healthcare claims databases, she wondered 

whether there are plans to use Sentinal as one of the options for that versus manufacturer led 

studies.

Dr. Fink responded that continued evaluation of vaccine following deployment under either an 

EUA or licensure would include assessments that are made at scheduled intervals, as well as 

continuous assessments that would include passive reporting as well as mechanisms such as 

rapid-cycle analyses (RCA). He noted that further information would be provided about some of 

these systems later in the day in a presentation on FDA and CDC plans for post-licensure or 

post-authorization surveillance. He clarified that observational studies, including those that 

leverage healthcare claims data, would not necessarily in and of themselves be a requirement 

for an EUA, but the FDA does see these as a very important part of continued follow-up during 

deployment.

Dr. Bernstein expressed appreciation for Dr. Fink’s concise and detailed summary of VRBPAC’s 

ongoing extraordinary and challenging work. Regarding the clinical considerations for EUA and 

why 2 months was chosen, he recalled that Dr. Fink mentioned that the median time was 2 

months. He requested clarity about whether it was the median or at least 2 months for all 

subjects.

Dr. Fink clarified that it is a median. At least half of the subjects will have at least 2 months of 

follow-up. It is expected that a high proportion of enrolled subjects will have at least 1 month of 

follow-up. They do recognize that the trials will continue to enroll, so it will not be feasible to 

demand that all subjects have a certain amount of follow-up to enable regulatory action and 

allow for deployment of the vaccine, especially in the face of very convincing efficacy data. The 

Phase 3 trials that are currently underway have enrolled very large numbers of subjects very 

rapidly, so they do not expect there to be any issues with the proportion of subjects who have 

safety follow-up.

Dr. Sanchez asked what the timeline for FDA approval is after VRBPAC makes a 

recommendation for a vaccine, and whether expanded access would pertain to a vaccine 

studied in persons 18 years of age being expanded to others like the pediatric population.
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Dr. Fink replied that for a vaccine to be made available under expanded access to a large 

number of recipients, there needs to be sufficient data to support a favorable benefit-risk 

determination in a population. He would not envision a scenario in which a vaccine would be 

made available to pediatric populations outside of anything other than a clinical trial without data 

to support favorable benefit-risk in the pediatric population. That would include safety and 

immunogenicity data to at least support effectiveness specifically in pediatric populations of the 

age groups that would be under consideration. Expanded access would not be a mechanism for 

offering vaccine to pediatric populations outside of a clinical trial in the absence of data in 

pediatric populations. Regarding timing, FDA expects EUA reviews and reviews of licensure

applications to be fairly expedited to address the needs of the ongoing pandemic. While he 

could not provide a definitive answer about how many days or weeks between a VRBPAC

meeting and vote that includes recommendations to authorize or include the vaccine and when 

that vaccine is actually made available through FDA action, it will be as expediently and as 

quickly as possible.

NVX-CoV2373 Vaccine Candidate

Filip Dubovsky MD, MPH

Chief Medical Officer

Novavax

Dr. Dubovsky reported on the Novavax NVX-CoV2373 vaccine candidate in terms of vaccine 

design, the non-human primate (NHP) protection study, Phase 1 Day 35 safety and 

immunogenicity data, Phase 2 Dose 1 and Dose 2 reactogenicity data, and plans for Phase 3. 

In terms of the NVX-CoV2373 vaccine design, this is a baculovirus-expressed recombinant 

protein. This is a full-length spike, including transmembrane domain and the usual 2P 

mutations. It self-assembles into a native conformation trimer and is further processed into a 

stable nanoparticle. The adjuvant is saponin-based and is a natural product from the bark of a 

tree. It is processed into purified form into cage-like structures. The antigen and adjuvant are coadministered into a vial of ready-to-use liquid that is stable at 2

0

-8

0 C.

In a protection study sponsored by Operation Warp Speed (OWS) that was conducted at Texas 

Biomedical Research Institute, rhesus macaques were vaccinated at Day 0 and Day 21 and 

were then challenged with 106 wild-type virus at Day 38. Subgenomic RNA was detected on 

Day 2 and Day 4 in the lower airway in the placebo group, which indicates that viral replication 

was ongoing. For both dose levels that were taken into clinical study, no RNA was detected 

indicating that no replication was detected. In the upper airway, replication was seen on days 2, 

4, and 7 in the placebo group. No viral replication was detected in the vaccine groups. This is 

consistent with the other data collected from other NHP studies, as well as in small animals.

Regarding the clinical development plan, the first human Phase 1 study was conducted in 

Australia with 131 subjects 18 to 59 years of age. Based on the results from this study, Novavax 

launched 3 studies. One was a Phase 2 study in the US and Australia in 1288 subjects 18 to 84 

years of age. At the same time, a Phase 2b study was launched in South Africa that was 

recently expanded to 4400 subjects and includes a small human immunodeficiency virus (HIV)-

positive cohort. A 15,000 Phase 3 study was started in the United Kingdom (UK), which includes 

a small sub-study with inactivate influenza vaccine (IIV) co-administration to ensure that there 

are no safety or immunogenicity issues with that. Based on confirmation of the dose and safety 

from the Phase 2 study, Novavax is launching a large Phase 3 study in the US and Mexico with 

over 30,000 individuals.
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The Phase 1 study, which was published in September 2020, is fully enrolled and safety and 

immunogenicity follow-up is ongoing. This is the study of the 131 subjects ages 18 to 59 years 

of age. There were 5 dose groups: placebo, 25 μg with no adjuvant given twice, 25 μg with 

adjuvant given twice, a high-dose adjuvant group, and a group that had 2 doses of 5 μg and 2 

doses of 25 μg given twice. The study sites, investigators, contract research organization 

(CRO), and participants are blinded to individual vaccine/placebo allocation. Day 35 (14 days 

after Dose 2) safety and immunogenicity data, which is the basis of the publication, were 

reviewed by an independent Safety Monitoring Committee (SMC) and submitted to the FDA in 

advance of the Phase 2 study. The Day 35 safety summary for NVX-CoV2373 is consistent with 

previous nanoparticle vaccine with Matrix-M1. No SAEs were identified for NVX-CoV2373.There 

were no AESIs, including potentially immune-mediated medical condition AESIs, and no 

confirmed COVID-19 AESIs. All AEs were mild and moderate and were balanced in active 

arms. 

In terms of the local reactogenicity symptoms collected 7 days after each dose, the majority of 

symptoms were none or mild. Pain and tenderness were the most commonly reported. The 

mean duration was less than 2 days for each of these events. Regarding reactogenicity 

symptoms, the majority of subjects reported none or mild and the mean duration was less than 

2 days for both local and systemic reactogenicity symptoms. There were more systemic

symptoms after Dose 2 versus Dose 1 in the placebo and active groups. The most common 

symptoms reported were headache, fatigue, and myalgia. Once again, the mean duration was 

less than 2 days.

Regarding the anti-spike immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) 

kinetics, after 2 doses delivered on Day 0 and Day 21 there was pretty much no response. After 

the 2 doses with no adjuvant, there was a bump after Dose 2 that was stable throughout the 

observation period. The single dose of adjuvanted vaccine had a nice response after dose 1, 

which stabilized. There was a nice bump after Dose 2 that remained at high levels. From this 

data, Novavax concluded that adjuvanted vaccine is better than non-adjuvanted vaccine and 

furthermore, the 2 doses are superior to a single dose. There is a large dose-sparing effect with 

the adjuvant, because the 5 μg and 25 μg dose groups are comparable.

Regarding the peak immune responses on Day 35 anti-S IgG ELISA and 100% wild-type 

neutralization responses, the 2 dose groups with adjuvants performed quite well in terms of the 

IgG. Convalescent sera was donated by Dr. Pedro A. Piedra of Baylor College of Medicine. This 

is an un-curated panel serum that has the same samples on both the IgG and the neutralization 

responses. Seroconversion of 100% was achieved for IgG and neutralization. Furthermore, in a 

post-hoc analysis IgG was 5-fold to 7-fold higher than for convalescent sera and 3- to 4-fold for 

the neutralization. In addition, the confidence intervals do not overlap. To determine the quality 

of the immune response, a correlation between the neutralization response and the IgG 

response was assessed. For the Baylor convalescent serum, there is a nice correlation between 

IgG and neutralization. This indicates that when people get sick with wild-type infection, they 

generate antibodies and those antibodies neutralize the virus. For the 25 μg group with no 

adjuvant, the correlation breaks down. The adjuvanted dose groups recapitulated the pattern 

seen with wild-type seroconversion and the correlation is tight again. To Novavax, this indicated 

that the Matric-M1 adjuvant is important in generating desired immune responses, with a 

functional immune response against a broad range of antibody titer. This is thought to be 

important from a safety perspective because some people have postulated that antibody does 

not neutralize and may lead to enhanced illness in the future.
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Turning to the intracellular immune response among the placebo, 2-dose 5 μg + Matrix-M, and 

2-dose 25 μg + Matrix-M groups. In the placebo group, the Th1 immune response was flat. 

However, a signal was detected for IL2, IFNg, and TNFa in the other two groups. On the Th2 

cytokines, they probed for IL5 and IL13 and found a small increase in those cytokines. This 

recapitulates what they have seen in small animal models, indicating that this adjuvanted 

platform is capable of generating a Th1-bias immune response. This is consistent with previous 

evaluation of this platform in humans. Looking at polyfunctional CD4 T-cells, there was a 

relatively large proportion of CD4 cells that generate double and triple cytokines for both dose 

groups, especially when compared to the double cytokines for the Th2 analysis. The beginning 

strategy was to look for CD45+ CCR7- CD4 cells. They postulated that this would help with the 

memory response going into the future.

Novavax Phase 1 study conclusions are that reactogenicity and safety profiles are reassuring 

for both the 5 μg and 25 μg dose groups when formulated with Matrix-M1 adjuvant. In terms of 

immunogenicity, the Matrix-M1 adjuvant is required to induce an optimal functional immune 

response, 2 doses of vaccine administered 21 days apart are superior to a single dose, 5 μg 

and 25 μg induce comparable immune responses when formulated with Matrix-M1, and MatrixM1 induces a Th1 biased immune response with high levels of neutralizing antibody. The safety 

and immunogenicity profile of both 5 μg and 25 μg formulated with Matrix-M1 and administered 

on Day 0, 21 is acceptable for further clinical evaluation.

The Phase 2 study of 1288 adults ages 18 to 84 in the US and Australia is fully enrolled, Dose 2 

has been administered, and safety and immunogenicity follow-up is ongoing. The study sites, 

investigators, CRO, and participants are blinded to individual vaccine/placebo allocation. 

Reactogenicity data were reviewed by the SMC and the FDA in advance of the Phase 3 study. 

Regarding local reactogenicity events in 2 Dose adjuvanted groups, pain and tenderness were 

reported most frequently. Increased rates were seen in the adjuvanted groups, especially after 

Dose 2, and reactogenicity was attenuated in adults ≥60 years of age. In terms of local 

reactogenicity events in the 2-dose adjuvanted groups compared to placebo, pain and

tenderness were reported most frequently. Increased rates are seen in adjuvanted groups, 

especially after Dose 2. Reactogenicity events were attenuated in adults >60 years of age, 

which was exactly as expected based on previous experience. The aggregated terms were the 

same as previously (e.g., pain, tenderness, erythema, swelling). In terms of systemic 

reactogenicity events in the 2-dose adjuvanted groups, fatigue, headache, and myalgia were 

reported most frequently. Increased rates were seen in the adjuvanted groups, especially after 

Dose 2. Reactogenicity was attenuated in adults >60 years of age.

The Phase 3 pivotal safety and efficacy study will be conducted in the United States (US) and 

Mexico. This is a randomized, observer-blinded, placebo-controlled study in which participants 

are randomized 2:1 to receive 5 μg + Matrix-M1 vaccine or placebo with 2 doses 0.5ml 

administered on Day 0 and Day 21. The study will include up to 30,000 adults >18 years of age 

across the US and Mexico. The plan is to target at least 25% participants ≥ 65 years of age, at 

least 25% with high-risk co-morbidities, at least 15% black/African Americans, 10% to 20% 

LatinX, and 1% to 2% Native Americans. This is an endpoint-driven study with efficacy 

evaluations at 72, 108, and 144 cases. The primary endpoint is prevention of PCR-confirmed 

mild, moderate, or severe COVID-19 illness occurring 7 days after Dose 2 in baseline 

seronegative adults. Safety follow-up will be conducted through 2 years.
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In summary, the NVX-CoV2373 vaccine candidate is based on the baculovirus/nanoparticle 

platform technology. The safety database includes over 12,100 nanoparticle vaccinees (RSV, 

influenza, Ebola) and over 2,500 nanoparticle vaccinees adjuvanted with Matrix-M1. Vaccine 

presentation will be in 10-dose vials with transportation and storage at 20-8

0 C. The vaccine is 

preservative-free and no admixing or reconstitution is required. A 0.5 ml dose is administered 

intramuscularly 21 days apart. The preliminary safety profile is reassuring with a favorable

reactogenicity profile. A peak immune response is observed 14 days after Dose 2. There is a 

favorable immunologic phenotype, with a robust neutralizing antibody response and 

polyfunctional CD4+ Th1-biased cellular immune response. Efficacy evaluation is ongoing.

Discussion Points

Dr. Romero requested further information about when in the patients’ illness the convalescent 

serum was obtained. In addition, he asked whether the protein is locked into the pre-binding or 

post-binding conformation in the vaccine.

Dr. Dubovsky indicated that the details of the convalescent serum are highlighted in the 

publication. In general, they were a median of 19 days after diagnosis. A small number were 

hospitalized, a small number were asymptomatic, and the vast majority were those who were 

considered to have moderate illness who presented to the emergency department (ED) for care, 

which is where they were recruited. The full-length protein has the stabilizing 2P mutations, 

which locks it into conformation.

Dr. Glenn added that it is in the pre-binding conformation and that the structure was published 

recently in Science.

Dr. Frey asked what the thinking was about the mechanism that would cause the AEs or local 

and systemic events post-vaccination to increase after the second dose, whether both vaccines 

are being given in the same arm, and whether that and/or the use of the adjuvant might play a 

role in this.

Dr. Dubovsky indicated that they recommend, but do not mandate, that the vaccine be given in 

alternate arms so that they can follow the local events. It is very typical for AEs to increase after 

Dose 2 because the immune response also bumps after Dose 2. These local reactogenicity 

events are thought to be related to the immune responses generated with vaccination, which is 

consistent with what has been seen previously and with what was seen in the Novavax Phase 3 

influenza program. The unadjuvanted groups had a lower level of reactogenicity.

Regarding the Phase 3 planned trial, Dr. Szilagyi inquired as to what proportion of the 30,000 

adults will be in the US.

Dr. Dunkle indicated that the estimate is that roughly 10% of the population will be in Mexico 

and 90% will be in the US.

Dr. Lee observed that with all of these vaccines, it seemed that local and systemic reactions 

were extremely common and should be anticipated regardless of COVID vaccine type. She 

recalled that one of Dr. Dubovsky’s slides showed a Grade 4 reaction for which she requested 

further information.

Dr. Dubovsky said that they think the Grade 4 reaction was a fever of >400that occurred in the 

placebo group. They are blinded to the individual, but that is what was indicated by the SMC. 
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Given that saline is not believed to cause high fevers, the current opinion is that this is likely to 

be a data entry error. These are uncleaned live data, so this may be resolved as the cleaning 

progresses. Based on the reactogenicity profile. This is quite favorable as there was not a fever 

signal in the Phase 1 study at all. This is comparable to other licensed vaccines.

Dr. Fryhofer (AMA) observed that on Slides 18 and 19, reactogenicity is noted as being 

attenuated in adults 60 years of age and older and she wondered whether that was an 

indication that this vaccine may not work as well in older individuals.

Dr. Dubovsky indicated that this is a response that is seen with most vaccines. It is known that 

immune responses are attenuated in older adults, given that immunosenescence is part of what 

occurs in life and the impact on efficacy is unknown. The immunogenicity data are not yet 

available to them, but may help to understand what is going on.

Dr. Whitney-Williams (NMA) noticed in the Phase 2 trials that there were 240 HIV+ patients and 

wondered whether there are any plans to include that group in the Phase 3 trials.

Dr. Dubovsky indicated that the 240 HIV+ patients are in the South African study where HIV 

rates are extremely high, so part of the discussion with the regulators and the society groups 

there was the need to include those because that is the population that will be vaccinated in the 

future. Once safety and immunogenicity in that population are understood, they will be better 

positioned to make future plans. Those cohorts are being vaccinated currently, so there should 

be data soon.

Dr. Dunkle added that the Phase 3 trial does not exclude stable HIV-infected individuals.

Dr. Ault asked whether Novavax has any plans for Phase 2 or 3 trial in pregnancy. They 

recently published results in the New England Journal of Medicine (NEJM) for a respiratory 

syncytial virus (RSV) vaccine that uses the same platform in pregnant women.

Dr. Dubovsky indicated that they are in discussions with regulatory agencies about how to best 

go forward. The data that were published were not with the Matrix adjuvant, so there are other 

considerations that need to be assessed. They are concluding their development and 

reproductive toxicology (DART) study and will base decisions on that.

Janssen Investigational COVID-19 Vaccine Program

Jerald Sadoff, MD 

Lead Clinical Investigator

Senior Advisor, Clinical Development

Janssen Infectious Diseases and Vaccines

Dr. Sadoff presented an update on Janssen’s investigational COVID-19 vaccine program. The 

foundation of Janssen’s investigational COVID-19 vaccine is its proprietary AdVac® Technology 

Platform. Janssen uses a replication incompetent human adenovirus 26 (Ad26), which 

expresses the target antigen. They have taken out a region of the virus so that it cannot 

replicate. It invades the cells and makes the transgene and its own antigens, but it cannot 

assemble them into a replicating virus. The antigen is not on the surface of the virus. It is only 

on the surface of the cells that the virus enters and is membrane bound. This vaccine has 

induced very good humoral and cellular antibody responses against structural proteins with 

neutralizing activity and/or other unique functionalities, as well as cellular CD4-T cell responses 

with a Th1 signature and CD8 T-cell responses. There has been no sign of vaccine-associated 

enhanced respiratory disease (ERD) in pre-clinical models after breakthrough infection. Janssen 
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has extensive clinical experience with its Ad26-based vaccines, with over 110,000 participants 

vaccinated. These Ad26-based vaccines have shown to have a favorable safety and tolerability 

profile in the populations studied to date. On July 1, 2020, Johnson & Johnson received 

approval from the European Medicines Agency (EMA) for Janssen’s Ad26-based preventive 

Ebola vaccine.

Janssen took the approach of looking at a number of vaccine constructs because of instability 

problems that were noted before, and of looking at theoretical considerations. Janssen has had 

a lot of experience with its RSV and HIV programs on how to construct stable expression 

vectors, so they assessed stabilization, signal peptide, expression of antigen, manufacturability 

of vaccine, and immunogenicity in pre-clinical animal models. Based on that, they were able to 

find a vaccine candidate that was clearly superior in terms of its immunogenicity and the other 

considerations, Ad26.COV2.S. It encodes a full length membrane-bound S-protein with 

stabilization mutations and a native initial signal sequence. After a single dose of Ad26.COV2.S, 

they were able to show protection in the lower and upper respiratory tract of SARS-CoV-2 

challenged NHP. In other data, they have done down dosing studies and have shown that even 

when the vaccine is reduced, they have still been able to get substantial protection. This leads 

to the belief that the immunogenicity achieved will be protective.

Based on that, Janssen began a Phase 1/2a study, COV1001, to assess the safety, 

reactogenicity, and immunogenicity of this investigational vaccine in healthy adults 18 to 55 

years of age (Cohort 1; N=400) and adults 65 years of age and older (Cohort 3; N=375) at 2 

different dose levels (5x1010 viral particles and 1x1011 viral particles) administered as a 1 dose 

or 2 dose regimen. They have the data on the 1 dose regimen and are currently accumulating 

the data on the 2 dose, so Dr. Sadoff focused mainly on the data after 1 dose. Cohort 2 is 

comprised of 270 participants 18 to 55 years of age in whom duration of the immune response, 

the ability to boost at various times if necessary, and anamnestic responses will be examined. 

There were very good seroconversion rates with the ELISA at 99% at a slightly lower dose and 

a similar 99% with very reasonable geometric mean titers (GMTs) for neutralizing antibody 

levels. There were very few differences between the elderly and younger adults in terms of 

immune response, and there was a rise between Day 15 and Day 29. The wild-type virus 

neutralizing antibodies (wtVNA) showed very good response rates as well of 92% at both doses, 

with a similar response in the elderly with comparable GMTs and overlaps. The GMTs rose 

quicker for the neutralizing antibodies, with a very good response at Day 14. Therefore, in the 

Phase 3 trial, they will start counting cases 2 weeks after single dose immunization. From this 

data, it is clear that there are no differences in immunogenicity between the younger and elderly 

groups in terms of ELISA or wtVNA, and they seem to be at the flat part of the dose response 

curve, which allows them to pick the lower dose as a single dose regimen going forward.

There was also a very good T-cell response in both groups of 76% and 83% for the 2 different 

doses in the younger age group and slightly lower in the older age group at 60% and 67%. 

These are Th1 responses measured by IFNg and/or IL-2. Only 2 individuals responded with Th2 

and the rest were completely negative. The ratio in those 2 between the Th1 and Th2 was 28.9 

and 20.2. Clearly, a Th1-type response dominated in both younger adults and the elderly with 

practically no Th2 response at all. With this vector, they also are able to induce fairly high 

percentages of CD8 T-cell functional responses that express gamma interferon and may play a 

role in protection as well, although they have yet to prove that. The CD8 responses are 51% 

and 65% in the younger age group and slightly lower at 36% and 24% in the older age group, 

which reflects a fairly high percentage of CD8 T-cell responses. They have a stringent test for 

discriminating between background and the higher responses compared to some other 

techniques that have been used, so these GMTs might be somewhat lower than normally seen.
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This vaccine does cause some systemic AEs based on blinded data between the groups. 

Among the 402 subjects in Cohort 1, approximately 50% to 60% overall had systemic AEs. All 

were transient and lasted no more than 1 to 2 days before resolving completely. In terms of 

pyrexia, there was some fever in Cohort 1 that was considered Grade 3. These were very 

responsive to anti-pyrectics and they did not judge that any-pyrectics needed to be used 

prophylactically. In Cohort 3, there were far fewer systemic reactions and fever rates were very 

low with no Grade 3 fevers. Once again, reactogenicity was much lower in the older cohort than 

the younger cohort but the immunogenicity seemed comparable. Based on this, Janssen 

designed a Phase 3 efficacy trial, COV3001. 

COV3001 is a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study 

evaluating the efficacy and safety of Ad26.COV2.S for the prevention of SARS-CoV-2-mediated 

COVID-19. The primary endpoint is moderate to severe illness. The study is being conducted in 

Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the US with a target of about 

50% of the subjects being in the US. From the beginning, there has been a plan to enroll a 

diverse population. This study does not have a fixed stop interim analysis. A continuous, 

sequential monitoring technique is used for safety and efficacy instead. This study is being 

conducted in healthy adults 18 years of age and above. The estimated enrollment is 60,000 and 

participants will receive a single dose of 5x1010 of Ad26.COV2.S or placebo. The endpoints are 

the number of participants with first occurrence of molecularly confirmed moderate to severe 

COVID-19 with seronegative status. The hope is to have a planned follow-up of up to 2 years. 

Janssen will attempt to follow participants as long as possible regardless of what happens, but 

there are plans for how analytically to deal with dropouts and people who want to receive the 

vaccine or knowing whether they received vaccine or placebo.

In terms of the Phase 3 pause, pauses are not uncommon in these types of studies. Janssen is 

dedicated to the safety of its participants. This particular pause was in an individual who had a 

safety event and was subject to automatic stopping or pausing rules. This was judged by the 

DSMB to be appropriate. Janssen evaluated this case extensively with the DSMB and outside 

experts. It is a complicated case that had multiple potential causes, which have not completely 

been determined. However, it is believed that there is no relationship between vaccination and 

the event. In consultation with the FDA, the DSMB agreed to restart the trials. The trial has 

restarted in the US and enrollment is continuing. Janssen plans to disclose the clinical data for 

its COVID-19 trials once those data are presented or published at prespecified milestones, and 

will proactively disclose the regulated trial holds as requested by health authorities. Janssen is 

planning to deploy this vaccine widely once a signal is reached and there is approval from the 

FDA and other regulatory agencies. The plan is to put it in a 2R glass vial that has 5 doses per 

vial, 10 doses per carton, and 8 cartons per shipper. The anticipated storage conditions under 

an EUA would be storage by Janssen at -200 C for up to 2 years, in end-user storage at 20to 80

C for up to 3 months, and after first use at 20to 80 C for up to 6 hours. More data are evolving 

with the hope that there will be much longer stability of up to 9 months or longer like Janssen’s 

other vaccines in this platform.

Discussion Points

To respond to Dr. Ault’s question regarding pregnancy trials, Dr. Sadoff reported that Janssen is 

currently conducting studies in its Ebola program in pregnant women. As soon as the toxicology 

data are available within the next month, they will be planning to start studies in pregnant 

women because they understand how important it is in this age group to be able to vaccinate.
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Dr. Poehling recalled that the data on the AE profile had both doses combined, but she 

wondered whether there was a plan to assess those data by the dose. She also requested that 

Dr. Sadoff expand on the discussion that the vast majority of the CD4 T-cells were in the Th1 

biased response with the exception of the 1 subject in each age group who had a ratio of 

Th1/Th2.

Dr. Sadoff said that on the Th1/Th2, they feel that the Th1 bias in the animals models may be 

strongly indicative of not being the type of pattern seen with ERD based on vaccine. That in 

combination with antibody is a telling signal of this. If there is a Th2 response with a 

predominantly Th1-type response in that individual in combination with neutralizing antibody, 

seems to be the type of immune response that is not associated enhanced disease. In terms of 

the AE profile, the FDA and other regulatory agencies have seen unblinded data on the limited 

number of individuals and there is a trend for less reactogenicity in the lower dose group. The 

plan is to publish these data after they have the second dose safety data from the 2-dose 

regimen of the ongoing study. They would then publish the safety data in the two groups in 

terms of the lower and higher dose, which should be available fairly soon. They want to maintain 

blinding in the Phase 1 study until they have looked at the safety data in the elderly age group at 

the second dose. 

Dr. Szilagyi was interested that the primary outcome in the Phase 3 study is moderate to severe 

disease in healthy adults and wondered whether that meant that adults with diabetes, cardiac 

disease, lung disease, obesity, et cetera are excluded. In addition, he asked what percentage of 

enrollees would be in the US.

Dr. Sadoff indicated that the primary endpoint of the trial is moderate to severe disease. In the 

safety run in, comorbidities associated with accelerated disease are excluded. That will include 

the first 2000 participants in the younger age group and the first 2000 in the older age group. 

They can have other comorbidities. After those first 4000 are enrolled, in each age group 

separately, the plan is to enroll individuals with all of the comorbidities associated with 

accelerated disease. Diabetes, hypertension, et cetera will be a major part of the trial. The 

moderate definition was picked primarily based on their experience with vaccines against 

respiratory diseases, with vaccines having a better chance of working with more severe disease 

and a lower level of protection against mild upper respiratory disease. This provides two 

reasons to go from a moderate to severe endpoint, including a better chance for the vaccine to 

show its true effectiveness and a more clinically relevant endpoint to some extent. They are 

looking very carefully at mild disease. They have built 3, 6, and 12 month blood draws into the 

trial to look for seroconversion against the virus. This is an assay that does not include the S 

protein so that it is not interfered with by the vaccine to look for asymptomatic disease, so they 

should have a very good understanding of the vaccine’s effectiveness against asymptomatic 

and all other forms of the disease. Furthermore, they are monitoring every case that they find by 

collecting nasal swabs and saliva samples every other day until two consecutive samples are 

negative. Then, they will compare the control to the vaccine group to determine whether the 

vaccine has an effect on the viral load even in the breakthrough cases. They are doing this 

because in a recent RSV challenge study conducted, they showed very good effectiveness of 

the vaccine in the upper respiratory tract to prevent infections. In the breakthrough cases, the 

number of viral particles and live virus in the recipients of the vaccine were dramatically lower 

than in the non-vaccine group. So, there may be an effect on transmission even if there is not 

complete protection in the upper respiratory tract. Therefore, they are measuring that as well. At 

least 50% of participants are intended to be from the US.
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Dr. Kimberlin (AAP Red Book) commended the manufacturers on their rapid yet deliberative 

approaches to this unprecedented situation and the need for a safe and effective vaccine. 

Toward that end, transparency as they all have done with their Phase 3 protocols is critically 

important. He expressed interest in knowing more about the subject halt for the Phase 3 study 

that was discussed in very broad terms. He thought everyone would benefit more by knowing 

what system that was related to.

Dr. Sadoff indicated that they have been very transparent about the case with the regulatory 

agencies, IRBs, and investigators. They have been reluctant to discuss the case in public 

because the study is still blinded and there is a matter of patient confidentiality that they are very 

concerned about. At this point, they have not felt it appropriate to disclose the nature of the AE 

other than to mention that it has been fully discussed with independent consultants, the IRBs, 

the IBMC, and the regulatory agencies, including the FDA, and that have all agreed that the 

study should go forward. They will be disclosing as much information as they can in a timely 

manner when it is appropriate, but fully respecting the patient’s confidentiality. That is basically 

why they have not given information that might lead to speculation, which is not warranted 

based on the data they have.

Dr. Fryhofer (AMA) asked whether the diversity data of the trial participants will be posted on the 

website. She expressed the hope that Janssen understands how important transparency is in 

terms of developing vaccine confidence and asked if they could share the age of the person 

who had the safety event. In terms of the Th1 T-cell response and vaccine enhanced respiratory 

problems, she asked whether they are looking at thrombotic or inflammatory responses in the 

study.

Dr. Sadoff indicated that they will be posting the diversity figures just like the other companies 

and will be very transparent about that. They agree that transparency is very important for many 

reasons, so they will disclose as much information as possible that does not in any way violate 

patient confidentiality. This was a young individual in the younger age group. Thrombotic events 

are not AESI, but they are assessing this very closely. Every individual in the trial receives an 

electronic device, pulse oximeter, and thermometer. There is a broad trigger for symptoms that 

may be anything related to COVID. Patients can immediately begin taking their temperature and 

oxygenation levels, even for the mildest cases. Any thrombotic event is considered a trigger to 

immediately call the site or their own doctor. That is electronically triggered automatically when 

something similar to a thrombotic event occurs. 

Dr. Lee noted that in comparison to the convalescent sera, the slide showing the ELISA and the 

neutralizing antibody assays looked somewhat lower and she wondered whether that was 

thought to be meaningful in any way. Secondly, she asked how convalescent sera could be 

standardized and if this is comparable across trials since assumably these all come from 

different lots and locations.

Dr. Sadoff said that while he did not go into the technical details, on that slide there was a 

dotted line across the top for the neutralizing antibody. That line represents the upper level 

quantitation. That means that there were quite a few sera in both the younger and elderly group

that could have higher dilutions that had not been measured yet. The GMTs will go up 

somewhat, but he would say that they were slightly lower than the convalescent sera. He 

strongly agreed with the need standardization of these sera so that they can directly look from a 

comparison point of view to learn how relevant it is. They have looked at several panels and 

have different results from different panels. One was higher and another was lower, so they 

think that standardization would be useful for the field and would encourage that to occur. As far
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as implications, they think that the convalescent sera is probably adequate. It is not yet known 

how difficult this virus is to neutralize and whether extremely high titers or low titers are needed.

Given the abbreviated timeline, Ms. McNally asked whether Dr. Sadoff could be more specific 

about the timely manner for disclosing more information about the unexplained illness in the 

study pause.

Dr. Sadoff indicated that they will be disclosing the database on the dose ranging. The blinded 

data on doses versus safety and immunogenicity would be done fairly shortly when the second 

dose evaluations are completed. In terms of evaluating more information about the pause and 

the case, that will be determined based on confidentiality and unblinding considerations. It may 

turn out that they will be able to disclose more information in a short period of time, depending 

on how the case evolves and also whether confidentiality issues may not be an issue at some 

point.

Dr. O’Leary (PIDS) echoed the sentiments that confidence in these vaccines is so crucially 

important, transparency takes on extra weight in the current environment. While the 

confidentiality concerns may very well be justified, from the perspective of the public in a trial of 

thousands of people, that will be hard to accept. Therefore, he encouraged them to be as 

transparent as possible.

Dr. Sadoff said that they understand that the dynamic between the two is a very delicate 

balance that has to be judged and continuously judged. They will take the comments into 

consideration and appreciate them. There has been some discussion about pediatric trials. 

Their view is that they would like to start pediatric trials in at least 12 to 18 year olds as soon as 

possible. Based on the safety and immunogenicity seen in that age group, they will move into 

the younger age groups as well because they think the pediatric population is very important to 

consider for vaccination, with safety being a very important consideration.

Dr. Kimberlin (AAP Red Book) asked how many subjects were enrolled before the halting event 

occurred in one subject.

Dr. Sadoff said he would have to acquire that number and report back. The trial just began in 

September, so there are not yet many thousands of subjects.

Dr. Maldonado (AAP) voiced very strong support for transparency, especially with regard to 

pediatrics. While she recognized that children under 18 years of age are considered to be in tier 

3, it is critical during this time given the sentiments around vaccines in general and the 

downstream impact of vaccine confidence in all immunizations that these particular trials will 

have on pediatric populations and the ability to control preventable infectious diseases. Families 

want to make sure that their healthy children are going to be protected not only from this 

devastating illness, but also from others. Every single family and pediatrician must be confident 

in this vaccine. While it is known that the populations with highest risk are not children, in order 

to reduce the ultimate goal of reducing transmission and achieving herd immunity, pediatric 

populations must be engaged. This is a critical group. Pediatricians know how to vaccinate. 

They do this all of the time and they depend upon the AAP and CDC for their guidance and that 

guidance is always dependent upon transparency.

Dr. Sadoff stressed that Janssen plans studies in children as soon as possible and very 

carefully in terms of safety. 
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COVID-19 Vaccine Implementation Planning Update

Janell Routh, MD, MHS CAPT, USPHS

Deputy, Implementation Planning Unit Vaccine Task Force

National Center for Immunization & Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Routh provided an update on vaccine implementation planning. She reminded everyone that 

the overarching objectives for the COVID-19 vaccination program are to: 1) ensure the safety 

and effectiveness of COVID-19 vaccines in order to build and maintain confidence in this 

program; 2) reduce mortality, morbidity, and incidence of COVID-19 disease; 3) help minimize

disruption to society and the economy, including maintaining healthcare capacity; and 4) ensure 

equity in vaccine allocation and distribution in a multisectoral fashion. These objectives help to 

frame the work in which CDC is engaging with its jurisdictional partners in order to confirm their 

readiness to receive and administer vaccine product. These principles guide the planning efforts 

and push everyone toward readiness for the implementation of this program.

She shared an illustrative scenario for planning purposes, explaining that it would be adapted 

based on clinical and manufacturing information and that distribution would adjust as the volume 

of vaccine doses increases. Final prioritization will be decided by ACIP. On September 16, 

2020, CDC published the “COVID-19 Vaccination Program Interim Playbook for Jurisdiction 

Operations.” All 64 jurisdictions returned a COVID-19 vaccination plan and federal agency plans

have been received from the Veteran’s Affairs (VA), Indian Health Services (IHS), Department 

of Defense (DoD), Department of State (DOS), and the Bureau of Prisons (BOP). The plans 

were reviewed by at least three CDC subject matter experts (SMEs) and feedback was 

returned. Information about plans will be updated on the CDC website.

Not surprisingly, jurisdictional plans showed strengths and challenges. In terms of strengths, 

jurisdictions have organized their planning around the allocation phasing assumptions, set out 

clear plans to train and equip providers on the Vaccine Adverse Event Reporting System 

(VAERS), laid out deep operational details for second dose reminders (e.g., text, email, 

automated call) some of which are already live. Challenges include ensuring that public health 

messaging plans and expedited procedures for emergency communications are in place, that all 

data systems to administer and track vaccine have been identified, and that additional planning 

is in place to ensure equitable access to vaccine distribution in later phases.

In terms of next steps for vaccine implementation now that the plans have been returned and 

feedback incorporated, the goal is for jurisdictions to be ready by November 15, 2020 based on 

projections of vaccine availability. This includes having signed Data Use Agreements (DUAs) to 

ensure tracking of uptake, identifying pockets of low vaccination, identifying and intervening in 

coverage disparities, and allocating vaccine product. By this time, vaccination provider sites

should be identified and enrolled, especially of those sites that can administer vaccine product 

to Phase 1 populations and that can position ultra-cold product after possible EUA. Jurisdictions 

are to confirm that the selected facilities are enrolled in the Vaccine Tracking System (VTrckS)

to order and receive product. State capacity will be augmented through federal pharmacy 

partnerships to support vaccination in long-term care facilities (LTCFs). Microplanning will 

continue to ensure readiness across various scenarios. Pharmacies can help to increase 

access to vaccines. Almost 90% of Americans live within a 10-mile radius of a pharmacy.
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For Phase 2, a general pharmacy partnership strategy has been developed for the COVID-19 

Vaccine Program. Once there is an adequate supply of COVID-19 vaccine to support broader

vaccination efforts, it will be important to help jurisdictions increase access to COVID-19 vaccine 

for the general population in Phase 2. The federal government is partnering with pharmacies 

nationwide to increase access to vaccine. Partners who enroll in this program will receive a 

direct allocation of COVID-19 vaccine when supply is sufficient and vaccine is recommended for 

use beyond the initial critical populations. Pharmacy partners under consideration include 

national chains, large regional chains, and networks of independent pharmacies and regional 

chains. Of the eligible US pharmacies, 55% have already enrolled. A list of partners will be 

shared with jurisdictions shortly. Leveraging all resources and public and private partners will 

allow for the successful administration of the COVID-19 vaccination program. The CDC vaccine 

website contains information and resources for the general public, providers, and jurisdictions.

Vaccinate with Confidence for COVID-19 Vaccines

CAPT Amanda Cohn, MD

Chief Medical Officer (Acting), Office of Vaccine Policy, Preparedness, and Global Health

Office of the Director, National Center for Immunization & Respiratory Diseases

Centers for Disease Control and Prevention

Executive Secretary, Advisory Committee on Immunization Practices

Dr. Cohn provided an update on CDC’s Vaccine with Confidence strategy. There has been a 

considerable decline in COVID-19 vaccine acceptability in the past 4 months due to concerns 

about side effects, efficacy, risk perception/need for vaccine, and associated costs. Attributes 

that make COVID-19 vaccine more acceptable include HCP saying that the vaccine is safe, 

making the vaccine free of cost, having high potential for the vaccine to help get people back to 

work and school, and ensuring easy access to the vaccine. Individuals across the demand 

continuum will have concerns, which are understandable and must be addressed with empathy 

and transparency. Concerns among HCP is a risk for overall vaccine confidence, given that 

HCP are the most trusted source for health information. Various communities will have unique 

experiences informing COVID-19 vaccine perceptions, which can be addressed through 

engagement with community organizations and leaders to communicate clear and accurate 

information about COVID-19 vaccines.

Vaccinate with Confidence is a national strategy to reinforce confidence in COVID-19 vaccines

with the key priorities to protect communities, empower families, and stop myths. The objectives 

are to: 1) regularly share clear and accurate COVID-19 vaccine information and take

visible actions to build trust in the vaccine, the vaccinator, and the system; 2) promote 

confidence among HCP in their decision to get vaccinated and to recommend vaccination to 

their patients; and 3) engage communities in a sustainable, equitable and inclusive way—using 

two-way communication to listen, increase collaboration, and build trust in COVID-19 vaccine. 

There are tactics, sample products, and tools for each objective.

Vaccinate with Confidence is not an advertising, marketing, or communications campaign. 

Instead, it is a cohesive framework to support health departments, healthcare providers,

immunization partners, and community partners and leaders’ promotion of COVID-19 vaccines. 

This national strategy includes evidence-based content to amplify messages that enable an 

individual to make the decision to vaccinate, which is critical to ensuring that safe and effective 

COVID-19 vaccines can help control and reduce the impact of this pandemic. CDC is seeking 

feedback from a wide range of partners on the Vaccinate with Confidence for COVID-19 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Vaccines Framework, and will send a short email to share with colleagues to review and provide 

input in addition to the input collected during this meeting.

Discussion Points (Routh & Cohn)

❑ From the broader healthcare perspective, there has been under-investment in vaccine 

implementation planning: 

→ ACIP expressed hope that going forward, CDC and others would be fully supported 

in this endeavor versus adding one more task to the already complex delivery 

system. Funding investments in this type of work is critical.

→ Assuming that COVID-19 vaccine implementation will ramp up from January through 

March with more to do in April, there is concern that the Coronavirus Aid, Relief, and 

Economic Security (CARES) Act Provider Relief Fund that has paid for increases in 

the workforce will run out on December 31, 2020. Consideration must be given to 

what can be done at the state and local health department levels in terms of 

implementing COVID-19 vaccine activities if additional funding is not forthcoming.

→ State and local jurisdiction funds are likely to depend upon local legislatures.

→ There are major deficits in the healthcare delivery system, especially in primary care. 

More targeted support is needed for private practice to continue to deliver all types of 

vaccines.

→ Implementation is where actual impact will happen or not. The same level of 

investment that has been made in vaccine development must be made in 

implementation. There must be national investment. While state support is important, 

federal support is crucial. This cannot be done in everyone’s “free time.” In order for 

implementation to be successful, the federal government must make a significant 

investment.

→ Typically, ACIP approves a vaccine and then leaves implementation up to the states. 

This situation offers a good opportunity for ACIP to permanently change the model 

by which it operates.

❑ The planning process for delivering vaccines to children will be very different from the 

process for adults, given that the majority of children’s vaccines are given in pediatric offices 

and many providers do no participate in Vaccines for Children (VFC). Although children are 

likely to be the last in line and pediatric trials are just beginning, planning for delivery to 

children should be done now.

❑ Much can be learned from influenza vaccines (e.g., make vaccination simple and easy, use 

reminders, use already planned visits, fund and support these activities where possible).

❑ While each of the 64 jurisdictions presented creative and unique plans based on their own 

jurisdictional issues that should be beneficial, it is crucial to keep in mind that different 

communities have different issues regarding vaccine acceptance, such as communities of 

color and Tribes:

→ Many communities of color experience issues due to ongoing systemic racism and 

disparities that lead them to have distrust. Therefore, it is critical to work with 

communities of color to engender and earn trust, while being completely up front. It is 

particularly important to engage with community-based organizations (CBOs) and 

doctors of color who practice in these communities.
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→ Concerns from Tribes focus on the very compressed timeline that does not allow for 

the IHS to engage in meaningful conversations. Tribes are being asked to make 

decisions about distribution, prioritization, et cetera without having all of the 

information they feel they need. Despite efforts to address these concerns, issues 

remain about how vaccine will be distributed, ordered, and reported on. Many Tribes 

want to be ready, but they are challenged by whether to choose distribution through 

states or through IHS. It is preferable to have both doors open.

❑ Confidence in receiving COVID-19 vaccine must be increased within the HCP workforce. If 

the group they trust the most will not take these vaccines, patients are not going to want to 

take them either:

→ Lack of confidence among HCPs can be boosted by providing them with language 

that helps them answer questions about such topics as how vaccine was licensed so 

quickly when other vaccines take 15 years. 

→ HCPs are constantly being asked whether they trust COVID-19 vaccines, to which 

some respond that when CDC and FDA say they trust it, HCPs will recommend it.

→ Given that HCPs are the most trusted vaccine administrators, perhaps language 

should be included that permits them to be vaccinated in the first phase. Many 

private practitioners do not have access to personal protective equipment (PPE), yet 

they are the ones on the frontline to whom patients turn.

❑ Workers Compensation must be addressed.

❑ CDC is producing content that will be shared with partners in the near future. It is imperative 

for partners, HCP organizations, and community partners to amplify these messages as this 

will be much more powerful than messages coming just from CDC or HHS. 

❑ Private practitioners have expressed interest in being able to order and receive vaccines 

through VTrckS. CDC encouraged them to speak with their local jurisdictions to enroll as 

providers in VTrckS, through which they can also order/receive vaccine.

❑ The two components of DUAs, identified and de-identified data, need to be separated in 

order to move quickly as vaccines become available.

❑ Many COVID-19 vaccines will require 2 doses, making it critical to be able to ascertain what 

vaccine was given for Dose 1 and when Dose 2 is needed:

→ Efforts to determine this information with existing Immunization Information Systems 

(IIS) can be frustrating. 

→ State IIS for adults have lagged behind.

→ Ensuring that people received both doses and the correct products is very important 

to CDC, so immunization cards will accompany ancillary kits in order to have both IIS 

records and paper and pen solutions.
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CBER Plans for Monitoring COVID-19 Vaccine Safety and Effectiveness

Steve Anderson, PhD, MPP

Director, Office of Biostatistics & Epidemiology

Center for Biologics Evaluation and Research

Food and Drug Administration

Dr. Anderson reviewed FDA’s active post-licensure safety surveillance systems and Center for 

Biologics Evaluation and Research (CBER) plans for monitoring COVID-19 vaccine safety and

effectiveness. FDA and CDC have weekly and bi-weekly coordination meetings on VAERS and 

pharmacovigilance activities between the CBER Office of Biostatistics and Epidemiology (OBE)

and the OBE Division of Epidemiology (DE) and the CDC Immunization Safety Office (ISO). 

CBER DE physicians will be reviewing the SAE reports from VAERS for COVID-19 vaccines. 

This will include review of individual reports, death reports, aggregate analyses, case-series, et

cetera. FDA will utilize statistical data-mining methods to detect disproportional reporting of 

specific vaccine AE combinations to identify AEs that are more frequently reported.

COVID-19 vaccine monitoring data considerations include rapid data access for near real time 

surveillance, large databases comprised of tens of millions of patients for evaluating vaccine 

rare SAEs, data representing the integrated care spectrum (e.g., outpatient, physician, inpatient, 

et cetera), high quality data to assess and confirm potential AEs or safety concerns for COVID19 vaccines, and data with significant clinical detail or medical chart access. The FDA Biologics 

Effectiveness and Safety (BEST) system includes several partners, represents a variety of 

healthcare settings, and has an emphasis on inclusion of electronic health records (EHR), some 

claims, and linked claims-EHR data. BEST is a modern surveillance system that is able to

perform a diversity of queries and studies. There has been an ongoing FDA-CMS partnership 

on vaccine safety since 2002. CMS data cover a very large population of approximately 55 

million elderly US beneficiaries ≥65 years of age. Given that over 92% of US elderly individuals 

use Medicare, this database represents the elderly population and not a sample. It represents a 

variety of healthcare settings and consists of claims data with access to medical charts. Not all 

claims and EHR data systems can be used to address a vaccine safety or effectiveness 

regulatory question, and each data system has its limitations in terms of the populations, 

healthcare settings, clinical detail, necessary parameters, data lag, exposures, and outcomes 

that are captured.

In terms of COVID-19 vaccine safety surveillance planning, the FDA will utilize RCA to monitor 

10 to 20 safety outcomes of interest to be determined based on: 1) pre-market review of 

sponsor safety data submitted to the FDA; 2) coordination with federal partners, international 

regulatory partners and organizations, academic experts, and others; and 3) literature and 

regulatory experience with similar vaccines, novel vaccine platforms, and using other relevant 

data. Dr. Anderson shared the following draft working list of possible AE outcomes:

• Guillain-Barré syndrome

• Acute disseminated encephalomyelitis

• Transverse myelitis/encephalitis/ myelitis/ 

encephalomyelitis/meningoencephalitis/meningitis 

/encepholapathy

• Convulsions/seizures

• Stroke

• Narcolepsy and cataplexy

• Anaphylaxis

• Acute myocardial infarction

• Myocarditis/pericarditis

• Autoimmune disease

• Deaths

• Pregnancy and birth outcomes

• Other acute demyelinating diseases

• Non-anaphylactic allergic reactions

• Thrombocytopenia

• Disseminated intravascular coagulation

• Venous thromboembolism

• Arthritis and arthralgia/joint pain

• Kawasaki disease

• Multisystem Inflammatory Syndrome in Children

• Vaccine enhanced disease
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In terms of experience, the FDA has conducted near real-time surveillance for annual influenza

vaccine and Guillain-Barre Syndrome (GBS) since 2007 and Sentinel rapid surveillance for the 

2017-2018 seasonal influenza vaccine to evaluate 6 health outcomes of interest.

Epidemiological analyses will require the capability to resolve potential safety signals identified 

from near real-time surveillance, TreeScan® signal detection efforts, and other sources. This 

may involve rapid queries and small epidemiological studies and/or larger self-controlled, 

cohort, comprehensive protocol-based studies. There may be limited information available at 

the time of licensure on the level and duration of effectiveness. Manufacturers may conduct 

certain COVID-19 vaccine effectiveness (VE) post-licensure studies. FDA may conduct COVID19 general effectiveness studies, including subpopulations of interest; duration of protection 

studies; or other types of studies. FDA is coordinating COVID-19 VE efforts with the 

CDC/NCIRD through monthly and bi-monthly meetings.

The FDA, CMS, and CDC have extensive experience with the data and methods needed to

conduct VE studies having produced several VE and relative VE for influenza and zoster 

vaccines and duration of effectiveness analysis of Zostavax® vaccine. Dr. Anderson 

emphasized that COVID-19 vaccine monitoring is a large US government effort that involves 

regular meetings, planned sharing of protocols, discussion of safety and effectiveness outcomes 

of interest, and coordinated planning and conduct of surveillance activities between the FDA, 

CDC, CMS, VA, and DoD.

Post-Authorization Safety Monitoring Plans

Tom Shimabukuro, MD, MPH, MBA

Immunization Safety Office

Vaccine Safety Team

CDC COVID-19 Vaccine Planning Unit (VPU)

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Dr. Shimabukuro provided an overview and continued the discussion of post-authorization/postlicensure safety monitoring of COVID-19 vaccines. He reported that ACIP has established a 

COVID-19 Vaccine Safety Technical Sub-Group (VaST) to advise CDC and other federal 

partners on planning and preparation for post-authorization/post-licensure safety monitoring of 

COVID-19 vaccines and independently review and evaluate safety data. Postauthorization/post-licensure safety data on COVID-19 vaccines will be presented regularly

during public ACIP meetings. During this meeting, he provided updates on Vaccine Safety 

Datalink (VSD) monitoring, the CISA Project clinical consult service, HCP’s role in reporting AEs 

to VAERS, and HCP’s role in facilitating patient enrollment into the V-SAFE smartphone-based 

active surveillance system. VSD planned monitoring and evaluation for COVID-19 vaccine 

safety includes: 1) near real-time sequential monitoring using RCA; 2) monitoring for vaccinemediated enhanced disease (VMED); 3) studies to evaluate COVID-19 vaccine safety during 

pregnancy, including fetal death and infant outcomes; tree-temporal scan data mining; and 4) a 

variety of projects to assess changes in healthcare utilization during COVID-19 and impact on 

AE monitoring; utility of smartphone technology to enhance vaccine safety monitoring; 

multisystem inflammatory syndrome in children and adults (MIS-C and MIS-A) as vaccine AEs; 

safety in an expanded underserved VSD population; and knowledge, attitudes, and beliefs 

around acceptance/refusal of COVID-19 vaccination.
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CISA Project clinical consult service supports US HCP and health departments on complex

clinical vaccine safety questions and assists with evaluations of patients with AEs after receiving 

COVID-19 vaccine or in making clinical decisions about administering COVID-19 vaccine to a 

person who may be at increased risk for an AE. Advice from CDC and the CISA Project is 

meant to assist in decision-making versus providing direct patient management and is available 

to US healthcare providers and health departments by contacting CDC-INFO. HCPs have been 

CDC’s longstanding partners for reporting vaccine AEs to VAERS. VAERS depends upon HCPs 

to identify and report suspected AEs, even if they are not sure if a vaccine caused an AE. The 

Health Insurance Portability and Accountability Act (HIPAA) permits reporting of vaccine AEs 

and medical documentation to VAERS for public health purposes. HCP participation in VAERS 

reporting will enable public health officials to have accurate and timely information on the safety 

of COVID-19 vaccines. Specific guidance on VAERS reporting for vaccines authorized for use

under EUA will be forthcoming.

V-SAFE is a new smartphone-based active surveillance program for COVID-19 vaccine safety

that uses text messaging to initiate web-based survey monitoring and conducts electronic health 

checks on vaccine recipients. Health checks are conducted daily for the first week postvaccination and weekly thereafter until 6 weeks post-vaccination. There are additional health 

checks at 3, 6, and 12 months post-vaccination. V-SAFE includes active telephone follow-up 

through the VAERS program with vaccine recipients reporting a clinically important event during 

any V-SAFE health check. A VAERS report will be taken during telephone follow-up, if 

appropriate. V-SAFE captures information on pregnancy status and enables follow-up on 

pregnant women as well. V-SAFE will allow for estimation of rates of local and systemic 

reactogenicity and rates of clinically important AE following COVID-19 vaccination and 

symptoms and conditions associated with these AEs. HCPs will play an important role in VSAFE enrollment by providing a one-page information sheet to patients at the time of 

vaccination (to be created by CDC) and counseling patients on the importance of enrolling in VSAFE. CDC will provide information on how to briefly counsel patients on V-SAFE. Of note, VSAFE will be translated into at least 5 other languages.

ACIP COVID-19 Vaccine Safety Technical Sub-Group

Melinda Wharton, MD, MPH

Director, Immunization Services Division 

National Center for Immunization & Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Wharton described the ACIP COVID-19 VaST in more detail. VaST was organized in June 

2020 and is comprised of independent expert consultants, ACIP members, liaison 

representatives, and federal agency SMEs. The focus of VaST is to prioritize AESI, develop 

USG plans for safety monitoring, and create a communication framework. VaST was built off of 

lessons learned from H1N1 vaccine safety monitoring. There was consensus that a Federal 

Advisory Committee Act (FACA)-chartered subgroup would ensure transparency, 

independence, and public accountability. VaST is currently comprised of ACIP and National 

Vaccine Advisory Committee (NVAC) representation, 7 independent expert consultants, ACIP 

ex officio members (NIH, FDA, OIDP, CMS, HRSA, IHS), and a VA and DoD liaison. The 

VaST’s post-implementation objectives are to: 1) review, evaluate, and interpret postauthorization/approval COVID-19 vaccine safety data; 2) serve as the central hub for technical 

SMEs from federal agencies conducting post-authorization/approval safety monitoring to share

vaccine safety surveillance data; 3) advise on analyses, interpretation, and data presentation; 

and 4) liaise with the ACIP COVID-19 Vaccines WG on issues of safety data presentation to the 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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ACIP and application of safety data to policy decisions. The VaST’s deliverables include 

development of frequent COVID-19 vaccine safety technical reports for internal ACIP and CDC 

and federal partner use, and frequent COVID-19 vaccine safety data summaries for public 

release.

Discussion Points (Anderson, Shimabukuro, Wharton)

Given that safety surveillance is critical, this immense and collaborative effort is impressive. 

While the EHR can be a useful tool for data mining, finding AEs, and ensuring vaccines are 

distributed, it also has pitfalls that need to be stressed. Confidentiality goes without saying, but 

the biggest concern is that the use of the EHR is burdensome in terms of implementation and 

use when data registration or data mining are involved. For private practice, this is burdensome 

and costly. If this is required and there is a cost to integrate it into the health record, it could fail 

in the community setting.

The emphasis on collaboration among government agencies and groups working on vaccine 

safety in terms of harmonizing outcomes of interest, regular communication, and sharing data is 

very important and is applauded. This type of collaboration and coordination should continue 

through the entire process so that signals are investigated. This also should help to ensure that 

communicating to the public is well-coordinated, transparent, and consistent.

It was observed that safety monitoring may be difficult in settings outside of VAERS and 

registries, such as monitoring vaccines administered in workplaces where employers have their 

own health insurance plans. This is an area that FDA is exploring.

Concern was expressed about the ability of the systems described to monitor for MIS-C, wildtype or vaccine-induced, particularly with respect to the case definition requirement of a positive 

test or exposure to a suspected or confirmed case within 4 weeks prior to symptom onset.

Concern was expressed about access to V-SAFE in under-served areas. It is important to be 

mindful that while most people have access to some form of communication, indigent 

populations may not have ongoing access to care. In addition, V-SAFE communication must be 

culturally sensitive.

Lessons learned from children being at home and not in school is that there are many barriers. 

As hard as it may be to believe, not everybody has internet access and many people purchase 

phone minutes for phones that are not smartphones. It would be beneficial to track or record VSAFE use, perhaps by Zip Code, to ensure that it is inclusive of all communities in terms of 

access and recording long-term effects from the vaccine.

Consideration should be given to modernizing VAERS to accept data from EHRs and/or 

registries.
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Modeling Strategies for the Initial Allocation of SARS-CoV-2 Vaccines

Matthew Biggerstaff, ScD, MPH 

Data, Analytics, and Modeling Task Force

Centers for Disease Control and Prevention 

Dr. Biggerstaff presented modeling strategies for the initial allocation of SARS-CoV-2 vaccines.

The question posed to the group to model was, “What is the potential impact, in terms of 

preventing COVID-19 infections and deaths, of initially allocating vaccine to one of the following 

groups after vaccinating HCP in Phase 1A: Adults aged 65+, adults with high-risk medical 

conditions, and essential workers?” He described in detail the population stratification, vaccine 

product assumptions, completeness of protection, vaccine allocation assumptions for Phase 1a 

and Phase 1b, epidemic dynamics, administration assumptions, and approximate timing of 

vaccine rollout (before incidence rises, as incidence rises, as incidence falls). In terms of 

findings, initially vaccinating high-risk adults or essential workers in Phase 1B averts

approximately 1% to 5% more infections compared to targeting age 65+. This difference is 

greatest in the scenario in which the vaccine is introduced before incidence rises. The findings 

are robust to assumptions of reduced VE in older populations. Initially vaccinating age 65+ in 

Phase 1b averts approximately 1% to 4% more deaths compared to targeting high-risk adults or 

essential workers. As before, this difference is greatest in the scenario in which the vaccine is 

introduced before incidence rises. The percentage of deaths averted changes if VE is reduced 

in older populations. Initially vaccinating high-risk adults, age 65+, or essential workers in Phase 

1b averts a similar percentage of deaths across the scenarios. Initially vaccinating age 65+ in

Phase 1b averts approximately 2% to 11% more deaths compared to targeting high-risk adults 

or essential workers. Again, this difference is greatest in the scenario where the vaccine is

introduced before incidence rises. The findings are robust to assumptions of reduced VE in 

older populations, but the percentage averted drops.

There are limitations to the study. The efficacy and ability of the vaccine candidates to prevent 

transmission, as well as the time vaccine may become available, is currently unknown. Modeled 

epidemic trajectories are only for illustration and are not forecasts. Overall averted burden

should be interpreted cautiously, given that it will be sensitive to the future trajectory of the 

epidemic; findings reflect an idealized rollout with minimal delays and 100% uptake; and the aim 

of this study was to demonstrate the relative impact of different initial vaccine allocation

strategies. The following inputs were assumed and will require reassessment as more

information becomes available: 1) all infections confer protective immunity; 2) immunity, either 

naturally- or vaccine-acquired, does not wane significantly within a year of infection or 

immunization; 3) given exposure, younger age groups are just as likely to become infected as

older age groups (susceptibility independent of age); 4) individuals with comorbidities are just as 

likely as their peers to practice social distancing and other protective behaviors; and 5) there 

was no reduction in VE among those with high-risk medical conditions. The findings are 

consistent in sensitivity analyses where the percentage of the population infected prior to 

vaccine introduction was varied. In terms of consistency with external literature, a review of 

peer-reviewed and pre-publication studies that model the impact of vaccination under different 

initial allocation strategies shows general agreement with the results presented here.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Discussion Points

This is an incredible, elegant, and impressive analysis and enormous amount of work.

From a clinical and public health medical consultant point of view, the assumptions in the model 

make sense. VE may be somewhat high, but it is reasonable.

Consider modeling the impact of poor nutrition, falling behind in school, and possible abuse and 

neglect if older adults are vaccinated first and schools remain closed. The modeling team noted 

that this is possible but may require a more complex framework such as agent-based models 

that model people and societal parameters.

Consider modeling hospitalizations and not just deaths. The modeling team noted that they 

started with infections and deaths because those estimates are easier to obtain, but infections 

and hospitalizations can be incorporated in future versions.

Consider modeling congregate care settings. The modeling team indicated that this was already 

done and was presented by Dr. Slayton during the August 2020 ACIP meeting. The take-away 

from that study was that vaccinating staff in these settings may be more beneficial than just 

vaccinating residents, likely because of infection-blocking such that the infection is not 

introduced into the congregate setting.

It is critical for ACIP to address equity and disproportionate impact on disadvantaged 

populations. Approaching this from a race/ethnicity standpoint is probably not the best 

approach.

Updates to COVID-19 Immunity and Epidemiology to Inform Vaccine Policy

Megan Wallace, DrPH, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Wallace provided updates to COVID-19 immunity and epidemiology to inform vaccine policy, 

including an overview of US COVID-19 epidemiology, COVID-19 post-infection immunity, 

COVID-19 reinfection, and epidemiology of COVID-19 in pregnant women. As of October 29th, 

there were 8,834,393 cases of COVID-19 and 227,045 COVID-19 deaths. From March 1, 2020 

through October 17, 2020, the number of specimens tested and percent positive for SARS-CoV2 from combined laboratories reporting to CDC was 6.3% at Week 42. In terms of what happens 

to anti-SARS-CoV-2 antibodies after infection, Rhesus macaques challenged with SARS-CoV-2 

developed binding and neutralizing antibody responses. Re-challenge of rhesus macaques 

boosted SARS-CoV-2 antibody responses. In humans with SARS-CoV-2 infection, serum 

antibodies decline between the acute phase and 2 months post-discharge. In HCP with a history 

of mild SARS-CoV-2 infection, serum antibodies waned 2 months post-infection. Among 

hospitalized persons with SARS-CoV-2, neutralizing antibody titers demonstrated little to no 

decrease over 75 days since symptom onset. Pertaining to whether persons infected with 

SARS-CoV-2 mount cellular immune responses, in symptomatic COVID-19 patients, SARSCoV-2 memory B-cells did not wane at the same rate as serum antibodies. Recovered COVID19 patients have SARS-CoV-2-specific CD4+ T-cells and CD8+ T-cells. In conclusion, repeat 

exposure to SARS-CoV-2 may cause boosting of immune response. Several studies have now 

observed waning of serum antibodies in COVID-19 patients after a few months. However, the 

implications for protection are unknown. Neutralizing antibody titers demonstrated little or no 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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decrease at 75 days post-symptom onset. SARS-CoV-2 specific cellular B- and T-cell 

responses have been detected in COVID-19 patients. Memory B cells did not wane as fast as 

serum antibody titers.

Discussion Points

Pregnant and lactating women should not be excluded from high priority populations for COVID 

strategies and treated separately. More than 75% of the HCP workforce are females. For 

instance, pregnant HCP and first responders who are pregnant should be prioritized alongside 

their non-pregnant peers.

Though reinfection appears to be uncommon at this point, it will be beneficial to have further 

guidance on this as soon as possible.

The summary about what is known and unknown about reinfection was phenomenal. However, 

using language such as reinfection is “likely uncommon within 3 months” suggests more is 

known that actually is. Perhaps “may be uncommon within 3 months” would be less challenging 

for management.

It is imperative for messaging around vaccine to emphasizes that vaccines are not likely to be 

100% effective and that other measures must be utilized in combination with vaccines. The 

vaccine is not a panacea and will not result in immediate full herd immunity.

Dr. James Lee invited health care institutions and local/state public health entities interesting in 

discussing more about reinfections to email eocevent461@cdc.gov. 

Ethical Principles for Phased Allocation of COVID-19 Vaccines

Mary E. Chamberland, MD, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Chamberland discussed ethical principles for phased allocation of COVID-19 vaccines, 

which the COVID-19 Vaccine WG developed to assist ACIP in the identification of groups for 

early allocation of COVID-19 vaccine in the setting of a constrained supply. During the 

September 2020 ACIP meeting, 5 interim ethical principles were endorsed: Maximizing Benefits 

and Minimizing Harms, Equity, Justice, Fairness, and Transparency. During the July through 

August ACIP meetings, possible groups for Phase 1 vaccination were explored, including HCP

in Phase 1a and essential workers (non-HCP), persons with high-risk underlying medical 

conditions, and adults aged ≥65 years in Phase 1b. The WG reviewed COVID-19 vaccine 

allocation frameworks including those from Johns Hopkins University (JHU), National 

Academies, and the World Health Organization (WHO). In addition, they reviewed the ethical 

literature and consulted with experts in health equity, ethics, and Grading of Recommendation 

Assessment, Development and Evaluation (GRADE). The interim ethical principles were 

updated to guide phased allocation and a manuscript was drafted on ethical principles to 

address key questions to guide allocation planning, and a health equity domain was 

incorporated into the Evidence to Recommendations (EtR) Framework. There are now 4 ethical 

principles (Maximizing Benefits and Minimizing Harms, Promote Justice, Mitigate Health 

Inequities, and Promote Transparency), and updates to the interim version included folding 

fairness into justice and styling the principles as action phrases. A series of Key Questions was 

developed to: 1) facilitate “translation” of the ethical principles; 2) assist ACIP in developing its 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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national recommendations for early phase COVID-19 vaccine allocation; and 3) serve as a tool 

for State, Tribal, Local, and Territorial (STLT) health authorities as they develop vaccination 

implementation plans. Although ethical principles are fundamental for stewardship of a limited 

supply of vaccine, they also will be applicable when COVID-19 vaccines are more widely

available. Dr. Mary Chamberland described in detail each Key Question for COVID-19 vaccine 

allocation planning stratified by ethical principles.

Application of the principle of transparency across the entirety of the allocation decision-making 

process is essential for building public trust and confidence and being clear about the level of 

certainty in available evidence. Methods and data used for ACIP recommendations are publicly 

available and include public participation. ACIP meetings are open to the public and are 

available on-line. Comments can be made to the Federal Register and/or during ACIP meetings

and when ACIP engages with stakeholders and partners. Allocation of a limited supply of 

vaccine is complicated by efforts to address multiple goals, most notably reducing morbidity and 

mortality and minimizing disruption to society, the economy, and healthcare capacity. If the 

goals of a vaccination program are not clearly prioritized, it will be difficult to draw distinctions 

between groups for early phase allocation. There is increasing consensus among allocation 

frameworks for early vaccination of HCP, suggesting that maintenance of healthcare capacity as 

the highest priority. If vaccine supply remains constrained, ethical principles can help to guide 

identification of subsets of other groups for subsequent early phase allocation. The next steps 

for the WG are to seek ACIP’s views on the updated ethical principles and key questions, 

publish ACIP’s ethical principles, and engage in further discussion about application of the 

ethical principles to help inform Phase 1 allocation recommendations. The WG requested 

feedback on how application of these principles and key questions could be made more useful 

to STLT health authorities for COVID-19 vaccine allocation planning.

Discussion Points

While there was agreement with and endorsement of the principles, some members were 

struggling with how they fit into the overall pandemic response—especially having seen

projections earlier showing that it seems to matter less who gets the vaccine first as far as 

numbers of infections and deaths. That is, the principles seem less important than how soon the 

vaccine gets deployed.

The WG pointed out that the modeling work measured only one dimension of the impact, 

aversion of cases and deaths. The ethical principles takes a more holistic view of several 

dimensions in the context of limited vaccine supply being guided by ethnical, scientific, and 

implementation considerations.

The Key Questions to help guide and integrate the process seem beneficial and are greatly 

appreciated.

One thing that will go a long way with the general population, especially in terms of trust and 

disparities, is a mechanism for reporting how vaccine products are actually being allocated. 
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One decision with which ACIP will be faced will be assessing the data in terms of benefits and 

risks for various groups once a vaccine is available. If a vaccine becomes available in the next 

month or two, this will be a relatively short timeframe for efficacy and safety data. With no longterm safety data, it will be difficult to balance the benefits versus long-term issues that 

historically have arisen. Balancing the scientific and ethnical aspects is going to be difficult.

The slide on promoting transparency harkens back to the earlier comments about Tribes and 

the dynamic tension that a compressed timeline is going to create.

W ’s Inter ret tion o t e t 

Sara Oliver MD, MSPH 

Co-Lead ACIP COVID-19 Vaccine WG

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Oliver presented the ACIP COVID-19 Vaccine WG’s interpretation of the data. In terms of 

COVID-19 vaccine and prior infection, data from Phase 3 trials for any possible vaccineassociated enhanced disease or reactogenicity after prior infection are not yet available. In the 

absence of concerning data from Phase 3 trials, having positive PCR, antigen, or antibody 

results is not a contraindication to receive COVID-19 vaccine. Any vaccine recommendations 

that rely on knowledge of prior immunity/antibody testing would be difficult to implement. In 

terms of COVID-19 vaccine and breastfeeding women in Tier 1a, most WG members agreed 

that breastfeeding would not be a contraindication to receive a COVID-19 vaccine. However, 

this needs to be evaluated for each vaccine, especially if any live virus/vector vaccines are 

authorized/licensed. Regarding pregnant women in Tier 1a, limited data on pregnancy are

expected from Phase 3 trials. The WG did not reach a consensus. The majority felt that if a 

woman is recommended to receive the vaccine in an early allocation phase, pregnancy should 

be a precaution but not a contraindication to receive a COVID-19 vaccine. The WG emphasized 

the need to allow women to make an informed decision, providing all current knowledge of 

COVID-19 vaccines/platforms with pregnancy and risk of disease. Concerning pregnancy 

diagnosed after receipt of the first dose of COVID-19 vaccine, the majority of the WG felt that 

the second dose could be given at the recommended interval. A minority of the WG felt that the 

second dose should be postponed until the second trimester or until after pregnancy, 

emphasizing the need to allow women to make an informed decision.

Regarding the WG’s interpretation of the modeling data, the differences among the 3 strategies 

are thought to be minimal. Ethical principles and implementation considerations may greatly 

contribute to selecting the optimal sequence in Phase Ib. The largest impact in averted deaths 

and infections is the timing of vaccine introduction in relation to increases in COVID-19 cases. It 

is important to emphasize the need to continue non-pharmaceutical interventions (e.g., wearing 

a mask, social distancing) while awaiting available vaccine. Many factors will inform 

interpretation of modeling data and allocation decisions, such as VE in older adults, a vaccine’s 

ability to prevent severe disease or transmission, and whether the goal is to prevent the greatest 

number of infections or greatest number of deaths. For vaccine candidates, both Novavax and 

Janssen are planning and enrolling large Phase 3 efficacy trials of 30,000 to 60,000 people. The 

primary endpoints include symptomatic, virologically confirmed COVID-19 disease. Both 

companies are attempting to enroll diverse populations in terms of race and ethnicity, age (<65 

years and ≥65 years of age), and underlying medical conditions.
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Concerning implementation and distribution, the WG’s interpretation is that Phase 2/3 data from 

the vaccines show induction of binding and neutralizing antibodies as well as T-cell responses, 

favorable safety/reactogenicity profiles, supporting advance to Phase 3 trials. Both platforms 

have prior experience from other vaccines. Safety pauses are expected with large clinical trials, 

indicating the process is working appropriately. For the current Phase 3 clinical trials, the WG 

stressed the importance of enrolling diverse study participants, the importance of harmonizing 

safety and efficacy endpoints across all Phase 3 trials to the extent possible, and the need to 

report maternal and fetal outcomes for women who become pregnant during the clinical trials. 

The WG supports FDA’s guidance for ensuring that Phase 3 trials conduct ongoing assessment

of long-term safety and efficacy, and that issuance of an EUA is not grounds to unblind followup in an ongoing clinical trial.

Discussion Points

The American College of Obstetricians and Gynecologists (ACOG) urged ACIP to incorporate 

pregnant and lactating women clearly and explicitly in the prioritization framework should an 

EUA be issued.

The American Academy of Pediatrics (AAP) agreed with the ACOG statement and defers to 

them on matters of pregnancy and pregnant women. AAP also emphasized the need to move to 

pediatric trials when the data suggest that it is safe to do so and should monitor fetal outcomes.

It is important for pregnant and lactating women to make an informed decision. CDC is 

engaging ACOG and AAP and is working with colleagues with expertise in this area to develop 

materials that can be provided at the time of vaccination.

Related to the unblinding of clinical trials should an EUA become available, particularly for 

participants in vaccine trials in which efficacy and safety are demonstrated, it is troubling that 

participants potentially will not have the benefit of receiving vaccine once efficacy is 

demonstrated. These volunteers have assumed the risk of study participation and in most 

clinical trial circumstance would be among the first to potentially benefit once efficacy is 

demonstrated. It is recognized that this is an issue that must be dealt with by the FDA and 

VRBPAC.

Policy Questions, EtR Framework

Kathleen Dooling, MD MPH

Co-Lead ACIP COVID-19 Vaccine WG

Medical Officer, National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Dooling reviewed the COVID-19 vaccine policy questions for the EtR framework and critical 

and important outcomes. As a reminder, the goals of the COVID-19 vaccine program are to: 1) 

ensure the safety and effectiveness of COVID-19 vaccines; 2) reduce transmission, morbidity, 

and mortality of COVID-19 disease; 3) help minimize disruption to society and economy, 

including maintaining healthcare capacity; and 4) ensure equity in vaccine allocation and 

distribution. The two ACIP policy questions proposed by the WG are: 1) Should COVID-19 

Vaccine “A” be recommended to adults in the US?; and 2) Who should be recommended to 

receive COVID-19 Vaccine “A” during Phase 1? The EtR framework assesses the domains of 

Public Health Problem, Benefits and Harms, Values, Acceptability, Feasibility, Resource Use, 

and Equity. Dr. Dooling reviewed the population, intervention, comparison, outcomes (PICO) for 

vaccine policy for Question #1, including the critical and important benefits and harms identified 
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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by the WG. The WG’s next steps for Policy Question #1 (Vaccine Recommendations) are to 

populate the EtR framework, start GRADEing the vaccine evidence and incorporating Phase 3 

data when available, and discuss clinical guidance for special populations, concomitant 

administration, and scheduling. For Policy Question #2 (Allocation Recommendations), the 

WG’s next steps are to publish the ethical principles manuscript and incorporate the latest 

information regarding science, implementation, and ethics to further refine Phase 1 allocation. 

For the health equity domain criterion question, the following sub-questions were posed: 1) Are 

there any groups or settings that might be disadvantaged in relation to the problem or options 

that are considered?; 2) Are there plausible reasons for anticipating differences in the relative 

effectiveness of the option for disadvantaged groups or settings?; 3) Are there different baseline 

conditions across groups or settings that affect the absolute effectiveness of the option or the 

importance of the problem for disadvantaged groups or settings? Are there important 

considerations that should be made when implementing the intervention (option) in order to 

ensure that inequities are reduced, if possible, and that they are not increased?

Discussion Points

There was support for the two policy questions being evaluated separately and the important 

and beneficial outcome of serial PCRs for asymptomatic infection.

This is an unprecedented situation in which consideration may need to be given to conditional 

recommendations, which should incorporate the principles of informed consent and some higher 

level of clinical decision-making. 

Perhaps consideration should be given to getting the vaccine out as quickly as possible in 

response to the modeling data suggesting that the faster vaccines are administered, the more 

deaths that will be prevented.

This does not take into consideration any time-phased protection or safety other than the data 

that will be provided should an EUA come through in a relatively short period of time. This is a 

virus like nothing they have seen previously, so the unknown and negative possibilities are 

always a consideration. They can look at objective information and arrive at a conclusion to 

move forward with allocation, but that presumes that there is not going to be some later 

problem.

Following participants for a mean of 2 months after the second dose as a timepoint to start 

making final decisions about safety is troubling. Concerns prevailed on making quick decisions 

on safety. While it is true that most AEs of interest will be captured in the first 6 weeks, there will 

be a need for long-term studies, particularly due to the potential for vaccine-enhanced disease. 

This highlights the need for a dynamic decision-making process.

The WG has considered mortality, morbidity, and preventing spread in a lumped manner. In the 

context of unknowns, perhaps those should be disaggregated.

The questions fit the PICO perfectly, with the caveat that there may be changes. There must be 

flexibility over time and flexibility in implementation. Local areas will have to deal with the reality 

of whether to save doses for Dose 2.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Given the uncertainties, perhaps the WG should review the data on a monthly basis and update 

the recommendations to account for concerns in balance with benefits and harms.

While the focus on safety is very important, it is also crucial to understand durability of the 

immune response.

The ethical principles will be very important to local jurisdictions. Concrete guidance will be 

needed in terms of equity and a sense of fairness in terms of how allocations actually are 

implemented.

Frequent messaging of information about COVID-19 vaccines will be very important to public 

confidence.
Advisory Committee on Immunization Practices (ACIP) Summary Report October 28, 29, & 30 2020

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Upon reviewing the foregoing version of the October 28, 29, & 30, 2020 ACIP meeting minutes, 

Dr. Jose Romero, 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.

Certification 
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Department of Health and Human Services 

Centers for Disease Control and Prevention 

Advisory Committee on Immunization Practices 

July 1, 2019 – December 31, 2020 

CHAIR 

ROMERO, José R., MD, FAAP 

Professor of Pediatrics 

Horace C. Cabe Endowed Chair in Infectious Diseases Director, 

Pediatric Infectious Diseases Section 

University of Arkansas for Medical Sciences and Arkansas Children's Hospital 

Director, Clinical Trials Research 

Arkansas Children's Hospital Research Institute 

Little Rock, AR 

Term: 10/30/2018-06/30/2021 

 

EXECUTIVE SECRETARY 

COHN, Amanda, MD 

Senior Advisor for Vaccines 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Atlanta, GA 

 

MEMBERS 

ATMAR, Robert L., MD 

John S. Dunn Clinical Research Professor in Infectious Diseases 

Departments of Medicine and Molecular Virology & Microbiology 

Baylor College of Medicine 

Chief, Infectious Diseases Service 

Ben Taub General Hospital, Harris Health System 

Houston, TX 

Term: 7/1/2016 – 6/30/2020 

AULT, Kevin A., MD, FACOG, FIDSA 

Professor and Division Director 

Department of Obstetrics and Gynecology 

University of Kansas Medical Center 

Kansas City, KS 

Term: 10/26/2018 – 6/30/2022 

 

ACIP Membership Roster
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BAHTA, Lynn, RN, MPH, CPH 

Immunization Program Clinical Consultant 

Infectious Disease, Epidemiology, Prevention & Control Division 

Minnesota Department of Health 

Saint Paul, Minnesota 

Term: 7/1/2019 – 6/30/2023 

BELL, Beth P., MD, MPH 

Clinical Professor 

Department of Global Health, School of Public Health 

University of Washington 

Seattle, WA 

Term: 7/1/2019 – 6/30/2023 

BERNSTEIN, Henry, DO, MHCM, FAAP 

Professor of Pediatrics 

Zucker School of Medicine at Hofstra/Northwell 

Cohen Children’s Medical Center 

New Hyde Park, NY 

Term: 11/27/2017-06/30/2021 

FREY, Sharon E., M.D. 

Professor and Associate Director of Clinical Research 

Clinical Director, Center for Vaccine Development 

Division of Infectious Diseases, Allergy and Immunology 

Saint Louis University Medical School 

Saint Louis, MO 

Term: 11/27/2017-06/30/2021 

HUNTER, Paul, MD 

Associate Professor of Family Medicine and Community Health 

University of Wisconsin School of Medicine and Public Health 

Associate Medical Director 

City of Milwaukee Health Department 

Milwaukee, WI 

Term: 7/1/2016 – 6/30/2020 

LEE, Grace M., MD, MPH 

Associate Chief Medical Officer for Practice Innovation 

Lucile Packard Children’s Hospital 

Professor of Pediatrics, Stanford University School of Medicine 

Stanford, CA 

Term: 7/1/2016 – 6/30/2020 
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MCNALLY, Veronica V., JD 

President and CEO 

Franny Strong Foundation 

West Bloomfield, Michigan 

Term: 10/31/2018 – 6/30/2022 

POEHLING, Katherine A., MD, MPH 

Professor of Pediatrics and Epidemiology and Prevention Director, 

Pediatric Population Health 

Department of Pediatrics 

Wake Forest School of Medicine 

Winston-Salem, NC 

Term: 7/1/2019 – 6/30/2023 

SÁNCHEZ, Pablo J., M.D.

Professor of Pediatrics 

The Ohio State University – Nationwide Children’s Hospital 

Divisions of Neonatal-Perinatal Medicine and Pediatric Infectious Diseases 

Director, Clinical & Translational Research (Neonatology) 

Center for Perinatal Research 

The Research Institute at Nationwide Children's Hospital 

Columbus, Ohio

Term: 7/1/2019 – 6/30/2023 

SZILAGYI, Peter, MD, MPH 

Professor of Pediatrics 

Executive Vice-Chair and Vice-Chair for Research 

Department of Pediatrics 

University of California, Los Angeles (UCLA) 

Los Angeles, California 

Term: 7/1/2016 – 6/30/2020 

TALBOT, Helen Keipp, MD 

Associate Professor of Medicine 

Vanderbilt University

Nashville, TN 

Term: 10/29/2018 – 6/30/2022 

 

EX OFFICIO MEMBERS 

Centers for Medicare and Medicaid Services (CMS) 

HANCE, Mary Beth 

Senior Policy Advisor 

Division of Quality, Evaluations and Health Outcomes 

Children and Adults Health Programs Group 

Center for Medicaid, CHIP and Survey & Certification 

Centers for Medicare and Medicaid Services 

Baltimore, MD 
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Food and Drug Administration (FDA) 

FINK, Doran, MD, PhD 

Deputy Director, Clinical, Division of Vaccines and Related Products Applications Office of 

Vaccines Research and Review 

Center for Biologics Evaluation and Research 

Food and Drug Administration 

Silver Spring, MD

Health Resources and Services Administration (HRSA) 

RUBIN, Mary, MD 

Chief Medical Officer 

Division of Injury Compensation Programs 

Rockville, MD

Indian Health Service (IHS) 

WEISER, Thomas, MD, MPH 

Medical Epidemiologist 

Portland Area Indian Health Service 

Portland, OR 

Office of Infectious Disease and HIV/AIDS Policy (OIDP) 

KIM, David, MD CAPT, 

US Public Health Service Director Division of Vaccines 

Washington, DC 

National Institutes of Health (NIH) 

BEIGEL, John, M.D. 

Associate Director for Clinical Research 

Division of Microbiology and Infectious Diseases 

National Institute of Allergy and Infectious Diseases (NIAID) Bethesda, MD 

LIAISON REPRESENTATIVES 

American Academy of Family Physicians (AAFP) 

ROCKWELL, Pamela G, DO 

Associate Professor, Department of Family Medicine, 

University of Michigan Medical School 

Medical Director, Dominos Farms Family Medicine Ann 

Arbor, MI 

American Academy of Pediatrics (AAP) 

MALDONADO, Yvonne, MD 

Senior Associate Dean for Faculty Development and Diversity 

Professor of Pediatrics and Health Research and Policy 

Chief, Division of Pediatric Infectious Diseases 

Stanford University School of Medicine 

Stanford, CA 
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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) 

CHAI, Thevy S, MD 

Director of Medical Services 

Campus Health Services 

University of North Carolina at Chapel Hill 

Chapel Hill, NC

American College Health Association (ACHA) (alternate) 

MCMULLEN, Sharon, RN, MPH, FACHA 

Assistant Vice President of Student & Campus Life for Health and Wellbeing 

Cornell Health 

Ithaca, NY 

American College of Nurse Midwives (ACNM) 

HAYES, Carol E., CNM, MN, MPH Lead 

Clinician 

Clinical Quality Compliance and Management 

Planned Parenthood Southeast 

Atlanta, GA 

American College of Nurse Midwives (ACNM) (alternate) 

MEHARRY, Pamela M., PHD, CNM 

Midwifery Educator, Human Resources for Health 

In partnership with University of Rwanda and University of Illinois, Chicago 

American College of Obstetricians and Gynecologists (ACOG) 

ECKERT, Linda O., MD, FACOG 

Professor, Department of Obstetrics & Gynecology 

Adjunct Professor, Department of Global Health 

University of Washington 

Seattle, WA
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American College of Physicians (ACP) 

GOLDMAN, Jason M. MD, FACP 

Affiliate Assistant Professor of Clinical Biomedical Science, Florida Atlantic 

University, Boca Raton, Florida 

Private Practice 

Coral Springs, FL 

American Geriatrics Society (AGS) 

SCHMADER, Kenneth, MD 

Professor of Medicine-Geriatrics 

Geriatrics Division Chief 

Duke University and Durham VA Medical Centers

Durham, NC 

 eric ’s e lt Insur nce l ns I 

GLUCKMAN, Robert A., MD, MACP 

Chief Medical Officer, Providence Health Plans 

Beaverton, OR

American Immunization Registry Association (AIRA) 

COYLE, Rebecca, MSEd 

Executive Director, AIRA

Washington, DC 

American Medical Association (AMA) 

FRYHOFER, Sandra Adamson, MD 

Adjunct Associate Professor of Medicine 

Emory University School of Medicine

Atlanta, GA 

American Nurses Association (ANA) 

RITTLE, Charles (Chad), DNP, MPH, RN 

Assistant Professor, Nursing Faculty 

Chatham University, School of Health Sciences

Pittsburgh, PA 

American Osteopathic Association (AOA) 

GROGG, Stanley E., DO 

Associate Dean/Professor of Pediatrics 

Oklahoma State University-Center for Health Sciences 

Tulsa, OK 

American Pharmacists Association (APhA) 

FOSTER, Stephan L., PharmD CAPT (Ret) 

U.S.P.H.S. 

Professor, College of Pharmacy 

University of Tennessee Health Sciences Center 

Memphis, TN 
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Association of Immunization Managers (AIM) 

HOWELL, Molly, MPH Immunization Program Manager 

North Dakota Department of Health 

Bismarck, ND

 

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) 

SHAH, Nirav D, MD, JD

Director 

Maine Center for Disease Control and Prevention

Augusta, ME

Biotechnology Industry Organization (BIO) 

ARTHUR, Phyllis A., MBA 

Senior Director, Vaccines, Immunotherapeutics and Diagnostics Policy 

Washington, DC

Council of State and Territorial Epidemiologists (CSTE) 

HAHN, Christine, MD State 

Epidemiologist 

Office of Epidemiology, Food Protection and Immunization Idaho 

Department of Health and Welfare

Boise, ID 

Council of State and Territorial Epidemiologists (CSTE) (alternate) 

LETT, Susan, MD, MPH 

Medical Director, Immunization Program 

Division of Epidemiology and Immunization 

Massachusetts Department of Public Health 

Boston, MA 

Canadian National Advisory Committee on Immunization (NACI) 

QUACH, Caroline, MD, MSc 

Pediatric Infectious Disease Specialist and Medical Microbiologist 

Medical Lead, Infection Prevention and Control Unit 

Medical Co-director – Laboratory Medicine, Optilab 

Montreal-CHUM 

Montreal, Québec, Canada 

Infectious Diseases Society of America (IDSA) 

BAKER, Carol J, MD 

Professor of Pediatrics 

Molecular Virology and Microbiology 

Baylor College of Medicine

Houston, TX 
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International Society for Travel Medicine (ISTM)

BARNETT, Elizabeth D, MD

Professor of Pediatrics

Boston University School of Medicine

Boston, MA

National Association of County and City Health Officials (NACCHO) 

ZAHN, Matthew, MD 

Medical Director, Epidemiology 

Orange County Health Care Agency 

Santa Ana, CA 

National Association of County and City Health Officials (NACCHO) (alternate) 

DUCHIN, Jeffrey, MD 

Health Officer and Chief, Communicable Disease Epidemiology and Immunization Section 

Public Health - Seattle and King County 

Professor in Medicine, Division of Allergy and Infectious Diseases 

University of Washington School of Medicine and School of Public Health

Seattle, WA

National Association of Pediatric Nurse Practitioners (NAPNAP) 

STINCHFIELD, Patricia A., RN, MS, CPNP 

Director, Infectious Disease/Immunology/Infection Control 

Children's Hospitals and Clinics of Minnesota

St. Paul, MN 

National Foundation for Infectious Diseases (NFID) 

SCHAFFNER, William, MD 

Chairman, Department of Preventive Medicine 

Vanderbilt University School of Medicine 

Nashville, TN 

National Foundation for Infectious Diseases (NFID) (alternate) 

DALTON, Marla, PE, CAE 

Executive Director & CEO 

National Foundation for Infectious Diseases (NFID) 

Bethesda, MD

National Medical Association (NMA) 

WHITLEY-WILLIAMS, Patricia, MD 

Professor and Chair 

University of Medicine and Dentistry of New Jersey 

Robert Wood Johnson Medical School 

New Brunswick, NJ 
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Pediatric Infectious Diseases Society (PIDS) 

O’LEARY, Sean, MD, MPH 

Associate Professor of Pediatrics 

Pediatric Infectious Diseases 

General Academic Pediatrics 

Children’s Hospital Colorado 

University of Colorado School of Medicine 

Pediatric Infectious Diseases Society (PIDS) (alternate)

SAWYER, Mark H, MD 

Professor of Clinical Pediatrics 

University of California, San Diego School of Medicine 

San Diego, CA 

Pharmaceutical Research and Manufacturers of America (PhRMA) 

ROBERTSON, Corey, MD, MPH 

Senior Director, US Medical, 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) 

DREES, Marci, MD, MS 

Chief Infection Prevention Officer & Hospital Epidemiologist 

ChristianaCare 

Wilmington, DE 

Associate Professor of Medicine Sidney Kimmel Medical College at Thomas Jefferson 

University 

Philadelphia, PA